ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
INVIRASE 200 mg hard capsules.
2.
One capsule contains 200 mg of saquinavir as saquinavir mesilate.
Excipient: Contains lactose anhydrous: 63.3 mg.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
Light brown and green, opaque hard capsule with the marking “ROCHE” and the code “0245” on each
half of the capsule shell.
4.
Invirase is indicated for the treatment of HIV-1 infected adult patients. Invirase should only be given
in combination with ritonavir and other antiretroviral medicinal products (see section 4.2).
Therapy with Invirase should be initiated by a physician experienced in the management of HIV
infection.
Adults and adolescents over the age of 16 years:
In combination with ritonavir
The recommended dose of Invirase is 1000 mg (5 x 200 mg capsules) two times daily with ritonavir
100 mg two times daily in combination with other antiretroviral agents. For treatment-naive patients
initiating treatment with Invirase/ritonavir, the recommended starting dose of Invirase is 500 mg (1 x
500 mg film-coated tablet) two times daily with ritonavir 100 mg two times daily in combination with
other antiretroviral agents for the first 7 days of treatment (see Summary of Product Characteristics for
INVIRASE 500 mg film-coated tablets). After 7 days, the recommended dose of Invirase is 1000 mg
two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents.
Patients switching immediately from treatment with another protease inhibitor taken with ritonavir or
from a non-nucleoside reverse transcriptase inhibitor based regimen, without a wash-out period,
should however initiate and continue Invirase at the standard recommended dose of 1000 mg two
times daily with ritonavir 100 mg two times daily.
Invirase capsules should be swallowed whole and taken at the same time as ritonavir with or after food
(see section 5.2).
Renal impairment:
No dosage adjustment is necessary for patients with mild to moderate renal impairment. Caution
should be exercised in patients with severe renal impairment (see section 4.4).
Hepatic impairment:
No dosage adjustment is necessary for HIV-infected patients with mild hepatic impairment. No dosage
2
adjustment seems warranted for patients with moderate hepatic impairment based on limited data.
Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic response is
recommended due to increased variability of the exposure in this population. Invirase/ritonavir is
contraindicated in patients with decompensated hepatic impairment (see sections 4.3 and 4.4).
Children under the age of 16 and adults over 60 years:
The experience with Invirase in children below the age of 16 and adults over 60 years is limited. In
children, as in adults, Invirase should only be given in combination with ritonavir.
Invirase is contraindicated in patients with:
hypersensitivity to the active substance or to any of the excipients
decompensated liver disease (see section 4.4)
congenital or documented acquired QT prolongation
electrolyte disturbances, particularly uncorrected hypokalaemia
clinically relevant bradycardia
clinically relevant heart failure with reduced left-ventricular ejection fraction
previous history of symptomatic arrhythmias
concurrent therapy with any of the following drugs, which may interact and result in
potentially life-threatening undesirable effects (see sections 4.4, 4.5 and 4.8):
-
drugs that prolong the QT and/or PR interval (see sections 4.4 and 4.5)
-
midazolam administered orally (for caution on parenterally administered midazolam, see
section 4.5), triazolam (potential for prolonged or increased sedation, respiratory
depression)
-
simvastatin, lovastatin (increased risk of myopathy including rhabdomyolysis)
-
ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine, and methylergonovine)
(potential for acute ergot toxicity)
-
rifampicin (risk of severe hepatocellular toxicity) (see sections 4.4, 4.5, and 4.8).
Considerations when initiating Invirase therapy:
Invirase should not be given as the sole protease
inhibitor. Invirase should only be given in combination with ritonavir (see section 4.2).
Patients should be informed that saquinavir is not a cure for HIV infection and that they may continue
to acquire illnesses associated with advanced HIV infection, including opportunistic infections.
Patients should also be advised that they might experience undesirable effects associated with co-
administered medications.
Cardiac conduction and repolarisation abnormalities:
Dose-dependent prolongations of QT and PR intervals have been observed in healthy volunteers
receiving ritonavir-boosted Invirase (see section 5.1).
Concomitant use of ritonavir-boosted
Invirase with other medicinal products that prolong the QT and/or PR interval is therefore
contraindicated (see section 4.3).
Since the magnitude of QT and PR prolongation increases with increasing concentrations of
saquinavir, the recommended dose of ritonavir-boosted Invirase should not be exceeded. Ritonavir-
boosted Invirase at a dose of 2000 mg once daily with ritonavir 100 mg once daily has not been
studied with regard to the risk of QT prolongation and is not recommended. Other medicinal products
known to increase the plasma concentration of ritonavir-boosted Invirase should be used with caution.
Women and elderly patients may be more susceptible to drug-associated effects on the QT and/or PR
interval.
3
Clinical Management:
Consideration should be given for performing baseline and follow-up electrocardiograms after
initiation of treatment, e.g. in patients taking concomitant medication known to increase the exposure
of saquinavir (see section 4.5). If signs or symptoms suggesting cardiac arrhythmia occur, continuous
monitoring of ECG should be performed. Ritonavir-boosted Invirase should be discontinued if
arrhythmias are demonstrated, or if prolongation occurs in the QT or PR interval.
Patients initiating therapy with ritonavir-boosted Invirase
:
-
An ECG should be performed prior to initiation of treatment: patients with a QT interval
> 450 msec should not use ritonavir-boosted Invirase.
-
For patients with a baseline QT interval < 450 msec, an on-treatment ECG is suggested
after approximately 3 to 4 days of therapy. Patients demonstrating a subsequent increase
in QT-interval to > 480 msec or prolongation over pre-treatment by > 20 msec should
discontinue ritonavir-boosted Invirase.
Patients stable on ritonavir-boosted Invirase and requiring concomitant medication with
potential to increase the exposure of saquinavir or patients on medication with potential to
increase the exposure of saquinavir and requiring concomitant ritonavir-boosted Invirase where
no alternative therapy is available and the benefits outweigh the risks:
-
An ECG should be performed prior to initiation of the concomitant therapy: patients with
a QT interval > 450 msec should not initiate the concomitant therapy (see section 4.5).
-
For patients with a baseline QT interval < 450 msec, an on-treatment ECG should be
performed. For patients demonstrating a subsequent increase in QT-interval to > 480 msec
or increase by > 20 msec after commencing concomitant therapy, the physician should use
best clinical judgment to discontinue either ritonavir-boosted Invirase or the concomitant
therapy or both.
Essential Patient Information:
Prescribers must ensure that patients
are fully informed
regarding the following information on
cardiac conduction and repolarisation abnormalities:
-
Patients initiating therapy with ritonavir boosted Invirase should be warned of the
arrhythmogenic risk associated with QT and PR prolongation and told to report any sign
or symptom suspicious of cardiac arrhythmia (e.g., chest palpitations, syncope,
presyncope) to their physician.
-
Physicians should inquire about any known familial history of sudden death at a young
age as this may be suggestive of congenital QT prolongation.
-
Patients should be advised of the importance not to exceed the recommended dose.
-
Each patient (or patient’s caregiver) should be reminded to read the Package Leaflet
included in the Invirase Package.
Liver disease:
The safety and efficacy of saquinavir/ritonavir has not been established in patients with
significant underlying liver disorders, therefore saquinavir/ritonavir should be used cautiously in this
patient population. Invirase/ritonavir is contraindicated in patients with decompensated liver disease
(see section 4.3). 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.
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.
No dosage adjustment seems warranted for patients with moderate hepatic impairment based on
limited data. Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic
response is recommended due to increased variability of the exposure in this population (see sections
4.2 and 5.2). There have been reports of exacerbation of chronic liver dysfunction, including portal
4
hypertension, in patients with underlying hepatitis B or C, cirrhosis and other underlying liver
abnormalities.
Renal impairment:
Renal clearance is only a minor elimination pathway, the principal route of
metabolism and excretion for saquinavir being via the liver. Therefore, no initial dose adjustment is
necessary for patients with renal impairment. However, patients with severe renal impairment have not
been studied and caution should be exercised when prescribing saquinavir/ritonavir in this population.
Patients with chronic diarrhoea or malabsorption:
No information on boosted saquinavir and only
limited information on the safety and efficacy of unboosted saquinavir is available for patients
suffering from chronic diarrhoea or malabsorption. It is unknown whether patients with such
conditions could receive subtherapeutic saquinavir levels.
Children under the age of 16 and adults over 60 years:
The experience with Invirase in children
below the age of 16 and adults over 60 years is limited. In children, as in adults, Invirase should only
be given in combination with ritonavir.
Lactose intolerance:
Invirase 200 mg capsules contain lactose. Patients with rare hereditary problems
of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not
take this medicine.
Patients with haemophilia:
There have been reports of increased bleeding, including spontaneous skin
haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors.
In some patients additional
factor VIII was given. In more than half
of the reported cases, treatment
with protease inhibitors was continued
or reintroduced 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.
Diabetes mellitus and hyperglycaemia:
New onset diabetes mellitus, hyperglycaemia or exacerbation
of existing diabetes mellitus has been reported in patients receiving protease inhibitors. In some of
these patients, the hyperglycaemia was severe and in some cases was 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.
Lipodystrophy:
Combination antiretroviral therapy has been associated with the redistribution of body
fat (lipodystrophy) in HIV infected 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).
Osteonecrosis:
Although the aetiology 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.
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.
5
Interaction with ritonavir:
The recommended dose of Invirase and ritonavir is 1000 mg Invirase plus
100 mg ritonavir twice daily. Higher doses of ritonavir have been shown to be associated with an
increased incidence of adverse events. Co-administration of saquinavir and ritonavir has led to severe
adverse events, mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-
existing liver disease.
Interaction with tipranavir:
Concomitant use of boosted saquinavir and tipranavir, co-administered
with low dose ritonavir in a dual-boosted regimen, results in a significant decrease in saquinavir
plasma concentrations (see section 4.5). Therefore, the co-administration of boosted saquinavir and
tipranavir, co-administered with low dose ritonavir, is not recommended.
Interaction with HMG-CoA reductase inhibitors:
Caution must be exercised if Invirase/ritonavir is
used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A4. In this
situation a reduced dose of atorvastatin should be considered. If treatment with a HMG-CoA reductase
inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5).
Oral contraceptives:
Because concentration of ethinyl estradiol may be decreased when co-
administered with Invirase/ritonavir, alternative or additional contraceptive measures should be used
when oestrogen-based oral contraceptives are co-administered (see section 4.5).
Glucocorticoids:
Concomitant use of boosted saquinavir and fluticasone or other glucocorticoids that
are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs
the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (see
section 4.5).
Interaction with efavirenz:
The combination of saquinavir and ritonavir with efavirenz has been
shown to be associated with an increased risk of liver toxicity; liver function should be monitored
when saquinavir and ritonavir are co-administered with efavirenz. No clinically significant alterations
of either saquinavir or efavirenz concentration were noted in studies in healthy volunteers or in HIV-
infected patients (see section 4.5).
Most drug interaction studies with saquinavir have been completed with unboosted Invirase or
unboosted saquinavir soft capsules (Fortovase). A limited number of studies have been completed with
ritonavir boosted Invirase or ritonavir boosted saquinavir soft capsules.
Observations from drug interaction studies done with unboosted saquinavir might not be
representative of the effects seen with saquinavir/ritonavir therapy. Furthermore, results seen with
saquinavir soft capsules may not predict the magnitude of these interactions with Invirase/ritonavir.
The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4
responsible for 90 % of the hepatic metabolism. Additionally,
in vitro
studies have shown that
saquinavir is a substrate and an inhibitor for P-glycoprotein (P-gp). Therefore, medicinal products that
either share this metabolic pathway or modify CYP3A4 and/or P-gp activity (see
"Other potential
interactions"
) may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also
modify the pharmacokinetics of other medicinal products that are substrates for CYP3A4 or P-gp.
Ritonavir can affect the pharmacokinetics of other medicinal products because it is a potent inhibitor
of CYP3A4 and P-gp. Therefore, when saquinavir is co-administered with ritonavir, consideration
should be given to the potential effects of ritonavir on other medicinal products (see the Summary of
Product Characteristics for Norvir).
Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers
receiving Invirase/ritonavir (see sections 4.3, 4.4 and 5.1), additive effects on QT and PR interval
prolongation may occur. Therefore, concomitant use of ritonavir-boosted Invirase with other
6
medicinal products that prolong the QT and/or PR interval is contraindicated. The combination of
Invirase/ritonavir with drugs known to increase the exposure of saquinavir is not recommended and
should be avoided when alternative treatment options are available. If concomitant use is deemed
necessary because the potential benefit to the patient outweighs the risk, particular caution is
warranted (see section 4.4; for information on individual drugs, see Table 1).
7
Table 1: Interactions and dose recommendations with other medicinal products
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
Antiretroviral agents
Nucleoside reverse transcriptase inhibitors (NRTIs)
-
Zalcitabine and/or
Zidovudine
(saquinavir/ritonavir)
-
No pharmacokinetic interaction
studies have been completed.
Interaction with zalcitabine is
unlikely due to different routes of
metabolism and excretion.
For zidovudine (200 mg every 8
hours) a 25 % decrease in AUC
was reported when combined with
ritonavir (300 mg every 6 hours).
The pharmacokinetics of ritonavir
remained unchanged.
-
No dose adjustment required.
-
Zalcitabine and/or
Zidovudine
(unboosted saquinavir)
-
Saquinavir
Zalcitabine
Zidovudine
Didanosine
400 mg single dose
(saquinavir/ritonavir
1600/100 mg qd)
Saquinavir AUC 30%
Saquinavir C
max
25%
Saquinavir C
min
No dose adjustment required.
Tenofovir disoproxil
fumarate 300 mg qd
(saquinavir/ritonavir
1000/100 mg bid)
Saquinavir AUC 1%
Saquinavir C
max
7%
Saquinavir C
min
No dose adjustment required.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
-
Delavirdine
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Delavirdine
(unboosted saquinavir)
-
Saquinavir AUC ↑ 348%.
There are limited safety and no
efficacy data available from the use
of this combination. In a small,
preliminary study, hepatocellular
enzyme elevations occurred in 13 %
of subjects during the first several
weeks of the delavirdine and
saquinavir combination (6 % Grade
3 or 4).
-
Hepatocellular changes should be
monitored frequently if this
combination is prescribed.
Efavirenz 600 mg qd
(saquinavir/ritonavir
1600/200 mg qd,
or
saquinavir/ritonavir
1000/100 mg bid,
or
saquinavir/ritonavir
1200/100 mg qd)
Saquinavir
Efavirenz
No dose adjustment required.
-
Nevirapine
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Nevirapine
(unboosted saquinavir)
-
Saquinavir AUC 24%
Nevirapine AUC
-
No dose adjustment required.
Key:
reduced, ↑ increased, unchanged, ↑↑ markedly increased
8
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
HIV protease inhibitors (PIs)
Atazanavir 300 mg qd
(saquinavir/ritonavir
1600/100 mg qd)
Saquinavir AUC ↑ 60%
Saquinavir C
max
↑ 42%
Ritonavir AUC ↑ 41%
Ritonavir C
max
↑ 34%
Atazanavir
No clinical data available for the
combination of saquinavir/ritonavir
1000/100 mg bid and atazanavir.
Contraindicated in combination with
Invirase/ritonavir due to the potential
for life threatening cardiac
arrhythmia (see sections 4.3 and 4.4).
Fosamprenavir
700 mg bid
(saquinavir/ritonavir
1000/100 mg bid)
Saquinavir AUC 15%
Saquinavir C
max
9%
Saquinavir C
min
24% (remained
above the target threshold for
effective therapy.)
No dose adjustment required for
Invirase/ritonavir.
-
Indinavir
(saquinavir/ritonavir)
-
Low dose ritonavir increases the
concentration of indinavir.
Increased concentrations of indinavir
may result in nephrolithiasis.
-
Indinavir 800 mg tid
(saquinavir 600-1200 mg
single dose)
-
Saquinavir AUC ↑ 4.6-7.2 fold
Indinavir
No safety and efficacy data
available for this combination.
Appropriate doses of combination
not established.
Lopinavir/ritonavir
400/100 mg bid
(saquinavir 1000 mg bid in
combination with 2 or 3
NRTIs)
Saquinavir
Ritonavir (effectiveness as boosting
agent not modified).
Lopinavir (based on historical
comparison with unboosted lopinavir)
Contraindicated in combination with
Invirase/ritonavir due to the potential
for life threatening cardiac
arrhythmia (see sections 4.3 and 4.4).
-
Nelfinavir 1250 mg bid
(saquinavir/ritonavir
1000/100 mg bid)
- SaquinavirAUC↑ 13%
(90% CI: 27 - 74↑)
Saquinavir C
max
↑ 9%
(90% CI: 27 - 61↑ )
Nelfinavir AUC 6%
(90% CI: 28 - 22↑)
Nelfinavir C
max
5%
(90% CI: 23 - 16↑)
-
Combination not recommended.
-
Nelfinavir 750 mg tid
(unboosted saquinavir
1200 mg tid)
-
Saquinavir AUC ↑ 392%
Saquinavir C
max
↑ 179%
Nelfinavir AUC ↑ 18%
Nelfinavir C
max
-
Quadruple therapy, including
saquinavir soft capsules and
nelfinavir in addition to two
nucleoside reverse transcriptase
inhibitors gave a more durable
response (prolongation of time to
virological relapse) than triple
therapy with either single protease
inhibitor. Concomitant
administration of nelfinavir and
saquinavir soft capsules resulted
in a moderate increase in the
incidence of diarrhoea.
9
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
Ritonavir 100 mg bid
(saquinavir 1000 mg bid)
Saquinavir ↑
Ritonavir
In HIV-infected patients, Invirase or
saquinavir soft capsules in
combination with ritonavir at doses of
1000/100 mg twice daily provide a
systemic exposure of saquinavir over
a 24 hour period similar to or greater
than that achieved with saquinavir
soft capsules 1200 mg three times
daily (see section 5.2).
This is the approved combination
regimen. No dose adjustment is
recommended.
Tipranavir/ritonavir
(saquinavir/ritonavir)
Saquinavir C
min
78%
Dual-boosted protease inhibitor
combination therapy in multiple-
treatment experienced HIV-positive
adults.
Concomitant administration of
tipranavir, co-administered with low
dose ritonavir, with
saquinavir/ritonavir, is not
recommended. If the combination is
considered necessary, monitoring of
the saquinavir plasma levels is
strongly encouraged.
HIV fusion inhibitor
Enfuvirtide
(saquinavir/ritonavir
1000/100 mg bid)
Saquinavir
Enfuvirtide
No clinically significant interaction
was noted.
No dose adjustment required.
Other medicinal products
Antiarrhythmics
Bepridil
Lidocaine (systemic)
Quinidine
Hydroquinidine
(saquinavir/ritonavir)
Concentrations of bepridil, systemic
lidocaine, quinidine or
hydroquinidine may be increased
when co-administered with
Invirase/ritonavir.
Contraindicated in combination with
Invirase/ritonavir due to potentially
life threatening cardiac arrhythmia
(see sections 4.3 and 4.4).
Amiodarone
flecainide
propafenone
(saquinavir/ritonavir)
Concentrations of amiodarone,
flecainide or propafenone may be
increased when co-administered with
Invirase/ritonavir.
Contraindicated in combination with
saquinavir/ritonavir due to
potentially life threatening cardiac
arrhythmia (see section 4.3).
Dofetilide
(saquinavir/ritonavir)
Although specific studies have not
been performed, co-administration of
Invirase/ritonavir with medicinal
products that are mainly metabolised
by CYP3A4 pathway may result in
elevated plasma concentrations of
these medicinal products.
Contraindicated in combination with
Invirase/ritonavir due to potentially
life threatening cardiac arrhythmia
(see sections 4.3 and 4.4).
Ibutilide
Sotalol
(saquinavir/ritonavir)
Contraindicated in combination with
Invirase/ritonavir due to the potential
for life threatening cardiac
arrhythmia (see sections 4.3 and 4.4).
Anticoagulant
Warfarin
(saquinavir/ritonavir)
Concentrations of warfarin may be
affected.
INR (international normalised ratio)
monitoring recommended.
Anticonvulsants
-
Carbamazepine
Phenobarbital
Phenytoin
-
Interaction with Invirase/ritonavir
not studied.
10
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
(saquinavir/ritonavir)
-
Carbamazepine
Phenobarbital
Phenytoin
(unboosted saquinavir)
-
These medicinal products will
induce CYP3A4 and may therefore
decrease saquinavir concentrations.
Antidepressants
Tricyclic antidepressants
(e.g. amitriptyline,
imipramine)
(saquinavir/ritonavir)
Invirase/ritonavir may increase
concentrations of tricyclic
antidepressants.
Contraindicated in combination with
Invirase/ritonavir due to potentially
life threatening cardiac arrhythmia
(see sections 4.3 and 4.4).
-
Nefazodone
(saquinavir/ritonavir)
-
Interaction with
saquinavir/ritonavir not evaluated.
-
Nefazodone
(unboosted saquinavir)
-
Nefazodone inhibits CYP3A4.
Saquinavir concentrations may be
increased.
-
Combination not recommended.
Trazodone
(ritonavir)
Plasma concentrations of trazodone
may increase.
Adverse events of nausea, dizziness,
hypotension and syncope have been
observed following coadministration
of trazodone and ritonavir.
Contraindicated in combination with
Invirase/ritonavir due to potentially
life threatening cardiac arrhythmia
(see sections 4.3 and 4.4).
Antihistamines
Terfenadine
Astemizole
(saquinavir/ritonavir)
Terfenadine AUC ↑, associated with a
prolongation of QTc intervals.
A similar interaction with astemizole
is likely.
Terfenadine and astemizole are
contraindicated with boosted or
unboosted saquinavir (see section
4.3).
Mizolastine
(saquinavir/ritonavir)
Contraindicated in combination with
Invirase/ritonavir due to the potential
for life threatening cardiac
arrhythmia (see sections 4.3 and 4.4).
Anti-infectives
-
Clarithromycin
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Clarithromycin
500 mg bid
(unboosted saquinavir
1200 mg tid)
-
Saquinavir AUC ↑ 177 %
Saquinavir C
max
↑ 187 %
Clarithromycin AUC ↑ 40 %
Clarithromycin C
max
↑ 40 %
-
Contraindicated in combination
with Invirase/ritonavir due to the
potential for life threatening
cardiac arrhythmia (see sections
4.3 and 4.4).
-
Erythromycin
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Contraindicated in combination
with Invirase/ritonavir due to the
potential for life threatening
cardiac arrhythmia (see sections
4.3 and 4.4).
-
Erythromycin
250 mg qid
(unboosted saquinavir
1200 mg tid)
-
Saquinavir AUC ↑ 99 %
Saquinavir C
max
↑ 106 %
-
No dose adjustment required.
-
Streptogramin antibiotics
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Streptogramin antibiotics
(unboosted saquinavir)
-
Streptogramin antibiotics such as
quinupristin/dalfopristin inhibit
CYP3A4. Saquinavir
concentrations may be increased.
-
Monitoring for saquinavir toxicity
recommended.
11
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
-
Halofantrine
Pentamidine
Sparfloxacin
(saquinavir/ritonavir)
-
-
Contraindicated in combination
with Invirase/ritonavir due to the
potential for life threatening
cardiac arrhythmia (see sections
4.3 and 4.4).
Antifungals
Ketoconazole 200 mg qd
(saquinavir/ritonavir
1000/100 mg bid)
Saquinavir AUC
Saquinavir C
max
Ritonavir AUC
Ritonavir C
max
Ketoconazole AUC ↑ 168%
(90% CI 146%-193%)
Ketoconazole C
max
↑ 45%
(90% CI 32%-59%)
No dose adjustment required when
saquinavir/ritonavir combined with
200 mg/day ketoconazole. High
doses of ketoconazole
(> 200 mg/day) are not
recommended.
-
Itraconazole
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Itraconazole
(unboosted saquinavir)
-
Itraconazole is a moderately potent
inhibitor of CYP3A4. An
interaction is possible.
Monitoring for saquinavir toxicity
recommended.
Fluconazole/miconazole
(saquinavir/ritonavir)
Interaction with Invirase/ritonavir not
studied.
12
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
Antimycobacterials
Rifampicin 600 mg qd
(saquinavir/ritonavir
1000/100 mg bid)
In a clinical study 11 of 17 (65 %)
healthy volunteers developed severe
hepatocellular toxicity with
transaminase elevations up to > 20-
fold the upper limit of normal after 1
to 5 days of co-administration.
Rifampicin is contraindicated in
combination with Invirase/ritonavir
(see section 4.3).
Rifabutin 150 mg q3d
(saquinavir/ritonavir
1000/100 mg bid)
Saquinavir AUC
0-12
13%
(90% CI: 31 - 9↑)
Saquinavir C
max
15%
(90% CI: 32 - 7↑)
Ritonavir AUC
0-12
(90% CI: 10 - 9↑)
Ritonavir C
max
(90% CI: 8 - 7↑)
No dose adjustment of
saquinavir/ritonavir 1000/100 mg bid
is required if ritonavir-boosted
Invirase is administered in
combination with rifabutin.
Rifabutin active moiety*
AUC
0-72
↑ 134%
(90% CI 109%-162%)
Rifabutin active moiety*
C
max
↑ 130%
(90% CI 98%-167%)
Rifabutin AUC
0-72
↑ 53%
(90% CI 36%-73%)
Rifabutin C
max
↑ 86%
(90% CI 57%-119%)
* Sum of rifabutin + 25-O-desacetyl
rifabutin metabolite
Rifabutin 150 mg q4d
(saquinavir/ritonavir
1000/100 mg bid)
Rifabutin active moiety*
AUC
0-96
↑ 60%
(90% CI 43%-79%)
Rifabutin active moiety*
C
max
↑ 111%
(90% CI 75%-153%)
Rifabutin AUC
0-96
(90% CI 10 - 13↑)
Rifabutin C
max
↑ 68%
(90% CI 38%-105%)
The recommended dose of rifabutin
is 150 mg twice weekly on set days
(for example Mondays and
Thursdays), with the dose of
Invirase/ritonavir unchanged
(1000/100 mg bid).
Monitoring of neutropenia and the
liver enzyme levels is recommended.
Tapering the rifabutin dose to
150 mg every four days could be
justified in cases of marked
neutropenia.
* Sum of rifabutin + 25-O-desacetyl
rifabutin metabolite
Benzodiazepines
Midazolam 7.5 mg
single dose (oral)
(saquinavir/ritonavir
1000/100 mg bid)
Midazolam AUC ↑ 12.4 fold
Midazolam C
max
↑ 4.3 fold
Midazolam t
1/2
↑ from 4.7 h to 14.9 h
No data are available on concomitant
use of ritonavir boosted saquinavir
with intravenous midazolam. Studies
of other CYP3A modulators and i.v.
midazolam suggest a possible 3-4 fold
increase in midazolam plasma levels.
Co-administration of
Invirase/ritonavir with orally
administered
midazolam is
contraindicated (see section 4.3).
Caution should be used with co-
administration of Invirase and
parenteral midazolam.
If Invirase is co-administered with
parenteral midazolam it should be
done in an intensive care unit (ICU)
13
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
or similar setting which ensures close
clinical monitoring and appropriate
medical management in case of
respiratory depression and/or
prolonged sedation. Dosage
adjustment should be considered,
especially if more than a single dose
of midazolam is administered.
Alprazolam
Clorazepate
Diazepam
Flurazepam
(saquinavir/ritonavir)
Concentrations of these medicinal
products may be increased when co-
administered with Invirase/ritonavir.
Careful monitoring of patients with
regard to sedative effects is
warranted. A decrease in the dose of
the benzodiazepine may be required.
Triazolam
(saquinavir/ritonavir)
Concentrations of triazolam may be
increased when co-administered with
Invirase/ritonavir.
Contraindicated in combination with
saquinavir/ritonavir, due to the risk
of potentially prolonged or increased
sedation and respiratory depression
(see section 4.3).
Calcium channel blockers
Felodipine, nifedipine,
nicardipine, diltiazem,
nimodipine, verapamil,
amlodipine, nisoldipine,
isradipine
(saquinavir/ritonavir)
Concentrations of these medicinal
products may be increased when co-
administered with Invirase/ritonavir.
Caution is warranted and clinical
monitoring of patients is
recommended.
Corticosteroids
-
Dexamethasone
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Dexamethasone
(unboosted saquinavir)
-
Dexamethasone induces CYP3A4
and may decrease saquinavir
concentrations.
-
Use with caution. Saquinavir may
be less effective in patients taking
dexamethasone.
Fluticasone propionate
50 mcg qid, intranasal
(ritonavir 100 mg bid)
Fluticasone propionate ↑
Intrinsic cortisol 86%
(90% CI 82%-89%)
Greater effects may be expected when
fluticasone propionate is inhaled.
Systemic corticosteroid effects
including Cushing’s syndrome and
adrenal suppression have been
reported in patients receiving
ritonavir and inhaled or intranasally
administered fluticasone propionate;
this could also occur with other
corticosteroids metabolised via the
P450 3A pathway e.g. budesonide.
Concomitant administration of
boosted saquinavir and fluticasone
propionate and other corticosteroids
metabolised via the P450 3A
pathway (e.g. budesonide) is not
recommended unless the potential
benefit of treatment outweighs the
risk of systemic corticosteroid effects
(see section 4.4).
Dose reduction of the glucocorticoid
should be considered with close
monitoring of local and systemic
effects or a switch to a
glucocorticoid, which is not a
substrate for CYP3A4 (e.g.
beclomethasone).
In case of withdrawal of
glucocorticoids progressive dose
reduction may have to be performed
over a longer period.
Effects of high fluticasone systemic
exposure on ritonavir plasma levels
yet unknown.
14
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
Medicinal products that are substrates of P-glycoprotein
Digitalis glycosides
Digoxin 0.5 mg
single dose
(saquinavir/ritonavir
1000/100 mg bid)
Digoxin AUC
0-72
↑ 49%
Digoxin C
max
↑ 27%
Digoxin levels may differ over time.
Large increments of digoxin may be
expected when saquinavir/ritonavir is
introduced in patients already treated
with digoxin.
Caution should be exercised when
Invirase/ritonavir and digoxin are co-
administered. The serum
concentration of digoxin should be
monitored and a dose reduction of
digoxin should be considered if
necessary.
Histamine H
2
-receptor antagonist
-
Ranitidine
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Ranitidine
(unboosted saquinavir)
-
Saquinavir AUC ↑ 67 %
-
Increase not thought to be
clinically relevant. No dose
adjustment of saquinavir
recommended.
HMG-CoA reductase inhibitors
Pravastatin
Fluvastatin
(saquinavir/ritonavir)
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.
Simvastatin
Lovastatin
(saquinavir/ritonavir)
Simvastatin ↑↑
Lovastatin ↑↑
Plasma concentrations highly
dependent on CYP3A4 metabolism.
Increased concentrations of
simvastatin and lovastatin have been
associated with rhabdomyolysis.
These medicinal products are
contraindicated for use with
Invirase/ritonavir (see section 4.3).
Atorvastatin
(saquinavir/ritonavir)
Atorvastatin is less dependent on
CYP3A4 for metabolism.
When used with Invirase/ritonavir,
the lowest possible dose of
atorvastatin should be administered
and the patient should be carefully
monitored for signs/symptoms of
myopathy (muscle weakness, muscle
pain, rising plasma creatinine
kinase).
Immunosuppressants
Ciclosporin
Tacrolimus
Rapamycin
(saquinavir/ritonavir)
Concentrations of these medicinal
products increase several fold when
co-administered with
Invirase/ritonavir.
Careful therapeutic drug monitoring
is necessary for immunosuppressants
when co-administered with
Invirase/ritonavir.
Narcotic analgesics
Methadone 60-120 mg qd
(saquinavir/ritonavir
1000/100 mg bid)
Methadone AUC 19 %
(90 % CI 9 % to 29 %)
None of the 12 patients experienced
withdrawal symptoms.
Contraindicated in combination with
Invirase/ritonavir due to the potential
for life threatening cardiac
arrhythmia (see sections 4.3 and 4.4).
Neuroleptics
Pimozide
(saquinavir/ritonavir)
Concentrations of pimozide may be
increased when co-administered with
Invirase/ritonavir.
Due to a potential for life threatening
cardiac arrhythmias,
Invirase/ritonavir is contra-indicated
in combination with pimozide (see
section 4.3).
15
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
Clozapine
Haloperidol
Mesoridazine
Phenothiazines
Sertindole
Sultopride
Thioridazine
Ziprasidone
(saquinavir/ritonavir)
Contraindicated in combination with
Invirase/ritonavir due to the potential
for life threatening cardiac
arrhythmia (see sections 4.3 and 4.4).
Oral contraceptives
Ethinyl estradiol
(saquinavir/ritonavir)
Concentration of ethinyl estradiol
may be decreased when co-
administered with Invirase/ritonavir.
Alternative or additional
contraceptive measures should be
used when oestrogen-based oral
contraceptives are co-administered.
Phosphodiesterase type 5 (PDE5) inhibitors
-
Sildenafil
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Sildenafil 100 mg
(single dose)
(unboosted saquinavir
1200 mg tid)
-
Saquinavir
Sildenafil C
max
↑ 140 %
Sildenafil AUC ↑ 210 %
-
Sildenafil is a substrate of
CYP3A4.
-
Contraindicated in combination
with Invirase/ritonavir due to the
potential for life threatening
cardiac arrhythmia (see sections
4.3 and 4.4).
Vardenafil
(saquinavir/ritonavir)
Concentrations of vardenafil may be
increased when co-administered with
Invirase/ritonavir.
Contraindicated in combination with
Invirase/ritonavir due to the potential
for life threatening cardiac
arrhythmia (see sections 4.3 and 4.4).
Tadalafil
(saquinavir/ritonavir)
Concentrations of tadalafil may be
increased when co-administered with
Invirase/ritonavir.
Contraindicated in combination with
Invirase/ritonavir due to the potential
for life threatening cardiac
arrhythmia (see sections 4.3 and 4.4).
Proton pump inhibitors
Omeprazole 40 mg qd
(saquinavir/ritonavir
1000/100 mg bid)
Saquinavir AUC ↑ 82%
(90 % CI 44-131 %)
Saquinavir C
max
↑ 75%
(90 % CI 38-123 %)
Ritonavir
Combination not recommended.
Other proton pump
inhibitors
(saquinavir/ritonavir
1000/100 mg bid)
No data are available on the
concomitant administration of
Invirase/ritonavir and other proton
pump inhibitors.
Combination not recommended.
Others
Ergot alkaloids (e.g.
ergotamine,
dihydroergotamine,
ergonovine, and
methylergonovine)
(saquinavir/ritonavir)
Invirase/ritonavir may increase ergot
alkaloids exposure, and consequently,
increase the potential for acute ergot
toxicity.
The concomitant use of
Invirase/ritonavir and ergot alkaloids
is contra-indicated (see section 4.3).
-
Grapefruit juice
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Grapefruit juice
(single dose)
(unboosted saquinavir)
-
Saquinavir ↑ 50% (normal strength
grapefruit juice)
-
Saquinavir ↑ 100% (double
strength grapefruit juice)
-
Increase not thought to be
clinically relevant. No dose
adjustment required.
16
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
-
Garlic capsules
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
Garlic capsules
(dose approx. equivalent
to two 4 g cloves of
garlic daily)
(unboosted saquinavir
1200 mg tid)
-
Saquinavir AUC 51 %
Saquinavir C
trough
49 % (8 hours
post dose)
Saquinavir C
max
54 %.
-
Patients on saquinavir treatment
must not take garlic capsules due
to the risk of decreased plasma
concentrations and loss of
virological response and possible
resistance to one or more
components of the antiretroviral
regimen.
-
St. John’s wort
(saquinavir/ritonavir)
-
Interaction with Invirase/ritonavir
not studied.
-
St. John’s wort
(unboosted saquinavir)
-
Plasma levels of saquinavir can be
reduced by concomitant use of the
herbal preparation St. John’s wort
(Hypericum perforatum)
. This is
due to induction of drug
metabolising enzymes and/or
transport proteins by St. John’s
wort.
-
Herbal preparations containing St.
John’s wort must not be used
concomitantly with Invirase. If a
patient is already taking St. John’s
wort, stop St. John’s wort, check
viral levels and if possible
saquinavir levels. Saquinavir
levels may increase on stopping
St. John’s wort, and the dose of
saquinavir may need adjusting.
The inducing effect of St. John’s
wort may persist for at least 2
weeks after cessation of treatment.
Other potential interactions
Medicinal products that are substrates of CYP3A4
e.g. dapsone,
disopyramide, quinine,
fentanyl, and alfentanyl
(unboosted saquinavir)
Although specific studies have not
been performed, co-administration of
Invirase/ritonavir with medicinal
products that are mainly metabolised
by CYP3A4 pathway may result in
elevated plasma concentrations of
these medicinal products.
Contraindicated in combination with
Invirase/ritonavir due to potentially
life threatening cardiac arrhythmia
(see sections 4.3 and 4.4).
Gastroenterological medicinal products
Metoclopramide
It is unknown whether medicinal
products which reduce the
gastrointestinal transit time could lead
to lower saquinavir plasma
concentrations.
Cisapride
(saquinavir/ritonavir)
Although specific studies have not
been performed, co-administration of
Invirase/ritonavir with medicinal
products that are mainly metabolised
by CYP3A4 pathway may result in
elevated plasma concentrations of
these medicinal products.
Contraindicated in combination with
Invirase/ritonavir due to potentially
life threatening cardiac arrhythmia
(see sections 4.3 and 4.4).
Diphemanil
(saquinavir/ritonavir)
Contraindicated in combination with
Invirase/ritonavir due to potentially
life threatening cardiac arrhythmia
(see sections 4.3 and 4.4).
Vasodilators (peripheral)
Vincamine i.v.
Contraindicated in combination with
Invirase/ritonavir due to the potential
17
Medicinal product by
therapeutic area (dose of
Invirase used in study)
Interaction
Recommendations concerning co-
administration
for life threatening cardiac
arrhythmia (see sections 4.3 and 4.4).
Pregnancy
:
Evaluation of experimental animal studies does not indicate direct or indirect harmful
effects with respect to the development of the embryo or foetus, the course of gestation and peri- and
post-natal development. Clinical experience in pregnant women is limited: Congenital malformations,
birth defects and other disorders (without a congenital malformation) have been reported rarely in
pregnant women who had received saquinavir in combination with other antiretroviral agents.
However, so far the available data are insufficient and do not identify specific risks for the unborn
child. Saquinavir should be used during pregnancy only if the potential benefit justifies the potential
risk to the foetus (see section 5.3).
Lactation
:
There are no laboratory animal or human data available on secretion of saquinavir in breast
milk. The potential for adverse reactions to saquinavir in nursing infants cannot be assessed, and
therefore, breast-feeding should be discontinued prior to receiving saquinavir. It is recommended that
HIV-infected women do not breast feed their infants under any circumstances in order to avoid
transmission of HIV.
Invirase may have a minor influence on the ability to drive and use machines. Dizziness and fatigue
have been reported during treatment with Invirase. No studies on the effects on the ability to drive and
use machines have been performed.
The following adverse events with an at least possible relationship to ritonavir boosted saquinavir (i.e.
adverse reactions) were reported most frequently: nausea, diarrhoea, fatigue, vomiting, flatulence, and
abdominal pain.
For comprehensive dose adjustment recommendations and drug-associated adverse reactions for
ritonavir and other medicinal products used in combination with saquinavir, physicians should refer to
the Summary of Product Characteristics for each of these medicinal products.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse reactions from clinical trials where saquinavir was boosted with ritonavir
Limited data is available from two studies where the safety of saquinavir soft capsule (1000 mg twice
daily) used in combination with low dose ritonavir (100 mg twice daily) for at least 48 weeks was
studied in 311 patients. Adverse reactions in these two pivotal studies are summarised in Table 2. The
list also includes marked laboratory abnormalities that have been observed with the saquinavir soft
capsule in combination with ritonavir (at 48 weeks).
18
Table 2: Incidences of Adverse Reactions and marked laboratory abnormalities from the MaxCmin1
and MaxCmin2 study. (Very common ( 10 %); common ( 1 % and < 10 %))
Body System
Frequency of Reaction
Adverse Reactions
Grades 3&4
All Grades
Blood and the lymphatic system disorders
Common
Anaemia
Anaemia
Immune system disorders
Common
Hypersensitivity
Metabolism and nutrition disorders
Common
Diabetes mellitus
Diabetes mellitus, anorexia, increased
appetite
Psychiatric disorders
Common
Decreased libido, sleep disorder
Nervous System Disorders
Common
Paraesthesia, peripheral neuropathy,
dizziness, dysgeusia, headache
Respiratory, thoracic and mediastinal disorders
Common
Dyspnoea
Gastrointestinal disorders
Very common
Diarrhoea, nausea
Common
Diarrhoea, nausea,
vomiting
Vomiting, abdominal distension,
abdominal pain, upper abdominal pain,
constipation, dry mouth, dyspepsia,
eructation, flatulence, lip dry, loose
stools
Skin and subcutaneous tissue disorders
Common
Acquired lipodystrophy Acquired lipodystrophy, alopecia, dry
skin, eczema, lipoatrophy, pruritus,
rash
Musculoskeletal and connective tissue disorders
Common
Muscle spasms
General disorders and administration site conditions
Common
Fatigue
Asthenia, fatigue, increased fat tissue,
malaise
Investigations
Very common
Increased alanine aminotransferase,
increased aspartate aminotransferase,
increased blood cholesterol, increased
blood triglycerides, increased low
density lipoprotein, decreased platelet
count
Common
Increased blood amylase, increased
blood bilirubin, increased blood
creatinine, decreased haemoglobin,
decreased lymphocyte count, decreased
white blood cell count
Post-marketing experience with saquinavir
Serious and non-serious adverse reactions from post-marketing spontaneous reports (where saquinavir
was taken as the sole protease inhibitor or in combination with ritonavir), not mentioned previously in
section 4.8, for which a causal relationship to saquinavir cannot be excluded, are summarised below.
As these data come from the spontaneous reporting system, the frequency of the adverse reactions is
unknown.
19
Immune system disorders: Hypersensitivity.
Metabolism and nutrition disorders:
-
Diabetes mellitus or hyperglycaemia sometimes associated with ketoacidosis (see section 4.4).
-
Lipodystrophy: Combination antiretroviral therapy has been associated with redistribution of
body fat (lipodystrophy) in HIV infected patients including the loss of peripheral and facial
subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and
dorsicervical fat accumulation (buffalo hump).
-
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
Nervous system disorders: Somnolence, convulsions.
Vascular disorders: There have been reports of increased bleeding, including spontaneous skin
haematomas and haemarthroses, in haemophilic patients type A and B treated with protease
inhibitors (see section 4.4).
Hepato-biliary disorders: Hepatitis.
Musculoskeletal, connective tissue and bone disorders: Increased CPK, myalgia, myositis and
rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination
with nucleoside analogues. Cases of osteonecrosis have been reported, particularly in patients
with generally acknowledged risk factors, advanced HIV disease or long-term exposure to
combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).
Renal and urinary disorders: Renal impairment.
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).
There is limited experience of overdose with saquinavir. Whereas acute or chronic overdose of
saquinavir alone did not result in major complications, in combination with other protease inhibitors,
overdose symptoms and signs such as general weakness, fatigue, diarrhoea, nausea, vomiting, hair loss,
dry mouth, hyponatraemia, weight loss and orthostatic hypotension have been observed. There is no
specific antidote for overdose with saquinavir. Treatment of overdose with saquinavir should consist
of general supportive measures, including monitoring of vital signs and ECG, and observations of the
patient’s clinical status. If indicated, prevention of further absorption can be considered. Since
saquinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the
active substance.
5.
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: Antiviral agent, ATC code J05A E01
Mechanism of action:
The HIV protease is an essential viral enzyme required for the specific
cleavage of viral gag and gag-pol polyproteins. Saquinavir selectively inhibits the HIV protease,
thereby preventing the creation of mature infectious virus particles.
20
QT and PR prolongation on electrocardiogram:
The effects of therapeutic (1000/100 mg twice daily)
and supra-therapeutic (1500/100 mg twice daily) doses of Invirase/ritonavir on the QT interval were
evaluated in a 4-way crossover, double-blind, placebo- and active-controlled (moxifloxacin 400 mg)
study in healthy male and female volunteers aged 18 to 55 years old (N=59). On Day 3 of dosing,
ECG measurements were done over a period of 20 hours. The Day 3 timepoint was chosen since the
pharmacokinetic exposure was maximum on that day in a previous 14-day multiple dose
pharmacokinetic study. On Day 3, mean C
max
values were approximately 3-fold and 4-fold higher with
the therapeutic and supra-therapeutic doses, respectively, relative to the mean C
max
observed at steady
state with the therapeutic dose administered to HIV patients. On Day 3, the upper 1-sided 95%
confidence interval of the maximum mean difference in pre-dose baseline-corrected QTcS (study
specific heart rate corrected QT) between the active drug and placebo arms was > 10 msec for the two
ritonavir-boosted Invirase treatment groups (see results in Table 3). While the supra-therapeutic dose
of Invirase/ritonavir appeared to have a greater effect on the QT interval than the therapeutic dose of
Invirase/ritonavir, it is not sure if maximum effect for both doses has been observed. In the therapeutic
and the supra-therapeutic arm 11% and 18% of subjects, respectively, had a QTcS between 450 and
480 msec. There was no QT prolongation > 500 msec and no torsade de pointes in the study (see also
section 4.4).
Table 3: Maximum mean of ddQTcS
†
(msec) on day 3 for therapeutic dose of Invirase/ritonavir,
supra-therapeutic dose of Invirase/ritonavir and active control moxifloxacin in healthy volunteers
Treatment
Post-Dose
Time Point
Mean
ddQTcS
Standard
Error
Upper 95%-CI of
ddQTcS
Invirase/ritonavir
1000/100 mg BID
12 hours
18.86
1.91
22.01
Invirase/ritonavir
1500/100 mg BID
20 hours
30.22
1.91
33.36
Moxifloxacin^ 4 hours 12.18 1.93 15.36
†
Derived difference of pre-dose baseline corrected QTcS between active treatment and placebo arms
^ 400 mg was administered only on Day 3
Note: QTcS in this study was QT/RR
0.319
for males and QT/RR
0.337
for females, which are similar to
Fridericia’s correction (QTcF=QT/RR
0.333
).
In this study, PR interval of > 200 msec was also observed in 40% and 47% of subjects receiving
Invirase/ritonavir 1000/100 mg twice daily and 1500/100 mg twice daily, respectively, on Day 3. PR
intervals of > 200 msec were seen in 3% of subjects in the active control group (moxifloxacin) and 5%
in the placebo arm. The maximum mean PR interval changes relative to the pre-dose baseline value
were 25 msec and 34 msec in the two ritonavir-boosted Invirase treatment groups, 1000/100 mg twice
daily and 1500/100 mg twice daily, respectively (also see section 4.4).
Events of syncope/presyncope occurred at a higher than expected rate and were seen more frequently
under treatment with saquinavir (11 of 13). The clinical relevance of these findings from this study in
healthy volunteers to the use of Invirase/ritonavir in HIV-infected patients is unclear, but doses
exceeding Invirase/ritonavir 1000/100 mg twice daily should be avoided.
Antiviral activity in vitro:
Saquinavir demonstrates antiviral activity against a panel of laboratory
strains and clinical isolates of HIV-1 with typical EC
50
and EC
90
values in the range 1-10 nM and 5-50
nM, respectively, with no apparent difference between subtype B and non-B clades. The
corresponding serum (50% human serum) adjusted EC
50
ranged from 25-250 nM. Clinical isolates of
HIV-2 demonstrated EC
50
values in the range of 0.3-2.4 nM.
Resistance
Antiviral activity according to baseline genotype and phenotype:
21
Genotypic and phenotypic clinical cut-offs predicting the clinical efficacy of ritonavir boosted
saquinavir have been derived from retrospective analyses of the RESIST 1 and 2 clinical studies and
analysis of a large hospital cohort (Marcelin et al 2007).
Baseline saquinavir phenotype (shift in susceptibility relative to reference, PhenoSense Assay) was
shown to be a predictive factor of virological outcome. Virological response was first observed to
decrease when the fold shift exceeded 2.3-fold; whereas virological benefit was not observed when the
fold shift exceeded 12-fold.
Marcelin et al (2007) identified nine protease codons (L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I,
I62V, G73S/T, V82A/F/S/T, I84V, L90M) that were associated with decreased virological response to
saquinavir/ritonavir (1000/100 mg twice daily) in 138 saquinavir naive patients. The presence of 3 or
more mutations was associated with reduced response to saquinavir/ritonavir.
The association between
the number of these saquinavir-associated resistance mutations and virological response was
confirmed in an independent clinical study (RESIST 1 and 2) involving a more heavily treatment
experienced patient population, including 54% who had received prior saquinavir (p=0.0133, see
Table 4). The G48V mutation, previously identified in vitro as a saquinavir signature mutation, was
present at baseline in virus from three patients, none of whom responded to therapy.
Table 4: Virological response to saquinavir/ritonavir stratified by the number of baseline saquinavir-
associated resistance mutations
Number of
Saquinavir
Associated
Resistance
Mutations
at Baseline*
Marcelin et al (2007)
RESIST 1 & 2
SQV Naive Population
SQV Naive/Experienced Population
N=138
Change in Baseline
Plasma HIV-1 RNA at
Weeks 12-20
N=114
Change in Baseline
Plasma HIV-1 RNA at
Week 4
0
35
-2.24
2
-2.04
1
29
-1.88
3
-1.69
2
24
-1.43
14
-1.57
3
30
-0.52
28
-1.41
4
9
-0.18
40
-0.75
5
6
-0.11
17
-0.44
6
5
-0.30
9
0.08
7
0
-
1
0.24
*
Saquinavir Mutation Score Mutations: L10F/I/M/R/V, I15A/V, K20I/M/R/T, L24I, I62V, G73S/T,
V82A/F/S/T, I84V, L90M
Clinical results from studies with treatment naïve and experienced patients
In the MaxCmin1 study, the safety and efficacy of saquinavir soft capsules/ritonavir 1000/100 mg
twice daily plus 2 NRTIs/Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) was compared
to indinavir/ritonavir 800/100 mg twice daily plus 2 NRTIs/NNRTIs in over 300 (both protease
inhibitor treatment naïve and experienced) subjects. The combination of saquinavir and ritonavir
exhibited a superior virological activity compared with the indinavir and ritonavir arm when switch
from the assigned treatment was counted as virological failure.
In the MaxCmin2 study, the safety and efficacy of saquinavir soft capsules/ritonavir 1000/100 mg
twice daily plus 2 NRTIs/NNRTIs was compared with lopinavir/ritonavir 400/100 mg twice daily plus
2 NRTIs/NNRTIs in 324 (both protease inhibitor treatment naïve and experienced) subjects. None of
the subjects in the lopinavir/ritonavir arm had been exposed to lopinavir prior to randomisation
whereas 16 of the subjects in the saquinavir/ritonavir arm had previously been exposed to saquinavir.
22
Table 5: Subject Demographics MaxCmin1 and MaxCmin2
†
MaxCmin1
MaxCmin2
SQV/r
IDV/r
SQV/r
LPV/r
N=148
N=158
N=161
N=163
Sex
Male
82%
74%
81%
76%
Race (White/Black/Asian) %
86/9/1
82/12/4
75/19/1
74/19/2
Age, median, yrs
39
40
40
40
CDC Category C (%)
32%
28%
32%
31%
Antiretroviral naïve (%)
28%
22%
31%
34%
PI naïve (%)
41%
38%
48%
48%
Median Baseline HIV-1 RNA,
log
10
copies/ml (IQR)
4.0
(1.7-5.1)
3.9
(1.7-5.2)
4.4
(3.1-5.1)
4.6
(3.5-5.3)
Median Baseline CD4
+
Cell
Count, cells/mm
3
(IQR)
272
(135-420)
280
(139-453)
241
(86-400)
239
(95-420)
†
data from clinical study report
23
Table 6: Outcomes at Week 48 MaxCmin1 and MaxCmin2
†
Outcomes
MaxCmin1
MaxCmin2
SQV/r
IDV/r
SQV/r
LPV/r
Initiated assigned treatment,
n (%)
148
(94%)
158
(99%)
161
(94%)
163
(98%)
Discontinued assigned
treatment, n (%)
40
(27%)
64
(41%)
48
(30%)
23
(14%)
P=0.01
P=0.001
Virological failure ITT/e*
#
36/148 (24%) 41/158 (26%)
53/161 (33%)
29/163 (18%)
P=0.76
P=0.002
Proportion with VL < 50
copies/ml at week 48, ITT/e
#
97/144
(67%)
106/154
(69%)
90/158
(57%)
106/162
(65%)
P >0.05
‡
P=0.12
Proportion with VL < 50
copies/ml at week 48,
On Treatment
82/104
(79%)
73/93
(78%)
84/113
(74%)
97/138
(70%)
P>0.05
‡
P=0.48
Median increase in CD4 cell
count at week 48 (cells/mm
3
)
85
73
110
106
*
For both studies: For patients entering study with VL < 200 copies/ml, VF defined as
>
200 copies/ml. MaxCmin1: For those entering with VL
>
200 copies/ml, VF defined as any
increase
>
0.5 logs and/or VL
>
50,000 copies/ml at week 4,
>
5,000 copies/ml at week 12, or
>
200 copies/ml at week 24 or thereafter. MaxCmin2: any rise
>
0.5 log at a specific visit;
<
0.5 log reduction if VL
>
200 copies/ml at week 4;
<
1.0 log reduction from base line if
VL
>
200 copies/ml at week 12; and a VL
>
200 copies/ml at week 24.
#
ITT/e = Intent-to-treat/exposed
†
Data from clinical study report
‡
Data from
MaxCmin1 publication
5.2
Pharmacokinetic properties
Saquinavir is essentially completely metabolised by CYP3A4. Ritonavir inhibits the metabolism of
saquinavir, thereby increasing ("boosting") the plasma levels of saquinavir.
Absorption and bioavailability in adults:
In HIV-infected patients, Invirase in combination with
ritonavir at doses of 1000/100 mg twice daily provides saquinavir systemic exposures over a 24-hour
period similar to or greater than those achieved with saquinavir soft capsules 1200 mg tid (see Table
7). The pharmacokinetics of saquinavir is stable during long-term treatment.
24
Table 7: Mean (% CV) AUC, C
max
and C
min
of saquinavir in patients following multiple dosing of
Invirase, saquinavir soft capsules, Invirase/ritonavir, and saquinavir soft capsules/ritonavir
Treatment
N
AUCτ
(ng·h/ml)
AUC
0-24
(ng·h/ml)
†
C
max
(ng/ml)
C
min
(ng/ml)
Invirase (hard capsule)
600 mg tid
10
866 (62)
2,598
197 (75)
75 (82)
saquinavir soft capsule
1200 mg tid
31
7,249 (85)
21,747
2,181 (74)
216 (84)
Invirase (tablet)
1000 mg bid plus
ritonavir 100 mg bid*
(fasting condition)
22
10,320
(2,530-30,327)
20,640
1509
(355-4,101)
313
(70-1,725)
††
Invirase (tablet)
1000 mg bid plus
ritonavir 100 mg bid*
(high fat meal)
22
34,926
(11,826-
105,992)
69,852
5208
(1,536-14,369)
1,179
(334-5,176)
††
τ = dosing interval, i.e. 8 hour for tid and 12 h for bid dosing
C
min
= the observed plasma concentration at the end of the dose interval
bid = twice daily
tid = three times daily
* results are geometric mean (min - max)
†
derived from tid or bid dosing schedule
††
C
trough
values
Absolute bioavailability averaged 4 % (CV 73 %, range: 1 % to 9 %) in 8 healthy volunteers who
received a single 600 mg dose (3 x 200 mg hard capsule) of Invirase following a heavy breakfast. The
low bioavailability is thought to be due to a combination of incomplete absorption and extensive first-
pass metabolism. Gastric pH has been shown to be only a minor component in the large increase in
bioavailability seen when given with food. The absolute bioavailability of saquinavir co-administered
with ritonavir has not been established in humans.
In combination with ritonavir, bioequivalence of Invirase hard capsules and film-coated tablets was
demonstrated under fed conditions.
Effective therapy in treatment naïve patients is associated with a C
min
of approximately 50 ng/ml and
an AUC
0-24
of about 20,000 ng·h/ml. Effective therapy in treatment experienced patients is associated
with a C
min
of approximately 100 ng/ml and an AUC
0-24
of about 20,000 ng·h/ml.
In vitro studies have shown that saquinavir is a substrate for P-glycoprotein (P-gp).
Effect of food:
In a cross-over study in 22 HIV-infected patients treated with Invirase/ritonavir
1000 mg/100 mg twice daily and receiving three consecutive doses under fasting conditions or after a
high-fat, high-calorie meal (46 g fat, 1,091 Kcal), the AUC
0-12
, C
max
and C
trough
values of saquinavir
under fasting conditions were about 70 per cent lower than with a high-fat meal. All but one of the
patients achieved C
trough
values of saquinavir above the therapeutic threshold (100 ng/ml) in the fasted
state. There were no clinically significant differences in the pharmacokinetic profile of ritonavir in
fasting and fed conditions but the ritonavir C
trough
(geometric mean 245 vs. 348 ng/ml) was lower in
the fasting state compared to the administration with a meal. Invirase/ritonavir should be administered
with or after food.
Distribution in adults:
Saquinavir partitions extensively into the tissues. The mean steady-state
volume of distribution following intravenous administration of a 12 mg dose of saquinavir was 700 l
(CV 39 %). It has been shown that saquinavir is approximately 97 % bound to plasma proteins up to
30 g/ml. In two patients receiving Invirase 600 mg three times daily, cerebrospinal fluid
concentrations of saquinavir were negligible when compared to concentrations from matching plasma
samples.
25
Metabolism and elimination in adults:
In vitro
studies using human liver microsomes have shown
that the metabolism of saquinavir is cytochrome P450 mediated with the specific isoenzyme, CYP3A4,
responsible for more than 90 % of the hepatic metabolism. Based on
in vitro
studies, saquinavir is
rapidly metabolised to a range of mono- and di-hydroxylated inactive compounds. In a mass balance
study using 600 mg
14
C-saquinavir (n = 8), 88 % and 1 % of the orally administered radioactivity, was
recovered in faeces and urine, respectively, within 4 days of dosing. In an additional four subjects
administered 10.5 mg
14
C-saquinavir intravenously, 81 % and 3 % of the intravenously administered
radioactivity was recovered in faeces and urine, respectively, within 4 days of dosing. 13 % of
circulating saquinavir in plasma was present as unchanged compound after oral administration and the
remainder as metabolites. Following intravenous administration 66 % of circulating saquinavir was
present as unchanged compound and the remainder as metabolites, suggesting that saquinavir
undergoes extensive first pass metabolism.
In vitro
experiments have shown that the hepatic
metabolism of saquinavir becomes saturable at concentrations above 2 g/ml.
Systemic clearance of saquinavir was high, 1.14 l/h/kg (CV 12 %), slightly above the hepatic plasma
flow, and constant after intravenous doses of 6, 36 and 72 mg. The mean residence time of saquinavir
was 7 hours (n = 8).
Special populations
Effect of gender following treatment with Invirase/ritonavir:
A gender difference was observed with
females showing higher saquinavir exposure than males (AUC on average 56 % higher and C
max
on
average 26 % higher) in the bioequivalence study comparing Invirase 500 mg film coated tablets with
Invirase 200 mg hard capsules both in combination with ritonavir. There was no evidence that age and
body-weight explained the gender difference in this study. Limited data from controlled clinical
studies with the approved dosage regimen do not indicate a major difference in the efficacy and safety
profile between men and women.
Patients with hepatic impairment:
The effect of hepatic impairment on the steady state
pharmacokinetics of saquinavir/ritonavir (1000 mg/100 mg twice daily for 14 days) was investigated
in 7 HIV-infected patients with moderate liver impairment (Child Pugh Grade B score 7 to 9). The
study included a control group consisting of 7 HIV-infected patients with normal hepatic function
matched with the hepatically impaired patients for age, gender, weight and tobacco use. The mean
(% coefficient of variation in parentheses) values for saquinavir AUC
0-12
and C
max
were 24.3
(102%) µg·hr/ml and 3.6 (83%) µg/ml, respectively, for HIV-infected patients with moderate hepatic
impairment. The corresponding values in the control group were 28.5 (71%) µg·hr/ml and 4.3
(68%) µg/ml. The geometric mean ratio (ratio of pharmacokinetic parameters in hepatically impaired
patients to patients with normal liver function) (90% confidence interval) was 0.7 (0.3 to 1.6) for both
AUC
0-12
and C
max
, which suggests approximately 30% reduction in the pharmacokinetic exposure in
patients with moderate hepatic impairment. Results are based on total concentrations (protein-bound
and unbound). Concentrations unbound at steady-state were not assessed. No dosage adjustment seems
warranted for patients with moderate hepatic impairment based on limited data. Close monitoring of
safety (including signs of cardiac arrhythmia) and of virologic response is recommended due to
increased variability of the exposure in this population
(see sections 4.2 and 4.4).
5.3 Preclinical safety data
A
cute and chronic toxicity:
Saquinavir was well tolerated in oral acute and chronic toxicity studies in
mice, rats, dogs and marmosets.
Mutagenesis:
Mutagenicity and genotoxicity studies, with and without metabolic activation where
appropriate, have shown that saquinavir has no mutagenic activity
in vitro
in either bacterial (Ames
test) or mammalian cells (Chinese hamster lung V79/HPRT test). Saquinavir does not induce
chromosomal damage
in vivo
in the mouse micronucleus assay or
in vitro
in human peripheral blood
lymphocytes and does not induce primary DNA damage
in vitro
in the unscheduled DNA synthesis
test.
26
Carcinogenesis:
There was no evidence of carcinogenic activity after the administration of saquinavir
mesilate for 96 to 104 weeks to rats and mice. The plasma exposures (AUC values) in rats (maximum
dose 1000 mg/kg/day) and in mice (maximum dose 2500 mg/kg/day) were lower than the expected
plasma exposures obtained in humans at the recommended clinical dose of ritonavir boosted Invirase.
Reproductive toxicity:
Fertility, peri- and postnatal development were not affected, and embryotoxic /
teratogenic effects were not observed in rats or rabbits at plasma exposures lower than those achieved
in humans at the recommended clinical dose of ritonavir boosted Invirase. Distribution studies in these
species showed that the placental transfer of saquinavir is low (less than 5% of maternal plasma
concentrations).
6.
6.1 List of excipients
Capsule filling:
Lactose (anhydrous),
Microcrystalline cellulose,
Povidone,
Sodium starch glycollate,
Talc,
Magnesium stearate.
Capsule shell:
Gelatine,
Iron oxide black, red and yellow (E172),
Indigo carmine (E132),
Titanium dioxide (E171).
Printing ink:
Titanium dioxide (E 171),
Shellac,
Soya lecithin,
Polydimethylsiloxane.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original container.
6.5 Nature and contents of container
Amber glass bottles with plastic screw cap containing 270 capsules of Invirase.
6.6 Special precautions for disposal
No special requirements.
27
7.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8.
EU/1/96/026/001
9.
Date of first authorisation: 04 October 1996
Date of last renewal: 04 October 2006
Detailed information on this product is available on the website of the European Medicines Agency
28
1.
ritonavir. The Marketing Authorisation Holder (MAH) of Invirase conducted two studies (supra-
therapeutic dose finding study [NP 21562] and thorough QTc study [NP 21249]) to investigate the
effect of saquinavir boosted with ritonavir (SQV/r) on the QT interval in healthy volunteers. These
studies were assessed by the CHMP in the scope of a type II variation in June 2010
(EMEA/H/C/113/II/085). The thorough QTc-study showed a dose dependent, significant prolongation
of the QT interval and PR interval with both therapeutic and supra-therapeutic dose regimens of
saquinavir.
Based on the data available in the framework of the type II variation and on the increase of the QT
prolongation observed, the European Commission initiated a review under Article 20 of Regulation
(EC) No 726/2004.
Efficacy
The efficacy of saquinavir in HIV-infected patients has been demonstrated in the past 14 years.
Invirase was the first PI being approved followed by other nine PIs, some of which are currently
considered first line treatment. Invirase has been recognised as currently being used in second- or
third-line therapy as an alternative PI in patients who are intolerant to or have experienced clinical
adverse events (e.g. diarrhea) or laboratory abnormalities (e.g. increased liver function tests or lipid
levels).
There is some uncertainty about the superior tolerability and better lipid profile claimed for Invirase
compared to other PIs since the studies of comparative efficacy and tolerability for saquinavir versus
other PIs (indinavir, lopinavir) have some limitations due to their design and compliance to treatment
(higher pill burden of SQV/r 1000mg/100mg bid). However, some European guidelines still refer
Invirase in first line treatment.
Safety
Results of a thorough QT/QTc study (NP 21249) in healthy volunteers demonstrated dose dependent
QT and PR prolongation with the therapeutic dose of saquinavir 1000 mg boosted with ritonavir 100
mg bid on day 3 and has identified an average maximum prolongation of QT interval by 18.86
milliseconds (ms) at 12 hours post dose compared to a single dose of moxifloxacin 400 mg of 12.18
ms at 4 hrs post dose. There were no reports of QT prolongation >500 ms nor of Torsades de Points
(TdP) in this study. There was one case of first degree atriovascular (AV) block that resulted in
discontinuation of treatment.
The QT prolongation seen in this study was greater than that seen with moxifloxacin control.
Dedicated QT studies of other protease inhibitors have not shown such degree of prolongation.
However cross-study comparisons should be interpreted with caution due to differences in study
80
