ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
CRIXIVAN 100 mg hard capsules
2.
Each hard capsule contains indinavir sulphate corresponding to 100 mg of indinavir.
Excipient: Each 100 mg capsule contains 37.4 mg lactose.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
The capsules are semi–translucent white and coded CRIXIVAN™ 100 mg in green.
4.
CRIXIVAN is indicated in combination with antiretroviral nucleoside analogues for the treatment of
HIV-1 infected adults, adolescents, and children 4 years of age and older. In adolescents and children,
the benefit of indinavir therapy versus the increased risk of nephrolithiasis should particularly be
considered (see section 4.4).
CRIXIVAN should be administered by physicians who are experienced in the treatment of HIV
infection. On the basis of current pharmacodynamic data, indinavir must be used in combination with
other antiretroviral agents. When indinavir is administered as monotherapy resistant viruses rapidly
emerge (see section 5.1).
Adults
The recommended dosage of CRIXIVAN is 800 mg orally every 8 hours.
Data from published studies suggest that CRIXIVAN 400 mg in combination with ritonavir 100 mg,
both administered orally twice daily, may be an alternative dosing regimen. The suggestion is based on
limited published data (see section 5.2).
If co-administered with ritonavir, CRIXIVAN may be administered with or without food.
Children and adolescents (4 to 17 years of age)
The recommended dosage of CRIXIVAN for patients 4 to 17 years of age is 500 mg/m
2
(dose adjusted
from calculated body surface area [BSA] based on height and weight) orally every 8 hours (see table
below). This dose should not exceed the equivalent of the adult dose of 800 mg every 8 hours.
CRIXIVAN hard capsules should only be given to children who are able to swallow hard capsules.
CRIXIVAN has not been studied in children under the age of 4 years (see section 5.1 and 5.2).
2
Paediatric dose (500 mg/
m
2
) to be administered every 8 hours
Body
Surface
Area (m
2
)
CRIXIVAN dose
Every 8 hours (mg)
0.50
300
1.00
500
1.25
600
1.50
800
General administration recommendations
The hard capsules should be swallowed whole.
Since CRIXIVAN must be taken at intervals of 8 hours, a schedule convenient for the patient should
be developed. For optimal absorption, CRIXIVAN should be administered without food but with
water 1 hour before or 2 hours after a meal. Alternatively, CRIXIVAN may be administered with a
low–fat, light meal.
To ensure adequate hydration, it is recommended that adults drink at least 1.5 litres of liquids during
the course of 24 hours. It is also recommended that children who weigh less than 20 kg drink at least
75 ml/kg/day and that children who weigh 20 to 40 kg drink at least 50 ml/kg/day.
Medical management in patients with one or more episodes of nephrolithiasis must include adequate
hydration and may include temporary interruption of therapy (e.g., 1 to 3 days) during the acute
episode of nephrolithiasis or discontinuation of therapy (see section 4.4).
Special dosing considerations in adults
A dosage reduction of CRIXIVAN to 600 mg every 8 hours should be considered when administering
itraconazole or ketoconazole concurrently (see section 4.5).
In patients with mild–to–moderate hepatic impairment due to cirrhosis, the dosage of CRIXIVAN
should be reduced to 600 mg every 8 hours. The recommendation is based on limited pharmacokinetic
data (see section 5.2). Patients with severe hepatic impairment have not been studied; therefore, no
dosing recommendations can be made (see section 4.4).
Safety in patients with impaired renal function has not been studied; however, less than 20 % of
indinavir is excreted in the urine as unchanged drug or metabolites (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
Indinavir with or without ritonavir should not be administered concurrently with medicinal products
with narrow therapeutic windows and which are substrates of CYP3A4. Inhibition of CYP3A4 by both
CRIXIVAN and ritonavir could result in elevated plasma concentrations of these medicines,
potentially causing serious or life-threatening reactions.
CRIXIVAN with or without ritonavir should not be administered concurrently with amiodarone,
terfenadine, cisapride, astemizole, alprazolam, triazolam, midazolam administered orally (for caution
on parenterally administered midazolam, see section 4.5), pimozide, ergot derivatives, simvastatin or
lovastatin (see section 4.4).
Combination of rifampicin with CRIXIVAN with or without concomitant low-dose ritonavir is
contraindicated (see section 4.5). Concurrent use of indinavir with herbal preparations containing St
John’s wort (Hypericum perforatum) is contraindicated (see section 4.5).
3
0.75
400
In addition, indinavir with ritonavir should not be administered with alfuzosin, meperidine, piroxicam,
propoxyphene, bepridil, encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine,
clorazepate, diazepam, estazolam and flurazepam.
Ritonavir should not be given with indinavir to patients with decompensated liver disease as ritonavir
is principally metabolized and eliminated by the liver (see section 4.4).
When CRIXIVAN is used with ritonavir, consult the Summary of Product Characteristics of ritonavir
for additional contraindications.
Nephrolithiasis and tubulointerstitial nephritis
Nephrolithiasis has occurred with indinavir therapy in adult and paediatric patients. The frequency of
nephrolithiasis is higher in paediatric patients than in adult patients. In some cases, nephrolithiasis has
been associated with renal insufficiency or acute renal failure; in the majority of these cases renal
insufficiency and acute renal failure were reversible. If signs and symptoms of nephrolithiasis,
including flank pain with or without haematuria (including microscopic haematuria) occur, temporary
interruption of therapy (e.g. for 1–3 days) during the acute episode of nephrolithiasis or
discontinuation of therapy may be considered. Paediatric patients who experience flank pain should be
evaluated for the possibility of nephrolithiasis. Evaluation may consist of urinalysis, serum BUN and
creatinine, and ultrasound of the bladder and kidneys. The long–term effects of nephrolithiasis in
paediatric patients are unknown. Adequate hydration is recommended in all patients on indinavir (see
section 4.2 and 4.8).
Cases of interstitial nephritis with medullary calcification and cortical atrophy have been observed in
patients with asymptomatic severe leucocyturia (> 100 cells/high power field). In patients at increased
risk such as children, urinary screening should be considered. If persistent severe leucocyturia is
found, further investigation might be warranted.
Medicinal product interactions
Indinavir should be used cautiously with other medicinal products that are potent inducers of
CYP3A4. Co–administration may result in decreased plasma concentrations of indinavir and as a
consequence an increased risk for suboptimal treatment and facilitation of development of resistance
(see section 4.5).
If indinavir is given with ritonavir, the potential interaction may be increased. The Interactions section
of the SPC for ritonavir should also be consulted for information about potential interactions.
Atazanavir as well as indinavir are associated with indirect (unconjugated) hyperbilirubinemia due to
inhibition of UDP-glucuronosyltransferase (UGT). Combinations of atazanavir with or without
ritonavir and Crixivan have not been studied and co-administration of these medicinal products is not
recommended due to risk of worsening of these adverse effects.
Concomitant use of indinavir with lovastatin or simvastatin is not recommended due to an increased
risk of myopathy including rhabdomyolysis. Based on an interaction study with lopinavir/ritonavir,
combination of rosuvastatin and protease inhibitors is not recommended. Caution must also be
exercised if indinavir is used concurrently with atorvastatin. The interaction of indinavir or
indinavir/ritonavir with pravastatin or fluvastatin is not known (see section 4.5).
Co–administration of CRIXIVAN with sildenafil, tadalafil and vardenafil (PDE5 inhibitors) are
expected to substantially increase the plasma concentrations of these compounds and may result in an
increase in PDE5 inhibitor–associated adverse events, including hypotension, visual changes, and
priapism (see section 4.5).
4
Acute haemolytic anaemia
Acute haemolytic anaemia has been reported which in some cases was severe and progressed rapidly.
Once a diagnosis is apparent, appropriate measures for the treatment of haemolytic anaemia should be
instituted which may include discontinuation of indinavir.
Hyperglycaemia
New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been
reported in patients receiving protease inhibitors (PIs). In some of these the hyperglycaemia was
severe and in some cases also associated with ketoacidosis. Many patients had confounding medical
conditions, some of which required therapy with agents that have been associated with the
development of diabetes mellitus or hyperglycaemia.
Fat redistribution
Combination antiretroviral therapy has been associated with the redistribution of body fat
(lipodystrophy) in HIV patients. The long term consequences of these events are currently unknown.
Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs
and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A
higher risk of lipodystrophy has been associated with individual factors such as older age, and with
drug related factors such as longer duration of antiretroviral treatment and associated metabolic
disturbances. Clinical examination should include evaluation for physical signs of fat redistribution.
Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid
disorders should be managed as clinically appropriate (see section 4.8).
Liver disease
The safety and efficacy of indinavir has not been established in patients with significant underlying
liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral
therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of
concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information
for these medicinal products.
The safety and efficacy of indinavir/ritonavir has not been established in patients with significant
underlying liver disorders and should not be used in this patient population.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
An increased incidence of nephrolithiasis has been observed in patients with underlying liver disorders
when treated with indinavir.
Immune Reactivation Syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically,
such reactions have been observed within the first few weeks or months of initiation of CART.
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections,
and
Pneumocystis carinii
pneumonia. Any inflammatory symptoms should be evaluated and treatment
instituted when necessary.
Patients with coexisting conditions
There have been reports of increased bleeding, including spontaneous skin haematomas and
haemarthroses, in haemophiliac patients type A and B treated with PIs. In some patients additional
factor VIII was given. In more than a half of the reported cases, treatment with PIs was continued or
re-introduced if treatment had been discontinued. A causal relationship has been evoked, although the
mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware
of the possibility of increased bleeding.
5
Patients with mild–to–moderate hepatic insufficiency due to cirrhosis will require a dosage reduction
of indinavir due to decreased metabolism of indinavir (see section 4.2). Patients with severe hepatic
impairment have not been studied. In the absence of such studies, caution should be exercised as
increased levels of indinavir may occur.
Safety in patients with impaired renal function has not been studied; however, less than 20 % of
indinavir is excreted in the urine as unchanged drug or metabolites (see section 4.2).
Osteonecrosis:
Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been
reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience
joint aches and pain, joint stiffness or difficulty in movement.
Lactose
This medicinal product contains 299.2 mg of lactose in each 800 mg dose (maximum single dose).
This quantity is not likely to induce symptoms of lactose intolerance (milk intolerance).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicine.
Interaction studies have only been performed in adults. The relevance of the results from these studies
in paediatric patients is unknown.
The metabolism of indinavir is mediated by the cytochrome P450 enzyme CYP3A4. Therefore, other
substances that either share this metabolic pathway or modify CYP3A4 activity may influence the
pharmacokinetics of indinavir. Similarly, indinavir might also modify the pharmacokinetics of other
substances that share this metabolic pathway. Boosted indinavir (indinavir with ritonavir) may have
additive pharmacokinetic effects on substances that share the CYP3A4 pathway as both
ritonavir and
indinavir inhibit the cytochrome P450 enzyme CYP3A4.
Indinavir with or without ritonavir should not be administered concurrently with medicinal products
with narrow therapeutic windows and which are substrates of CYP3A4. Inhibition of CYP3A4 by both
CRIXIVAN and ritonavir could result in elevated plasma concentrations of these medicines,
potentially causing serious or life-threatening reactions. CRIXIVAN with or without ritonavir should
not be administered concurrently with amiodarone, terfenadine, cisapride, astemizole, alprazolam,
triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see
Table 1 and 2 below), pimozide, ergot derivatives, simvastatin or lovastatin. In addition, indinavir with
ritonavir should not be administered with alfuzosin, meperidine, piroxicam, propoxyphene, bepridil,
encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine, clorazepate, diazepam, estazolam
and flurazepam.
Concurrent use of indinavir with rifampicin or herbal preparations containing St John’s wort
(Hypericum perforatum) is contraindicated.
Drugs listed above are not repeated in Table 1 and 2 unless specific interaction data is available.
Refer also to sections 4.2 and 4.3.
6
Table 1. Interactions and dose recommendations with other medical products –
UNBOOSTED
INDINAVIR
Interactions between indinavir and other medicinal products are listed in the tables below (increase is
indicated as “↑”, decrease as “↓”, no change (≤ +/- 20 %) as “↔”, single dose as “SD”, once daily as
“QD”, twice daily as “BID”, three times daily as “TID”, and four times daily as "QID").
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
ANTI-INFECTIVES
Antiretrovirals
NRTIs
Didanosine
Formulation with buffer
No
formal interaction study has been
performed. A normal (acidic) gastric pH may
be necessary for optimum absorption of
indinavir whereas acid rapidly degrades
didanosine which is formulated with buffering
agents to increase pH.
Antiretroviral activity was unaltered when
didanosine was administered 3 hours after
treatment with indinavir.
Indinavir and didanosine
formulations containing
buffer should be
administered at least one
hour apart on an empty
stomach.
Didanosine enteric-coated
400 mg SD
(Indinavir 800 mg SD)
Indinavir:
(Relative to Indinavir 800 mg SD alone)
Didanosine:
Can be administered
without any restrictions
with respect to time of
administration or food.
Stavudine 40 mg BID
(Indinavir 800 mg TID)
Indinavir AUC:
Indinavir C
min
:↔
(Relative to Indinavir 800 mg TID alone)
Indinavir and NRTIs can be
co-administered without
dose adjustment.
Stavudine AUC: ↑ 21 %
Stavudine C
min
: not evaluated
Zidovudine 200 mg TID
(Indinavir 1,000 mg TID)
Indinavir AUC:
Indinavir C
min
:
(Relative to Indinavir 1,000 mg TID alone)
Zidovudine AUC:
Zidovudine C
min
: ↑ 51 %
Zidovudine/Lamivudine
200/150 mg TID
(Indinavir 800 mg TID)
Indinavir AUC:
Indinavir C
min
:
(Relative to Indinavir 800 mg TID alone)
Zidovudine AUC: ↑ 39 %
Zidovudine C
min
:
Lamivudine AUC:
Lamivudine C
min
:
7
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
NNRTIs
Delavirdine 400 mg TID
(Indinavir 600 mg TID)
Indinavir AUC: ↑ 53 %
Indinavir C
min
↑ 298 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of
CRIXIVAN to 400-600 mg
every 8 hours should be
considered.
Delavirdine 400 mg TID
Indinavir 400 mg TID
Indinavir AUC: ↔
Indinavir C
min
: ↑ 118 %
(Relative to Indinavir 800 mg TID alone)
Delavirdine:
Efavirenz 600 mg QD
(Indinavir 1,000 mg TID)
Indinavir AUC:
46 %
Indinavir C
min
:
57 %
(Relative to Indinavir 800 mg TID alone)
An increased dose (1,000 mg TID) of indinavir
does not compensate for the inducing effect of
efavirenz.
No specific dose
recommendation can be
given
.
Efavirenz 200 mg QD
(Indinavir 800 mg TID)
Indinavir AUC:
31 %
Indinavir C
min
:
40 %
Efavirenz AUC:
Nevirapine 200 mg BID
(Indinavir 800 mg TID)
Indinavir AUC:
28 %
Nevirapine:
(CYP3A induction)
A dose increase of indinavir
to 1,000 mg every 8 hours
should be considered if
given with nevirapine.
PIs
Amprenavir 1,200 mg BID
(Indinavir 1,200 mg BID)
Amprenavir AUC: ↑ 90 %
Indinavir:
↔
The appropriate doses for
this combination, with
respect to efficacy and
safety, have not been
established.
Atazanavir
Interaction not studied
Combination of atazanavir
with or without ritonavir
and Crixivan are not
recommended due to
increased risk of
hyperbilirubinemia (see
section 4.4).
8
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
Ritonavir 100 mg BID
(Indinavir 800 mg BID)
Indinavir AUC
24hr
:
178
%
Indinavir C
min
:
11-fold;
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC:
72 %
Ritonavir C
min
:
62 %
The appropriate doses for
this combination, with
respect to efficacy and
safety, have not been
established. Preliminary
clinical data suggest that
CRIXIVAN 400 mg in
combination with ritonavir
100 mg, both administered
orally twice daily, may be
an alternative dosing
regimen (see section 5.2). A
boosted dose of 800 mg
indinavir/100 mg ritonavir
twice daily results in
increased risk of adverse
events.
Ritonavir 200 mg BID
(Indinavir 800 mg BID)
Indinavir AUC
24hr
:
266 %
Indinavir C
min
:
24-fold;
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC:
96 %
Ritonavir C
min
:
371 %
Ritonavir 400 mg BID
(Indinavir 800 mg BID)
Indinavir AUC
24hr
:
220 %
Indinavir C
min
:↑ 24-fold
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC
24hr
:
Ritonavir 400 mg BID
(Indinavir 400 mg BID)
Indinavir AUC
24hr
:
68 %
Indinavir C
min
: ↑ 10-fold
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC
24hr
:
Ritonavir 100 mg BID
(Indinavir 400 mg BID)
Indinavir AUC and C
min
: ↔
(Relative to Indinavir 800 mg TID alone*)
(
*
)
historical controls
Saquinavir 600 mg SD (hard
gel capsule formulation)
(Indinavir 800 mg TID)
Saquinavir AUC:
500 %
Saquinavir C
min
:
190 %
(Relative to saquinavir 600 mg SD (hard gel
formulation) alone)
The appropriate doses for
this combination, with
respect to efficacy and
safety, have not been
established.
Saquinavir 800 mg SD (soft
gel capsule formulation)
(Indinavir 800 mg TID)
Saquinavir AUC:
620 %
Saquinavir C
min
:
450 %
(Relative to saquinavir 800 mg SD (soft gel
formulation) alone)
Saquinavir 1,200 mg SD (soft
gel capsule formulation)
(Indinavir 800 mg TID)
Saquinavir AUC:
360 %
Saquinavir C
min
:
450 %
(Relative to saquinavir 1,200 mg (soft gel
formulation) alone)
The design of the study does not allow for
definitive evaluation of the effect of saquinavir
on indinavir, but suggests there is less than a
two–fold increase in indinavir AUC
8h
during
co–administration with saquinavir
9
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
Antibiotics
Sulphamethoxazole/
Trimethoprim
800 mg/160 mg BID
(Indinavir 400 mg QID)
Indinavir AUC and C
min
:
(Relative to Indinavir 400 mg QID alone)
Sulphamethoxazole AUC and C
min
:
Indinavir and
sulphamethoxazole/
trimethoprim can be co-
administered without dose
adjustment.
Antifungals
Fluconazole 400 mg QD
(Indinavir 1,000 mg TID)
Indinavir AUC: ↓ 24 %
Indinavir C
min
:
(Relative to Indinavir 1,000 mg TID alone)
Indinavir and fluconazole
can be co-administered
without dose adjustment.
Itraconazole 200 mg BID
(Indinavir 600 mg TID)
Indinavir AUC:
Indinavir C
min
: ↑ 49 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of
CRIXIVAN to 600 mg
every 8 hours is
recommended with
administering itraconazole
concurrently.
Ketoconazole 400 mg QD
(Indinavir 600 mg TID)
Indinavir AUC: ↓ 20 %
Indinavir C
min
: ↑ 29 %
(Relative to Indinavir 800 mg TID alone)
Indinavir AUC ↓ 56 %
Indinavir C
min
↓ 27 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of
CRIXIVAN to 600 mg
every 8 hours should be
considered.
Ketoconazole 400 mg QD
(Indinavir 400 mg TID)
Anti-Mycobacterial
Isoniazid 300 mg QD
(Indinavir 800 mg TID)
Indinavir AUC and C
min
: ↔
(Relative to Indinavir 800 mg TID alone)
Isoniazid AUC and C
min
:
Indinavir and isoniazid can
be co-administered without
dose adjustment.
Rifabutin 300 mg QD
(Indinavir 800 mg TID)
Indinavir AUC ↓ 34 %
Indinavir C
min
: ↓ 39 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of rifabutin
and dose increase of
Crixivan has not been
confirmed in clinical
studies. Therefore co-
administration is not
recommended. If rifabutin
treatment is required,
alternative agents for
treating HIV infection
should be sought.
Rifabutin AUC: ↑ 173 %
Rifabutin C
min
: ↑ 244 %
(Relative to rifabutin 300 mg QD alone)
Rifabutin 150 mg QD
(Indinavir 800 mg TID)
Indinavir AUC: ↓ 32 %
Indinavir C
min
: ↓ 40 %
(Relative to Indinavir 800 mg TID alone)
Rifabutin AUC*: ↑ 54 %
Rifabutin C
min*
: ↑ 99 %
(*Relative to rifabutin 300 mg QD alone. No
data has been obtained comparing rifabutin
150 mg QD in combination with indinavir
800 mg TID with a reference dose of 150 mg
rifabutin alone)
Rifampicin 600 mg QD
(Indinavir 800 mg TID)
Indinavir AUC:
92 %
(Relative to Indinavir 800 mg TID alone)
This effect is due to an induction of CYP3A4
by rifampicin.
The use of rifampicin with
indinavir is contraindicated.
10
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
ANALGESICS
Methadone 20-60 mg QD
(Indinavir 800 mg TID)
Indinavir AUC: ↔
(Relative to Indinavir 800 mg TID historical
controls)
Methadone AUC and C
min
:
Indinavir and methadone
can be co-administered
without dose adjustment.
ANTIARRHYTHMICS
Quinidine 200 mg SD
(Indinavir 400 mg SD)
Indinavir AUC and C
min
: ↔
(Relative to Indinavir 400 mg SD)
Quinidine concentration expected (CYP3A4
inhibition by indinavir)
Caution is warranted and
therapeutic concentration
monitoring is recommended
for quinidine when
coadministered with
CRIXIVAN. The use of
indinavir/ritonavir with
quinidine is contraindicated.
ANTIASTHMATIC
Theophylline 250 mg SD
(Indinavir 800 mg TID)
Theophylline AUC and C
min
: ↔
Indinavir and theophylline
can be co-administered
without dose adjustment.
ANTICOAGULANT
Warfarin
Not studied, combined administration may
result in increased warfarin levels.
Dose adjustment of
warfarin may be required.
ANTICONVULSANTS
Carbamazepine, phenobarbital
phenytoin
Indinavir inhibits CYP3A4 and as a result is
expected to increase the plasma concentrations
of these anticonvulsants. Concomitant use of
medicinal products that are inducers of
CYP3A4, such as carbamazepine,
phenobarbital and phenytoin may reduce
indinavir plasma concentrations.
Careful monitoring of
therapeutic and adverse
effects is recommended
when these medicines are
concomitantly administered
with indinavir.
ANTIDEPRESSANTS
Venlafaxine 50 mg TID
(Indinavir 800 mg SD)
Indinavir AUC:
28 %
(Relative to Indinavir 800 mg SD alone)
Venlafaxine and active metabolite O-
desmethyl-venlafaxine: ↔
The clinical significance of
this finding is unknown.
CALCIUM CHANNEL BLOCKERS
Dihydropyridine: e.g.,
felodipine, nifedipine,
nicardipine
dihydropyridine calcium channel blocker
concentration
Caution is warranted and
clinical monitoring of
patients is recommended.
Calcium channel blockers are metabolized by
CYP3A4 which is inhibited by indinavir.
11
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
HERBAL MEDICATIONS
St. John’s wort (Hypericum
perforatum) 300 mg TID
(Indinavir 800 mg TID)
Indinavir AUC:
54 %
Indinavir C
min
: ↓ 81 %
(Relative to Indinavir 800 mg TID alone)
Reduction in indinavir concentrations due to
induction of drug metabolising and/or transport
proteins by St. John’s wort.
Herbal preparations
containing St. John’s wort
are contraindicated with
Crixivan. If a patient is
already taking St. John’s
wort, stop St. John’s wort,
check viral levels and if
possible indinavir levels.
Indinavir levels may
increase on stopping St.
John’s wort, and the dose of
CRIXIVAN may need
adjusting. The inducing
effect may persist up to
2 weeks after cessation of
treatment with St. John’s
wort.
HISTAMINE H
2
ANTAGONIST
Cimetidine 600 mg BID
(Indinavir 400 mg SD)
Indinavir AUC and C
min
:
(Relative to Indinavir 400 mg SD alone)
Indinavir and cimetidine
can be co-administered
without dose adjustment.
HMG-CoA REDUCTASE INHIBITIORS
Lovastatin, simvastatin
Indinavir inhibits CYP3A4 and as a result is
expected to markedly increase the plasma
concentrations of these HMG-CoA reductase
inhibitors, which are highly dependent on
CYP3A4 metabolism.
Combination
contraindicated due to an
increased risk of myopathy
including rhabdomyolysis.
Rosuvastatin
Interaction not studied.
Interaction study with Lopinavir/ritonavir +
rosuvastatin:
Rosuvastatin AUC ↑ 2.08-fold
Rosuvastatin Cmax ↑ 4.66-fold
(Mechanism unknown)
Combination not
recommended
Atorvastatin
atorvastatin concentration
Atorvastatin is less dependent on CYP3A4 for
metabolism than lovastatin or simvastatin
Use the lowest possible
dose of atorvastatin with
careful monitoring. Caution
is advised.
Pravastatin, fluvastatin
Interaction not studied
Metabolism of pravastatin and fluvastatin is not
dependent on CYP3A4. Interaction via effects
on transport proteins cannot be excluded.
Interaction unknown. If no
alternative treatment is
available, use with careful
monitoring.
IMMUNOSUPPRESSIVES
Cyclosporine A
Cyclosporine A (CsA) levels markedly increase
in patients on PIs, including indinavir.
CsA levels require
progressive dose adjustment
using therapeutic drug
monitoring.
ORAL CONTRACEPTIVES
Norethindrone/ethinyl
estradiol 1/35 1 mcg QD
(Indinavir 800 mg TID)
Norethindrone AUC: ↑ 26 %
Norethindrone C
min
: ↑ 44 %
Indinavir and
norethindrone/ethinyl
estradiol 1/35 can be co-
administered without dose
adjustment.
12
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
PDE5 INHIBITOR
Sildenafil 25 mg SD
(Indinavir 800 mg TID)
Indinavir AUC:
11 %
Sildenafil AUC
340 %
Sildenafil dose should not
exceed a maximum of
25 mg in a 48-hour period
in patients receiving
concomitant indinavir
therapy.
Coadministration of CRIXIVAN with sildenafil
is likely to result in an increase of sildenafil by
competitive inhibition of metabolism.
Vardenafil 10 mg SD
(Indinavir 800 mg TID)
Vardenafil AUC: ↑ 16-fold
Vardenafil dose should not
exceed a maximum of
2.5 mg in a 24-hour period
in patients receiving
concomitant indinavir
therapy.
Coadministration of CRIXIVAN with
vardenafil is likely to result in an increase of
vardenafil by competitive inhibition of
metabolism.
Tadalafil
Interaction not studied
Tadalafil dose should not
exceed a maximum of
10 mg in a 72 hour period
in patients receiving
concomitant indinavir
therapy.
Coadministration of CRIXIVAN with tadalafil
is likely to result in an increase of tadalafil by
competitive inhibition of metabolism.
SEDATIVES/HYPNOTICS
Midazolam (parenteral)
Not studied, combined administrations are
expected to significantly increase
concentrations of midazolam, particularly when
midazolam is given orally.
CRIXIVAN and oral
midazolam should not be
coadministered (see
section 4.3). Caution should
be used with
coadministration of
CRIXIVAN and parenteral
midazolam. If CRIXIVAN
is coadministered with
parenteral midazolam, it
should be done in an
intensive care unit with
close clinical monitoring in
case of respiratory
depression and/or prolonged
sedation. Dosage
adjustment for midazolam
should be considered,
especially if more than a
single dose of midazolam is
administered.
Midazolam is extensively metabolized by
CYP3A4.
STEROIDS
Dexamethasone
Interaction not studied
↑ dexamethasone exposure expected (CYP3A
inhibition).
↓ indinavir plasma concentrations may be
expected (CYP3A induction).
Careful monitoring of
therapeutic and adverse
effects is recommended
when dexamethasone is
concomitantly administered
with indinavir.
Table 2. Interactions and dose recommendations with other medical products –
INDINAVIR
BOOSTED WITH RITONAVIR.
No specific interaction studies have been performed with the
boosted dose 400 mg indinavir with 100 mg ritonavir.
Interactions between indinavir/ritonavir and other medicinal products are listed in the tables below
(increase is indicated as “↑”, decrease as “↓”, no change (≤ +/- 20 %) as “↔”, single dose as “SD”,
once daily as “QD”, twice daily as “BID”, three times daily as “TID”, and four times daily as "QID").
13
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
ANTI-INFECTIVES
Antiretrovirals
Amprenavir
Amprenavir 1,200 mg BID AUC ↑90 % with
800 mg TID indinavir alone (see Table 1).
Amprenavir 600 mg BID AUC ↑ 64 % with
100 mg BID ritonavir alone (relative to
amprenavir 1,200 mg BID alone). Ritonavir
increases the serum levels of amprenavir as a
result of CYP3A4 inhibition.
There are no interaction data available on the
coadministration of indinavir/ritonavir and
amprenavir.
The appropriate doses for this
combination, with respect to
efficacy and safety, have not
been established. Ritonavir
oral solution should not be co-
administered with amprenavir
oral solution to children due to
the risk of toxicity from
excipients in the two
formulations.
Efavirenz 600 mg QD
(Indinavir/ritonavir 800/100
BID)
Indinavir AUC:
25 %
Indinavir C
min
↓ 50 %
(Relative to Indinavir/ritonavir 800/100 BID
alone)
Dose increases of
indinavir/ritonavir when given
in combinatin with efavirenz
have not been studied.
Ritonavir AUC ↓ 36 %
Ritonavir C
min
:
39 %
Efavirenz AUC and C
min
: ↔
Anti-Mycobacterial
Rifabutin
Interaction with indinavir/ritonavir not studied
Decreased indinavir concentrations and
increased rifabutin concentrations are
expected.
No dose recommendations for
indinavir/ritonavir with
rifabutin could be given,
therefore the combination is
not recommended. If rifabutin
treatment is required,
alternative agents for treating
HIV infection should be
sought.
Rifampicin
Rifampicin is a strong CYP3A4 inducer and
has been shown to cause a 92 % decrease in
indinavir AUC which can result in virological
failure and resistance development. During
attempts to overcome the decreased exposure
by increasing the dose of other protease
inhibitors with ritonavir, a high frequency of
liver reactions was seen.
The combination of rifampicin
and CRIXIVAN with
concomitant low-dose
ritonavir is contraindicated
(see section 4.3).
Other Anti-infectives
Atovaquone
Interaction with indinavir/ritonavir not studied
Ritonavir induces glucuronidation and as a
result is expected to decrease the plasma
concentrations of atovaquone.
Careful monitoring of
therapeutic and adverse effects
is recommended when
atovaquone is concomitantly
administered with
indinavir/ritonavir.
Erythromycin, Itraconazole
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of erythromycin and
itraconazole.
Careful monitoring of
therapeutic and adverse effects
is recommended when
erythromycin or itraconazole
are concomitantly
administered with
indinavir/ritonavir.
14
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
Ketoconazole
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of ketoconazole. Co-
administration of ritonavir and ketoconazole
caused an increased incidence of
gastrointestinal and hepatic adverse events.
Careful monitoring of
therapeutic and adverse effects
is recommended when
ketoconazole is concomitantly
administered with
indinavir/ritonavir. A dose
reduction of ketoconazole
should be considered when co-
administered with
indinavir/ritonavir.
ANALGESICS
Fentanyl
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of fentanyl.
Careful monitoring of
therapeutic and adverse effects
is recommended when
fentanyl is concomitantly
administered with
indinavir/ritonavir.
Methadone
Interaction with indinavir/ritonavir not studied
There is no significant effect of unboosted
indinavir on methadone AUC (see Table 1
above).
Increased methadone dose
may be necessary when
concomitantly administered
with indinavir/ritonavir. Dose
adjustment should be
considered based on the
patient’s clinical response to
methadone therapy.
Decreases in methadone AUC has been
observed with other ritonavir-boosted protease
inhibitors.
Ritonavir may induce glucuronidation of
methadone.
Morphine
Interaction with indinavir/ritonavir not studied
Morphine levels may be decreased due to
induction of glucuronidation by
coadministered ritonavir.
Careful monitoring of
therapeutic and adverse effects
is recommended when
morphine is concomitantly
administered with
indinavir/ritonavir.
ANTIARRTHYMICS
Digoxin 0.4 mg SD
Ritonavir 200 mg BID
Interaction with indinavir/ritonavir not studied
Digoxin AUC:
22 %
Ritonavir may increase
digoxin levels due to
modification of P-glycoprotein
mediated digoxin efflux.
Careful monitoring of digoxin
levels is recommended when
digoxin is concomitantly
administered with
indinavir/ritonavir.
ANTICOAGULANT
Warfarin
Ritonavir 400 mg BID
Interaction with indinavir/ritonavir not studied
R-warfarin levels may be decreased leading to
reduced anticoagulation due to induction of
CYP1A2 and CYP2C9 by ritonavir.
Anticoagulation parameters
should be monitored when
warfarin is coadministered
with indinavir/ritonavir.
ANTICONVULSANTS
Carbamazepine
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of carbamazepine.
Careful monitoring of
therapeutic and adverse effects
is recommended when
carbamazepine is
concomitantly administered
with indinavir/ritonavir.
15
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
Divalproex, lamotrigine,
phenytoin
Interaction with indinavir/ritonavir not studied
Ritonavir induces oxidation by CYP2C9 and
glucuronidation and as a result is expected to
decrease the plasma concentrations of
anticonvulsants.
Careful monitoring of serum
levels or therapeutic effects is
recommended when these
medicines are concomitantly
administered with
indinavir/ritonavir. Phenytoin
may decrease serum levels of
ritonavir.
ANTIDEPRESSANTS
Trazodone 50 mg SD
Ritonavir 200 mg BID
Interaction with indinavir/ritonavir not studied
Trazodone AUC:
2.4-fold
An increase in the incidence in trazodone-
related adverse events was noted when
coadministered with ritonavir.
The combination of trazodone
with indinavir/ritonavir should
be used with caution, initiating
trazodone at the lowest dosage
and monitoring for clinical
response and tolerability.
ANTIHISTAMINES
Fexofenadine
Interaction with indinavir/ritonavir not studied
Ritonavir may modify P-glycoprotein
mediated fexofenadine efflux when
coadministered resulting in increased
concentrations of fexofenadine.
Careful monitoring of
therapeutic and adverse effects
is recommended when
fexofenadine is concomitantly
administered with
indinavir/ritonavir.
Loratidine
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of loratidine.
Careful monitoring of
therapeutic and adverse effects
is recommended when
loratidine is concomitantly
administered with
indinavir/ritonavir.
CALCIUM CHANNEL BLOCKERS
Dilitazem 120 mg QD
(Indinavir/ritonavir 800/100
BID)
Dilitazem AUC
0-24hr
:
43 %
Indinavir/ritonavir AUCs: ↔
Dose modification of calcium
channel blockers should be
considered when co-
administered with
indinavir/ritonavir as it may
result in an increased
response.
Amlodipine 5 mg QD
(Indinavir/ritonavir 800/100
BID)
Amlodipine AUC
0-24hr
:
80 %
Indinavir/ritonavir AUCs: ↔
HMG-CoA REDUCTASE INHIBITORS
Same recommendations as for
indinavir without ritonavir
boosting (see Table 1).
IMMUNOSUPPRESSIVES
Cyclosporine A
(Indinavir/ritonavir 800/100
BID)
Following initiation of indinavir/ritonavir
800/100 BID or lopinavir/ritonavir 400/100
BID, dose reduction of cyclosporine A to
5-20 % of prior dose was needed to maintain
cyclosporine A levels within therapeutic range
in one study.
Cyclosporine A dose
adjustments should be made
according to measured
cyclosporine A trough blood
levels.
Tacrolimus
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of tacrolimus.
Careful monitoring of
therapeutic and adverse effects
is recommended when
tacrolimus is concomitantly
administered with
indinavir/ritonavir.
PDE5 INHIBITOR
Sildenafil, tadalafil
Interaction not studied.
For sildenafil and tadalafil,
same recommendations as for
indinavir without ritonavir
boosting (see Table 1).
16
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
Vardenafil
Interaction not studied.
Vardenafil dose should not
exceed a maximum of 2.5 mg
in a 72-hour period when
given with a boosted protease
inhibitor.
SEDATIVES/HYPNOTICS
Buspirone
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of buspirone.
Careful monitoring of
therapeutic and adverse effects
is recommended when
buspirone is concomitantly
administered with
indinavir/ritonavir.
Midazolam (parenteral)
Interaction with indinavir/ritonavir
Not studied, combined administrations are
expected to significantly increase
concentrations of midazolam, particularly
when midazolam is given orally (CYP3A4
inhibition).
CRIXIVAN with ritonavir and
oral midazolam should not be
coadministered (see
section 4.3). Caution should
be used with coadministration
of CRIXIVAN with ritonavir
and parenteral midazolam. If
CRIXIVAN with ritonavir is
coadministered with parenteral
midazolam, it should be done
in an intensive care unit with
close clinical monitoring in
case of respiratory depression
and/or prolonged sedation.
Dosage adjustment for
midazolam should be
considered, especially if more
than a single dose of
midazolam is administered.
STEROIDS
Dexamethasone
Interaction with indinavir/ritonavir not studied
↑ dexamethasone exposure expected (CYP3A
inhibition).
↓ indinavir plasma concentrations may be
expected (CYP3A induction).
Careful monitoring of
therapeutic and adverse effects
is recommended when
dexamethasone is
concomitantly administered
with indinavir/ritonavir.
For information regarding diet or the effect of food on indinavir absorption (see section 4.2 and 5.2).
Use during pregnancy
There are no adequate and well-controlled studies in pregnant patients. Indinavir should be used
during pregnancy only if the potential benefit justifies the potential risk to the foetus. Given that
substantially lower antepartum exposures have been observed in a small study of HIV-infected
pregnant patients and the limited data in this patient population, indinavir use is not recommended in
HIV-infected pregnant patients (see section 5.2).
Hyperbilirubinaemia, reported predominantly as elevated indirect bilirubin, has occurred in 14 % of
patients during treatment with indinavir. Because it is unknown whether indinavir will exacerbate
physiologic hyperbilirubinaemia in neonates, careful consideration must be given to the use of
indinavir in pregnant women at the time of delivery (see section 4.8).
In Rhesus monkeys, administration of indinavir to neonates caused a mild exacerbation of the transient
physiologic hyperbilirubinaemia seen in this species after birth. Administration of indinavir to
17
pregnant Rhesus monkeys during the third trimester did not cause a similar exacerbation in neonates;
however, only limited placental transfer of indinavir occurred.
Use during lactation
It is recommended that HIV−infected women do not breast−feed their infants under any circumstances
in order to avoid transmission of HIV. It is not known whether indinavir is excreted in human milk.
Mothers should be instructed to discontinue breast−feeding during treatment.
No studies on the effects on the ability to drive and use machines have been performed. There are no
data to suggest that indinavir affects the ability to drive and use machines. However, patients should be
informed that dizziness and blurred vision have been reported during treatment with indinavir.
Nephrolithiasis occurred in approximately 10 % of patients treated with the recommended (unboosted)
dose of CRIXIVAN in a pooled analysis of controlled clinical trials (see also below table and in
section 4.4).
Clinical adverse reactions reported by the investigators as possibly, probably, or definitely related to
CRIXIVAN in ≥ 5 % of patients treated with CRIXIVAN monotherapy or in combination with
NRTI(s) (n = 309) for 24 weeks are listed below. Many of these adverse reactions were also identified
as common pre–existing or frequently occurring medical conditions in this population. These adverse
reactions were: nausea (35.3 %), headache (25.2 %), diarrhoea (24.6 %), asthenia/fatigue (24.3 %),
rash (19.1 %), taste perversion (19.1 %), dry skin (16.2 %), abdominal pain (14.6 %), vomiting
(11.0 %), dizziness (10.7 %). With the exception of dry skin, rash, and taste perversion, the incidence
of clinical adverse reactions was similar or higher among patients treated with antiretroviral nucleoside
analogue controls than among patients treated with CRIXIVAN monotherapy or in combination with
NRTI(s). This overall safety profile remained similar for 107 patients treated with CRIXIVAN
monotherapy or in combination with NRTI(s) for up to 48 weeks. Adverse reactions, including
nephrolithiasis, may lead to treatment interruption.
In controlled clinical trials conducted world–wide, indinavir was administered alone or in combination
with other antiretroviral agents (zidovudine, didanosine, stavudine, and/or lamivudine) to
approximately 2,000 patients, the majority of whom were adult Caucasian males (15 % females).
Indinavir did not alter the type, frequency, or severity of known major adverse effects associated with
the use of zidovudine, didanosine, or lamivudine.
The following adverse reactions have been reported during clinical studies in adults and/or post-
marketing use for CRIXIVAN monotherapy and/or CRIXIVAN with combination antiretroviral
therapy (CART).
Very common (≥ 1/10); Common (≥ 1/100, < 1/10); Uncommon (≥ 1/1,000, < 1/100);
Rare (≥ 1/10,000, < 1/1,000); Very rare (< 1/10,000); not known (cannot be estimated from the
available data). Adverse reactions have also been reported during post-marketing experience* as they
are derived from spontaneous reports, incidences cannot be determined.
18
System Organ Class
Frequency
Adverse reactions
CRIXIVAN
Blood and lymphatic system
disorders
Very
common
increases in MCV, decreases in neutrophils
Not known*
increased spontaneous bleeding in patients with
haemophilia, anemia including acute haemolytic
anaemia, thrombocytopenia (see section 4.4).
Immune system disorders
Not known* anaphylactoid reactions
Metabolism and nutrition
disorders
Not known* new onset diabetes mellitus or hyperglycaemia, or
exacerbation of pre-existing diabetes mellitus,
hypertriglyceridaemia, hypercholesterolaemia, body
fat changes (lipomatosis, lipoatrophy) (see
section 4.4).
Nervous system disorders
Very
common
headache, dizziness
Common
insomnia, hypoaesthesia; paraesthesia
Not known*
oral paraesthesia.
Gastrointestinal disorders
Very
common
nausea, vomiting, diarrhoea, dyspepsia
Common
flatulence, dry mouth, acid regurgitation
Not known*
hepatitis, including reports of hepatic failure,
pancreatitis.
Hepato-biliary disorders
Very
Common
isolated asymptomatic hyperbilirubinaemia,
increased ALT and AST
Not known*
liver function abnormalities
Skin and subcutaneous tissue
disorders
Very
common
rash, dry skin
Common
pruritus
Not known*
rash including erythema multiforme and Stevens
Johnson syndrome, hypersensitivity vasculitis,
alopecia, hyperpigmentation, urticaria; ingrown
toenails and/or paronychia
Musculoskeletal and connective
tissue disorders
Common
myalgia
Not known*
myositis, rhabdomyolysis, increased CPK,
osteonecrosis(see section 4.4).
19
System Organ Class
Frequency
Adverse reactions
CRIXIVAN
Renal and urinary disorders
Very
common
haematuria, proteinuria, crystalluria
Common
nephrolithiasis, dysuria.
Not known*
nephrolithiasis, in some cases with renal
insufficiency or acute renal failure; pyelonephritis,
interstitial nephritis, sometimes associated with
indinavir crystal deposits. In some patients,
resolution of the interstitial nephritis did not occur
following discontinuation of indinavir therapy;
renal insufficiency, renal failure, leucocyturia
(see section 4.4).
General disorders and
administration site conditions
Very
common
asthenia/fatigue, taste perversion, abdominal pain.
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see section 4.4).
Nephrolithiasis
Nephrolithiasis, including flank pain with or without haematuria (including microscopic haematuria),
has been reported in approximately 10 % (252/2,577) of patients receiving CRIXIVAN in clinical
trials at the recommended dose compared to 2.2 % in the control arms. In general, these events were
not associated with renal dysfunction and resolved with hydration and temporary interruption of
therapy (e.g., 1–3 days).
Hyperbilirubinaemia
Isolated asymptomatic hyperbilirubinaemia (total bilirubin ≥ 2.5 mg/dl, 43 mcmol/l) was reported
predominantly as elevated indirect bilirubin and rarely associated with elevations in ALT, AST, or
alkaline phosphatase, has occurred in approximately 14 % of patients treated with CRIXIVAN alone
or in combination with other antiretroviral agents. Most patients continued treatment with CRIXIVAN
without dosage reduction and bilirubin values gradually declined toward baseline.
Hyperbilirubinaemia occurred more frequently at doses exceeding 2.4 g/day compared to doses less
than 2.4 g/day.
Paediatric Patients
In clinical trials in paediatric patients (≥ 3 years), the adverse experience profile was similar to that for
adult patients except for a higher frequency of nephrolithiasis of 29 % (20/70) in paediatric patients
treated with CRIXIVAN at the recommended dose. Asymptomatic pyuria of unknown etiology was
noted in 10.9 % (6/55) of pediatric patients who received CRIXIVAN at the recommended dose of
500 mg/m
2
every 8 hours. Some of these events were associated with mild elevation of serum
creatinine.
20
There have been reports of human overdose with CRIXIVAN. The most commonly reported
symptoms were gastro-intestinal (e.g., nausea, vomiting, diarrhoea) and renal (e.g., nephrolithiasis,
flank pain, haematuria).
It is not known whether indinavir is dialyzable by peritoneal or haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Protease inhibitor, ATC code JO5AE02
Mechanism of action
Indinavir inhibits recombinant HIV–1 and HIV–2 protease with an approximate tenfold selectivity for
HIV–1 over HIV–2 proteinase. Indinavir binds reversibly to the protease active site and inhibits
competitively the enzyme, thereby preventing cleavage of the viral precursor polyproteins that occurs
during maturation of the newly formed viral particle. The resulting immature particles are non–
infectious and are incapable of establishing new cycles of infection. Indinavir did not significantly
inhibit the eukaryotic proteases human renin, human cathepsin D, human elastase, and human factor
Xa.
Microbiology
Indinavir at concentrations of 50 to 100 nM mediated 95 % inhibition (IC
95
) of viral spread (relative to
an untreated virus–infected control) in human T–lymphoid cell cultures and primary human
monocytes/macrophages infected with HIV−1 variants LAI, MN, RF, and a macrophage–tropic variant
SF–162, respectively. Indinavir at concentrations of 25 to 100 nM mediated 95 % inhibition of viral
spread in cultures of mitogen–activated human peripheral blood mononuclear cells infected with
diverse, primary clinical isolates of HIV−1, including isolates resistant to zidovudine and non–
nucleoside reverse transcriptase inhibitors (NNRTIs). Synergistic antiretroviral activity was observed
when human T–lymphoid cells infected with the LAI variant of HIV–1 were incubated with indinavir
and either zidovudine, didanosine, or NNRTIs.
Drug resistance
Loss of suppression of viral RNA levels occurred in some patients; however, CD4 cell counts were
often sustained above pre–treatment levels. When loss of viral RNA suppression occurred, it was
typically associated with replacement of circulating susceptible virus with resistant viral variants.
Resistance was correlated with the accumulation of mutations in the viral genome that resulted in the
expression of amino acid substitutions in the viral protease.
At least eleven amino acid sites in the protease have been associated with indinavir resistance: L10,
K20, L24, M46, I54, L63, I64, A71, V82, I84, and L90. The basis for their contributions to resistance,
however, is complex. None of these substitutions was either necessary or sufficient for resistance. For
example, no single substitution or pair of substitutions was capable of engendering measurable
(≥ four–fold) resistance to indinavir, and the level of resistance was dependent on the ways in which
multiple substitutions were combined. In general, however, higher levels of resistance resulted from
the co–expression of greater numbers of substitutions at the eleven identified positions. Among
patients experiencing viral RNA rebound during indinavir monotherapy at 800 mg q8h, substitutions
at only three of these sites were observed in the majority of patients: V82 (to A or F), M46 (to I or L),
and L10 (to I or R). Other substitutions were observed less frequently. The observed amino acid
substitutions appeared to accumulate sequentially and in no consistent order, probably as a result of
ongoing viral replication.
21
It should be noted that the decrease in suppression of viral RNA levels was seen more frequently when
therapy with indinavir was initiated at doses lower than the recommended oral dose of 2.4 g/day.
Therefore, therapy with indinavir should be initiated at the recommended dose to increase
suppression of viral replication and therefore inhibit the emergence of resistant virus.
The concomitant use of indinavir with nucleoside analogues (to which the patient is naive) may lessen
the risk of the development of resistance to both indinavir and the nucleoside analogues. In one
comparative trial, combination therapy with nucleoside analogues (triple therapy with zidovudine plus
didanosine) conferred protection against the selection of virus expressing at least one resistance–
associated amino acid substitution to both indinavir (from 13/24 to 2/20 at therapy week 24) and to the
nucleoside analogues (from 10/16 to 0/20 at therapy week 24).
Cross resistance
HIV−1 patient isolates with reduced susceptibility to indinavir expressed varying patterns and degrees
of cross–resistance to a series of diverse HIV PIs, including ritonavir and saquinavir. Complete
cross−resistance was noted between indinavir and ritonavir; however, cross−resistance to saquinavir
varied among isolates. Many of the protease amino acid substitutions reported to be associated with
resistance to ritonavir and saquinavir were also associated with resistance to indinavir.
Pharmacodynamic effects
Adults
Treatment with indinavir alone or in combination with other antiretroviral agents (i.e., nucleoside
analogues) has so far been documented to reduce viral load and increase CD4 lymphocytes in patients
with CD4 cell counts below 500 cells/mm
3
.
In one published study, 20 HIV-infected patients with undetectable plasma viral load (< 200 copies
/ml) receiving indinavir 800 mg every 8 hours were switched in an open, cross-over design to
indinavir/ritonavir 400/100 mg every 12 hours. Eighteen patients completed the study to week 48.
Viral load remained < 200 copies/mL for 48 weeks in all patients.
Another published study evaluated the efficacy and safety of indinavir/ritonavir 400/100 mg every
12 hours in 40 antiretroviral-naïve patients. Thirty subjects completed 48 weeks of treatment. At
week 4, the indinavir Cmin was 500 ng/mL with substantial trough variability (range 5 to
8,100 ng/mL). By intent to treat analysis 65 % of patients had HIV RNA < 400 copies/mL and 50 %
had viral load < 50 copies/mL; by on-treatment analysis 96 % of patients had HIV RNA
< 400 copies/mL and 74 % had viral load < 50 copies/mL.
Eighty antiretroviral naïve patients were entered into a third published study. In this open label non-
randomized single arm study, patients were treated with stavudine and lamivudine plus
indinavir/ritonavir 400/100 mg every 12 hours. Sixty-two patients completed the study to week 96. In
the intent to treat and on treatment analyses the proportion of patients with HIV RNA of
< 50 copies/mL was 68.8 % and 88.7 %, respectively, at week 96.
Indinavir alone or in combination with nucleoside analogues (zidovudine/stavudine and lamivudine)
has been shown to delay clinical progression rate compared with nucleoside analogues and to provide
a sustained effect on viral load and CD4 count.
In zidovudine experienced patients, indinavir, zidovudine and lamivudine in combination compared
with lamivudine added to zidovudine reduced the probability of AIDS defining illness or death
(ADID) at 48 weeks from 13 % to 7 %. Similarly, in antiretroviral naive patients, indinavir with and
without zidovudine compared with zidovudine alone reduced the probability of ADID at 48 weeks
from 15 % with zidovudine alone to approximately 6 % with indinavir alone or in combination with
zidovudine.
Effects on viral load were consistently more pronounced in patients treated with indinavir in
combination with nucleoside analogues, but the proportion of patients with serum viral RNA below
22
the limit of quantification (500 copies/ml) varied between studies, at week 24 from 40 % to more than
80 %. This proportion tends to remain stable over prolonged periods of follow–up. Similarly, effects
on CD4 cell count tend to be more pronounced in patients treated with indinavir in combination with
nucleoside analogues compared with indinavir alone. Within studies, this effect is sustained also after
prolonged periods of follow–up.
Paediatric patients
Two clinical trials in 41 paediatric patients (4 to 15 years of age) were designed to characterise the
safety, antiretroviral activity, and pharmacokinetics of indinavir in combination with stavudine and
lamivudine. In one study, at week 24, the proportion of patients with plasma viral RNA below
400 copies/ml was 60 %; the mean increase in CD4 cell counts was 242 cells/mm
3
; and the mean
increase in percent CD4 cell counts was 4.2 %. At week 60, the proportion of patients with plasma
viral RNA below 400 copies/ml was 59 %. In another study, at week 16, the proportion of patients
with plasma viral RNA below 400 copies/ml was 59 %; the mean increase in CD4 cell counts was
73 cells/mm
3
; and the mean increase in percent CD4 cell counts was 1.2 %. At week 24, the proportion
of patients with plasma viral RNA below 400 copies/ml was 60 %.
5.2 Pharmacokinetic properties
Absorption
Indinavir is rapidly absorbed in the fasted state with a time to peak plasma concentration of 0.8 hours
± 0.3 hours (mean ± S.D.). A greater than dose–proportional increase in indinavir plasma
concentrations was observed over the 200 – 800 mg dose range. Between 800-mg and 1,000-mg dose
levels, the deviation from dose–proportionality is less pronounced. As a result of the short half–life,
1.8 ± 0.4 hours, only a minimal increase in plasma concentrations occurred after multiple dosing. The
bioavailability of a single 800-mg dose of indinavir was approximately 65 % (90 % CI, 58 – 72 %).
Data from a steady state study in healthy volunteers indicate that there is a diurnal variation in the
pharmacokinetics of indinavir. Following a dosage regimen of 800 mg every 8 hours, measured peak
plasma concentrations (C
max
) after morning, afternoon and evening doses were 15,550 nM, 8,720 nM
and 8,880 nM, respectively. Corresponding plasma concentrations at 8 hours post dose were 220 nM,
210 nM and 370 nM, respectively. The relevance of these findings for ritonavir boosted indinavir is
unknown. At steady state following a dosage regimen of 800 mg every 8 hours, HIV–seropositive
adult patients in one study achieved geometric means of: AUC
0-8h
of 27,813 nM*h (90 % confidence
interval = 22,185, 34,869), peak plasma concentrations 11,144 nM (90 % confidence interval = 9,192,
13,512) and plasma concentrations at 8 hours post dose 211 nM (90 % confidence interval = 163,274).
Food effect
At steady state following a dosage regimen of 800 mg/100 mg of indinavir/ritonavir every 12 hours
with a low-fat meal, healthy volunteers in one study achieved geometric means: AUC
0-12h
116,067 nM*h (90 % confidence interval = 101,680, 132,490), peak plasma concentrations 19,001 nM
(90 % confidence interval = 17,538, 20,588), and plasma concentrations at 12 hours post dose
2,274 nM (90 % confidence interval = 1,701, 3,042). No significant difference in exposure was seen
when the regimen was given with a high-fat meal.
Indinavir boosted regimen. Limited data are available on the pharmacokinetics of indinavir in
association with low dose ritonavir. The pharmacokinetics of indinavir (400 mg) with ritonavir
(100 mg) dosed twice daily was examined in two studies. Pharmacokinetic analysis in one study was
performed on nineteen of the patients, with a median (range) indinavir AUC 0-12 hr, Cmax, and Cmin
of 25,421 nM*h (21,489 - 36,236 nM*h), 5,758 nM (5,056 – 6,742 nM) and 239 (169 – 421 nM),
respectively. The pharmacokinetic parameters in the second study were comparable.
In HIV−infected paediatric patients, a dosage regimen of indinavir hard capsules, 500 mg/m
2
every
8 hours, produced AUC
0–8hr
values of 27,412 nM*h, peak plasma concentrations of 12,182 nM, and
plasma concentrations at 8 hours post dose of 122 nM. The AUC and peak plasma concentrations were
generally similar to those previously observed in HIV–infected adults receiving the recommended
23
dose of 800 mg every 8 hours; it should be observed that the plasma concentrations 8 hours post dose
were lower.
During pregnancy, it has been demonstrated that the systemic exposure of indinavir is relevantly
decreased (PACTG 358. Crixivan, 800 mg every 8 hours + zidovudine 200 mg every 8 hours and
lamivudine 150 mg twice a day). The mean indinavir plasma AUC
0-8hr
at week 30-32 of gestation
(n = 11) was 9,231 nM∗hr, which is 74 % (95 % CI: 50 %, 86 %) lower than that observed 6 weeks
postpartum. Six of these 11 (55 %) patients had mean indinavir plasma concentrations 8 hours post-
dose (C
min
) below assay threshold of reliable quantification. The pharmacokinetics of indinavir in these
11 patients at 6 weeks postpartum were generally similar to those observed in non-pregnant patients in
another study (see section 4.6).
Administration of indinavir with a meal high in calories, fat, and protein resulted in a blunted and
reduced absorption with an approximate 80 % reduction in AUC and an 86 % reduction in C
max
.
Administration with light meals (e.g., dry toast with jam or fruit conserve, apple juice, and coffee with
skimmed or fat–free milk and sugar or corn flakes, skimmed or fat–free milk and sugar) resulted in
plasma concentrations comparable to the corresponding fasted values.
The pharmacokinetics of indinavir taken as indinavir sulphate salt (from opened hard capsules) mixed
in apple sauce were generally comparable to the pharmacokinetics of indinavir taken as hard capsules,
under fasting conditions. In HIV–infected paediatric patients, the pharmacokinetic parameters of
indinavir in apple sauce were: AUC
0–8hr
of 26,980 nM*h; peak plasma concentration of 13,711 nM;
and plasma concentration at 8 hours post dose of 146 nM.
Distribution
Indinavir was not highly bound to human plasma proteins (39 % unbound).
There are no data concerning the penetration of indinavir into the central nervous system in humans.
Biotransformation
Seven major metabolites were identified and the metabolic pathways were identified as
glucuronidation at the pyridine nitrogen, pyridine–N–oxidation with and without 3’–hydroxylation on
the indane ring, 3’–hydroxylation of indane, p–hydroxylation of phenylmethyl moiety, and N–
depyridomethylation with and without the 3’–hydroxylation.
In vitro
studies with human liver
microsomes indicated that CYP3A4 is the only P450 isozyme that plays a major role in the oxidative
metabolism of indinavir. Analysis of plasma and urine samples from subjects who received indinavir
indicated that indinavir metabolites had little proteinase inhibitory activity.
Elimination
Over the 200–1,000-mg dose range administered in both volunteers and HIV infected patients, there
was a slightly greater than dose–proportional increase in urinary recovery of indinavir. Renal clearance
(116 ml/min) of indinavir is concentration–independent over the clinical dose range. Less than 20 % of
indinavir is excreted renally. Mean urinary excretion of unchanged drug following single dose
administration in the fasted state was 10.4 % following a 700-mg dose, and 12.0 % following a
1,000-mg dose. Indinavir was rapidly eliminated with a half–life of 1.8 hours.
Characteristics in patients
Pharmacokinetics of indinavir do not appear to be affected by race.
There are no clinically significant differences in the pharmacokinetics of indinavir in HIV seropositive
women compared to HIV seropositive men.
Patients with mild–to–moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence
of decreased metabolism of indinavir resulting in approximately 60 % higher mean AUC following a
400-mg dose. The mean half–life of indinavir increased to approximately 2.8 hours.
24
5.3 Preclinical safety data
Crystals have been seen in the urine of rats, one monkey, and one dog. The crystals have not been
associated with drug–induced renal injury. An increase in thyroidal weight and thyroidal follicular cell
hyperplasia, due to an increase in thyroxine clearance, was seen in rats treated with indinavir at doses
≥ 160 mg/kg/day. An increase in hepatic weight occurred in rats treated with indinavir at doses
≥ 40 mg/kg/day and was accompanied by hepatocellular hypertrophy at doses ≥ 320 mg/kg/day.
The maximum non–lethal oral dose of indinavir was at least 5,000 mg/kg in rats and mice, the highest
dose tested in acute toxicity studies.
Studies in rats indicated that uptake into brain tissue was limited, distribution into and out of the
lymphatic system was rapid, and excretion into the milk of lactating rats was extensive. Distribution of
indinavir across the placental barrier was significant in rats, but limited in rabbits.
Mutagenicity
Indinavir did not have any mutagenic or genotoxic activity in studies with or without metabolic
activation.
Carcinogenicity
No carcinogenicity was noted in mice at the maximum tolerated dose, which corresponded to a
systemic exposure approximately 2 to 3 times higher than the clinical exposure. In rats, at similar
exposure levels, an increased incidence of thyroid adenomas was seen, probably related to an increase
in release of thyroid stimulating hormone secondary to an increase in thyroxine clearance. The
relevance of the findings to humans is likely limited.
Developmental Toxicity
Developmental toxicity studies were performed in rats, rabbits and dogs (at doses which produced
systemic exposures comparable to or slightly greater than human exposure) and revealed no evidence
of teratogenicity. No external or visceral changes were observed in rats, however, increases in the
incidence of supernumerary ribs and of cervical ribs were seen. No external, visceral, or skeletal
changes were observed in rabbits or dogs. In rats and rabbits, no effects on embryonic/foetal survival
or foetal weights were observed. In dogs, a slight increase in resorptions was seen; however, all
foetuses in medication–treated animals were viable, and the incidence of live foetuses in medication–
treated animals was comparable to that in controls.
6.
6.1 List of excipients
Capsule content
- anhydrous lactose
- magnesium stearate
Capsule shell:
- gelatin
- titanium dioxide (E 171)
- printing ink: titanium dioxide (E 171), indigo carmine (E 132), and iron oxide (E 172).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
25
6.4 Special precautions for storage
Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.
6.5 Nature and contents of container
HDPE bottles with a polypropylene cap and a foil induction cap containing 180 capsules.
6.6 Special precautions for disposal
The bottles contain desiccant canisters that should remain in the container.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8.
EU/1/96/024/010
9.
Date of first authorisation: 04/10/1996
Date of latest renewal: 07/10/2006
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu
26
1.
CRIXIVAN 200 mg hard capsules
2.
Each hard capsule contains indinavir sulphate corresponding to 200 mg of indinavir.
Excipient: Each 200 mg capsule contains 74.8 mg lactose.
For a full list of excipients, see section 6.1
3.
Hard capsule.
The capsules are semi–translucent white and coded CRIXIVAN™ 200 mg in blue.
4.
CRIXIVAN is indicated in combination with antiretroviral nucleoside analogues for the treatment of
HIV–1 infected adults, adolescents, and children 4 years of age and older. In adolescents and children,
the benefit of indinavir therapy versus the increased risk of nephrolithiasis should particularly be
considered (see section 4.4).
CRIXIVAN should be administered by physicians who are experienced in the treatment of HIV
infection. On the basis of current pharmacodynamic data, indinavir must be used in combination with
other antiretroviral agents. When indinavir is administered as monotherapy resistant viruses rapidly
emerge (see section 5.1).
Adults
The recommended dosage of CRIXIVAN is 800 mg orally every 8 hours.
Data from published studies suggest that CRIXIVAN 400 mg in combination with ritonavir 100 mg,
both administered orally twice daily, may be an alternative dosing regimen. The suggestion is based on
limited published data (see section 5.2).
If co-administered with ritonavir, CRIXIVAN may be administered with or without food.
Children and adolescents (4 to 17 years of age)
The recommended dosage of CRIXIVAN for patients 4 to 17 years of age is 500 mg/m
2
(dose adjusted
from calculated body surface area [BSA] based on height and weight) orally every 8 hours (see table
below). This dose should not exceed the equivalent of the adult dose of 800 mg every 8 hours.
CRIXIVAN hard capsules should only be given to children who are able to swallow hard capsules.
CRIXIVAN has not been studied in children under the age of 4 years (see section 5.1 and 5.2).
27
Paediatric dose (500 mg/
m
2
) to be administered every 8 hours
Body Surface
Area (m
2
)
CRIXIVAN dose
Every 8 hours (mg)
0.50
300
0.75
400
1.25
600
1.50
800
General administration recommendations
The hard capsules should be swallowed whole.
Since CRIXIVAN must be taken at intervals of 8 hours, a schedule convenient for the patient should
be developed. For optimal absorption, CRIXIVAN should be administered without food but with
water 1 hour before or 2 hours after a meal. Alternatively, CRIXIVAN may be administered with a
low–fat, light meal.
To ensure adequate hydration, it is recommended that adults drink at least 1.5 litres of liquids during
the course of 24 hours. It is also recommended that children who weigh less than 20 kg drink at least
75 ml/kg/day and that children who weigh 20 to 40 kg drink at least 50 ml/kg/day.
Medical management in patients with one or more episodes of nephrolithiasis must include adequate
hydration and may include temporary interruption of therapy (e.g., 1 to 3 days) during the acute
episode of nephrolithiasis or discontinuation of therapy (see section 4.4).
Special dosing considerations in adults
A dosage reduction of CRIXIVAN to 600 mg every 8 hours should be considered when administering
itraconazole or ketoconazole concurrently (see section 4.5).
In patients with mild–to–moderate hepatic impairment due to cirrhosis, the dosage of CRIXIVAN
should be reduced to 600 mg every 8 hours. The recommendation is based on limited pharmacokinetic
data (see section 5.2). Patients with severe hepatic impairment have not been studied; therefore, no
dosing recommendations can be made (see section 4.4).
Safety in patients with impaired renal function has not been studied; however, less than 20 % of
indinavir is excreted in the urine as unchanged drug or metabolites (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
Indinavir with or without ritonavir should not be administered concurrently with medicinal products
with narrow therapeutic windows and which are substrates of CYP3A4. Inhibition of CYP3A4 by both
CRIXIVAN and ritonavir could result in elevated plasma concentrations of these medicines,
potentially causing serious or life-threatening reactions.
CRIXIVAN with or without ritonavir should not be administered concurrently with amiodarone,
terfenadine, cisapride, astemizole, alprazolam, triazolam, midazolam administered orally (for caution
on parenterally administered midazolam, see section 4.5), pimozide, ergot derivatives, simvastatin or
lovastatin (see section 4.4).
Combination of rifampicin with CRIXIVAN with or without concomitant low-dose ritonavir is
contraindicated (see section 4.5). Concurrent use of indinavir with herbal preparations containing St
John’s wort (Hypericum perforatum) is contraindicated (see section 4.5).
28
1.00
500
In addition, indinavir with ritonavir should not be administered with alfuzosin, meperidine, piroxicam,
propoxyphene, bepridil, encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine,
clorazepate, diazepam, estazolam and flurazepam.
Ritonavir should not be given with indinavir to patients with decompensated liver disease as ritonavir
is principally metabolized and eliminated by the liver (see section 4.4).
When CRIXIVAN is used with ritonavir, consult the Summary of Product Characteristics of ritonavir
for additional contraindications.
Nephrolithiasis and tubulointerstitial nephritis
Nephrolithiasis has occurred with indinavir therapy in adult and paediatric patients. The frequency of
nephrolithiasis is higher in paediatric patients than in adult patients. In some cases, nephrolithiasis has
been associated with renal insufficiency or acute renal failure; in the majority of these cases renal
insufficiency and acute renal failure were reversible. If signs and symptoms of nephrolithiasis,
including flank pain with or without haematuria (including microscopic haematuria) occur, temporary
interruption of therapy (e.g. for 1–3 days) during the acute episode of nephrolithiasis or
discontinuation of therapy may be considered. Paediatric patients who experience flank pain should be
evaluated for the possibility of nephrolithiasis. Evaluation may consist of urinalysis, serum BUN and
creatinine, and ultrasound of the bladder and kidneys. The long–term effects of nephrolithiasis in
paediatric patients are unknown. Adequate hydration is recommended in all patients on indinavir (see
section 4.2 and 4.8).
Cases of interstitial nephritis with medullary calcification and cortical atrophy have been observed in
patients with asymptomatic severe leucocyturia (> 100 cells/high power field). In patients at increased
risk such as children, urinary screening should be considered. If persistent severe leucocyturia is
found, further investigation might be warranted.
Medicinal products nteractions
Indinavir should be used cautiously with other medicinal products that are potent inducers of
CYP3A4. Co–administration may result in decreased plasma concentrations of indinavir and as a
consequence an increased risk for suboptimal treatment and facilitation of development of resistance
(see section 4.5).
If indinavir is given with ritonavir, the potential interaction may be increased. The Interactions section
of the SPC for ritonavir should also be consulted for information about potential interactions.
Atazanavir as well as indinavir are associated with indirect (unconjugated) hyperbilirubinemia due to
inhibition of UDP-glucuronosyltransferase (UGT). Combinations of atazanavir with or without
ritonavir and Crixivan have not been studied and co-administration of these medicinal products is not
recommended due to risk of worsening of these adverse effects.
Concomitant use of indinavir with lovastatin or simvastatin is not recommended due to an increased
risk of myopathy including rhabdomyolysis. Based on an interaction study with lopinavir/ritonavir,
combination of rosuvastatin and protease inhibitors is not recommended. Caution must also be
exercised if indinavir is used concurrently with atorvastatin. The interaction of indinavir or
indinavir/ritonavir with pravastatin or fluvastatin is not known (see section 4.5).
Co–administration of CRIXIVAN with sildenafil, tadalafil and vardenafil (PDE5 inhibitors) are
expected to substantially increase the plasma concentrations of these compounds and may result in an
increase in PDE5 inhibitor–associated adverse events, including hypotension, visual changes, and
priapism (see section 4.5).
29
Acute haemolytic anaemia
Acute haemolytic anaemia has been reported which in some cases was severe and progressed rapidly.
Once a diagnosis is apparent, appropriate measures for the treatment of haemolytic anaemia should be
instituted which may include discontinuation of indinavir.
Hyperglycaemia
New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been
reported in patients receiving protease inhibitors (PIs). In some of these the hyperglycaemia was
severe and in some cases also associated with ketoacidosis. Many patients had confounding medical
conditions, some of which required therapy with agents that have been associated with the
development of diabetes mellitus or hyperglycaemia.
Fat redistribution
Combination antiretroviral therapy has been associated with the redistribution of body fat
(lipodystrophy) in HIV patients. The long term consequences of these events are currently unknown.
Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs
and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A
higher risk of lipodystrophy has been associated with individual factors such as older age, and with
drug related factors such as longer duration of antiretroviral treatment and associated metabolic
disturbances. Clinical examination should include evaluation for physical signs of fat redistribution.
Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid
disorders should be managed as clinically appropriate (see section 4.8).
Liver disease
The safety and efficacy of indinavir has not been established in patients with significant underlying
liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral
therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of
concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information
for these medicinal products.
The safety and efficacy of indinavir/ritonavir has not been established in patients with significant
underlying liver disorders and should not be used in this patient population.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
An increased incidence of nephrolithiasis has been observed in patients with underlying liver disorders
when treated with indinavir.
Immune Reactivation Syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically,
such reactions have been observed within the first few weeks or months of initiation of CART.
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections,
and
Pneumocystis carinii
pneumonia. Any inflammatory symptoms should be evaluated and treatment
instituted when necessary.
Patients with coexisting conditions
There have been reports of increased bleeding, including spontaneous skin haematomas and
haemarthroses, in haemophiliac patients type A and B treated with PIs. In some patients additional
factor VIII was given. In more than a half of the reported cases, treatment with PIs was continued or
re-introduced if treatment had been discontinued. A causal relationship has been evoked, although the
mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware
of the possibility of increased bleeding.
30
Patients with mild–to–moderate hepatic insufficiency due to cirrhosis will require a dosage reduction
of indinavir due to decreased metabolism of indinavir (see section 4.2). Patients with severe hepatic
impairment have not been studied. In the absence of such studies, caution should be exercised as
increased levels of indinavir may occur.
Safety in patients with impaired renal function has not been studied; however, less than 20 % of
indinavir is excreted in the urine as unchanged drug or metabolites (see section 4.2).
Osteonecrosis:
Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been
reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience
joint aches and pain, joint stiffness or difficulty in movement.
Lactose
This medicinal product contains 299.2 mg of lactose in each 800 mg dose (maximum single dose).
This quantity is not likely to induce symptoms of lactose intolerance (milk intolerance).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicine.
Interaction studies have only been performed in adults. The relevance of the results from these studies
in paediatric patients is unknown.
The metabolism of indinavir is mediated by the cytochrome P450 enzyme CYP3A4. Therefore, other
substances that either share this metabolic pathway or modify CYP3A4 activity may influence the
pharmacokinetics of indinavir. Similarly, indinavir might also modify the pharmacokinetics of other
substances that share this metabolic pathway. Boosted indinavir (indinavir with ritonavir) may have
additive pharmacokinetic effects on substances that share the CYP3A4 pathway as both
ritonavir and
indinavir inhibit the cytochrome P450 enzyme CYP3A4.
Indinavir with or without ritonavir should not be administered concurrently with medicinal products
with narrow therapeutic windows and which are substrates of CYP3A4. Inhibition of CYP3A4 by both
CRIXIVAN and ritonavir could result in elevated plasma concentrations of these medicines,
potentially causing serious or life-threatening reactions. CRIXIVAN with or without ritonavir should
not be administered concurrently with amiodarone, terfenadine, cisapride, astemizole, alprazolam,
triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see
Table 1 and 2 below), pimozide, ergot derivatives, simvastatin or lovastatin. In addition, indinavir with
ritonavir should not be administered with alfuzosin, meperidine, piroxicam, propoxyphene, bepridil,
encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine, clorazepate, diazepam, estazolam
and flurazepam.
Concurrent use of indinavir with rifampicin or herbal preparations containing St John’s wort
(Hypericum perforatum) is contraindicated.
Drugs listed above are not repeated in Table 1 and 2 unless specific interaction data is available.
Refer also to sections 4.2 and 4.3.
31
Table 1. Interactions and dose recommendations with other medical products –
UNBOOSTED
INDINAVIR
Interactions between indinavir and other medicinal products are listed in the tables below (increase is
indicated as “↑”, decrease as “↓”, no change (≤ +/- 20 %) as “↔”, single dose as “SD”, once daily as
“QD”, twice daily as “BID”, three times daily as “TID”, and four times daily as "QID").
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
ANTI-INFECTIVES
Antiretrovirals
NRTIs
Didanosine
Formulation with buffer
No
formal interaction study has been
performed. A normal (acidic) gastric pH may
be necessary for optimum absorption of
indinavir whereas acid rapidly degrades
didanosine which is formulated with buffering
agents to increase pH.
Antiretroviral activity was unaltered when
didanosine was administered 3 hours after
treatment with indinavir.
Indinavir and didanosine
formulations containing
buffer should be
administered at least one
hour apart on an empty
stomach.
Didanosine enteric-coated
400 mg SD
(Indinavir 800 mg SD)
Indinavir:
(Relative to Indinavir 800 mg SD alone)
Didanosine:
Can be administered
without any restrictions
with respect to time of
administration or food.
Stavudine 40 mg BID
(Indinavir 800 mg TID)
Indinavir AUC:
Indinavir C
min
:↔
(Relative to Indinavir 800 mg TID alone)
Indinavir and NRTIs can be
co-administered without
dose adjustment.
Stavudine AUC: ↑ 21 %
Stavudine C
min
: not evaluated
Zidovudine 200 mg TID
(Indinavir 1,000 mg TID)
Indinavir AUC:
Indinavir C
min
:
(Relative to Indinavir 1,000 mg TID alone)
Zidovudine AUC:
Zidovudine C
min
: ↑ 51 %
Zidovudine/Lamivudine
200/150 mg TID
(Indinavir 800 mg TID)
Indinavir AUC:
Indinavir C
min
:
(Relative to Indinavir 800 mg TID alone)
Zidovudine AUC: ↑ 39 %
Zidovudine C
min
:
Lamivudine AUC:
Lamivudine C
min
:
32
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
NNRTIs
Delavirdine 400 mg TID
(Indinavir 600 mg TID)
Indinavir AUC: ↑ 53 %
Indinavir C
min
↑ 298 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of
CRIXIVAN to 400-600 mg
every 8 hours should be
considered.
Delavirdine 400 mg TID
Indinavir 400 mg TID
Indinavir AUC: ↔
Indinavir C
min
: ↑ 118 %
(Relative to Indinavir 800 mg TID alone)
Delavirdine:
Efavirenz 600 mg QD
(Indinavir 1,000 mg TID)
Indinavir AUC:
46 %
Indinavir C
min
:
57 %
(Relative to Indinavir 800 mg TID alone)
An increased dose (1,000 mg TID) of indinavir
does not compensate for the inducing effect of
efavirenz.
No specific dose
recommendation can be
given
.
Efavirenz 200 mg QD
(Indinavir 800 mg TID)
Indinavir AUC:
31 %
Indinavir C
min
:
40 %
Efavirenz AUC:
Nevirapine 200 mg BID
(Indinavir 800 mg TID)
Indinavir AUC:
28 %
Nevirapine:
(CYP3A induction)
A dose increase of indinavir
to 1,000 mg every 8 hours
should be considered if
given with nevirapine.
PIs
Amprenavir 1,200 mg BID
(Indinavir 1,200 mg BID)
Amprenavir AUC: ↑ 90 %
Indinavir:
↔
The appropriate doses for
this combination, with
respect to efficacy and
safety, have not been
established.
Atazanavir
Interaction not studied
Combination of atazanavir
with or without ritonavir
and Crixivan are not
recommended due to
increased risk of
hyperbilirubinemia (see
section 4.4).
33
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
Ritonavir 100 mg BID
(Indinavir 800 mg BID)
Indinavir AUC
24hr
:
178
%
Indinavir C
min
:
11-fold;
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC:
72 %
Ritonavir C
min
:
62 %
The appropriate doses for
this combination, with
respect to efficacy and
safety, have not been
established. Preliminary
clinical data suggest that
CRIXIVAN 400 mg in
combination with ritonavir
100 mg, both administered
orally twice daily, may be
an alternative dosing
regimen (see section 5.2). A
boosted dose of 800 mg
indinavir/100 mg ritonavir
twice daily results in
increased risk of adverse
events.
Ritonavir 200 mg BID
(Indinavir 800 mg BID)
Indinavir AUC
24hr
:
266 %
Indinavir C
min
:
24-fold;
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC:
96 %
Ritonavir C
min
:
371 %
Ritonavir 400 mg BID
(Indinavir 800 mg BID)
Indinavir AUC
24hr
:
220 %
Indinavir C
min
:↑ 24-fold
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC
24hr
:
Ritonavir 400 mg BID
(Indinavir 400 mg BID)
Indinavir AUC
24hr
:
68 %
Indinavir C
min
: ↑ 10-fold
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC
24hr
:
Ritonavir 100 mg BID
(Indinavir 400 mg BID)
Indinavir AUC and C
min
: ↔
(Relative to Indinavir 800 mg TID alone*)
(
*
)
historical controls
Saquinavir 600 mg SD (hard
gel capsule formulation)
(Indinavir 800 mg TID)
Saquinavir AUC:
500 %
Saquinavir C
min
:
190 %
(Relative to saquinavir 600 mg SD (hard gel
formulation) alone)
The appropriate doses for
this combination, with
respect to efficacy and
safety, have not been
established.
Saquinavir 800 mg SD (soft
gel capsule formulation)
(Indinavir 800 mg TID)
Saquinavir AUC:
620 %
Saquinavir C
min
:
450 %
(Relative to saquinavir 800 mg SD (soft gel
formulation) alone)
Saquinavir 1,200 mg SD (soft
gel capsule formulation)
(Indinavir 800 mg TID)
Saquinavir AUC:
360 %
Saquinavir C
min
:
450 %
(Relative to saquinavir 1,200 mg (soft gel
formulation) alone)
The design of the study does not allow for
definitive evaluation of the effect of saquinavir
on indinavir, but suggests there is less than a
two–fold increase in indinavir AUC
8h
during
co–administration with saquinavir
34
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
Antibiotics
Sulphamethoxazole/
Trimethoprim
800 mg/160 mg BID
(Indinavir 400 mg QID)
Indinavir AUC and C
min
:
(Relative to Indinavir 400 mg QID alone)
Sulphamethoxazole AUC and C
min
:
Indinavir and
sulphamethoxazole/
trimethoprim can be co-
administered without dose
adjustment.
Antifungals
Fluconazole 400 mg QD
(Indinavir 1,000 mg TID)
Indinavir AUC: ↓ 24 %
Indinavir C
min
:
(Relative to Indinavir 1,000 mg TID alone)
Indinavir and fluconazole
can be co-administered
without dose adjustment.
Itraconazole 200 mg BID
(Indinavir 600 mg TID)
Indinavir AUC:
Indinavir C
min
: ↑ 49 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of
CRIXIVAN to 600 mg
every 8 hours is
recommended with
administering itraconazole
concurrently.
Ketoconazole 400 mg QD
(Indinavir 600 mg TID)
Indinavir AUC: ↓ 20 %
Indinavir C
min
: ↑ 29 %
(Relative to Indinavir 800 mg TID alone)
Indinavir AUC ↓ 56 %
Indinavir C
min
↓ 27 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of
CRIXIVAN to 600 mg
every 8 hours should be
considered.
Ketoconazole 400 mg QD
(Indinavir 400 mg TID)
Anti-Mycobacterial
Isoniazid 300 mg QD
(Indinavir 800 mg TID)
Indinavir AUC and C
min
: ↔
(Relative to Indinavir 800 mg TID alone)
Isoniazid AUC and C
min
:
Indinavir and isoniazid can
be co-administered without
dose adjustment.
Rifabutin 300 mg QD
(Indinavir 800 mg TID)
Indinavir AUC ↓ 34 %
Indinavir C
min
: ↓ 39 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of rifabutin
and dose increase of
Crixivan has not been
confirmed in clinical
studies. Therefore co-
administration is not
recommended. If rifabutin
treatment is required,
alternative agents for
treating HIV infection
should be sought.
Rifabutin AUC: ↑ 173 %
Rifabutin C
min
: ↑ 244 %
(Relative to rifabutin 300 mg QD alone)
Rifabutin 150 mg QD
(Indinavir 800 mg TID)
Indinavir AUC: ↓ 32 %
Indinavir C
min
: ↓ 40 %
(Relative to Indinavir 800 mg TID alone)
Rifabutin AUC*: ↑ 54 %
Rifabutin C
min*
: ↑ 99 %
(*Relative to rifabutin 300 mg QD alone. No
data has been obtained comparing rifabutin
150 mg QD in combination with indinavir
800 mg TID with a reference dose of 150 mg
rifabutin alone)
Rifampicin 600 mg QD
(Indinavir 800 mg TID)
Indinavir AUC:
92 %
(Relative to Indinavir 800 mg TID alone)
This effect is due to an induction of CYP3A4
by rifampicin.
The use of rifampicin with
indinavir is contraindicated.
35
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
ANALGESICS
Methadone 20-60 mg QD
(Indinavir 800 mg TID)
Indinavir AUC: ↔
(Relative to Indinavir 800 mg TID historical
controls)
Methadone AUC and C
min
:
Indinavir and methadone
can be co-administered
without dose adjustment.
ANTIARRHYTHMICS
Quinidine 200 mg SD
(Indinavir 400 mg SD)
Indinavir AUC and C
min
: ↔
(Relative to Indinavir 400 mg SD)
Quinidine concentration expected (CYP3A4
inhibition by indinavir)
Caution is warranted and
therapeutic concentration
monitoring is recommended
for quinidine when
coadministered with
CRIXIVAN. The use of
indinavir/ritonavir with
quinidine is contraindicated.
ANTIASTHMATIC
Theophylline 250 mg SD
(Indinavir 800 mg TID)
Theophylline AUC and C
min
: ↔
Indinavir and theophylline
can be co-administered
without dose adjustment.
ANTICOAGULANT
Warfarin
Not studied, combined administration may
result in increased warfarin levels.
Dose adjustment of
warfarin may be required.
ANTICONVULSANTS
Carbamazepine, phenobarbital
phenytoin
Indinavir inhibits CYP3A4 and as a result is
expected to increase the plasma concentrations
of these anticonvulsants. Concomitant use of
medicinal products that are inducers of
CYP3A4, such as carbamazepine,
phenobarbital and phenytoin may reduce
indinavir plasma concentrations.
Careful monitoring of
therapeutic and adverse
effects is recommended
when these medicines are
concomitantly administered
with indinavir.
ANTIDEPRESSANTS
Venlafaxine 50 mg TID
(Indinavir 800 mg SD)
Indinavir AUC:
28 %
(Relative to Indinavir 800 mg SD alone)
Venlafaxine and active metabolite O-
desmethyl-venlafaxine: ↔
The clinical significance of
this finding is unknown.
CALCIUM CHANNEL BLOCKERS
Dihydropyridine: e.g.,
felodipine, nifedipine,
nicardipine
dihydropyridine calcium channel blocker
concentration
Caution is warranted and
clinical monitoring of
patients is recommended.
Calcium channel blockers are metabolized by
CYP3A4 which is inhibited by indinavir.
36
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
HERBAL MEDICATIONS
St. John’s wort (Hypericum
perforatum) 300 mg TID
(Indinavir 800 mg TID)
Indinavir AUC:
54 %
Indinavir C
min
: ↓ 81 %
(Relative to Indinavir 800 mg TID alone)
Reduction in indinavir concentrations due to
induction of drug metabolising and/or transport
proteins by St. John’s wort.
Herbal preparations
containing St. John’s wort
are contraindicated with
Crixivan. If a patient is
already taking St. John’s
wort, stop St. John’s wort,
check viral levels and if
possible indinavir levels.
Indinavir levels may
increase on stopping St.
John’s wort, and the dose of
CRIXIVAN may need
adjusting. The inducing
effect may persist up to
2 weeks after cessation of
treatment with St. John’s
wort.
HISTAMINE H
2
ANTAGONIST
Cimetidine 600 mg BID
(Indinavir 400 mg SD)
Indinavir AUC and C
min
:
(Relative to Indinavir 400 mg SD alone)
Indinavir and cimetidine
can be co-administered
without dose adjustment.
HMG-CoA REDUCTASE INHIBITIORS
Lovastatin, simvastatin
Indinavir inhibits CYP3A4 and as a result is
expected to markedly increase the plasma
concentrations of these HMG-CoA reductase
inhibitors, which are highly dependent on
CYP3A4 metabolism.
Combination
contraindicated due to an
increased risk of myopathy
including rhabdomyolysis.
Rosuvastatin
Interaction not studied.
Interaction study with Lopinavir/ritonavir +
rosuvastatin:
Rosuvastatin AUC ↑ 2.08-fold
Rosuvastatin Cmax ↑ 4.66-fold
(Mechanism unknown)
Combination not
recommended
Atorvastatin
atorvastatin concentration
Atorvastatin is less dependent on CYP3A4 for
metabolism than lovastatin or simvastatin
Use the lowest possible
dose of atorvastatin with
careful monitoring. Caution
is advised.
Pravastatin, fluvastatin
Interaction not studied
Metabolism of pravastatin and fluvastatin is not
dependent on CYP3A4. Interaction via effects
on transport proteins cannot be excluded.
Interaction unknown. If no
alternative treatment is
available, use with careful
monitoring.
IMMUNOSUPPRESSIVES
Cyclosporine A
Cyclosporine A (CsA) levels markedly increase
in patients on PIs, including indinavir.
CsA levels require
progressive dose adjustment
using therapeutic drug
monitoring.
ORAL CONTRACEPTIVES
Norethindrone/ethinyl
estradiol 1/35 1 mcg QD
(Indinavir 800 mg TID)
Norethindrone AUC: ↑ 26 %
Norethindrone C
min
: ↑ 44 %
Indinavir and
norethindrone/ethinyl
estradiol 1/35 can be co-
administered without dose
adjustment.
37
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
PDE5 INHIBITOR
Sildenafil 25 mg SD
(Indinavir 800 mg TID)
Indinavir AUC:
11 %
Sildenafil AUC
340 %
Sildenafil dose should not
exceed a maximum of
25 mg in a 48-hour period
in patients receiving
concomitant indinavir
therapy.
Coadministration of CRIXIVAN with sildenafil
is likely to result in an increase of sildenafil by
competitive inhibition of metabolism.
Vardenafil 10 mg SD
(Indinavir 800 mg TID)
Vardenafil AUC: ↑ 16-fold
Vardenafil dose should not
exceed a maximum of
2.5 mg in a 24-hour period
in patients receiving
concomitant indinavir
therapy.
Coadministration of CRIXIVAN with
vardenafil is likely to result in an increase of
vardenafil by competitive inhibition of
metabolism.
Tadalafil
Interaction not studied
Tadalafil dose should not
exceed a maximum of
10 mg in a 72 hour period
in patients receiving
concomitant indinavir
therapy.
Coadministration of CRIXIVAN with tadalafil
is likely to result in an increase of tadalafil by
competitive inhibition of metabolism.
SEDATIVES/HYPNOTICS
Midazolam (parenteral)
Not studied, combined administrations are
expected to significantly increase
concentrations of midazolam, particularly when
midazolam is given orally.
CRIXIVAN and oral
midazolam should not be
coadministered (see
section 4.3). Caution should
be used with
coadministration of
CRIXIVAN and parenteral
midazolam. If CRIXIVAN
is coadministered with
parenteral midazolam, it
should be done in an
intensive care unit with
close clinical monitoring in
case of respiratory
depression and/or prolonged
sedation. Dosage
adjustment for midazolam
should be considered,
especially if more than a
single dose of midazolam is
administered.
Midazolam is extensively metabolized by
CYP3A4.
STEROIDS
Dexamethasone
Interaction not studied
↑ dexamethasone exposure expected (CYP3A
inhibition).
↓ indinavir plasma concentrations may be
expected (CYP3A induction).
Careful monitoring of
therapeutic and adverse
effects is recommended
when dexamethasone is
concomitantly administered
with indinavir.
Table 2. Interactions and dose recommendations with other medical products –
INDINAVIR
BOOSTED WITH RITONAVIR.
No specific interaction studies have been performed with the
boosted dose 400 mg indinavir with 100 mg ritonavir.
Interactions between indinavir/ritonavir and other medicinal products are listed in the tables below
(increase is indicated as “↑”, decrease as “↓”, no change (≤ +/- 20 %) as “↔”, single dose as “SD”,
once daily as “QD”, twice daily as “BID”, three times daily as “TID”, and four times daily as "QID").
38
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
ANTI-INFECTIVES
Antiretrovirals
Amprenavir
Amprenavir 1,200 mg BID AUC ↑90 % with
800 mg TID indinavir alone (see Table 1).
Amprenavir 600 mg BID AUC ↑ 64 % with
100 mg BID ritonavir alone (relative to
amprenavir 1,200 mg BID alone). Ritonavir
increases the serum levels of amprenavir as a
result of CYP3A4 inhibition.
There are no interaction data available on the
coadministration of indinavir/ritonavir and
amprenavir.
The appropriate doses for this
combination, with respect to
efficacy and safety, have not
been established. Ritonavir
oral solution should not be co-
administered with amprenavir
oral solution to children due to
the risk of toxicity from
excipients in the two
formulations.
Efavirenz 600 mg QD
(Indinavir/ritonavir 800/100
BID)
Indinavir AUC:
25 %
Indinavir C
min
↓ 50 %
(Relative to Indinavir/ritonavir 800/100 BID
alone)
Dose increases of
indinavir/ritonavir when given
in combinatin with efavirenz
have not been studied.
Ritonavir AUC ↓ 36 %
Ritonavir C
min
:
39 %
Efavirenz AUC and C
min
: ↔
Anti-Mycobacterial
Rifabutin
Interaction with indinavir/ritonavir not studied
Decreased indinavir concentrations and
increased rifabutin concentrations are
expected.
No dose recommendations for
indinavir/ritonavir with
rifabutin could be given,
therefore the combination is
not recommended. If rifabutin
treatment is required,
alternative agents for treating
HIV infection should be
sought.
Rifampicin
Rifampicin is a strong CYP3A4 inducer and
has been shown to cause a 92 % decrease in
indinavir AUC which can result in virological
failure and resistance development. During
attempts to overcome the decreased exposure
by increasing the dose of other protease
inhibitors with ritonavir, a high frequency of
liver reactions was seen.
The combination of rifampicin
and CRIXIVAN with
concomitant low-dose
ritonavir is contraindicated
(see section 4.3).
Other Anti-infectives
Atovaquone
Interaction with indinavir/ritonavir not studied
Ritonavir induces glucuronidation and as a
result is expected to decrease the plasma
concentrations of atovaquone.
Careful monitoring of
therapeutic and adverse effects
is recommended when
atovaquone is concomitantly
administered with
indinavir/ritonavir.
Erythromycin, Itraconazole
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of erythromycin and
itraconazole.
Careful monitoring of
therapeutic and adverse effects
is recommended when
erythromycin or itraconazole
are concomitantly
administered with
indinavir/ritonavir.
39
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
Ketoconazole
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of ketoconazole. Co-
administration of ritonavir and ketoconazole
caused an increased incidence of
gastrointestinal and hepatic adverse events.
Careful monitoring of
therapeutic and adverse effects
is recommended when
ketoconazole is concomitantly
administered with
indinavir/ritonavir. A dose
reduction of ketoconazole
should be considered when co-
administered with
indinavir/ritonavir.
ANALGESICS
Fentanyl
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of fentanyl.
Careful monitoring of
therapeutic and adverse effects
is recommended when
fentanyl is concomitantly
administered with
indinavir/ritonavir.
Methadone
Interaction with indinavir/ritonavir not studied
There is no significant effect of unboosted
indinavir on methadone AUC (see Table 1
above).
Increased methadone dose
may be necessary when
concomitantly administered
with indinavir/ritonavir. Dose
adjustment should be
considered based on the
patient’s clinical response to
methadone therapy.
Decreases in methadone AUC has been
observed with other ritonavir-boosted protease
inhibitors.
Ritonavir may induce glucuronidation of
methadone.
Morphine
Interaction with indinavir/ritonavir not studied
Morphine levels may be decreased due to
induction of glucuronidation by
coadministered ritonavir.
Careful monitoring of
therapeutic and adverse effects
is recommended when
morphine is concomitantly
administered with
indinavir/ritonavir.
ANTIARRTHYMICS
Digoxin 0.4 mg SD
Ritonavir 200 mg BID
Interaction with indinavir/ritonavir not studied
Digoxin AUC:
22 %
Ritonavir may increase
digoxin levels due to
modification of P-glycoprotein
mediated digoxin efflux.
Careful monitoring of digoxin
levels is recommended when
digoxin is concomitantly
administered with
indinavir/ritonavir.
ANTICOAGULANT
Warfarin
Ritonavir 400 mg BID
Interaction with indinavir/ritonavir not studied
R-warfarin levels may be decreased leading to
reduced anticoagulation due to induction of
CYP1A2 and CYP2C9 by ritonavir.
Anticoagulation parameters
should be monitored when
warfarin is coadministered
with indinavir/ritonavir.
ANTICONVULSANTS
Carbamazepine
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of carbamazepine.
Careful monitoring of
therapeutic and adverse effects
is recommended when
carbamazepine is
concomitantly administered
with indinavir/ritonavir.
40
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
Divalproex, lamotrigine,
phenytoin
Interaction with indinavir/ritonavir not studied
Ritonavir induces oxidation by CYP2C9 and
glucuronidation and as a result is expected to
decrease the plasma concentrations of
anticonvulsants.
Careful monitoring of serum
levels or therapeutic effects is
recommended when these
medicines are concomitantly
administered with
indinavir/ritonavir. Phenytoin
may decrease serum levels of
ritonavir.
ANTIDEPRESSANTS
Trazodone 50 mg SD
Ritonavir 200 mg BID
Interaction with indinavir/ritonavir not studied
Trazodone AUC:
2.4-fold
An increase in the incidence in trazodone-
related adverse events was noted when
coadministered with ritonavir.
The combination of trazodone
with indinavir/ritonavir should
be used with caution, initiating
trazodone at the lowest dosage
and monitoring for clinical
response and tolerability.
ANTIHISTAMINES
Fexofenadine
Interaction with indinavir/ritonavir not studied
Ritonavir may modify P-glycoprotein
mediated fexofenadine efflux when
coadministered resulting in increased
concentrations of fexofenadine.
Careful monitoring of
therapeutic and adverse effects
is recommended when
fexofenadine is concomitantly
administered with
indinavir/ritonavir.
Loratidine
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of loratidine.
Careful monitoring of
therapeutic and adverse effects
is recommended when
loratidine is concomitantly
administered with
indinavir/ritonavir.
CALCIUM CHANNEL BLOCKERS
Dilitazem 120 mg QD
(Indinavir/ritonavir 800/100
BID)
Dilitazem AUC
0-24hr
:
43 %
Indinavir/ritonavir AUCs: ↔
Dose modification of calcium
channel blockers should be
considered when co-
administered with
indinavir/ritonavir as it may
result in an increased
response.
Amlodipine 5 mg QD
(Indinavir/ritonavir 800/100
BID)
Amlodipine AUC
0-24hr
:
80 %
Indinavir/ritonavir AUCs: ↔
HMG-CoA REDUCTASE INHIBITORS
Same recommendations as for
indinavir without ritonavir
boosting (see Table 1).
IMMUNOSUPPRESSIVES
Cyclosporine A
(Indinavir/ritonavir 800/100
BID)
Following initiation of indinavir/ritonavir
800/100 BID or lopinavir/ritonavir 400/100
BID, dose reduction of cyclosporine A to
5-20 % of prior dose was needed to maintain
cyclosporine A levels within therapeutic range
in one study.
Cyclosporine A dose
adjustments should be made
according to measured
cyclosporine A trough blood
levels.
Tacrolimus
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of tacrolimus.
Careful monitoring of
therapeutic and adverse effects
is recommended when
tacrolimus is concomitantly
administered with
indinavir/ritonavir.
PDE5 INHIBITOR
Sildenafil, tadalafil
Interaction not studied.
For sildenafil and tadalafil,
same recommendations as for
indinavir without ritonavir
boosting (see Table 1).
41
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
Vardenafil
Interaction not studied.
Vardenafil dose should not
exceed a maximum of 2.5 mg
in a 72-hour period when
given with a boosted protease
inhibitor.
SEDATIVES/HYPNOTICS
Buspirone
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of buspirone.
Careful monitoring of
therapeutic and adverse effects
is recommended when
buspirone is concomitantly
administered with
indinavir/ritonavir.
Midazolam (parenteral)
Interaction with indinavir/ritonavir
Not studied, combined administrations are
expected to significantly increase
concentrations of midazolam, particularly
when midazolam is given orally (CYP3A4
inhibition).
CRIXIVAN with ritonavir and
oral midazolam should not be
coadministered (see
section 4.3). Caution should
be used with coadministration
of CRIXIVAN with ritonavir
and parenteral midazolam. If
CRIXIVAN with ritonavir is
coadministered with parenteral
midazolam, it should be done
in an intensive care unit with
close clinical monitoring in
case of respiratory depression
and/or prolonged sedation.
Dosage adjustment for
midazolam should be
considered, especially if more
than a single dose of
midazolam is administered.
STEROIDS
Dexamethasone
Interaction with indinavir/ritonavir not studied
↑ dexamethasone exposure expected (CYP3A
inhibition).
↓ indinavir plasma concentrations may be
expected (CYP3A induction).
Careful monitoring of
therapeutic and adverse effects
is recommended when
dexamethasone is
concomitantly administered
with indinavir/ritonavir.
For information regarding diet or the effect of food on indinavir absorption (see section 4.2 and 5.2).
Use during pregnancy
There are no adequate and well-controlled studies in pregnant patients. Indinavir should be used
during pregnancy only if the potential benefit justifies the potential risk to the foetus. Given that
substantially lower antepartum exposures have been observed in a small study of HIV-infected
pregnant patients and the limited data in this patient population, indinavir use is not recommended in
HIV-infected pregnant patients (see section 5.2).
Hyperbilirubinaemia, reported predominantly as elevated indirect bilirubin, has occurred in 14 % of
patients during treatment with indinavir. Because it is unknown whether indinavir will exacerbate
physiologic hyperbilirubinaemia in neonates, careful consideration must be given to the use of
indinavir in pregnant women at the time of delivery (see section 4.8).
In Rhesus monkeys, administration of indinavir to neonates caused a mild exacerbation of the transient
physiologic hyperbilirubinaemia seen in this species after birth. Administration of indinavir to
42
pregnant Rhesus monkeys during the third trimester did not cause a similar exacerbation in neonates;
however, only limited placental transfer of indinavir occurred.
Use during lactation
It is recommended that HIV−infected women do not breast−feed their infants under any circumstances
in order to avoid transmission of HIV. It is not known whether indinavir is excreted in human milk.
Mothers should be instructed to discontinue breast−feeding during treatment.
No studies on the effects on the ability to drive and use machines have been performed. There are no
data to suggest that indinavir affects the ability to drive and use machines. However, patients should be
informed that dizziness and blurred vision have been reported during treatment with indinavir.
Nephrolithiasis occurred in approximately 10 % of patients treated with the recommended (unboosted)
dose of CRIXIVAN in a pooled analysis of controlled clinical trials (see also below table and in
section 4.4).
Clinical adverse reactions reported by the investigators as possibly, probably, or definitely related to
CRIXIVAN in ≥ 5 % of patients treated with CRIXIVAN monotherapy or in combination with
NRTI(s) (n = 309) for 24 weeks are listed below. Many of these adverse reactions were also identified
as common pre–existing or frequently occurring medical conditions in this population. These adverse
reactions were: nausea (35.3 %), headache (25.2 %), diarrhoea (24.6 %), asthenia/fatigue (24.3 %),
rash (19.1 %), taste perversion (19.1 %), dry skin (16.2 %), abdominal pain (14.6 %), vomiting
(11.0 %), dizziness (10.7 %). With the exception of dry skin, rash, and taste perversion, the incidence
of clinical adverse reactions was similar or higher among patients treated with antiretroviral nucleoside
analogue controls than among patients treated with CRIXIVAN monotherapy or in combination with
NRTI(s). This overall safety profile remained similar for 107 patients treated with CRIXIVAN
monotherapy or in combination with NRTI(s) for up to 48 weeks. Adverse reactions, including
nephrolithiasis, may lead to treatment interruption.
In controlled clinical trials conducted world–wide, indinavir was administered alone or in combination
with other antiretroviral agents (zidovudine, didanosine, stavudine, and/or lamivudine) to
approximately 2,000 patients, the majority of whom were adult Caucasian males (15 % females).
Indinavir did not alter the type, frequency, or severity of known major adverse effects associated with
the use of zidovudine, didanosine, or lamivudine.
The following adverse reactions have been reported during clinical studies in adults and/or post-
marketing use for CRIXIVAN monotherapy and/or CRIXIVAN with combination antiretroviral
therapy (CART).
Very common (≥ 1/10); Common (≥ 1/100, < 1/10); Uncommon (≥ 1/1,000, < 1/100);
Rare (≥ 1/10,000, < 1/1,000); Very rare (< 1/10,000); not known (cannot be estimated from the
available data). Adverse reactions have also been reported during post-marketing experience* as they
are derived from spontaneous reports, incidences cannot be determined.
43
System Organ Class
Frequency
Adverse reactions
CRIXIVAN
Blood and lymphatic system
disorders
Very
common
increases in MCV, decreases in neutrophils
Not known*
increased spontaneous bleeding in patients with
haemophilia, anemia including acute haemolytic
anaemia, thrombocytopenia (see section 4.4).
Immune system disorders
Not known* anaphylactoid reactions
Metabolism and nutrition
disorders
Not known* new onset diabetes mellitus or hyperglycaemia, or
exacerbation of pre-existing diabetes mellitus,
hypertriglyceridaemia, hypercholesterolaemia, body
fat changes (lipomatosis, lipoatrophy) (see
section 4.4).
Nervous system disorders
Very
common
headache, dizziness
Common
insomnia, hypoaesthesia; paraesthesia
Not known*
oral paraesthesia.
Gastrointestinal disorders
Very
common
nausea, vomiting, diarrhoea, dyspepsia
Common
flatulence, dry mouth, acid regurgitation
Not known*
hepatitis, including reports of hepatic failure,
pancreatitis.
Hepato-biliary disorders
Very
Common
isolated asymptomatic hyperbilirubinaemia,
increased ALT and AST
Not known*
liver function abnormalities
Skin and subcutaneous tissue
disorders
Very
common
rash, dry skin
Common
pruritus
Not known*
rash including erythema multiforme and Stevens
Johnson syndrome, hypersensitivity vasculitis,
alopecia, hyperpigmentation, urticaria; ingrown
toenails and/or paronychia
Musculoskeletal and connective
tissue disorders
Common
myalgia
Not known*
myositis, rhabdomyolysis, increased CPK,
osteonecrosis(see section 4.4).
44
System Organ Class
Frequency
Adverse reactions
CRIXIVAN
Renal and urinary disorders
Very
common
haematuria, proteinuria, crystalluria
Common
nephrolithiasis, dysuria.
Not known*
nephrolithiasis, in some cases with renal
insufficiency or acute renal failure; pyelonephritis,
interstitial nephritis, sometimes associated with
indinavir crystal deposits. In some patients,
resolution of the interstitial nephritis did not occur
following discontinuation of indinavir therapy;
renal insufficiency, renal failure, leucocyturia (see
section 4.4).
General disorders and
administration site conditions
Very
common
asthenia/fatigue, taste perversion, abdominal pain.
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see section 4.4).
Nephrolithiasis
Nephrolithiasis, including flank pain with or without haematuria (including microscopic haematuria),
has been reported in approximately 10 % (252/2,577) of patients receiving CRIXIVAN in clinical
trials at the recommended dose compared to 2.2 % in the control arms. In general, these events were
not associated with renal dysfunction and resolved with hydration and temporary interruption of
therapy (e.g., 1–3 days).
Hyperbilirubinaemia
Isolated asymptomatic hyperbilirubinaemia (total bilirubin ≥ 2.5 mg/dl, 43 mcmol/l) was reported
predominantly as elevated indirect bilirubin and rarely associated with elevations in ALT, AST, or
alkaline phosphatase, has occurred in approximately 14 % of patients treated with CRIXIVAN alone
or in combination with other antiretroviral agents. Most patients continued treatment with CRIXIVAN
without dosage reduction and bilirubin values gradually declined toward baseline.
Hyperbilirubinaemia occurred more frequently at doses exceeding 2.4 g/day compared to doses less
than 2.4 g/day.
Paediatric Patients
In clinical trials in paediatric patients (≥ 3 years), the adverse experience profile was similar to that for
adult patients except for a higher frequency of nephrolithiasis of 29 % (20/70) in paediatric patients
treated with CRIXIVAN at the recommended dose. Asymptomatic pyuria of unknown etiology was
noted in 10.9 % (6/55) of pediatric patients who received CRIXIVAN at the recommended dose of
500 mg/m
2
every 8 hours. Some of these events were associated with mild elevation of serum
creatinine.
45
There have been reports of human overdose with CRIXIVAN. The most commonly reported
symptoms were gastro-intestinal (e.g., nausea, vomiting, diarrhoea) and renal (e.g., nephrolithiasis,
flank pain, haematuria).
It is not known whether indinavir is dialyzable by peritoneal or haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Protease inhibitor, ATC code JO5AE02
Mechanism of action
Indinavir inhibits recombinant HIV–1 and HIV–2 protease with an approximate tenfold selectivity for
HIV–1 over HIV–2 proteinase. Indinavir binds reversibly to the protease active site and inhibits
competitively the enzyme, thereby preventing cleavage of the viral precursor polyproteins that occurs
during maturation of the newly formed viral particle. The resulting immature particles are non–
infectious and are incapable of establishing new cycles of infection. Indinavir did not significantly
inhibit the eukaryotic proteases human renin, human cathepsin D, human elastase, and human factor
Xa.
Microbiology
Indinavir at concentrations of 50 to 100 nM mediated 95 % inhibition (IC
95
) of viral spread (relative to
an untreated virus–infected control) in human T–lymphoid cell cultures and primary human
monocytes/macrophages infected with HIV−1 variants LAI, MN, RF, and a macrophage–tropic variant
SF–162, respectively. Indinavir at concentrations of 25 to 100 nM mediated 95 % inhibition of viral
spread in cultures of mitogen–activated human peripheral blood mononuclear cells infected with
diverse, primary clinical isolates of HIV−1, including isolates resistant to zidovudine and non–
nucleoside reverse transcriptase inhibitors (NNRTIs). Synergistic antiretroviral activity was observed
when human T–lymphoid cells infected with the LAI variant of HIV–1 were incubated with indinavir
and either zidovudine, didanosine, or NNRTIs.
Drug resistance
Loss of suppression of viral RNA levels occurred in some patients; however, CD4 cell counts were
often sustained above pre–treatment levels. When loss of viral RNA suppression occurred, it was
typically associated with replacement of circulating susceptible virus with resistant viral variants.
Resistance was correlated with the accumulation of mutations in the viral genome that resulted in the
expression of amino acid substitutions in the viral protease.
At least eleven amino acid sites in the protease have been associated with indinavir resistance: L10,
K20, L24, M46, I54, L63, I64, A71, V82, I84, and L90. The basis for their contributions to resistance,
however, is complex. None of these substitutions was either necessary or sufficient for resistance. For
example, no single substitution or pair of substitutions was capable of engendering measurable
(≥ four–fold) resistance to indinavir, and the level of resistance was dependent on the ways in which
multiple substitutions were combined. In general, however, higher levels of resistance resulted from
the co–expression of greater numbers of substitutions at the eleven identified positions. Among
patients experiencing viral RNA rebound during indinavir monotherapy at 800 mg q8h, substitutions
at only three of these sites were observed in the majority of patients: V82 (to A or F), M46 (to I or L),
and L10 (to I or R). Other substitutions were observed less frequently. The observed amino acid
substitutions appeared to accumulate sequentially and in no consistent order, probably as a result of
ongoing viral replication.
46
It should be noted that the decrease in suppression of viral RNA levels was seen more frequently when
therapy with indinavir was initiated at doses lower than the recommended oral dose of 2.4 g/day.
Therefore, therapy with indinavir should be initiated at the recommended dose to increase
suppression of viral replication and therefore inhibit the emergence of resistant virus.
The concomitant use of indinavir with nucleoside analogues (to which the patient is naive) may lessen
the risk of the development of resistance to both indinavir and the nucleoside analogues. In one
comparative trial, combination therapy with nucleoside analogues (triple therapy with zidovudine plus
didanosine) conferred protection against the selection of virus expressing at least one resistance–
associated amino acid substitution to both indinavir (from 13/24 to 2/20 at therapy week 24) and to the
nucleoside analogues (from 10/16 to 0/20 at therapy week 24).
Cross resistance
HIV−1 patient isolates with reduced susceptibility to indinavir expressed varying patterns and degrees
of cross–resistance to a series of diverse HIV PIs, including ritonavir and saquinavir. Complete
cross−resistance was noted between indinavir and ritonavir; however, cross−resistance to saquinavir
varied among isolates. Many of the protease amino acid substitutions reported to be associated with
resistance to ritonavir and saquinavir were also associated with resistance to indinavir.
Pharmacodynamic effects
Adults
Treatment with indinavir alone or in combination with other antiretroviral agents (i.e., nucleoside
analogues) has so far been documented to reduce viral load and increase CD4 lymphocytes in patients
with CD4 cell counts below 500 cells/mm
3
.
In one published study, 20 HIV-infected patients with undetectable plasma viral load
(< 200 copies/mL) receiving indinavir 800 mg every 8 hours were switched in an open, cross-over
design to indinavir/ritonavir 400/100 mg every 12 hours. Eighteen patients completed the study to
week 48. Viral load remained < 200 copies/mL for 48 weeks in all patients.
Another published study evaluated the efficacy and safety of indinavir/ritonavir 400/100 mg every
12 hours in 40 antiretroviral-naïve patients. Thirty subjects completed 48 weeks of treatment. At
week 4, the indinavir Cmin was 500 ng/mL with substantial trough variability (range 5 to
8,100 ng/mL). By intent to treat analysis 65 % of patients had HIV RNA < 400 copies/mL and 50 %
had viral load < 50 copies/mL; by on-treatment analysis 96 % of patients had HIV RNA
< 400 copies/mL and 74 % had viral load < 50 copies/mL.
Eighty antiretroviral naïve patients were entered into a third published study. In this open label non-
randomized single arm study, patients were treated with stavudine and lamivudine plus
indinavir/ritonavir 400/100 mg every 12 hours. Sixty-two patients completed the study to week 96. In
the intent to treat and on treatment analyses the proportion of patients with HIV RNA of
< 50 copies/mL was 68.8 % and 88.7 %, respectively, at week 96.
Indinavir alone or in combination with nucleoside analogues (zidovudine/stavudine and lamivudine)
has been shown to delay clinical progression rate compared with nucleoside analogues and to provide
a sustained effect on viral load and CD4 count.
In zidovudine experienced patients, indinavir, zidovudine and lamivudine in combination compared
with lamivudine added to zidovudine reduced the probability of AIDS defining illness or death
(ADID) at 48 weeks from 13 % to 7 %. Similarly, in antiretroviral naive patients, indinavir with and
without zidovudine compared with zidovudine alone reduced the probability of ADID at 48 weeks
from 15 % with zidovudine alone to approximately 6 % with indinavir alone or in combination with
zidovudine.
Effects on viral load were consistently more pronounced in patients treated with indinavir in
combination with nucleoside analogues, but the proportion of patients with serum viral RNA below
47
the limit of quantification (500 copies/ml) varied between studies, at week 24 from 40 % to more than
80 %. This proportion tends to remain stable over prolonged periods of follow–up. Similarly, effects
on CD4 cell count tend to be more pronounced in patients treated with indinavir in combination with
nucleoside analogues compared with indinavir alone. Within studies, this effect is sustained also after
prolonged periods of follow–up.
Paediatric patients
Two clinical trials in 41 paediatric patients (4 to 15 years of age) were designed to characterise the
safety, antiretroviral activity, and pharmacokinetics of indinavir in combination with stavudine and
lamivudine. In one study, at week 24, the proportion of patients with plasma viral RNA below
400 copies/ml was 60 %; the mean increase in CD4 cell counts was 242 cells/mm
3
; and the mean
increase in percent CD4 cell counts was 4.2 %. At week 60, the proportion of patients with plasma
viral RNA below 400 copies/ml was 59 %. In another study, at week 16, the proportion of patients
with plasma viral RNA below 400 copies/ml was 59 %; the mean increase in CD4 cell counts was
73 cells/mm
3
; and the mean increase in percent CD4 cell counts was 1.2 %. At week 24, the proportion
of patients with plasma viral RNA below 400 copies/ml was 60 %.
5.2 Pharmacokinetic properties
Absorption
Indinavir is rapidly absorbed in the fasted state with a time to peak plasma concentration of 0.8 hours
± 0.3 hours (mean ± S.D.). A greater than dose–proportional increase in indinavir plasma
concentrations was observed over the 200 – 800 mg dose range. Between 800–mg and 1,000–mg dose
levels, the deviation from dose–proportionality is less pronounced. As a result of the short half–life,
1.8 ± 0.4 hours, only a minimal increase in plasma concentrations occurred after multiple dosing. The
bioavailability of a single 800–mg dose of indinavir was approximately 65 % (90 % CI, 58 – 72 %).
Data from a steady state study in healthy volunteers indicate that there is a diurnal variation in the
pharmacokinetics of indinavir. Following a dosage regimen of 800 mg every 8 hours, measured peak
plasma concentrations (C
max
) after morning, afternoon and evening doses were 15,550 nM, 8,720 nM
and 8,880 nM, respectively. Corresponding plasma concentrations at 8 hours post dose were 220 nM,
210 nM and 370 nM, respectively. The relevance of these findings for ritonavir boosted indinavir is
unknown. At steady state following a dosage regimen of 800 mg every 8 hours, HIV–seropositive
adult patients in one study achieved geometric means of: AUC
0-8h
of 27,813 nM*h (90 % confidence
interval = 22,185, 34,869), peak plasma concentrations 11,144 nM (90 % confidence interval = 9,192,
13,512) and plasma concentrations at 8 hours post dose 211 nM (90 % confidence interval = 163,
274).
Food effect
At steady state following a dosage regimen of 800 mg/100 mg of indinavir/ritonavir every 12 hours
with a low-fat meal, healthy volunteers in one study achieved geometric means: AUC
0-12h
116,067 nM*h (90 % confidence interval = 101,680, 132,490), peak plasma concentrations 19,001 nM
(90 % confidence interval = 17,538, 20,588), and plasma concentrations at 12 hours post dose
2,274 nM (90 % confidence interval = 1,701, 3,042). No significant difference in exposure was seen
when the regimen was given with a high-fat meal.
Indinavir boosted regimen. Limited data are available on the pharmacokinetics of indinavir in
association with low dose ritonavir. The pharmacokinetics of indinavir (400 mg) with ritonavir
(100 mg) dosed twice daily was examined in two studies. Pharmacokinetic analysis in one study was
performed on nineteen of the patients, with a median (range) indinavir AUC 0-12hr, Cmax, and Cmin
of 25,421 nM*h (21,489 – 36,236 nM*h), 5,758 nM (5,056 – 6,742 nM) and 239 (169 – 421 nM),
respectively. The pharmacokinetic parameters in the second study were comparable.
In HIV−infected paediatric patients, a dosage regimen of indinavir hard capsules, 500 mg/m
2
every
8 hours, produced AUC
0–8hr
values of 27,412 nM*h, peak plasma concentrations of 12,182 nM, and
plasma concentrations at 8 hours post dose of 122 nM. The AUC and peak plasma concentrations were
generally similar to those previously observed in HIV–infected adults receiving the recommended
48
dose of 800 mg every 8 hours; it should be observed that the plasma concentrations 8 hours post dose
were lower.
During pregnancy, it has been demonstrated that the systemic exposure of indinavir is relevantly
decreased (PACTG 358. Crixivan, 800 mg every 8 hours + zidovudine 200 mg every 8 hours and
lamivudine 150 mg twice a day). The mean indinavir plasma AUC
0-8hr
at week 30-32 of gestation
(n = 11) was 9,231 nM∗hr, which is 74 % (95 % CI: 50 %, 86 %) lower than that observed 6 weeks
postpartum. Six of these 11 (55 %) patients had mean indinavir plasma concentrations 8 hours post-
dose (C
min
) below assay threshold of reliable quantification. The pharmacokinetics of indinavir in these
11 patients at 6 weeks postpartum were generally similar to those observed in non-pregnant patients in
another study (see section 4.6).
Administration of indinavir with a meal high in calories, fat, and protein resulted in a blunted and
reduced absorption with an approximate 80 % reduction in AUC and an 86 % reduction in C
max
.
Administration with light meals (e.g., dry toast with jam or fruit conserve, apple juice, and coffee with
skimmed or fat–free milk and sugar or corn flakes, skimmed or fat–free milk and sugar) resulted in
plasma concentrations comparable to the corresponding fasted values.
The pharmacokinetics of indinavir taken as indinavir sulphate salt (from opened hard capsules) mixed
in apple sauce were generally comparable to the pharmacokinetics of indinavir taken as hard capsules,
under fasting conditions. In HIV–infected paediatric patients, the pharmacokinetic parameters of
indinavir in apple sauce were: AUC
0–8hr
of 26,980 nM*h; peak plasma concentration of 13,711 nM;
and plasma concentration at 8 hours post dose of 146 nM.
Distribution
Indinavir was not highly bound to human plasma proteins (39 % unbound).
There are no data concerning the penetration of indinavir into the central nervous system in humans.
Biotransformation
Seven major metabolites were identified and the metabolic pathways were identified as
glucuronidation at the pyridine nitrogen, pyridine–N–oxidation with and without 3’–hydroxylation on
the indane ring, 3’–hydroxylation of indane, p–hydroxylation of phenylmethyl moiety, and N–
depyridomethylation with and without the 3’–hydroxylation.
In vitro
studies with human liver
microsomes indicated that CYP3A4 is the only P450 isozyme that plays a major role in the oxidative
metabolism of indinavir. Analysis of plasma and urine samples from subjects who received indinavir
indicated that indinavir metabolites had little proteinase inhibitory activity.
Elimination
Over the 200–1,000–mg dose range administered in both volunteers and HIV infected patients, there
was a slightly greater than dose–proportional increase in urinary recovery of indinavir. Renal clearance
(116 ml/min) of indinavir is concentration–independent over the clinical dose range. Less than 20 % of
indinavir is excreted renally. Mean urinary excretion of unchanged drug following single dose
administration in the fasted state was 10.4 % following a 700–mg dose, and 12.0 % following a 1,000–
mg dose. Indinavir was rapidly eliminated with a half–life of 1.8 hours.
Characteristics in patients
Pharmacokinetics of indinavir do not appear to be affected by race.
There are no clinically significant differences in the pharmacokinetics of indinavir in HIV seropositive
women compared to HIV seropositive men.
Patients with mild–to–moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence
of decreased metabolism of indinavir resulting in approximately 60 % higher mean AUC following a
400–mg dose. The mean half–life of indinavir increased to approximately 2.8 hours.
49
5.3 Preclinical safety data
Crystals have been seen in the urine of rats, one monkey, and one dog. The crystals have not been
associated with drug–induced renal injury. An increase in thyroidal weight and thyroidal follicular cell
hyperplasia, due to an increase in thyroxine clearance, was seen in rats treated with indinavir at doses
≥ 160 mg/kg/day. An increase in hepatic weight occurred in rats treated with indinavir at doses
≥ 40 mg/kg/day and was accompanied by hepatocellular hypertrophy at doses ≥ 320 mg/kg/day.
The maximum non–lethal oral dose of indinavir was at least 5,000 mg/kg in rats and mice, the highest
dose tested in acute toxicity studies.
Studies in rats indicated that uptake into brain tissue was limited, distribution into and out of the
lymphatic system was rapid, and excretion into the milk of lactating rats was extensive. Distribution of
indinavir across the placental barrier was significant in rats, but limited in rabbits.
Mutagenicity
Indinavir did not have any mutagenic or genotoxic activity in studies with or without metabolic
activation.
Carcinogenicity
No carcinogenicity was noted in mice at the maximum tolerated dose, which corresponded to a
systemic exposure approximately 2 to 3 times higher than the clinical exposure. In rats, at similar
exposure levels, an increased incidence of thyroid adenomas was seen, probably related to an increase
in release of thyroid stimulating hormone secondary to an increase in thyroxine clearance. The
relevance of the findings to humans is likely limited.
Developmental Toxicity
Developmental toxicity studies were performed in rats, rabbits and dogs (at doses which produced
systemic exposures comparable to or slightly greater than human exposure) and revealed no evidence
of teratogenicity. No external or visceral changes were observed in rats, however, increases in the
incidence of supernumerary ribs and of cervical ribs were seen. No external, visceral, or skeletal
changes were observed in rabbits or dogs. In rats and rabbits, no effects on embryonic/foetal survival
or foetal weights were observed. In dogs, a slight increase in resorptions was seen; however, all
foetuses in medication–treated animals were viable, and the incidence of live foetuses in medication–
treated animals was comparable to that in controls.
6.
6.1 List of excipients
Capsule content
- anhydrous lactose
- magnesium stearate
Capsule shell:
- gelatin
- titanium dioxide (E 171)
- printing ink: indigo carmine (E 132).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
50
6.4 Special precautions for storage
Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.
6.5 Nature and contents of container
HDPE bottles with a polypropylene cap and a foil induction cap containing 180, 270 or 360 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The bottles contain desiccant canisters that should remain in the container.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8.
EU/1/96/024/001
EU/1/96/024/002
EU/1/96/024/003
9.
Date of first authorisation: 04/10/1996
Date of latest renewal: 07/10/2006
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu
51
1.
CRIXIVAN 400 mg hard capsules
2.
Each hard capsule contains indinavir sulphate corresponding to 400 mg of indinavir.
Excipient: Each 400 mg capsule contains 149.6 mg of lactose.
For a full list of excipients, see section 6.1
3.
Hard capsule.
The capsules are semi–translucent white and coded CRIXIVAN™ 400 mg in green.
4.
CRIXIVAN is indicated in combination with antiretroviral nucleoside analogues for the treatment of
HIV–1 infected adults, adolescents, and children 4 years of age and older. In adolescents and children,
the benefit of indinavir therapy versus the increased risk of nephrolithiasis should particularly be
considered (see section 4.4).
CRIXIVAN should be administered by physicians who are experienced in the treatment of HIV
infection. On the basis of current pharmacodynamic data, indinavir must be used in combination with
other antiretroviral agents. When indinavir is administered as monotherapy resistant viruses rapidly
emerge (see section 5.1).
Adults
The recommended dosage of CRIXIVAN is 800 mg orally every 8 hours.
Data from published studies suggest that CRIXIVAN 400 mg in combination with ritonavir 100 mg,
both administered orally twice daily, may be an alternative dosing regimen. The suggestion is based on
limited published data (see section 5.2).
If co-administered with ritonavir, CRIXIVAN may be administered with or without food.
Children and adolescents (4 to 17 years of age)
The recommended dosage of CRIXIVAN for patients 4 to 17 years of age is 500 mg/m
2
(dose adjusted
from calculated body surface area [BSA] based on height and weight) orally every 8 hours (see table
below). This dose should not exceed the equivalent of the adult dose of 800 mg every 8 hours.
CRIXIVAN hard capsules should only be given to children who are able to swallow hard capsules.
CRIXIVAN has not been studied in children under the age of 4 years (see section 5.1 and 5.2).
52
Paediatric dose (500 mg/
m
2
) to be administered every 8 hours
Body Surface
Area (m
2
)
CRIXIVAN dose
Every 8 hours (mg)
0.50
300
0.75
400
1.25
600
1.50
800
General administration recommendations
The hard capsules should be swallowed whole.
Since CRIXIVAN must be taken at intervals of 8 hours, a schedule convenient for the patient should
be developed. For optimal absorption, CRIXIVAN should be administered without food but with
water 1 hour before or 2 hours after a meal. Alternatively, CRIXIVAN may be administered with a
low–fat, light meal.
To ensure adequate hydration, it is recommended that adults drink at least 1.5 litres of liquids during
the course of 24 hours. It is also recommended that children who weigh less than 20 kg drink at least
75 ml/kg/day and that children who weigh 20 to 40 kg drink at least 50 ml/kg/day.
Medical management in patients with one or more episodes of nephrolithiasis must include adequate
hydration and may include temporary interruption of therapy (e.g., 1 to 3 days) during the acute
episode of nephrolithiasis or discontinuation of therapy (see section 4.4).
Special dosing considerations in adults
A dosage reduction of CRIXIVAN to 600 mg every 8 hours should be considered when administering
itraconazole or ketoconazole concurrently (see section 4.5).
In patients with mild–to–moderate hepatic impairment due to cirrhosis, the dosage of CRIXIVAN
should be reduced to 600 mg every 8 hours. The recommendation is based on limited pharmacokinetic
data (see section 5.2). Patients with severe hepatic impairment have not been studied; therefore, no
dosing recommendations can be made (see section 4.4).
Safety in patients with impaired renal function has not been studied; however, less than 20 % of
indinavir is excreted in the urine as unchanged drug or metabolites (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients.
Indinavir with or without ritonavir should not be administered concurrently with medicinal products
with narrow therapeutic windows and which are substrates of CYP3A4. Inhibition of CYP3A4 by both
CRIXIVAN and ritonavir could result in elevated plasma concentrations of these medicines,
potentially causing serious or life-threatening reactions.
CRIXIVAN with or without ritonavir should not be administered concurrently with amiodarone,
terfenadine, cisapride, astemizole, alprazolam, triazolam, midazolam administered orally (for caution
on parenterally administered midazolam, see section 4.5), pimozide, ergot derivatives, simvastatin or
lovastatin (see section 4.4).
Combination of rifampicin with CRIXIVAN with or without concomitant low-dose ritonavir is
contraindicated (see section 4.5). Concurrent use of indinavir with herbal preparations containing St
John’s wort (Hypericum perforatum) is contraindicated (see section 4.5).
53
1.00
500
In addition, indinavir with ritonavir should not be administered with alfuzosin, meperidine, piroxicam,
propoxyphene, bepridil, encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine,
clorazepate, diazepam, estazolam and flurazepam.
Ritonavir should not be given with indinavir to patients with decompensated liver disease as ritonavir
is principally metabolized and eliminated by the liver (see section 4.4).
When CRIXIVAN is used with ritonavir, consult the Summary of Product Characteristics of ritonavir
for additional contraindications.
Nephrolithiasis and tubulointerstitial nephritis
Nephrolithiasis has occurred with indinavir therapy in adult and paediatric patients. The frequency of
nephrolithiasis is higher in paediatric patients than in adult patients. In some cases, nephrolithiasis has
been associated with renal insufficiency or acute renal failure; in the majority of these cases renal
insufficiency and acute renal failure were reversible. If signs and symptoms of nephrolithiasis,
including flank pain with or without haematuria (including microscopic haematuria) occur, temporary
interruption of therapy (e.g. for 1–3 days) during the acute episode of nephrolithiasis or
discontinuation of therapy may be considered. Paediatric patients who experience flank pain should be
evaluated for the possibility of nephrolithiasis. Evaluation may consist of urinalysis, serum BUN and
creatinine, and ultrasound of the bladder and kidneys. The long–term effects of nephrolithiasis in
paediatric patients are unknown. Adequate hydration is recommended in all patients on indinavir (see
section 4.2 and 4.8).
Cases of interstitial nephritis with medullary calcification and cortical atrophy have been observed in
patients with asymptomatic severe leucocyturia (> 100 cells/high power field). In patients at increased
risk such as children, urinary screening should be considered. If persistent severe leucocyturia is
found, further investigation might be warranted.
Medicinal product interactions
Indinavir should be used cautiously with other medicinal products that are potent inducers of
CYP3A4. Co–administration may result in decreased plasma concentrations of indinavir and as a
consequence an increased risk for suboptimal treatment and facilitation of development of resistance
(see section 4.5).
If indinavir is given with ritonavir, the potential interaction may be increased. The Interactions section
of the SPC for ritonavir should also be consulted for information about potential interactions.
Atazanavir as well as indinavir are associated with indirect (unconjugated) hyperbilirubinemia due to
inhibition of UDP-glucuronosyltransferase (UGT). Combinations of atazanavir with or without
ritonavir and Crixivan have not been studied and co-administration of these medicinal products is not
recommended due to risk of worsening of these adverse effects.
Concomitant use of indinavir with lovastatin or simvastatin is not recommended due to an increased
risk of myopathy including rhabdomyolysis. Based on an interaction study with lopinavir/ritonavir,
combination of rosuvastatin and protease inhibitors is not recommended. Caution must also be
exercised if indinavir is used concurrently with atorvastatin. The interaction of indinavir or
indinavir/ritonavir with pravastatin or fluvastatin is not known (see section 4.5).
Co–administration of CRIXIVAN with sildenafil, tadalafil and vardenafil (PDE5 inhibitors) are
expected to substantially increase the plasma concentrations of these compounds and may result in an
increase in PDE5 inhibitor–associated adverse events, including hypotension, visual changes, and
priapism (see section 4.5).
54
Acute haemolytic anaemia
Acute haemolytic anaemia has been reported which in some cases was severe and progressed rapidly.
Once a diagnosis is apparent, appropriate measures for the treatment of haemolytic anaemia should be
instituted which may include discontinuation of indinavir.
Hyperglycaemia
New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been
reported in patients receiving protease inhibitors (PIs). In some of these the hyperglycaemia was
severe and in some cases also associated with ketoacidosis. Many patients had confounding medical
conditions, some of which required therapy with agents that have been associated with the
development of diabetes mellitus or hyperglycaemia.
Fat redistribution
Combination antiretroviral therapy has been associated with the redistribution of body fat
(lipodystrophy) in HIV patients. The long term consequences of these events are currently unknown.
Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs
and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A
higher risk of lipodystrophy has been associated with individual factors such as older age, and with
drug related factors such as longer duration of antiretroviral treatment and associated metabolic
disturbances. Clinical examination should include evaluation for physical signs of fat redistribution.
Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid
disorders should be managed as clinically appropriate (see section 4.8).
Liver disease
The safety and efficacy of indinavir has not been established in patients with significant underlying
liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral
therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of
concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information
for these medicinal products.
The safety and efficacy of indinavir/ritonavir has not been established in patients with significant
underlying liver disorders and should not be used in this patient population.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
An increased incidence of nephrolithiasis has been observed in patients with underlying liver disorders
when treated with indinavir.
Immune Reactivation Syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically,
such reactions have been observed within the first few weeks or months of initiation of CART.
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections,
and
Pneumocystis carinii
pneumonia. Any inflammatory symptoms should be evaluated and treatment
instituted when necessary.
Patients with coexisting conditions
There have been reports of increased bleeding, including spontaneous skin haematomas and
haemarthroses, in haemophiliac patients type A and B treated with PIs. In some patients additional
factor VIII was given. In more than a half of the reported cases, treatment with PIs was continued or
re-introduced if treatment had been discontinued. A causal relationship has been evoked, although the
mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware
of the possibility of increased bleeding.
55
Patients with mild–to–moderate hepatic insufficiency due to cirrhosis will require a dosage reduction
of indinavir due to decreased metabolism of indinavir (see section 4.2). Patients with severe hepatic
impairment have not been studied. In the absence of such studies, caution should be exercised as
increased levels of indinavir may occur.
Safety in patients with impaired renal function has not been studied; however, less than 20 % of
indinavir is excreted in the urine as unchanged drug or metabolites (see section 4.2).
Osteonecrosis:
Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been
reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience
joint aches and pain, joint stiffness or difficulty in movement.
Lactose
This medicinal product contains 299.2 mg of lactose in each 800 mg dose (maximum single dose).
This quantity is not likely to induce symptoms of lactose intolerance (milk intolerance).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicine.
Interaction studies have only been performed in adults. The relevance of the results from these studies
in paediatric patients is unknown.
The metabolism of indinavir is mediated by the cytochrome P450 enzyme CYP3A4. Therefore, other
substances that either share this metabolic pathway or modify CYP3A4 activity may influence the
pharmacokinetics of indinavir. Similarly, indinavir might also modify the pharmacokinetics of other
substances that share this metabolic pathway. Boosted indinavir (indinavir with ritonavir) may have
additive pharmacokinetic effects on substances that share the CYP3A4 pathway as both
ritonavir and
indinavir inhibit the cytochrome P450 enzyme CYP3A4.
Indinavir with or without ritonavir should not be administered concurrently with medicinal products
with narrow therapeutic windows and which are substrates of CYP3A4. Inhibition of CYP3A4 by both
CRIXIVAN and ritonavir could result in elevated plasma concentrations of these medicines,
potentially causing serious or life-threatening reactions. CRIXIVAN with or without ritonavir should
not be administered concurrently with amiodarone, terfenadine, cisapride, astemizole, alprazolam,
triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see
Table 1 and 2 below), pimozide, ergot derivatives, simvastatin or lovastatin. In addition, indinavir with
ritonavir should not be administered with alfuzosin, meperidine, piroxicam, propoxyphene, bepridil,
encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine, clorazepate, diazepam, estazolam
and flurazepam.
Concurrent use of indinavir with rifampicin or herbal preparations containing St John’s wort
(Hypericum perforatum) is contraindicated.
Drugs listed above are not repeated in Table 1 and 2 unless specific interaction data is available.
Refer also to sections 4.2 and 4.3.
56
Table 1. Interactions and dose recommendations with other medical products –
UNBOOSTED
INDINAVIR
Interactions between indinavir and other medicinal products are listed in the tables below (increase is
indicated as “↑”, decrease as “↓”, no change (≤ +/- 20 %) as “↔”, single dose as “SD”, once daily as
“QD”, twice daily as “BID”, three times daily as “TID”, and four times daily as "QID").
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
ANTI-INFECTIVES
Antiretrovirals
NRTIs
Didanosine
Formulation with buffer
No
formal interaction study has been
performed. A normal (acidic) gastric pH may
be necessary for optimum absorption of
indinavir whereas acid rapidly degrades
didanosine which is formulated with buffering
agents to increase pH.
Antiretroviral activity was unaltered when
didanosine was administered 3 hours after
treatment with indinavir.
Indinavir and didanosine
formulations containing
buffer should be
administered at least one
hour apart on an empty
stomach.
Didanosine enteric-coated
400 mg SD
(Indinavir 800 mg SD)
Indinavir:
(Relative to Indinavir 800 mg SD alone)
Didanosine:
Can be administered
without any restrictions
with respect to time of
administration or food.
Stavudine 40 mg BID
(Indinavir 800 mg TID)
Indinavir AUC:
Indinavir C
min
:↔
(Relative to Indinavir 800 mg TID alone)
Indinavir and NRTIs can be
co-administered without
dose adjustment.
Stavudine AUC: ↑ 21 %
Stavudine C
min
: not evaluated
Zidovudine 200 mg TID
(Indinavir 1,000 mg TID)
Indinavir AUC:
Indinavir C
min
:
(Relative to Indinavir 1,000 mg TID alone)
Zidovudine AUC:
Zidovudine C
min
: ↑ 51 %
Zidovudine/Lamivudine
200/150 mg TID
(Indinavir 800 mg TID)
Indinavir AUC:
Indinavir C
min
:
(Relative to Indinavir 800 mg TID alone)
Zidovudine AUC: ↑ 39 %
Zidovudine C
min
:
Lamivudine AUC:
Lamivudine C
min
:
57
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
NNRTIs
Delavirdine 400 mg TID
(Indinavir 600 mg TID)
Indinavir AUC: ↑ 53 %
Indinavir C
min
↑ 298 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of
CRIXIVAN to 400-600 mg
every 8 hours should be
considered.
Delavirdine 400 mg TID
Indinavir 400 mg TID
Indinavir AUC: ↔
Indinavir C
min
: ↑ 118 %
(Relative to Indinavir 800 mg TID alone)
Delavirdine:
Efavirenz 600 mg QD
(Indinavir 1,000 mg TID)
Indinavir AUC:
46 %
Indinavir C
min
:
57 %
(Relative to Indinavir 800 mg TID alone)
An increased dose (1,000 mg TID) of indinavir
does not compensate for the inducing effect of
efavirenz.
No specific dose
recommendation can be
given
.
Efavirenz 200 mg QD
(Indinavir 800 mg TID)
Indinavir AUC:
31 %
Indinavir C
min
:
40 %
Efavirenz AUC:
Nevirapine 200 mg BID
(Indinavir 800 mg TID)
Indinavir AUC:
28 %
Nevirapine:
(CYP3A induction)
A dose increase of indinavir
to 1,000 mg every 8 hours
should be considered if
given with nevirapine.
PIs
Amprenavir 1,200 mg BID
(Indinavir 1,200 mg BID)
Amprenavir AUC: ↑ 90 %
Indinavir:
↔
The appropriate doses for
this combination, with
respect to efficacy and
safety, have not been
established.
Atazanavir
Interaction not studied
Combination of atazanavir
with or without ritonavir
and Crixivan are not
recommended due to
increased risk of
hyperbilirubinemia (see
section 4.4).
58
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
Ritonavir 100 mg BID
(Indinavir 800 mg BID)
Indinavir AUC
24hr
:
178
%
Indinavir C
min
:
11-fold;
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC:
72 %
Ritonavir C
min
:
62 %
The appropriate doses for
this combination, with
respect to efficacy and
safety, have not been
established. Preliminary
clinical data suggest that
CRIXIVAN 400 mg in
combination with ritonavir
100 mg, both administered
orally twice daily, may be
an alternative dosing
regimen (see section 5.2). A
boosted dose of 800 mg
indinavir/100 mg ritonavir
twice daily results in
increased risk of adverse
events.
Ritonavir 200 mg BID
(Indinavir 800 mg BID)
Indinavir AUC
24hr
:
266 %
Indinavir C
min
:
24-fold;
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC:
96 %
Ritonavir C
min
:
371 %
Ritonavir 400 mg BID
(Indinavir 800 mg BID)
Indinavir AUC
24hr
:
220 %
Indinavir C
min
:↑ 24-fold
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC
24hr
:
Ritonavir 400 mg BID
(Indinavir 400 mg BID)
Indinavir AUC
24hr
:
68 %
Indinavir C
min
: ↑ 10-fold
(Relative to Indinavir 800 mg TID alone*)
Ritonavir AUC
24hr
:
Ritonavir 100 mg BID
(Indinavir 400 mg BID)
Indinavir AUC and C
min
: ↔
(Relative to Indinavir 800 mg TID alone*)
(
*
)
historical controls
Saquinavir 600 mg SD (hard
gel capsule formulation)
(Indinavir 800 mg TID)
Saquinavir AUC:
500 %
Saquinavir C
min
:
190 %
(Relative to saquinavir 600 mg SD (hard gel
formulation) alone)
The appropriate doses for
this combination, with
respect to efficacy and
safety, have not been
established.
Saquinavir 800 mg SD (soft
gel capsule formulation)
(Indinavir 800 mg TID)
Saquinavir AUC:
620 %
Saquinavir C
min
:
450 %
(Relative to saquinavir 800 mg SD (soft gel
formulation) alone)
Saquinavir 1,200 mg SD (soft
gel capsule formulation)
(Indinavir 800 mg TID)
Saquinavir AUC:
360 %
Saquinavir C
min
:
450 %
(Relative to saquinavir 1,200 mg (soft gel
formulation) alone)
The design of the study does not allow for
definitive evaluation of the effect of saquinavir
on indinavir, but suggests there is less than a
two–fold increase in indinavir AUC
8h
during
co–administration with saquinavir
59
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
Antibiotics
Sulphamethoxazole/
Trimethoprim
800 mg/160 mg BID
(Indinavir 400 mg QID)
Indinavir AUC and C
min
:
(Relative to Indinavir 400 mg QID alone)
Sulphamethoxazole AUC and C
min
:
Indinavir and
sulphamethoxazole/
trimethoprim can be co-
administered without dose
adjustment.
Antifungals
Fluconazole 400 mg QD
(Indinavir 1,000 mg TID)
Indinavir AUC: ↓ 24 %
Indinavir C
min
:
(Relative to Indinavir 1,000 mg TID alone)
Indinavir and fluconazole
can be co-administered
without dose adjustment.
Itraconazole 200 mg BID
(Indinavir 600 mg TID)
Indinavir AUC:
Indinavir C
min
: ↑ 49 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of
CRIXIVAN to 600 mg
every 8 hours is
recommended with
administering itraconazole
concurrently.
Ketoconazole 400 mg QD
(Indinavir 600 mg TID)
Indinavir AUC: ↓ 20 %
Indinavir C
min
: ↑ 29 %
(Relative to Indinavir 800 mg TID alone)
Indinavir AUC ↓ 56 %
Indinavir C
min
↓ 27 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of
CRIXIVAN to 600 mg
every 8 hours should be
considered.
Ketoconazole 400 mg QD
(Indinavir 400 mg TID)
Anti-Mycobacterial
Isoniazid 300 mg QD
(Indinavir 800 mg TID)
Indinavir AUC and C
min
: ↔
(Relative to Indinavir 800 mg TID alone)
Isoniazid AUC and C
min
:
Indinavir and isoniazid can
be co-administered without
dose adjustment.
Rifabutin 300 mg QD
(Indinavir 800 mg TID)
Indinavir AUC ↓ 34 %
Indinavir C
min
: ↓ 39 %
(Relative to Indinavir 800 mg TID alone)
Dose reduction of rifabutin
and dose increase of
Crixivan has not been
confirmed in clinical
studies. Therefore co-
administration is not
recommended. If rifabutin
treatment is required,
alternative agents for
treating HIV infection
should be sought.
Rifabutin AUC: ↑ 173 %
Rifabutin C
min
: ↑ 244 %
(Relative to rifabutin 300 mg QD alone)
Rifabutin 150 mg QD
(Indinavir 800 mg TID)
Indinavir AUC: ↓ 32 %
Indinavir C
min
: ↓ 40 %
(Relative to Indinavir 800 mg TID alone)
Rifabutin AUC*: ↑ 54 %
Rifabutin C
min*
: ↑ 99 %
(*Relative to rifabutin 300 mg QD alone. No
data has been obtained comparing rifabutin
150 mg QD in combination with indinavir
800 mg TID with a reference dose of 150 mg
rifabutin alone)
Rifampicin 600 mg QD
(Indinavir 800 mg TID)
Indinavir AUC:
92 %
(Relative to Indinavir 800 mg TID alone)
This effect is due to an induction of CYP3A4
by rifampicin.
The use of rifampicin with
indinavir is contraindicated.
60
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
ANALGESICS
Methadone 20-60 mg QD
(Indinavir 800 mg TID)
Indinavir AUC: ↔
(Relative to Indinavir 800 mg TID historical
controls)
Methadone AUC and C
min
:
Indinavir and methadone
can be co-administered
without dose adjustment.
ANTIARRHYTHMICS
Quinidine 200 mg SD
(Indinavir 400 mg SD)
Indinavir AUC and C
min
: ↔
(Relative to Indinavir 400 mg SD)
Quinidine concentration expected (CYP3A4
inhibition by indinavir)
Caution is warranted and
therapeutic concentration
monitoring is recommended
for quinidine when
coadministered with
CRIXIVAN. The use of
indinavir/ritonavir with
quinidine is contraindicated.
ANTIASTHMATIC
Theophylline 250 mg SD
(Indinavir 800 mg TID)
Theophylline AUC and C
min
: ↔
Indinavir and theophylline
can be co-administered
without dose adjustment.
ANTICOAGULANT
Warfarin
Not studied, combined administration may
result in increased warfarin levels.
Dose adjustment of
warfarin may be required.
ANTICONVULSANTS
Carbamazepine, phenobarbital
phenytoin
Indinavir inhibits CYP3A4 and as a result is
expected to increase the plasma concentrations
of these anticonvulsants. Concomitant use of
medicinal products that are inducers of
CYP3A4, such as carbamazepine,
phenobarbital and phenytoin may reduce
indinavir plasma concentrations.
Careful monitoring of
therapeutic and adverse
effects is recommended
when these medicines are
concomitantly administered
with indinavir.
ANTIDEPRESSANTS
Venlafaxine 50 mg TID
(Indinavir 800 mg SD)
Indinavir AUC:
28 %
(Relative to Indinavir 800 mg SD alone)
Venlafaxine and active metabolite O-
desmethyl-venlafaxine: ↔
The clinical significance of
this finding is unknown.
CALCIUM CHANNEL BLOCKERS
Dihydropyridine: e.g.,
felodipine, nifedipine,
nicardipine
dihydropyridine calcium channel blocker
concentration
Caution is warranted and
clinical monitoring of
patients is recommended.
Calcium channel blockers are metabolized by
CYP3A4 which is inhibited by indinavir.
61
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
HERBAL MEDICATIONS
St. John’s wort (Hypericum
perforatum) 300 mg TID
(Indinavir 800 mg TID)
Indinavir AUC:
54 %
Indinavir C
min
: ↓ 81 %
(Relative to Indinavir 800 mg TID alone)
Reduction in indinavir concentrations due to
induction of drug metabolising and/or transport
proteins by St. John’s wort.
Herbal preparations
containing St. John’s wort
are contraindicated with
Crixivan. If a patient is
already taking St. John’s
wort, stop St. John’s wort,
check viral levels and if
possible indinavir levels.
Indinavir levels may
increase on stopping St.
John’s wort, and the dose of
CRIXIVAN may need
adjusting. The inducing
effect may persist up to
2 weeks after cessation of
treatment with St. John’s
wort.
HISTAMINE H
2
ANTAGONIST
Cimetidine 600 mg BID
(Indinavir 400 mg SD)
Indinavir AUC and C
min
:
(Relative to Indinavir 400 mg SD alone)
Indinavir and cimetidine
can be co-administered
without dose adjustment.
HMG-CoA REDUCTASE INHIBITIORS
Lovastatin, simvastatin
Indinavir inhibits CYP3A4 and as a result is
expected to markedly increase the plasma
concentrations of these HMG-CoA reductase
inhibitors, which are highly dependent on
CYP3A4 metabolism.
Combination
contraindicated due to an
increased risk of myopathy
including rhabdomyolysis.
Rosuvastatin
Interaction not studied.
Interaction study with Lopinavir/ritonavir +
rosuvastatin:
Rosuvastatin AUC ↑ 2.08-fold
Rosuvastatin Cmax ↑ 4.66-fold
(Mechanism unknown)
Combination not
recommended
Atorvastatin
atorvastatin concentration
Atorvastatin is less dependent on CYP3A4 for
metabolism than lovastatin or simvastatin
Use the lowest possible
dose of atorvastatin with
careful monitoring. Caution
is advised.
Pravastatin, fluvastatin
Interaction not studied
Metabolism of pravastatin and fluvastatin is not
dependent on CYP3A4. Interaction via effects
on transport proteins cannot be excluded.
Interaction unknown. If no
alternative treatment is
available, use with careful
monitoring.
IMMUNOSUPPRESSIVES
Cyclosporine A
Cyclosporine A (CsA) levels markedly increase
in patients on PIs, including indinavir.
CsA levels require
progressive dose adjustment
using therapeutic drug
monitoring.
ORAL CONTRACEPTIVES
Norethindrone/ethinyl
estradiol 1/35 1 mcg QD
(Indinavir 800 mg TID)
Norethindrone AUC: ↑ 26 %
Norethindrone C
min
: ↑ 44 %
Indinavir and
norethindrone/ethinyl
estradiol 1/35 can be co-
administered without dose
adjustment.
62
Medicinal products by
therapeutic areas
Interaction
Recommendations
concerning co-
administration
PDE5 INHIBITOR
Sildenafil 25 mg SD
(Indinavir 800 mg TID)
Indinavir AUC:
11 %
Sildenafil AUC
340 %
Sildenafil dose should not
exceed a maximum of
25 mg in a 48-hour period
in patients receiving
concomitant indinavir
therapy.
Coadministration of CRIXIVAN with sildenafil
is likely to result in an increase of sildenafil by
competitive inhibition of metabolism.
Vardenafil 10 mg SD
(Indinavir 800 mg TID)
Vardenafil AUC: ↑ 16-fold
Vardenafil dose should not
exceed a maximum of
2.5 mg in a 24-hour period
in patients receiving
concomitant indinavir
therapy.
Coadministration of CRIXIVAN with
vardenafil is likely to result in an increase of
vardenafil by competitive inhibition of
metabolism.
Tadalafil
Interaction not studied
Tadalafil dose should not
exceed a maximum of
10 mg in a 72 hour period
in patients receiving
concomitant indinavir
therapy.
Coadministration of CRIXIVAN with tadalafil
is likely to result in an increase of tadalafil by
competitive inhibition of metabolism.
SEDATIVES/HYPNOTICS
Midazolam (parenteral)
Not studied, combined administrations are
expected to significantly increase
concentrations of midazolam, particularly when
midazolam is given orally.
CRIXIVAN and oral
midazolam should not be
coadministered (see
section 4.3). Caution should
be used with
coadministration of
CRIXIVAN and parenteral
midazolam. If CRIXIVAN
is coadministered with
parenteral midazolam, it
should be done in an
intensive care unit with
close clinical monitoring in
case of respiratory
depression and/or prolonged
sedation. Dosage
adjustment for midazolam
should be considered,
especially if more than a
single dose of midazolam is
administered.
Midazolam is extensively metabolized by
CYP3A4.
STEROIDS
Dexamethasone
Interaction not studied
↑ dexamethasone exposure expected (CYP3A
inhibition).
↓ indinavir plasma concentrations may be
expected (CYP3A induction).
Careful monitoring of
therapeutic and adverse
effects is recommended
when dexamethasone is
concomitantly administered
with indinavir.
Table 2. Interactions and dose recommendations with other medical products –
INDINAVIR
BOOSTED WITH RITONAVIR.
No specific interaction studies have been performed with the
boosted dose 400 mg indinavir with 100 mg ritonavir.
Interactions between indinavir/ritonavir and other medicinal products are listed in the tables below
(increase is indicated as “↑”, decrease as “↓”, no change (≤ +/- 20 %) as “↔”, single dose as “SD”,
once daily as “QD”, twice daily as “BID”, three times daily as “TID”, and four times daily as "QID").
63
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
ANTI-INFECTIVES
Antiretrovirals
Amprenavir
Amprenavir 1,200 mg BID AUC ↑90 % with
800 mg TID indinavir alone (see Table 1).
Amprenavir 600 mg BID AUC ↑ 64 % with
100 mg BID ritonavir alone (relative to
amprenavir 1,200 mg BID alone). Ritonavir
increases the serum levels of amprenavir as a
result of CYP3A4 inhibition.
There are no interaction data available on the
coadministration of indinavir/ritonavir and
amprenavir.
The appropriate doses for this
combination, with respect to
efficacy and safety, have not
been established. Ritonavir
oral solution should not be co-
administered with amprenavir
oral solution to children due to
the risk of toxicity from
excipients in the two
formulations.
Efavirenz 600 mg QD
(Indinavir/ritonavir 800/100
BID)
Indinavir AUC:
25 %
Indinavir C
min
↓ 50 %
(Relative to Indinavir/ritonavir 800/100 BID
alone)
Dose increases of
indinavir/ritonavir when given
in combinatin with efavirenz
have not been studied.
Ritonavir AUC ↓ 36 %
Ritonavir C
min
:
39 %
Efavirenz AUC and C
min
: ↔
Anti-Mycobacterial
Rifabutin
Interaction with indinavir/ritonavir not studied
Decreased indinavir concentrations and
increased rifabutin concentrations are
expected.
No dose recommendations for
indinavir/ritonavir with
rifabutin could be given,
therefore the combination is
not recommended. If rifabutin
treatment is required,
alternative agents for treating
HIV infection should be
sought.
Rifampicin
Rifampicin is a strong CYP3A4 inducer and
has been shown to cause a 92 % decrease in
indinavir AUC which can result in virological
failure and resistance development. During
attempts to overcome the decreased exposure
by increasing the dose of other protease
inhibitors with ritonavir, a high frequency of
liver reactions was seen.
The combination of rifampicin
and CRIXIVAN with
concomitant low-dose
ritonavir is contraindicated
(see section 4.3).
Other Anti-infectives
Atovaquone
Interaction with indinavir/ritonavir not studied
Ritonavir induces glucuronidation and as a
result is expected to decrease the plasma
concentrations of atovaquone.
Careful monitoring of
therapeutic and adverse effects
is recommended when
atovaquone is concomitantly
administered with
indinavir/ritonavir.
Erythromycin, Itraconazole
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of erythromycin and
itraconazole.
Careful monitoring of
therapeutic and adverse effects
is recommended when
erythromycin or itraconazole
are concomitantly
administered with
indinavir/ritonavir.
64
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
Ketoconazole
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of ketoconazole. Co-
administration of ritonavir and ketoconazole
caused an increased incidence of
gastrointestinal and hepatic adverse events.
Careful monitoring of
therapeutic and adverse effects
is recommended when
ketoconazole is concomitantly
administered with
indinavir/ritonavir. A dose
reduction of ketoconazole
should be considered when co-
administered with
indinavir/ritonavir.
ANALGESICS
Fentanyl
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of fentanyl.
Careful monitoring of
therapeutic and adverse effects
is recommended when
fentanyl is concomitantly
administered with
indinavir/ritonavir.
Methadone
Interaction with indinavir/ritonavir not studied
There is no significant effect of unboosted
indinavir on methadone AUC (see Table 1
above).
Increased methadone dose
may be necessary when
concomitantly administered
with indinavir/ritonavir. Dose
adjustment should be
considered based on the
patient’s clinical response to
methadone therapy.
Decreases in methadone AUC has been
observed with other ritonavir-boosted protease
inhibitors.
Ritonavir may induce glucuronidation of
methadone.
Morphine
Interaction with indinavir/ritonavir not studied
Morphine levels may be decreased due to
induction of glucuronidation by
coadministered ritonavir.
Careful monitoring of
therapeutic and adverse effects
is recommended when
morphine is concomitantly
administered with
indinavir/ritonavir.
ANTIARRTHYMICS
Digoxin 0.4 mg SD
Ritonavir 200 mg BID
Interaction with indinavir/ritonavir not studied
Digoxin AUC:
22 %
Ritonavir may increase
digoxin levels due to
modification of P-glycoprotein
mediated digoxin efflux.
Careful monitoring of digoxin
levels is recommended when
digoxin is concomitantly
administered with
indinavir/ritonavir.
ANTICOAGULANT
Warfarin
Ritonavir 400 mg BID
Interaction with indinavir/ritonavir not studied
R-warfarin levels may be decreased leading to
reduced anticoagulation due to induction of
CYP1A2 and CYP2C9 by ritonavir.
Anticoagulation parameters
should be monitored when
warfarin is coadministered
with indinavir/ritonavir.
ANTICONVULSANTS
Carbamazepine
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of carbamazepine.
Careful monitoring of
therapeutic and adverse effects
is recommended when
carbamazepine is
concomitantly administered
with indinavir/ritonavir.
65
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
Divalproex, lamotrigine,
phenytoin
Interaction with indinavir/ritonavir not studied
Ritonavir induces oxidation by CYP2C9 and
glucuronidation and as a result is expected to
decrease the plasma concentrations of
anticonvulsants.
Careful monitoring of serum
levels or therapeutic effects is
recommended when these
medicines are concomitantly
administered with
indinavir/ritonavir. Phenytoin
may decrease serum levels of
ritonavir.
ANTIDEPRESSANTS
Trazodone 50 mg SD
Ritonavir 200 mg BID
Interaction with indinavir/ritonavir not studied
Trazodone AUC:
2.4-fold
An increase in the incidence in trazodone-
related adverse events was noted when
coadministered with ritonavir.
The combination of trazodone
with indinavir/ritonavir should
be used with caution, initiating
trazodone at the lowest dosage
and monitoring for clinical
response and tolerability.
ANTIHISTAMINES
Fexofenadine
Interaction with indinavir/ritonavir not studied
Ritonavir may modify P-glycoprotein
mediated fexofenadine efflux when
coadministered resulting in increased
concentrations of fexofenadine.
Careful monitoring of
therapeutic and adverse effects
is recommended when
fexofenadine is concomitantly
administered with
indinavir/ritonavir.
Loratidine
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of loratidine.
Careful monitoring of
therapeutic and adverse effects
is recommended when
loratidine is concomitantly
administered with
indinavir/ritonavir.
CALCIUM CHANNEL BLOCKERS
Dilitazem 120 mg QD
(Indinavir/ritonavir 800/100
BID)
Dilitazem AUC
0-24hr
:
43 %
Indinavir/ritonavir AUCs: ↔
Dose modification of calcium
channel blockers should be
considered when co-
administered with
indinavir/ritonavir as it may
result in an increased
response.
Amlodipine 5 mg QD
(Indinavir/ritonavir 800/100
BID)
Amlodipine AUC
0-24hr
:
80 %
Indinavir/ritonavir AUCs: ↔
HMG-CoA REDUCTASE INHIBITORS
Same recommendations as for
indinavir without ritonavir
boosting (see Table 1).
IMMUNOSUPPRESSIVES
Cyclosporine A
(Indinavir/ritonavir 800/100
BID)
Following initiation of indinavir/ritonavir
800/100 BID or lopinavir/ritonavir 400/100
BID, dose reduction of cyclosporine A to
5-20 % of prior dose was needed to maintain
cyclosporine A levels within therapeutic range
in one study.
Cyclosporine A dose
adjustments should be made
according to measured
cyclosporine A trough blood
levels.
Tacrolimus
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of tacrolimus.
Careful monitoring of
therapeutic and adverse effects
is recommended when
tacrolimus is concomitantly
administered with
indinavir/ritonavir.
PDE5 INHIBITOR
Sildenafil, tadalafil
Interaction not studied.
For sildenafil and tadalafil,
same recommendations as for
indinavir without ritonavir
boosting (see Table 1).
66
Medicinal products by
therapeutic areas
Interaction
Recommendations concerning
co-administration
Vardenafil
Interaction not studied.
Vardenafil dose should not
exceed a maximum of 2.5 mg
in a 72-hour period when
given with a boosted protease
inhibitor.
SEDATIVES/HYPNOTICS
Buspirone
Interaction with indinavir/ritonavir not studied
Indinavir and ritonavir inhibit CYP3A4 and as
a result are expected to increase the plasma
concentrations of buspirone.
Careful monitoring of
therapeutic and adverse effects
is recommended when
buspirone is concomitantly
administered with
indinavir/ritonavir.
Midazolam (parenteral)
Interaction with indinavir/ritonavir
Not studied, combined administrations are
expected to significantly increase
concentrations of midazolam, particularly
when midazolam is given orally (CYP3A4
inhibition).
CRIXIVAN with ritonavir and
oral midazolam should not be
coadministered (see
section 4.3). Caution should
be used with coadministration
of CRIXIVAN with ritonavir
and parenteral midazolam. If
CRIXIVAN with ritonavir is
coadministered with parenteral
midazolam, it should be done
in an intensive care unit with
close clinical monitoring in
case of respiratory depression
and/or prolonged sedation.
Dosage adjustment for
midazolam should be
considered, especially if more
than a single dose of
midazolam is administered.
STEROIDS
Dexamethasone
Interaction with indinavir/ritonavir not studied
↑ dexamethasone exposure expected (CYP3A
inhibition).
↓ indinavir plasma concentrations may be
expected (CYP3A induction).
Careful monitoring of
therapeutic and adverse effects
is recommended when
dexamethasone is
concomitantly administered
with indinavir/ritonavir.
For information regarding diet or the effect of food on indinavir absorption (see section 4.2 and 5.2).
Use during pregnancy
There are no adequate and well-controlled studies in pregnant patients. Indinavir should be used
during pregnancy only if the potential benefit justifies the potential risk to the foetus. Given that
substantially lower antepartum exposures have been observed in a small study of HIV-infected
pregnant patients and the limited data in this patient population, indinavir use is not recommended in
HIV-infected pregnant patients (see section 5.2).
Hyperbilirubinaemia, reported predominantly as elevated indirect bilirubin, has occurred in 14 % of
patients during treatment with indinavir. Because it is unknown whether indinavir will exacerbate
physiologic hyperbilirubinaemia in neonates, careful consideration must be given to the use of
indinavir in pregnant women at the time of delivery (see section 4.8).
In Rhesus monkeys, administration of indinavir to neonates caused a mild exacerbation of the transient
physiologic hyperbilirubinaemia seen in this species after birth. Administration of indinavir to
67
pregnant Rhesus monkeys during the third trimester did not cause a similar exacerbation in neonates;
however, only limited placental transfer of indinavir occurred.
Use during lactation
It is recommended that HIV−infected women do not breast−feed their infants under any circumstances
in order to avoid transmission of HIV. It is not known whether indinavir is excreted in human milk.
Mothers should be instructed to discontinue breast−feeding during treatment.
No studies on the effects on the ability to drive and use machines have been performed. There are no
data to suggest that indinavir affects the ability to drive and use machines. However, patients should be
informed that dizziness and blurred vision have been reported during treatment with indinavir.
Nephrolithiasis occurred in approximately 10 % of patients treated with the recommended (unboosted)
dose of CRIXIVAN in a pooled analysis of controlled clinical trials (see also below table and in
section 4.4).
Clinical adverse reactions reported by the investigators as possibly, probably, or definitely related to
CRIXIVAN in ≥ 5 % of patients treated with CRIXIVAN monotherapy or in combination with
NRTI(s) (n = 309) for 24 weeks are listed below. Many of these adverse reactions were also identified
as common pre–existing or frequently occurring medical conditions in this population. These adverse
reactions were: nausea (35.3 %), headache (25.2 %), diarrhoea (24.6 %), asthenia/fatigue (24.3 %),
rash (19.1 %), taste perversion (19.1 %), dry skin (16.2 %), abdominal pain (14.6 %), vomiting
(11.0 %), dizziness (10.7 %). With the exception of dry skin, rash, and taste perversion, the incidence
of clinical adverse reactions was similar or higher among patients treated with antiretroviral nucleoside
analogue controls than among patients treated with CRIXIVAN monotherapy or in combination with
NRTI(s). This overall safety profile remained similar for 107 patients treated with CRIXIVAN
monotherapy or in combination with NRTI(s) for up to 48 weeks. Adverse reactions, including
nephrolithiasis, may lead to treatment interruption.
In controlled clinical trials conducted world–wide, indinavir was administered alone or in combination
with other antiretroviral agents (zidovudine, didanosine, stavudine, and/or lamivudine) to
approximately 2,000 patients, the majority of whom were adult Caucasian males (15 % females).
Indinavir did not alter the type, frequency, or severity of known major adverse effects associated with
the use of zidovudine, didanosine, or lamivudine.
The following adverse reactions have been reported during clinical studies in adults and/or post-
marketing use for CRIXIVAN monotherapy and/or CRIXIVAN with combination antiretroviral
therapy (CART).
Very common (≥ 1/10); Common (≥ 1/100, < 1/10); Uncommon (≥ 1/1,000, < 1/100);
Rare (≥ 1/10,000, < 1/1,000); Very rare (< 1/10,000); not known (cannot be estimated from the
available data). Adverse reactions have also been reported during post-marketing experience* as they
are derived from spontaneous reports, incidences cannot be determined.
68
System Organ Class
Frequency
Adverse reactions
CRIXIVAN
Blood and lymphatic system
disorders
Very
common
increases in MCV, decreases in neutrophils
Not known*
increased spontaneous bleeding in patients with
haemophilia, anemia including acute haemolytic
anaemia, thrombocytopenia (see section 4.4).
Immune system disorders
Not known* anaphylactoid reactions
Metabolism and nutrition
disorders
Not known* new onset diabetes mellitus or hyperglycaemia, or
exacerbation of pre-existing diabetes mellitus,
hypertriglyceridaemia, hypercholesterolaemia, body
fat changes (lipomatosis, lipoatrophy) (see
section 4.4).
Nervous system disorders
Very
common
headache, dizziness
Common
insomnia, hypoaesthesia; paraesthesia
Not known*
oral paraesthesia.
Gastrointestinal disorders
Very
common
nausea, vomiting, diarrhoea, dyspepsia
Common
flatulence, dry mouth, acid regurgitation
Not known*
hepatitis, including reports of hepatic failure,
pancreatitis.
Hepato-biliary disorders
Very
Common
isolated asymptomatic hyperbilirubinaemia,
increased ALT and AST
Not known*
liver function abnormalities
Skin and subcutaneous tissue
disorders
Very
common
rash, dry skin
Common
pruritus
Not known*
rash including erythema multiforme and Stevens
Johnson syndrome, hypersensitivity vasculitis,
alopecia, hyperpigmentation, urticaria; ingrown
toenails and/or paronychia
Musculoskeletal and connective
tissue disorders
Common
myalgia
Not known*
myositis, rhabdomyolysis, increased CPK,
osteonecrosis (see section 4.4).
69
System Organ Class
Frequency
Adverse reactions
CRIXIVAN
Renal and urinary disorders
Very
common
haematuria, proteinuria, crystalluria
Common
nephrolithiasis, dysuria.
Not known*
nephrolithiasis, in some cases with renal
insufficiency or acute renal failure; pyelonephritis,
interstitial nephritis, sometimes associated with
indinavir crystal deposits. In some patients,
resolution of the interstitial nephritis did not occur
following discontinuation of indinavir therapy;
renal insufficiency, renal failure, leucocyturia (see
section 4.4).
General disorders and
administration site conditions
Very
common
asthenia/fatigue, taste perversion, abdominal pain.
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see section 4.4).
Nephrolithiasis
Nephrolithiasis, including flank pain with or without haematuria (including microscopic haematuria),
has been reported in approximately 10 % (252/2,577) of patients receiving CRIXIVAN in clinical
trials at the recommended dose compared to 2.2 % in the control arms. In general, these events were
not associated with renal dysfunction and resolved with hydration and temporary interruption of
therapy (e.g., 1–3 days).
Hyperbilirubinaemia
Isolated asymptomatic hyperbilirubinaemia (total bilirubin ≥ 2.5 mg/dl, 43 mcmol/l) was reported
predominantly as elevated indirect bilirubin and rarely associated with elevations in ALT, AST, or
alkaline phosphatase, has occurred in approximately 14 % of patients treated with CRIXIVAN alone
or in combination with other antiretroviral agents. Most patients continued treatment with CRIXIVAN
without dosage reduction and bilirubin values gradually declined toward baseline.
Hyperbilirubinaemia occurred more frequently at doses exceeding 2.4 g/day compared to doses less
than 2.4 g/day.
Paediatric Patients
In clinical trials in paediatric patients (≥ 3 years), the adverse experience profile was similar to that for
adult patients except for a higher frequency of nephrolithiasis of 29 % (20/70) in paediatric patients
treated with CRIXIVAN at the recommended dose. Asymptomatic pyuria of unknown etiology was
noted in 10.9 % (6/55) of pediatric patients who received CRIXIVAN at the recommended dose of
500 mg/m
2
every 8 hours. Some of these events were associated with mild elevation of serum
creatinine.
70
There have been reports of human overdose with CRIXIVAN. The most commonly reported
symptoms were gastro-intestinal (e.g., nausea, vomiting, diarrhoea) and renal (e.g., nephrolithiasis,
flank pain, haematuria).
It is not known whether indinavir is dialyzable by peritoneal or haemodialysis.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Protease inhibitor, ATC code JO5AE02
Mechanism of action
Indinavir inhibits recombinant HIV–1 and HIV–2 protease with an approximate tenfold selectivity for
HIV–1 over HIV–2 proteinase. Indinavir binds reversibly to the protease active site and inhibits
competitively the enzyme, thereby preventing cleavage of the viral precursor polyproteins that occurs
during maturation of the newly formed viral particle. The resulting immature particles are non–
infectious and are incapable of establishing new cycles of infection. Indinavir did not significantly
inhibit the eukaryotic proteases human renin, human cathepsin D, human elastase, and human factor
Xa.
Microbiology
Indinavir at concentrations of 50 to 100 nM mediated 95 % inhibition (IC
95
) of viral spread (relative to
an untreated virus–infected control) in human T–lymphoid cell cultures and primary human
monocytes/macrophages infected with HIV−1 variants LAI, MN, RF, and a macrophage–tropic variant
SF–162, respectively. Indinavir at concentrations of 25 to 100 nM mediated 95 % inhibition of viral
spread in cultures of mitogen–activated human peripheral blood mononuclear cells infected with
diverse, primary clinical isolates of HIV−1, including isolates resistant to zidovudine and non–
nucleoside reverse transcriptase inhibitors (NNRTIs). Synergistic antiretroviral activity was observed
when human T–lymphoid cells infected with the LAI variant of HIV–1 were incubated with indinavir
and either zidovudine, didanosine, or NNRTIs.
Drug resistance
Loss of suppression of viral RNA levels occurred in some patients; however, CD4 cell counts were
often sustained above pre–treatment levels. When loss of viral RNA suppression occurred, it was
typically associated with replacement of circulating susceptible virus with resistant viral variants.
Resistance was correlated with the accumulation of mutations in the viral genome that resulted in the
expression of amino acid substitutions in the viral protease.
At least eleven amino acid sites in the protease have been associated with indinavir resistance: L10,
K20, L24, M46, I54, L63, I64, A71, V82, I84, and L90. The basis for their contributions to resistance,
however, is complex. None of these substitutions was either necessary or sufficient for resistance. For
example, no single substitution or pair of substitutions was capable of engendering measurable
(≥ four–fold) resistance to indinavir, and the level of resistance was dependent on the ways in which
multiple substitutions were combined. In general, however, higher levels of resistance resulted from
the co–expression of greater numbers of substitutions at the eleven identified positions. Among
patients experiencing viral RNA rebound during indinavir monotherapy at 800 mg q8h, substitutions
at only three of these sites were observed in the majority of patients: V82 (to A or F), M46 (to I or L),
and L10 (to I or R). Other substitutions were observed less frequently. The observed amino acid
substitutions appeared to accumulate sequentially and in no consistent order, probably as a result of
ongoing viral replication.
71
It should be noted that the decrease in suppression of viral RNA levels was seen more frequently when
therapy with indinavir was initiated at doses lower than the recommended oral dose of 2.4 g/day.
Therefore, therapy with indinavir should be initiated at the recommended dose to increase
suppression of viral replication and therefore inhibit the emergence of resistant virus.
The concomitant use of indinavir with nucleoside analogues (to which the patient is naive) may lessen
the risk of the development of resistance to both indinavir and the nucleoside analogues. In one
comparative trial, combination therapy with nucleoside analogues (triple therapy with zidovudine plus
didanosine) conferred protection against the selection of virus expressing at least one resistance–
associated amino acid substitution to both indinavir (from 13/24 to 2/20 at therapy week 24) and to the
nucleoside analogues (from 10/16 to 0/20 at therapy week 24).
Cross resistance
HIV−1 patient isolates with reduced susceptibility to indinavir expressed varying patterns and degrees
of cross–resistance to a series of diverse HIV PIs, including ritonavir and saquinavir. Complete
cross−resistance was noted between indinavir and ritonavir; however, cross−resistance to saquinavir
varied among isolates. Many of the protease amino acid substitutions reported to be associated with
resistance to ritonavir and saquinavir were also associated with resistance to indinavir.
Pharmacodynamic effects
Adults
Treatment with indinavir alone or in combination with other antiretroviral agents (i.e., nucleoside
analogues) has so far been documented to reduce viral load and increase CD4 lymphocytes in patients
with CD4 cell counts below 500 cells/mm
3
.
In one published study, 20 HIV-infected patients with undetectable plasma viral load
(< 200 copies/ml) receiving indinavir 800 mg every 8 hours were switched in an open, cross-over
design to indinavir/ritonavir 400/100 mg every 12 hours. Eighteen patients completed the study to
week 48. Viral load remained < 200 copies/mL for 48 weeks in all patients.
Another published study evaluated the efficacy and safety of indinavir/ritonavir 400/100 mg every
12 hours in 40 antiretroviral-naïve patients. Thirty subjects completed 48 weeks of treatment. At
week 4, the indinavir Cmin was 500 ng/mL with substantial trough variability (range 5 to
8,100 ng/mL). By intent to treat analysis 65 % of patients had HIV RNA < 400 copies/mL and 50 %
had viral load < 50 copies/mL; by on-treatment analysis 96 % of patients had HIV RNA
< 400 copies/mL and 74 % had viral load < 50 copies/mL.
Eighty antiretroviral naïve patients were entered into a third published study. In this open label non-
randomized single arm study, patients were treated with stavudine and lamivudine plus
indinavir/ritonavir 400/100 mg every 12 hours. Sixty-two patients completed the study to week 96. In
the intent to treat and on treatment analyses the proportion of patients with HIV RNA of
< 50 copies/mL was 68.8 % and 88.7 %, respectively, at week 96.
Indinavir alone or in combination with nucleoside analogues (zidovudine/stavudine and lamivudine)
has been shown to delay clinical progression rate compared with nucleoside analogues and to provide
a sustained effect on viral load and CD4 count.
In zidovudine experienced patients, indinavir, zidovudine and lamivudine in combination compared
with lamivudine added to zidovudine reduced the probability of AIDS defining illness or death
(ADID) at 48 weeks from 13 % to 7 %. Similarly, in antiretroviral naive patients, indinavir with and
without zidovudine compared with zidovudine alone reduced the probability of ADID at 48 weeks
from 15 % with zidovudine alone to approximately 6 % with indinavir alone or in combination with
zidovudine.
Effects on viral load were consistently more pronounced in patients treated with indinavir in
combination with nucleoside analogues, but the proportion of patients with serum viral RNA below
72
the limit of quantification (500 copies/ml) varied between studies, at week 24 from 40 % to more than
80 %. This proportion tends to remain stable over prolonged periods of follow–up. Similarly, effects
on CD4 cell count tend to be more pronounced in patients treated with indinavir in combination with
nucleoside analogues compared with indinavir alone. Within studies, this effect is sustained also after
prolonged periods of follow–up.
Paediatric patients
Two clinical trials in 41 paediatric patients (4 to 15 years of age) were designed to characterise the
safety, antiretroviral activity, and pharmacokinetics of indinavir in combination with stavudine and
lamivudine. In one study, at week 24, the proportion of patients with plasma viral RNA below
400 copies/ml was 60 %; the mean increase in CD4 cell counts was 242 cells/mm
3
; and the mean
increase in percent CD4 cell counts was 4.2 %. At week 60, the proportion of patients with plasma
viral RNA below 400 copies/ml was 59 %. In another study, at week 16, the proportion of patients
with plasma viral RNA below 400 copies/ml was 59 %; the mean increase in CD4 cell counts was
73 cells/mm
3
; and the mean increase in percent CD4 cell counts was 1.2 %. At week 24, the proportion
of patients with plasma viral RNA below 400 copies/ml was 60 %.
5.2 Pharmacokinetic properties
Absorption
Indinavir is rapidly absorbed in the fasted state with a time to peak plasma concentration of 0.8 hours
± 0.3 hours (mean ± S.D.). A greater than dose–proportional increase in indinavir plasma
concentrations was observed over the 200 – 800 mg dose range. Between 800–mg and 1,000–mg dose
levels, the deviation from dose–proportionality is less pronounced. As a result of the short half–life,
1.8 ± 0.4 hours, only a minimal increase in plasma concentrations occurred after multiple dosing. The
bioavailability of a single 800–mg dose of indinavir was approximately 65 % (90 % CI, 58 – 72 %).
Data from a steady state study in healthy volunteers indicate that there is a diurnal variation in the
pharmacokinetics of indinavir. Following a dosage regimen of 800 mg every 8 hours, measured peak
plasma concentrations (C
max
) after morning, afternoon and evening doses were 15,550 nM, 8,720 nM
and 8,880 nM, respectively. Corresponding plasma concentrations at 8 hours post dose were 220 nM,
210 nM and 370 nM, respectively. The relevance of these findings for ritonavir boosted indinavir is
unknown. At steady state following a dosage regimen of 800 mg every 8 hours, HIV–seropositive
adult patients in one study achieved geometric means of: AUC
0-8h
of 27,813 nM*h (90 % confidence
interval = 22,185, 34,869), peak plasma concentrations 11,144 nM (90 % confidence interval = 9,192,
13,512) and plasma concentrations at 8 hours post dose 211 nM (90 % confidence interval = 163,274).
Food effect
At steady state following a dosage regimen of 800 mg/100 mg of indinavir/ritonavir every 12 hours
with a low-fat meal, healthy volunteers in one study achieved geometric means: AUC
0-12h
116,067 nM*h (90 % confidence interval = 101,680, 132,490), peak plasma concentrations 19,001 nM
(90 % confidence interval = 17,538, 20,588), and plasma concentrations at 12 hours post dose
2,274 nM (90 % confidence interval = 1,701, 3,042). No significant difference in exposure was seen
when the regimen was given with a high-fat meal.
Indinavir boosted regimen. Limited data are available on the pharmacokinetics of indinavir in
association with low dose ritonavir. The pharmacokinetics of indinavir (400 mg) with ritonavir
(100 mg) dosed twice daily was examined in two studies. Pharmacokinetic analysis in one study was
performed on nineteen of the patients, with a median (range) indinavir AUC 0-12hr, Cmax, and Cmin
of 25,421 nM*h (21,489 – 36,236 nM*h), 5,758 nM (5,056 – 6,742 nM) and 239 (169 – 421 nM),
respectively. The pharmacokinetic parameters in the second study were comparable.
In HIV−infected paediatric patients, a dosage regimen of indinavir hard capsules, 500 mg/m
2
every
8 hours, produced AUC
0–8hr
values of 27,412 nM*h, peak plasma concentrations of 12,182 nM, and
plasma concentrations at 8 hours post dose of 122 nM. The AUC and peak plasma concentrations were
generally similar to those previously observed in HIV–infected adults receiving the recommended
73
dose of 800 mg every 8 hours; it should be observed that the plasma concentrations 8 hours post dose
were lower.
During pregnancy, it has been demonstrated that the systemic exposure of indinavir is relevantly
decreased (PACTG 358. Crixivan, 800 mg every 8 hours + zidovudine 200 mg every 8 hours and
lamivudine 150 mg twice a day). The mean indinavir plasma AUC
0-8hr
at week 30-32 of gestation
(n = 11) was 9,231 nM∗hr, which is 74 % (95 % CI: 50 %, 86 %) lower than that observed 6 weeks
postpartum. Six of these 11 (55 %) patients had mean indinavir plasma concentrations 8 hours post-
dose (C
min
) below assay threshold of reliable quantification. The pharmacokinetics of indinavir in these
11 patients at 6 weeks postpartum were generally similar to those observed in non-pregnant patients in
another study (see section 4.6).
Administration of indinavir with a meal high in calories, fat, and protein resulted in a blunted and
reduced absorption with an approximate 80 % reduction in AUC and an 86 % reduction in C
max
.
Administration with light meals (e.g., dry toast with jam or fruit conserve, apple juice, and coffee with
skimmed or fat–free milk and sugar or corn flakes, skimmed or fat–free milk and sugar) resulted in
plasma concentrations comparable to the corresponding fasted values.
The pharmacokinetics of indinavir taken as indinavir sulphate salt (from opened hard capsules) mixed
in apple sauce were generally comparable to the pharmacokinetics of indinavir taken as hard capsules,
under fasting conditions. In HIV–infected paediatric patients, the pharmacokinetic parameters of
indinavir in apple sauce were: AUC
0–8hr
of 26,980 nM*h; peak plasma concentration of 13,711 nM;
and plasma concentration at 8 hours post dose of 146 nM.
Distribution
Indinavir was not highly bound to human plasma proteins (39 % unbound).
There are no data concerning the penetration of indinavir into the central nervous system in humans.
Biotransformation
Seven major metabolites were identified and the metabolic pathways were identified as
glucuronidation at the pyridine nitrogen, pyridine–N–oxidation with and without 3’–hydroxylation on
the indane ring, 3’–hydroxylation of indane, p–hydroxylation of phenylmethyl moiety, and N–
depyridomethylation with and without the 3’–hydroxylation.
In vitro
studies with human liver
microsomes indicated that CYP3A4 is the only P450 isozyme that plays a major role in the oxidative
metabolism of indinavir. Analysis of plasma and urine samples from subjects who received indinavir
indicated that indinavir metabolites had little proteinase inhibitory activity.
Elimination
Over the 200–1,000–mg dose range administered in both volunteers and HIV infected patients, there
was a slightly greater than dose–proportional increase in urinary recovery of indinavir. Renal clearance
(116 ml/min) of indinavir is concentration–independent over the clinical dose range. Less than 20 % of
indinavir is excreted renally. Mean urinary excretion of unchanged drug following single dose
administration in the fasted state was 10.4 % following a 700–mg dose, and 12.0 % following a 1,000–
mg dose. Indinavir was rapidly eliminated with a half–life of 1.8 hours.
Characteristics in patients
Pharmacokinetics of indinavir do not appear to be affected by race.
There are no clinically significant differences in the pharmacokinetics of indinavir in HIV seropositive
women compared to HIV seropositive men.
Patients with mild–to–moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence
of decreased metabolism of indinavir resulting in approximately 60 % higher mean AUC following a
400–mg dose. The mean half–life of indinavir increased to approximately 2.8 hours.
74
5.3 Preclinical safety data
Crystals have been seen in the urine of rats, one monkey, and one dog. The crystals have not been
associated with drug–induced renal injury. An increase in thyroidal weight and thyroidal follicular cell
hyperplasia, due to an increase in thyroxine clearance, was seen in rats treated with indinavir at doses
≥ 160 mg/kg/day. An increase in hepatic weight occurred in rats treated with indinavir at doses
≥ 40 mg/kg/day and was accompanied by hepatocellular hypertrophy at doses ≥ 320 mg/kg/day.
The maximum non–lethal oral dose of indinavir was at least 5,000 mg/kg in rats and mice, the highest
dose tested in acute toxicity studies.
Studies in rats indicated that uptake into brain tissue was limited, distribution into and out of the
lymphatic system was rapid, and excretion into the milk of lactating rats was extensive. Distribution of
indinavir across the placental barrier was significant in rats, but limited in rabbits.
Mutagenicity
Indinavir did not have any mutagenic or genotoxic activity in studies with or without metabolic
activation.
Carcinogenicity
No carcinogenicity was noted in mice at the maximum tolerated dose, which corresponded to a
systemic exposure approximately 2 to 3 times higher than the clinical exposure. In rats, at similar
exposure levels, an increased incidence of thyroid adenomas was seen, probably related to an increase
in release of thyroid stimulating hormone secondary to an increase in thyroxine clearance. The
relevance of the findings to humans is likely limited.
Developmental Toxicity
Developmental toxicity studies were performed in rats, rabbits and dogs (at doses which produced
systemic exposures comparable to or slightly greater than human exposure) and revealed no evidence
of teratogenicity. No external or visceral changes were observed in rats, however, increases in the
incidence of supernumerary ribs and of cervical ribs were seen. No external, visceral, or skeletal
changes were observed in rabbits or dogs. In rats and rabbits, no effects on embryonic/foetal survival
or foetal weights were observed. In dogs, a slight increase in resorptions was seen; however, all
foetuses in medication–treated animals were viable, and the incidence of live foetuses in medication–
treated animals was comparable to that in controls.
6.
6.1 List of excipients
Capsule content
- anhydrous lactose
- magnesium stearate
Capsule shell:
- gelatin
- titanium dioxide (E 171)
- printing ink: titanium dioxide (E 171), indigo carmine (E 132) and iron oxide (E 172).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years for HDPE bottles containing 18 hard capsules.
75
3 years for HDPE bottles containing 90 and 180 hard capsules.
6.4 Special precautions for storage
Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.
6.5 Nature and contents of container
HDPE bottles with a polypropylene cap and a foil induction cap containing 18, 90 or 180 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The bottles contain desiccant canisters that should remain in the container.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8.
EU/1/96/024/004
EU/1/96/024/005
EU/1/96/024/008
9.
Date of first authorisation: 04/10/1996
Date of latest renewal: 07/10/2006
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu
76
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
77
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Merck Sharp & Dohme B.V., Waarderweg 39, P.O. Box 581, 2003 PC Haarlem, The Netherlands
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EEFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
The Marketing Authorisation Holder will continue to submit annual Periodic Safety Update Reports.
78
ANNEX III
LABELLING AND PACKAGE LEAFLET
79
A. LABELLING
80
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CRIXIVAN 100 mg – pack of 180 capsules – Outer carton
1.
CRIXIVAN 100 mg hard capsules
Indinavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each hard capsule contains indinavir sulphate corresponding to 100 mg of indinavir.
3.
LIST OF EXCIPIENTS
Anhydrous lactose. See leaflet for further information.
4.
180 hard capsules
5.
METHOD AND ROUTES OF ADMINISTRATION
Oral use.
Hard capsules should be swallowed whole.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Desiccant should not be removed from the container.
Desiccant should not be swallowed.
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
:
Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.
81
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/96/024/010
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
CRIXIVAN 100 mg
82
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
CRIXIVAN 100 mg – pack of 180 capsules – Bottle label
1.
CRIXIVAN 100 mg hard capsules
Indinavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each hard capsule contains indinavir sulphate corresponding to 100 mg of indinavir.
3.
LIST OF EXCIPIENTS
Anhydrous lactose. See leaflet for further information.
4.
180 hard capsules
5.
METHOD AND ROUTES OF ADMINISTRATION
Oral use.
Hard capsules should be swallowed whole.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Desiccant should not be removed from the container.
Desiccant should not be swallowed.
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
:
Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.
83
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/96/024/010
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
84
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CRIXIVAN 200 mg – packs of 180, 270 and 360 capsules – Outer carton
1.
CRIXIVAN 200 mg hard capsules
Indinavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each hard capsule contains indinavir sulphate corresponding to 200 mg of indinavir.
3.
LIST OF EXCIPIENTS
Anhydrous lactose. See leaflet for further information.
4.
180 hard capsules
270 hard capsules
360 hard capsules
5.
METHOD AND ROUTES OF ADMINISTRATION
Oral use.
Hard capsules should be swallowed whole.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Desiccant should not be removed from the container.
Desiccant should not be swallowed.
8.
EXPIRY DATE
EXP
85
9.
SPECIAL STORAGE CONDITIONS
:
Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/96/024/001 180 hard capsules
EU/1/96/024/002 270 hard capsules
EU/1/96/024/003 360 hard capsules
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
CRIXIVAN 200 mg
86
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
CRIXIVAN 200 mg – packs of 180, 270 and 360 capsules – Bottle label
1.
CRIXIVAN 200 mg hard capsules
Indinavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each hard capsule contains indinavir sulphate corresponding to 200 mg of indinavir.
3.
LIST OF EXCIPIENTS
Anhydrous lactose. See leaflet for further information.
4.
180 hard capsules
270 hard capsules
360 hard capsules
5.
METHOD AND ROUTES OF ADMINISTRATION
Oral use.
Hard capsules should be swallowed whole.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Desiccant should not be removed from the container.
Desiccant should not be swallowed.
8.
EXPIRY DATE
EXP
87
9.
SPECIAL STORAGE CONDITIONS
:
Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/96/024/001 180 hard capsules
EU/1/96/024/002 270 hard capsules
EU/1/96/024/003 360 hard capsules
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
88
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CRIXIVAN 400 mg – packs of 90, 180 and 18 capsules – Outer carton
1.
CRIXIVAN 400 mg hard capsules
Indinavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each hard capsule contains indinavir sulphate corresponding to 400 mg of indinavir.
3.
LIST OF EXCIPIENTS
Anhydrous lactose. See leaflet for further information.
4.
90 hard capsules
180 hard capsules
18 hard capsules
5.
METHOD AND ROUTES OF ADMINISTRATION
Oral use.
Hard capsules should be swallowed whole.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Desiccant should not be removed from the container.
Desiccant should not be swallowed.
8.
EXPIRY DATE
EXP
89
9.
SPECIAL STORAGE CONDITIONS
:
Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/96/024/004 90 hard capsules
EU/1/96/024/005 180 hard capsules
EU/1/96/024/008 18 hard capsules
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
CRIXIVAN 400 mg
90
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
CRIXIVAN 400 mg – packs of 90, 180 and 18 capsules – Bottle label
1.
CRIXIVAN 400 mg hard capsules
Indinavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each hard capsule contains indinavir sulphate corresponding to 400 mg of indinavir.
3.
LIST OF EXCIPIENTS
Anhydrous lactose. See leaflet for further information.
4.
90 hard capsules
180 hard capsules
18 hard capsules
5.
METHOD AND ROUTES OF ADMINISTRATION
Oral use.
Hard capsules should be swallowed whole.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Desiccant should not be removed from the container.
Desiccant should not be swallowed.
8.
EXPIRY DATE
EXP
91
9.
SPECIAL STORAGE CONDITIONS
:
Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
EU/1/96/024/004 90 hard capsules
EU/1/96/024/005 180 hard capsules
EU/1/96/024/008 18 hard capsules
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
92
B. PACKAGE LEAFLET
93
PACKAGE LEAFLET: INFORMATION FOR THE USER
CRIXIVAN 100 mg hard capsules
indinavir
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What CRIXIVAN is and what it is used for
3.
How to take CRIXIVAN
4.
Possible side effects
5.
How to store CRIXIVAN
6.
Further information
1.
WHAT CRIXIVAN IS AND WHAT IT IS USED FOR
Pharmacotherapeutic Group
CRIXIVAN is a member of a class of medicinal products called protease inhibitors. It is active against
the Human Immunodeficiency Virus (HIV) helping to reduce the number of HIV particles in blood.
Therapeutic Indications
CRIXIVAN should be used in combination with other antiretroviral agents for the treatment of HIV–1
infected adult and paediatric patients.
CRIXIVAN has been shown to help reduce the risk of developing illnesses associated with HIV
disease. CRIXIVAN has also been shown to help lower the amount of HIV in your body (called “viral
load”) and raise your CD4 (T) cell count. CD4 cells play a role in maintaining a healthy immune
system to help fight infection. CRIXIVAN may not have these effects in all patients.
2.
BEFORE YOU TAKE CRIXIVAN
Do not take CRIXIVAN
- if you are allergic (hypersensitive) to indinavir or any of the other ingredients of CRIXIVAN.
Signs and symptoms of an allergic reaction may include: itchy skin, redness of the skin, wheals or
hives, swelling of the face, lips, tongue and/or throat, or difficulty breathing.
Do not take CRIXIVAN with or without ritonavir
-
if you take products containing rifampicin, amiodarone, terfenadine, astemizole, cisapride,
alprazolam, triazolam, oral (taken by mouth) midazolam (used to help you sleep and/or to
relieve anxiety), pimozide ergot derivatives such as ergot tartramine and ergot tartramine with
caffeine, St. John's wort (
Hypericum perforatum),
simvastatin or lovastatin.
In addition, do not take CRIXIVAN with ritonavir
-
if you take products containing alfuzosin, meperidine, piroxicam, propoxyphene, bepridil,
encainide, lecanide, propafenone, quinidine, fusidic acid, clozapine, clorazepate, diazepam,
stazolam, and flurazepam.
-
if you have decompensated liver disease.
94
2.
Before you take CRIXIVAN
When CRIXIVAN is used with ritonavir, please tell your doctor and refer to the package leaflet for
ritonavir for more information.
Take special care with CRIXIVAN
You should know that CRIXIVAN is not a cure for HIV infection and that you may continue to
develop infections or other illnesses associated with HIV disease. You should, therefore, remain under
the care of your doctor while taking CRIXIVAN.
HIV infection is a disease spread by contact with blood or sexual contact with an infected individual.
Treatment with CRIXIVAN has not been shown to reduce the risk of transmission of HIV to others
through sexual contact or blood contamination.
Please speak with your doctor if you have a history of liver disease. Patients with chronic hepatitis B
or C and treated with antiretroviral agents are at increased risk for severe and potentially fatal liver
adverse events and may require blood tests for control of liver function.
Redistribution, accumulation or loss of body fat may occur in patients receiving combination
antiretroviral therapy. Contact your doctor if you notice changes in body fat.
Bone problems
Some patients taking combination antiretroviral therapy may develop a bone disease called
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe
immunosuppression, higher body mass index, among others, may be some of the many risk factors for
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please
inform your doctor.
In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs
and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is
started. It is believed that these symptoms are due to an improvement in the body’s immune response,
enabling the body to fight infections that may have been present with no obvious symptoms. If you
notice anysymptoms of infection, please inform your doctor immediately.
Tell your doctor
-
about any past or present medical problems, including liver disease due to cirrhosis;
-
if you have kidney problems (including back pain with or without blood in your urine);
-
if you have allergies;
-
if you have high cholesterol and if you are taking cholesterol−lowering medicines called
“statins”;
-
if you have diabetes;
-
if you have haemophilia;
-
if you are intolerant to lactose because each hard capsule contains 37.4 mg lactose (anhydrous).
Children
CRIXIVAN can be taken by children 4 years of age and older who are able to swallow hard capsules.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
There are some medicines that should not be taken with CRIXIVAN with or without ritonavir (see Do
not take CRIXIVAN) or that require dosage changes of that medicine or CRIXIVAN (e.g.,
itraconazole, ketoconazole, cyclosporine, nevirapine, delavirdine and efavirenz).
95
Consult your doctor before taking certain cholesterol–lowering medicines (e.g., atorvastatin,
rosuvastatin, pravastatin, fluvastatin), antifungals (e.g., fluconazole), anticonvulsants (e.g.,
phenobarbital, phenytoin, carbamazepine), steroids (e.g., dexamethasone), protease inhibitors (e.g.,
amprenavir, saquinavir, atazanavir), medicines for impotence (e.g., sildenafil), blood thinners (e.g.,
warfarin), calcium channel blockers (e.g., amlodipine, felodipine–class of medicinal products used for
the treatment of hypertension and some specific heart disorders), sedative agents (e.g. midazolam
administered by injection), antidepressants (e.g., venlafaxine), oral contraceptives (e.g. "the Pill"),
medicines for asthma (e.g., theophylline) or any other medicines.
CRIXIVAN may be taken with a number of medicines that are commonly used in HIV infection
(zidovudine, didanosine, lamivudine, stavudine, quinidine, cimetidine, clarithromycin, isoniazid,
fluconazole, trimethoprim/sulfamethoxazole, methadone).
Some medications may interact with CRIXIVAN taken in combination with ritonavir. Please consult
with your physician regarding taking medications with CRIXIVAN and ritonavir.
Taking CRIXIVAN with food and drink
CRIXIVAN should be taken without food but with water. If co-administered with ritonavir,
CRIXIVAN may be administered with or without food. If water is not preferred, CRIXIVAN can be
taken with skimmed or low–fat milk, juice, coffee, or tea.
If CRIXIVAN cannot be taken without food, a low–fat light meal, such as dry toast with jam or fruit
conserve, juice and coffee with skimmed or low–fat milk and sugar, or a light meal such as corn flakes
with skimmed or low–fat milk and sugar is acceptable.
Taking CRIXIVAN with a meal that is high in calories, fat, and protein reduces your body’s ability to
absorb the medicine and in turn reduces its effectiveness.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant or intend to become pregnant.
If you are pregnant, you should take CRIXIVAN only if your doctor decides it is clearly needed.
It is not known whether CRIXIVAN is harmful to an unborn baby when taken by a pregnant woman.
Tell your doctor if you are breast−feeding.
It is recommended that HIV-infected women do not breast-feed their infants under any circumstances
in order to avoid transmission of HIV.
Driving and using machines
There is no specific information to suggest that CRIXIVAN affects your ability to drive and use
machinery. However, dizziness and blurred vision have been reported during treatment with
CRIXIVAN. Do not drive or operate machines if you experience these symptoms.
Important information about some of the ingredients of CRIXIVAN
This medicinal product contains 299.2 mg of lactose in each 800-mg dose (maximum single dose). If
you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicinal product.
3.
HOW TO TAKE CRIXIVAN
Always take Crixivan exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. The usual dose for adults is 800 mg every 8 hours. An alternative
dosing schedule for adults is CRIXIVAN 400 mg with ritonavir 100 mg both administered orally twice
a day.
The dose for children and adolescents will be determined by the doctor.
For all dosages, use a combination of the 100 mg, 200 mg or 400 mg hard capsules, as appropriate.
96
CRIXIVAN must be taken at regular intervals of 8 hours for full effectiveness and either 1 hour before
or 2 hours after a meal.
CRIXIVAN should be swallowed unchewed together with water.
It is important for adults to drink at least 1.5 litres (approximately 48 fluid ounces) of liquids during
each day while taking CRIXIVAN to help reduce the risk of forming kidney stones. It is also
important for children and adolescents to drink enough liquids during the course of the day. The doctor
will tell you the amount of liquids your child should drink.
Your doctor will tell you how long the treatment with CRIXIVAN will last.
If you take more CRIXIVAN than you should
In clinical studies, doses higher than 800 mg every 8 hours have not been shown to have any better
effect.
Contact your doctor if you have taken more than the prescribed dose of CRIXIVAN.
The most common signs and symptoms of overdose are: nausea, vomiting, diarrhoea, back pain and
blood in the urine. There is at present little information on the treatment of overdosage.
If you forget to take CRIXIVAN
If you have missed a dose, do not take it later in the day. Simply continue to follow your usual
schedule.
If you stop taking CRIXIVAN
It is important that you take CRIXIVAN exactly as your doctor prescribes. Do not stop taking it
because reducing or missing doses will increase the risk of the HI–Virus becoming resistant to
CRIXIVAN, in which case treatment with this medicine will become ineffective.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, CRIXIVAN can cause side effects, although not everybody gets them.
The following terms are used to describe how often side effects have been reported.
Very common (occurring in at least 1 in 10 patients treated)
Common (occurring in at least 1 of 100 and less than 1 of 10 patients treated)
Not known (cannot be estimated from the available data)
Blood and the lymphatic disorders
:
Not known: low red blood cell count
Immune system disorders:
Not known: allergic reactions (sometimes severe, including shock)
Nervous system disorders:
Very common: dizziness; headache;
Common: inability to sleep decreased or abnormal skin sensation
Not known: numbness of the mouth
Gastrointestinal disorders
:
Very common: nausea; vomiting; diarrhoea; an uncomfortable feeling in the stomach or belching after
eating
Common: wind; dry mouth; acid regurgitation
Not known: inflammation of the pancreas; inflammation of the liver; liver failure
97
Skin and subcutaneous tissue disorders:
Very common: dry skin; rash
Common: itching
Not known: severe skin reactions; hair loss; darkening skin colour; ingrown toenails with or without
infection
Musculoskeletal connective tissue and bone disorders:
Common: muscle pain
Renal and urinary disorders:
Common: pain on urination
Not known: infection of the kidneys, decreased kidney function, loss of renal function.
General disorders and administration site conditions:
Very common: weakness/fatigue; taste perversion; abdominal pain/swelling.
Ask your doctor or pharmacist for more information about side effects. Both have a more complete list
of side effects.
There have been reports of inflammation of the kidneys and kidney stones. In some of these patients,
this led to more severe kidney problems including kidney failure. In most cases, kidney impairment
and kidney failure were reversible. Call your doctor if you develop sudden severe back pain, with or
without blood in the urine, caused by kidney stones.
Your doctor will want to test your blood regularly to detect possible abnormalities such as rapid
breakdown of red blood cells (anaemia), elevation of liver enzyme levels, impairment of kidney
function, changes in blood sugar levels (hyperglycaemia).
In patients with haemophilia type A and B, there have been reports of increased bleeding while taking
this treatment or another protease inhibitor. Should this happen to you, seek immediate advice from
your doctor.
Inform your doctor as soon as possible if you develop severe muscle pain or weakness.
Severe muscle pain and weakness have occurred in patients taking protease inhibitors, including
CRIXIVAN, together with cholesterol–lowering medicines called “statins”. There have also been
reports of muscle pain, tenderness or weakness, particularly with combination antiretroviral therapy
including protease inhibitors and nucleoside analogues in patients not taking statins. On rare occasions
these muscle disorders have been serious (rhabdomyolysis).
Combination antiretroviral therapy may cause changes in body shape due to changes in fat
distribution. These may include loss of fat from legs, arms and face, increased fat in the abdomen
(belly) and other internal organs, breast enlargement and fatty lumps on the back of the neck (‘buffalo
hump’). The cause and long-term effects of these conditions are not known at this time. Combination
antiretroviral therapy may also cause raised lactic acid and sugar in the blood, hyperlipidaemia
(increased fats in the blood) and resistance to insulin.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE CRIXIVAN
Keep out of the reach and sight of children.
Do not use CRIXIVAN after the expiry date stated on the bottle or carton. The expiry date refers to the
last day of the month.
98
Store CRIXIVAN in the original bottle. Keep the bottle tightly closed in order to protect from
moisture. The bottles contain desiccant canisters that should remain in the bottle.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What CRIXIVAN contains
-
The active substance is indinavir sulphate. Each hard capsule contains indinavir sulphate
corresponding to 100 mg of indinavir.
-
The other excipients are anhydrous lactose, magnesium stearate, gelatin and titanium dioxide
(E 171). The capsules are printed with printing ink containing titanium dioxide (E 171), indigo
carmine (E 132) and iron oxide (E 172).
What CRIXIVAN look like and content of the pack
CRIXIVAN 100 mg hard capsules are supplied in HDPE bottles with a polypropylene cap and a foil
induction cap containing 180 capsules.
The capsules are semi-translucent white and coded CRIXIVAN
TM
100 mg in green.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon,
Hertfordshire EN11 9BU United Kingdom
Manufacturer: Merck Sharp & Dohme B.V., Waarderweg 39, Postbus 581, 2003 PC Haarlem
The Netherlands
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 2 373 42 11
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 2 373 42 11
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
MSD Magyarország Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
A.M.Mangion Ltd.
Tel: +356 2540 2600
medinfo_mt@merck.com
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme B.V.
Tel: +31 (0) 23 5153153
msdbvnl@merck.com
99
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) A/S
Tlf: +47 32 20 73 00
msdnorge@ msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750 (Nimi)
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
crixivan@msd.es
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0) 1 47 54 87 00
contact@msd-france.com
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 299 8700
medinfo_ireland@merck.com
Slovenija
Merck Sharp & Dohme, inovativna zdravila
d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Merck Sharp & Dohme (Italia) S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme (Middle East) Limited.
Τηλ: +357 22866700
info_cyprus@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 1400
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”.
Tel: +371 7364 224
msd_lv@merck.com.
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medinfo_uk@merck.com
100
Lietuva
UAB “Merck Sharp & Dohme”.
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
101
PACKAGE LEAFLET: INFORMATION FOR THE USER
CRIXIVAN 200 mg hard capsules
indinavir
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What CRIXIVAN is and what it is used for
3.
How to take CRIXIVAN
4.
Possible side effects
5.
How to store CRIXIVAN
6.
Further information
1.
WHAT CRIXIVAN IS AND WHAT IT IS USED FOR
Pharmacotherapeutic Group
CRIXIVAN is a member of a class of medicinal products called protease inhibitors. It is active against
the Human Immunodeficiency Virus (HIV) helping to reduce the number of HIV particles in blood.
Therapeutic Indications
CRIXIVAN should be used in combination with other antiretroviral agents for the treatment of HIV–1
infected adult and paediatric patients.
CRIXIVAN has been shown to help reduce the risk of developing illnesses associated with HIV
disease. CRIXIVAN has also been shown to help lower the amount of HIV in your body (called “viral
load”) and raise your CD4 (T) cell count. CD4 cells play a role in maintaining a healthy immune
system to help fight infection. CRIXIVAN may not have these effects in all patients.
2.
BEFORE YOU TAKE CRIXIVAN
Do not take CRIXIVAN
- if you are allergic (hypersensitive) to indinavir or any of the other ingredients of CRIXIVAN.
Signs and symptoms of an allergic reaction may include: itchy skin, redness of the skin, wheals or
hives, swelling of the face, lips, tongue and/or throat, or difficulty breathing.
Do not take CRIXIVAN with or without ritonavir
-
if you take products containing rifampicin, amiodarone, terfenadine, astemizole, cisapride,
alprazolam, triazolam, oral (taken by mouth) midazolam (used to help you sleep and/or to
relieve anxiety), pimozide ergot derivatives such as ergot tartramine and ergot tartramine with
caffeine, St. John's wort (
Hypericum perforatum),
simvastatin or lovastatin.
In addition, do not take CRIXIVAN with ritonavir
-
if you take products containing alfuzosin, meperidine, piroxicam, propoxyphene, bepridil,
encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine, clorazepate, diazepam,
estazolam, and flurazepam.
102
2.
Before you take CRIXIVAN
-
if you have decompensated liver disease.
When CRIXIVAN is used with ritonavir, please tell your doctor and refer to the package leaflet for
ritonavir for more information.
Take special care with CRIXIVAN
You should know that CRIXIVAN is not a cure for HIV infection and that you may continue to
develop infections or other illnesses associated with HIV disease. You should, therefore, remain under
the care of your doctor while taking CRIXIVAN.
HIV infection is a disease spread by contact with blood or sexual contact with an infected individual.
Treatment with CRIXIVAN has not been shown to reduce the risk of transmission of HIV to others
through sexual contact or blood contamination.
Please speak with your doctor if you have a history of liver disease. Patients with chronic hepatitis B
or C and treated with antiretroviral agents are at increased risk for severe and potentially fatal liver
adverse events and may require blood tests for control of liver function.
Redistribution, accumulation or loss of body fat may occur in patients receiving combination
antiretroviral therapy. Contact your doctor if you notice changes in body fat.
Bone problems
Some patients taking combination antiretroviral therapy may develop a bone disease called
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe
immunosuppression, higher body mass index, among others, may be some of the many risk factors for
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please
inform your doctor.
In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs
and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is
started. It is believed that these symptoms are due to an improvement in the body’s immune response,
enabling the body to fight infections that may have been present with no obvious symptoms. If you
notice any symptoms of infection, please inform your doctor immediately.
Tell your doctor
-
about any past or present medical problems, including liver disease due to cirrhosis;
-
if you have kidney problems (including back pain with or without blood in your urine);
-
if you have allergies;
-
if you have high cholesterol and if you are taking cholesterol−lowering medicines called
“statins”;
-
if you have haemophilia;
-
if you are intolerant to lactose because each hard capsule contains 74.8 mg lactose (anhydrous).
Children
CRIXIVAN can be taken by children 4 years of age and older who are able to swallow hard capsules.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
There are some medicines that should not be taken with CRIXIVAN with or without ritonavir (see Do
not take CRIXIVAN) or that require dosage changes of that medicine or CRIXIVAN (e.g.,
itraconazole, ketoconazole, cyclosporine, nevirapine, delavirdine and efavirenz).
103
-
if you have diabetes;
Consult your doctor before taking certain cholesterol–lowering medicines (e.g., atorvastatin,
rosuvastatin, pravastatin, fluvastatin), antifungals (e.g., fluconazole), anticonvulsants (e.g.,
phenobarbital, phenytoin, carbamazepine), steroids (e.g., dexamethasone), protease inhibitors (e.g.,
amprenavir, saquinavir, atazanavir), medicines for impotence (e.g., sildenafil), blood thinners (e.g.,
warfarin), calcium channel blockers (e.g., amlodipine, felodipine–class of medicinal products used for
the treatment of hypertension and some specific heart disorders), sedative agents (e.g. midazolam
administered by injection), antidepressants (e.g., venlafaxine), oral contraceptives (e.g. "the Pill"),
medicines for asthma (e.g., theophylline) or any other medicines.
CRIXIVAN may be taken with a number of medicines that are commonly used in HIV infection
(zidovudine, didanosine, lamivudine, stavudine, quinidine, cimetidine, clarithromycin, isoniazid,
fluconazole, trimethoprim/sulfamethoxazole, methadone).
Some medications may interact with CRIXIVAN taken in combination with ritonavir. Please consult
with your physician regarding taking medications with CRIXIVAN and ritonavir.
Taking CRIXIVAN with food and drink
CRIXIVAN should be taken without food but with water. If co-administered with ritonavir,
CRIXIVAN may be administered with or without food.
If water is not preferred, CRIXIVAN can be taken with skimmed or low–fat milk, juice, coffee, or tea.
If CRIXIVAN cannot be taken without food, a low–fat light meal, such as dry toast with jam or fruit
conserve, juice and coffee with skimmed or low–fat milk and sugar, or a light meal such as corn flakes
with skimmed or low–fat milk and sugar is acceptable.
Taking CRIXIVAN with a meal that is high in calories, fat, and protein reduces your body’s ability to
absorb the medicine and in turn reduces its effectiveness.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant or intend to become pregnant.
If you are pregnant, you should take CRIXIVAN only if your doctor decides it is clearly needed.
It is not known whether CRIXIVAN is harmful to an unborn baby when taken by a pregnant woman.
Tell your doctor if you are breast−feeding.
It is recommended that HIV-infected women do not breast-feed their infants under any circumstances
in order to avoid transmission of HIV.
Driving and using machines
There is no specific information to suggest that CRIXIVAN affects your ability to drive and use
machinery. However, dizziness and blurred vision have been reported during treatment with
CRIXIVAN. Do not drive or operate machines if you experience these symptoms.
Important information about some of the ingredients of CRIXIVAN
This medicinal product contains 299.2 mg of lactose in each 800-mg dose (maximum single dose). If
you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicinal product.
3.
HOW TO TAKE CRIXIVAN
Always take Crixivan exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. The usual dose for adults is 800 mg every 8 hours. An alternative
dosing schedule for adults is CRIXIVAN 400 mg with ritonavir 100 mg both administered orally twice
a day.
The dose for children and adolescents will be determined by the doctor.
For all dosages, use a combination of the 100–mg, 200–mg or 400–mg hard capsules, as appropriate.
104
CRIXIVAN must be taken at regular intervals of 8 hours for full effectiveness and either 1 hour before
or 2 hours after a meal.
CRIXIVAN should be swallowed unchewed together with water.
It is important for adults to drink at least 1.5 litres (approximately 48 fluid ounces) of liquids during
each day while taking CRIXIVAN to help reduce the risk of forming kidney stones. It is also
important for children and adolescents to drink enough liquids during the course of the day. The doctor
will tell you the amount of liquids your child should drink.
Your doctor will tell you how long the treatment with CRIXIVAN will last.
If you take more CRIXIVAN than you should
In clinical studies, doses higher than 800 mg every 8 hours have not been shown to have any better
effect.
Contact your doctor if you have taken more than the prescribed dose of CRIXIVAN.
The most common signs and symptoms of overdose are: nausea, vomiting, diarrhoea, back pain and
blood in the urine. There is at present little information on the treatment of overdosage.
If you forget to take CRIXIVAN
If you have missed a dose, do not take it later in the day. Simply continue to follow your usual
schedule.
If you stop taking CRIXIVAN
It is important that you take CRIXIVAN exactly as your doctor prescribes. Do not stop taking it
because reducing or missing doses will increase the risk of the HI–Virus becoming resistant to
CRIXIVAN, in which case treatment with this medicine will become ineffective.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, CRIXIVAN can cause side effects, although not everybody gets them.
The following terms are used to describe how often side effects have been reported.
Very common (occurring in at least 1 in 10 patients treated)
Common (occurring in at least 1 of 100 and less than 1 of 10 patients treated)
Not known (cannot be estimated from the available data)
Blood and the lymphatic disorders
:
Not known: low red blood cell count
Immune system disorders:
Not known: allergic reactions (sometimes severe, including shock)
Nervous system disorders:
Very common: dizziness; headache;
Common: inability to sleep decreased or abnormal skin sensation
Not known: numbness of the mouth
Gastrointestinal disorders
:
Very common: nausea; vomiting; diarrhoea; an uncomfortable feeling in the stomach or belching after
eating
Common: wind; dry mouth; acid regurgitation
Not known: inflammation of the pancreas; inflammation of the liver; liver failure
105
Skin and subcutaneous tissue disorders:
Very common: dry skin; rash
Common: itching
Not known: severe skin reactions; hair loss; darkening skin colour; ingrown toenails with or without
infection
Musculoskeletal connective tissue and bone disorders:
Common: muscle pain
Renal and urinary disorders:
Common: pain on urination
Not known: infection of the kidneys, decreased kidney function, loss of renal function.
General disorders and administration site conditions:
Very common: weakness/fatigue; taste perversion; abdominal pain/swelling.
Ask your doctor or pharmacist for more information about side effects. Both have a more complete list
of side effects.
There have been reports of inflammation of the kidneys and kidney stones. In some of these patients,
this led to more severe kidney problems including kidney failure. In most cases, kidney impairment
and kidney failure were reversible. Call your doctor if you develop sudden severe back pain, with or
without blood in the urine, caused by kidney stones.
Your doctor will want to test your blood regularly to detect possible abnormalities such as rapid
breakdown of red blood cells (anaemia), elevation of liver enzyme levels, impairment of kidney
function, changes in blood sugar levels (hyperglycaemia).
In patients with haemophilia type A and B, there have been reports of increased bleeding while taking
this treatment or another protease inhibitor. Should this happen to you, seek immediate advice from
your doctor.
Inform your doctor as soon as possible if you develop severe muscle pain or weakness.
Severe muscle pain and weakness have occurred in patients taking protease inhibitors, including
CRIXIVAN, together with cholesterol–lowering medicines called “statins”. There have also been
reports of muscle pain, tenderness or weakness, particularly with combination antiretroviral therapy
including protease inhibitors and nucleoside analogues in patients not taking statins. On rare occasions
these muscle disorders have been serious (rhabdomyolysis).
Combination antiretroviral therapy may cause changes in body shape due to changes in fat
distribution. These may include loss of fat from legs, arms and face, increased fat in the abdomen
(belly) and other internal organs, breast enlargement and fatty lumps on the back of the neck (‘buffalo
hump’). The cause and long-term effects of these conditions are not known at this time. Combination
antiretroviral therapy may also cause raised lactic acid and sugar in the blood, hyperlipidaemia
(increased fats in the blood) and resistance to insulin.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE CRIXIVAN
Keep out of the reach and sight of children.
Do not use CRIXIVAN after the expiry date stated on the bottle or carton. The expiry date refers to the
last day of the month.
106
Store CRIXIVAN in the original bottle. Keep the bottle tightly closed in order to protect from
moisture. The bottles contain desiccant canisters that should remain in the bottle.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What CRIXIVAN contains
-
The active substance is indinavir sulphate. Each hard capsule contains indinavir sulphate
corresponding to 200 mg of indinavir.
-
The other excipients are anhydrous lactose, magnesium stearate, gelatin and titanium dioxide
(E 171). The capsules are printed with printing ink containing indigo carmine (E 132).
What CRIXIVAN look like and content of the pack
CRIXIVAN 200 mg hard capsules are supplied in HDPE bottles with a polypropylene cap and a foil
induction cap containing 180, 270 or 360 capsules. Not all pack sizes may be marketed.
The capsules are semi-translucent white and coded CRIXIVAN
TM
200 mg in blue.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon,
Hertfordshire EN11 9BU United Kingdom
Manufacturer:
Merck Sharp & Dohme B.V.
,
Waarderweg 39
,
Postbus 581
,
2003 PC Haarlem
The Netherlands
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 2 373 42 11
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 2 373 42 11
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
MSD Magyarország Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
A.M.Mangion Ltd.
Tel: +356 2540 2600
medinfo_mt@merck.com
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme B.V.
Tel: +31 (0) 23 5153153
msdbvnl@merck.com
107
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) A/S
Tlf: +47 32 20 73 00
msdnorge@ msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750 (Nimi)
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
crixivan@msd.es
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0) 1 47 54 87 00
contact@msd-france.com
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 299 8700
medinfo_ireland@merck.com
Slovenija
Merck Sharp & Dohme, inovativna zdravila
d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Merck Sharp & Dohme (Italia) S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme (Middle East) Limited.
Τηλ: +357 22866700
info_cyprus@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 1400
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”.
Tel: +371 7364 224
msd_lv@merck.com.
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medinfo_uk@merck.com
108
Lietuva
UAB “Merck Sharp & Dohme”.
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
109
PACKAGE LEAFLET: INFORMATION FOR THE USER
CRIXIVAN 400 mg hard capsules
indinavir
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What CRIXIVAN is and what it is used for
3.
How to take CRIXIVAN
4.
Possible side effects
5.
How to store CRIXIVAN
6.
Further information
1.
WHAT CRIXIVAN IS AND WHAT IT IS USED FOR
Pharmacotherapeutic Group
CRIXIVAN is a member of a class of medicinal products called protease inhibitors. It is active against
the Human Immunodeficiency Virus (HIV) helping to reduce the number of HIV particles in blood.
Therapeutic Indications
CRIXIVAN should be used in combination with other antiretroviral agents for the treatment of HIV–1
infected adult and paediatric patients.
CRIXIVAN has been shown to help reduce the risk of developing illnesses associated with HIV
disease. CRIXIVAN has also been shown to help lower the amount of HIV in your body (called “viral
load”) and raise your CD4 (T) cell count. CD4 cells play a role in maintaining a healthy immune
system to help fight infection. CRIXIVAN may not have these effects in all patients.
2.
BEFORE YOU TAKE CRIXIVAN
Do not take CRIXIVAN
- if you are allergic (hypersensitive) to indinavir or any of the other ingredients of CRIXIVAN.
Signs and symptoms of an allergic reaction may include: itchy skin, redness of the skin, wheals or
hives, swelling of the face, lips, tongue and/or throat, or difficulty breathing.
Do not take CRIXIVAN with or without ritonavir
-
if you take products containing rifampicin, amiodarone, terfenadine, astemizole, cisapride,
alprazolam, triazolam, oral (taken by mouth) midazolam (used to help you sleep and/or to
relieve anxiety), pimozide ergot derivatives such as ergot tartramine and ergot tartramine with
caffeine, St. John's wort (
Hypericum perforatum),
simvastatin or lovastatin.
In addition, do not take CRIXIVAN with ritonavir
-
if you take products containing alfuzosin, meperidine, piroxicam, propoxyphene, bepridil,
encainide, flecanide, propafenone, quinidine, fusidic acid, clozapine, clorazepate, diazepam,
estazolam, and flurazepam.
110
2.
Before you take CRIXIVAN
-
if you have decompensated liver disease.
When CRIXIVAN is used with ritonavir, please tell your doctor and refer to the package leaflet for
ritonavir for more information.
Take special care with CRIXIVAN
You should know that CRIXIVAN is not a cure for HIV infection and that you may continue to
develop infections or other illnesses associated with HIV disease. You should, therefore, remain under
the care of your doctor while taking CRIXIVAN.
HIV infection is a disease spread by contact with blood or sexual contact with an infected individual.
Treatment with CRIXIVAN has not been shown to reduce the risk of transmission of HIV to others
through sexual contact or blood contamination.
Please speak with your doctor if you have a history of liver disease. Patients with chronic hepatitis B
or C and treated with antiretroviral agents are at increased risk for severe and potentially fatal liver
adverse events and may require blood tests for control of liver function.
Redistribution, accumulation or loss of body fat may occur in patients receiving combination
antiretroviral therapy. Contact your doctor if you notice changes in body fat.
Bone problems
Some patients taking combination antiretroviral therapy may develop a bone disease called
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe
immunosuppression, higher body mass index, among others, may be some of the many risk factors for
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please
inform your doctor.
In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs
and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is
started. It is believed that these symptoms are due to an improvement in the body’s immune response,
enabling the body to fight infections that may have been present with no obvious symptoms. If you
notice any symptoms of infection, please inform your doctor immediately.
Tell your doctor
-
about any past or present medical problems, including liver disease due to cirrhosis;
-
if you have kidney problems (including back pain with or without blood in your urine);
-
if you have allergies;
-
if you have high cholesterol and if you are taking cholesterol−lowering medicines called
“statins”;
-
if you have haemophilia;
-
if you are intolerant to lactose because each hard capsule contains 149.6 mg lactose
(anhydrous).
Children
CRIXIVAN can be taken by children 4 years of age and older who are able to swallow hard capsules.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
There are some medicines that should not be taken with CRIXIVAN with or without ritonavir (see Do
not take CRIXIVAN) or that require dosage changes of that medicine or CRIXIVAN (e.g.,
itraconazole, ketoconazole, cyclosporine, nevirapine, delavirdine and efavirenz).
111
-
if you have diabetes;
Consult your doctor before taking certain cholesterol–lowering medicines (e.g., atorvastatin,
rosuvastatin, pravastatin, fluvastatin), antifungals (e.g., fluconazole), anticonvulsants (e.g.,
phenobarbital, phenytoin, carbamazepine), steroids (e.g., dexamethasone), protease inhibitors (e.g.,
amprenavir, saquinavir, atazanavir), medicines for impotence (e.g., sildenafil), blood thinners (e.g.,
warfarin), calcium channel blockers (e.g., amlodipine, felodipine–class of medicinal products used for
the treatment of hypertension and some specific heart disorders), sedative agents (e.g. midazolam
administered by injection), antidepressants (e.g., venlafaxine), oral contraceptives (e.g. "the Pill"),
medicines for asthma (e.g., theophylline) or any other medicines.
CRIXIVAN may be taken with a number of medicines that are commonly used in HIV infection
(zidovudine, didanosine, lamivudine, stavudine, quinidine, cimetidine, clarithromycin, isoniazid,
fluconazole, trimethoprim/sulfamethoxazole, methadone).
Some medications may interact with CRIXIVAN taken in combination with ritonavir. Please consult
with your physician regarding taking medications with CRIXIVAN and ritonavir.
Taking CRIXIVAN with food and drink
CRIXIVAN should be taken without food but with water. If co-administered with ritonavir,
CRIXIVAN may be administered with or without food.
If water is not preferred, CRIXIVAN can be taken with skimmed or low–fat milk, juice, coffee, or tea.
If CRIXIVAN cannot be taken without food, a low–fat light meal, such as dry toast with jam or fruit
conserve, juice and coffee with skimmed or low–fat milk and sugar, or a light meal such as corn flakes
with skimmed or low–fat milk and sugar is acceptable.
Taking CRIXIVAN with a meal that is high in calories, fat, and protein reduces your body’s ability to
absorb the medicine and in turn reduces its effectiveness.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant or intend to become pregnant.
If you are pregnant, you should take CRIXIVAN only if your doctor decides it is clearly needed.
It is not known whether CRIXIVAN is harmful to an unborn baby when taken by a pregnant woman.
Tell your doctor if you are breast−feeding.
It is recommended that HIV-infected women do not breast-feed their infants under any circumstances
in order to avoid transmission of HIV.
Driving and using machines
There is no specific information to suggest that CRIXIVAN affects your ability to drive and use
machinery. However, dizziness and blurred vision have been reported during treatment with
CRIXIVAN. Do not drive or operate machines if you experience these symptoms.
Important information about some of the ingredients of CRIXIVAN
This medicinal product contains 299.2 mg of lactose in each 800-mg dose (maximum single dose). If
you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicinal product.
3.
HOW TO TAKE CRIXIVAN
Always take Crixivan exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. The usual dose for adults is 800 mg every 8 hours. An alternative
dosing schedule for adults is CRIXIVAN 400 mg with ritonavir 100 mg both administered orally twice
a day.
The dose for children and adolescents will be determined by the doctor.
For all dosages, use a combination of the 100–mg, 200–mg or 400–mg hard capsules, as appropriate.
112
CRIXIVAN must be taken at regular intervals of 8 hours for full effectiveness and either 1 hour before
or 2 hours after a meal.
CRIXIVAN should be swallowed unchewed together with water.
It is important for adults to drink at least 1.5 litres (approximately. 48 fluid ounces) of liquids during
each day while taking CRIXIVAN to help reduce the risk of forming kidney stones. It is also
important for children and adolescents to drink enough liquids during the course of the day. The doctor
will tell you the amount of liquids your child should drink.
Your doctor will tell you how long the treatment with CRIXIVAN will last.
If you take more CRIXIVAN than you should
In clinical studies, doses higher than 800 mg every 8 hours have not been shown to have any better
effect.
Contact your doctor if you have taken more than the prescribed dose of CRIXIVAN.
The most common signs and symptoms of overdose are: nausea, vomiting, diarrhoea, back pain and
blood in the urine. There is at present little information on the treatment of overdosage.
If you forget to take CRIXIVAN
If you have missed a dose, do not take it later in the day. Simply continue to follow your usual
schedule.
If you stop taking CRIXIVAN
It is important that you take CRIXIVAN exactly as your doctor prescribes. Do not stop taking it
because reducing or missing doses will increase the risk of the HI–Virus becoming resistant to
CRIXIVAN, in which case treatment with this medicine will become ineffective.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, CRIXIVAN can cause side effects, although not everybody gets them.
The following terms are used to describe how often side effects have been reported.
Very common (occurring in at least 1 in 10 patients treated)
Common (occurring in at least 1 of 100 and less than 1 of 10 patients treated)
Not known (cannot be estimated from the available data)
Blood and the lymphatic disorders
:
Not known: low red blood cell count
Immune system disorders:
Not known: allergic reactions (sometimes severe, including shock)
Nervous system disorders:
Very common: dizziness; headache;
Common: inability to sleep decreased or abnormal skin sensation
Not known: numbness of the mouth
Gastrointestinal disorders
:
Very common: nausea; vomiting; diarrhoea; an uncomfortable feeling in the stomach or belching after
eating
Common: wind; dry mouth; acid regurgitation
Not known: inflammation of the pancreas; inflammation of the liver; liver failure
113
Skin and subcutaneous tissue disorders:
Very common: dry skin; rash
Common: itching
Not known: severe skin reactions; hair loss; darkening skin colour; ingrown toenails with or without
infection
Musculoskeletal connective tissue and bone disorders:
Common: muscle pain
Renal and urinary disorders:
Common: pain on urination
Not known: infection of the kidneys, decreased kidney function, loss of renal function.
General disorders and administration site conditions:
Very common: weakness/fatigue; taste perversion; abdominal pain/swelling.
Ask your doctor or pharmacist for more information about side effects. Both have a more complete list
of side effects.
There have been reports of inflammation of the kidneys and kidney stones. In some of these patients,
this led to more severe kidney problems including kidney failure. In most cases, kidney impairment
and kidney failure were reversible. Call your doctor if you develop sudden severe back pain, with or
without blood in the urine, caused by kidney stones.
Your doctor will want to test your blood regularly to detect possible abnormalities such as rapid
breakdown of red blood cells (anaemia), elevation of liver enzyme levels, impairment of kidney
function, changes in blood sugar levels (hyperglycaemia).
In patients with haemophilia type A and B, there have been reports of increased bleeding while taking
this treatment or another protease inhibitor. Should this happen to you, seek immediate advice from
your doctor.
Inform your doctor as soon as possible if you develop severe muscle pain or weakness.
Severe muscle pain and weakness have occurred in patients taking protease inhibitors, including
CRIXIVAN, together with cholesterol–lowering medicines called “statins”. There have also been
reports of muscle pain, tenderness or weakness, particularly with combination antiretroviral therapy
including protease inhibitors and nucleoside analogues in patients not taking statins. On rare occasions
these muscle disorders have been serious (rhabdomyolysis).
Combination antiretroviral therapy may cause changes in body shape due to changes in fat
distribution. These may include loss of fat from legs, arms and face, increased fat in the abdomen
(belly) and other internal organs, breast enlargement and fatty lumps on the back of the neck (‘buffalo
hump’). The cause and long-term effects of these conditions are not known at this time. Combination
antiretroviral therapy may also cause raised lactic acid and sugar in the blood, hyperlipidaemia
(increased fats in the blood) and resistance to insulin.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE CRIXIVAN
Keep out of the reach and sight of children.
Do not use CRIXIVAN after the expiry date stated on the bottle or carton. The expiry date refers to the
last day of the month.
114
Store CRIXIVAN in the original bottle. Keep the bottle tightly closed in order to protect from
moisture. The bottles contain desiccant canisters that should remain in the bottle.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What CRIXIVAN contains
-
The active substance is indinavir sulphate. Each hard capsule contains indinavir sulphate
corresponding to 400 mg of indinavir.
-
The other excipients are anhydrous lactose, magnesium stearate, gelatin and titanium dioxide
(E 171). The capsules are printed with printing ink containing titanium dioxide (E 171), indigo
carmine (E 132) and iron oxide (E 172).
What CRIXIVAN look like and content of the pack
CRIXIVAN 400 mg hard capsules are supplied in HDPE bottles with a polypropylene cap and a foil
induction cap containing 18, 90 or 180 capsules. Not all pack sizes may be marketed.
The capsules are semi-translucent white and coded CRIXIVAN
TM
400 mg in green.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon,
Hertfordshire EN11 9BU United Kingdom
Manufacturer:
Merck Sharp & Dohme B.V.
,
Waarderweg 39
,
Postbus 581
,
2003 PC Haarlem
The Netherlands
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
Belgique/België/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 2 373 42 11
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 2 373 42 11
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
MSD Magyarország Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com
Česká republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
A.M.Mangion Ltd.
Tel: +356 2540 2600
medinfo_mt@merck.com
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme B.V.
Tel: +31 (0) 23 5153153
msdbvnl@merck.com
115
Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de
Norge
MSD (Norge) A/S
Tlf: +47 32 20 73 00
msdnorge@ msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750 (Nimi)
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
crixivan@msd.es
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
France
Laboratoires Merck Sharp & Dohme – Chibret
Tél: +33 (0) 1 47 54 87 00
contact@msd-france.com
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
informacao_doente@merck.com
Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 299 8700
medinfo_ireland@merck.com
Slovenija
Merck Sharp & Dohme, inovativna zdravila
d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Merck Sharp & Dohme (Italia) S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi
Κύπρος
Merck Sharp & Dohme (Middle East) Limited.
Τηλ: +357 22866700
info_cyprus@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 1400
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”.
Tel: +371 7364 224
msd_lv@merck.com.
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medinfo_uk@merck.com
116
Lietuva
UAB “Merck Sharp & Dohme”.
Tel.: +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
117
Source: European Medicines Agency
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