ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
PREZISTA 75 mg film-coated tablets
Each film-coated tablet contains 75 mg of darunavir (as ethanolate).
For a full list of excipients, see section 6.1.
Film-coated tablet.
White caplet shaped tablet of 9.2 mm, debossed with “75” on one side and “TMC” on the other side.
PREZISTA, co-administered with low dose ritonavir is indicated in combination with other
antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus
(HIV-1) infection.
PREZISTA 75 mg tablets may be used to provide suitable dose regimens (see section 4.2):
For the treatment of HIV-1 infection in antiretroviral treatment (ART) experienced adult
patients, including those that have been highly pre-treated.
For the treatment of HIV-1 infection in ART-experienced children and adolescents from the age
of 6 years and at least 20 kg body weight.
In deciding to initiate treatment with PREZISTA co-administered with low dose ritonavir careful
consideration should be given to the treatment history of the individual patient and the patterns of
mutations associated with different agents. Genotypic or phenotypic testing (when available) and
treatment history should guide the use of PREZISTA.
Therapy should be initiated by a physician experienced in the management of HIV infection. After
therapy with PREZISTA has been initiated, patients should be advised not to alter the dosage or
discontinue therapy without instruction of their physician.
PREZISTA must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in
combination with other antiretroviral medicinal products. The Summary of Product Characteristics of
ritonavir must therefore be consulted prior to initiation of therapy with PREZISTA.
Patients should be instructed to take PREZISTA with low dose ritonavir within 30 minutes after
completion of a meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5
and 5.2).
Adults
ART-experienced patients
The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily
taken with food. PREZISTA 75 mg tablets can be used to construct the twice daily 600 mg
regimen.
2
The use of 75 mg tablets to achieve the recommended dose is appropriate when there is a
possibility of hypersensitivity to specific colouring agents, or difficulty in swallowing the
300 mg or 600 mg tablets.
For ART-experienced adults with no darunavir resistance associated mutations (DRV-RAMs)*
and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10
6
/l,
a dose regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food may be
used (see the Summary of Product Characteristics for PREZISTA 400 mg tablets).
*
DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
ART-naïve patients
For dosage recommendations in ART-naïve patients see the Summary of Product Characteristics for
PREZISTA 400 mg tablets.
Paediatric population
ART-experienced paediatric patients (6 to 17 years of age and weighing at least 20 kg)
Recommended dose for treatment-experienced paediatric patients (6 to 17 years of age) for
PREZISTA tablets and ritonavir
Body weight (kg)
Dose
≥ 20 kg–< 30 kg
375 mg PREZISTA/50 mg ritonavir twice daily
≥ 30 kg–< 40 kg
450 mg PREZISTA/60 mg ritonavir twice daily
≥ 40 kg
600 mg PREZISTA/100 mg ritonavir twice daily
The recommended dose of PREZISTA with low dose ritonavir should not exceed the recommended
adult dose (600/100 mg twice daily).
The use of only 75 mg and 150 mg tablets to achieve the recommended dose of PREZISTA could be
appropriate when there is a possibility of hypersensitivity to specific colouring agents.
ART-experienced children less than 6 years of age or less than 20 kg body weight, and ART-naïve
paediatric patients
There are insufficient data on the use of PREZISTA with low dose ritonavir in children less than
6 years of age or less than 20 kg body weight. Hence, PREZISTA is not recommended for use in this
group (see sections 4.4 and 5.3).
Elderly
Limited information is available in this population and therefore PREZISTA should be used with
caution in this age group (see sections 4.4 and 5.2).
Hepatic impairment
Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with
mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however,
PREZISTA should be used with caution in these patients. No pharmacokinetic data are available in
patients with severe hepatic impairment. Severe hepatic impairment could result in an increase of
darunavir exposure and a worsening of its safety profile. Therefore, PREZISTA must not be used in
patients with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).
Renal impairment
No dose adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).
In case a dose of PREZISTA and/or ritonavir was missed within 6 hours of the time it is usually taken,
patients should be instructed to take the prescribed dose of PREZISTA and ritonavir with food as soon
as possible. If this was noticed later than 6 hours of the time it is usually taken, the missed dose should
not be taken and the patient should resume the usual dosing schedule.
This guidance is based on the 15 hour half-life of darunavir in the presence of ritonavir and the
recommended dosing interval of approximately 12 hours.
3
Hypersensitivity to the active substance or to any of the excipients.
Patients with severe (Child-Pugh Class C) hepatic impairment.
Combination of rifampicin with PREZISTA with concomitant low dose ritonavir is contraindicated
(see section 4.5).
The combination product lopinavir/ritonavir should not be used with PREZISTA because
co-administration causes large decreases in darunavir concentrations, which may in turn significantly
decrease the darunavir therapeutic effect (see section 4.5).
Herbal preparations containing St John’s wort (
Hypericum perforatum
) must not be used while taking
PREZISTA due to the risk of decreased plasma concentrations and reduced clinical effects of
darunavir (see section 4.5).
Co-administration of PREZISTA with low dose ritonavir, with active substances that are highly
dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with
serious and/or life-threatening events is contraindicated. These active substances include e.g.
antiarrhythmics (amiodarone, bepridil, quinidine, systemic lidocaine), alfuzosin, antihistamines
(astemizole, terfenadine), ergot derivatives (e.g. dihydroergotamine, ergonovine, ergotamine,
methylergonovine), gastrointestinal motility agents (cisapride), neuroleptics (pimozide, sertindole),
sedatives/hypnotics [triazolam, midazolam administered orally (for caution on parenterally
administered midazolam, see section 4.5)], sildenafil (when used for the treatment of pulmonary
arterial hypertension) and HMG-CoA reductase inhibitors (simvastatin and lovastatin) (see section
4.5).
Patients should be advised that current antiretroviral therapy does not cure HIV and has not been
proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate
precautions should continue to be employed.
Regular assessment of virological response is advised. In the setting of lack or loss of virological
response, resistance testing should be performed.
PREZISTA should only be used in combination with low dose ritonavir as a pharmacokinetic
enhancer (see section 5.2).
Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect
darunavir concentrations and is not recommended.
Darunavir binds predominantly to 1-acid glycoprotein. This protein binding is concentration
dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products
highly bound to 1-acid glycoprotein cannot be ruled out (see section 4.5).
ART-experienced patients – once daily dosing
PREZISTA/rtv 800/100 mg once daily in ART-experienced patients should not be used in patients
with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA
≥ 100,000 copies/ml or CD4+ cell count < 100 cells x 10
6
/l (see section 4.2). The efficacy and safety
of PREZISTA/rtv 800/100 mg once daily in combination with optimised background regimen (OBR)
for the treatment of HIV-1 infection in ART-experienced adults with no darunavir resistance
associated mutations (DRV-RAMs) was evaluated in one trial with a duration of 48 weeks.
Combinations with OBRs other than ≥ 2 NRTIs have not been studied in this population. Limited data
is available in patients with HIV-1 clades other than B (see section 5.1).
Paediatric population
4
PREZISTA is not recommended for use in children below 6 years of age or less than 20 kg body
weight (see sections 4.2 and 5.3).
Elderly
As limited information is available on the use of PREZISTA in patients aged 65 and over, caution
should be exercised in the administration of PREZISTA in elderly patients, reflecting the greater
frequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2
and 5.2).
Severe skin reactions
During the clinical development program (N=3,063), severe skin reactions, which may be
accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients.
Stevens-Johnson Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience
toxic epidermal necrolysis has been reported. Discontinue PREZISTA/rtv immediately if signs or
symptoms of severe skin reactions develop. These can include but are not limited to severe rash or
rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions,
conjunctivitis, hepatitis and/or eosinophilia
.
Rash occurred more commonly in treatment-experienced patients receiving regimens containing
PREZISTA + raltegravir compared to patients receiving PREZISTA without raltegravir or raltegravir
without PREZISTA (see section 4.8).
Darunavir contains a sulphonamide moiety. PREZISTA should be used with caution in patients with a
known sulphonamide allergy.
Hepatotoxicity
Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv.
During the clinical development program (N=3,063), hepatitis was reported in 0.5% of patients
receiving combination antiretroviral therapy with PREZISTA/rtv. Patients with pre-existing liver
dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function
abnormalities including severe and potentially fatal hepatic adverse events. In case of concomitant
antiviral therapy for hepatitis B or C, please refer to the relevant product information for these
medicinal products.
Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv and
patients should be monitored during treatment. Increased AST/ALT monitoring should be considered
in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment
elevations of transaminases, especially during the first several months of PREZISTA/rtv treatment.
If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of
liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver
tenderness, hepatomegaly) in patients using PREZISTA/rtv, interruption or discontinuation of
treatment should be considered promptly.
Patients with coexisting conditions
Hepatic impairment
The safety and efficacy of PREZISTA have not been established in patients with severe underlying
liver disorders and PREZISTA is therefore contraindicated in patients with severe hepatic impairment.
Due to an increase in the unbound darunavir plasma concentrations, PREZISTA should be used with
caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).
Renal impairment
No special precautions or dose adjustments are required in patients with renal impairment. As
darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be
significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or
dose adjustments are required in these patients (see sections 4.2 and 5.2).
5
Haemophiliac patients
There have been reports of increased bleeding, including spontaneous skin haematomas and
haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional
factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or
reintroduced if treatment had been discontinued. A causal relationship has been suggested, although
the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made
aware of the possibility of increased bleeding.
Diabetes mellitus/Hyperglycaemia
New onset diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been
reported in patients receiving antiretroviral therapy, including PIs. In some of these patients 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 and metabolic disorders
Combination antiretroviral therapy has been associated with 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 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 measurement of
fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate
(see section 4.8).
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.
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 weeks or months of initiation of CART. Relevant
examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and
pneumonia caused by
Pneumocystis jirovecii
(formerly known as
Pneumocystis carinii
). Any
inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition,
reactivation of herpes simplex and herpes zoster has been observed in clinical studies with PREZISTA
co-administered with low dose ritonavir.
Interactions with medicinal products
Several of the interaction studies have been performed at lower than recommended doses of darunavir.
The effects on co-administered medicinal products may thus be underestimated and clinical
monitoring of safety may be indicated. For full information on interactions with other medicinal
products see section 4.5.
Efavirenz in combination with PREZISTA/rtv 800/100 mg once daily may result in sub-optimal
darunavir C
min
. If efavirenz is to be used in combination with PREZISTA/rtv, the PREZISTA/rtv
600/100 mg twice daily regimen should be used. See the Summary of Product Characteristics for
PREZISTA 75 mg, 150 mg, 300 mg or 600 mg tablets (see section 4.5).
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and
strong inhibitors of CYP3A and Pgp (see section 4.5).
6
Darunavir and ritonavir are both inhibitors of the CYP3A isoform. Co-administration of darunavir and
ritonavir and medicinal products primarily metabolised by CYP3A may result in increased systemic
exposure to such medicinal products, which could increase or prolong their therapeutic effect and
adverse reactions.
PREZISTA co-administered with low dose ritonavir must not be combined with medicinal products
that are highly dependent on CYP3A for clearance and for which increased systemic exposure is
associated with serious and/or life-threatening events (narrow therapeutic index). These medicinal
products include amiodarone, bepridil, quinidine, systemic lidocaine, astemizole, alfuzosin,
terfenadine, sildenafil (when used for the treatment of pulmonary arterial hypertension), midazolam
administered orally, triazolam, cisapride, pimozide, sertindole, simvastatin, lovastatin and the ergot
alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine) (see section 4.3).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in
the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in
combination with ritonavir at 100 mg twice daily. Therefore, PREZISTA must only be used in
combination with low dose ritonavir as a pharmacokinetic enhancer (see sections 4.4 and 5.2).
A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes
CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and
inhibition of CYP2D6 activity in the presence of PREZISTA/rtv, which may be attributed to the
presence of low dose ritonavir. Co-administration of darunavir and ritonavir and medicinal products
which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result
in increased plasma concentrations of these medicinal products, which could increase or prolong their
therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir and medicinal
products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone)
may result in decreased systemic exposure to such medicinal products, which could decrease or
shorten their therapeutic effect.
Although the effect on CYP2C8 has only been studied
in vitro
, co-administration of darunavir and
ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone,
repaglinide) may result in decreased systemic exposure to such medicinal products, which could
decrease or shorten their therapeutic effect.
Medicinal products that affect darunavir/ritonavir exposure
Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity
would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma
concentrations of darunavir and ritonavir (e.g. rifampicin, St John’s wort, lopinavir).
Co-administration of darunavir and ritonavir and other medicinal products that inhibit CYP3A may
decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of
darunavir and ritonavir (e.g. indinavir, systemic azoles like ketoconazole and clotrimazole). These
interactions are described in the interaction table below.
Interaction table
Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products
are listed in the table below (not determined as “ND”). The direction of the arrow for each
pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being
within (↔), below (↓) or above (↑) the 80-125% range.
Several of the interaction studies (indicated by
#
in the table below) have been performed at lower than
recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The
effects on co-administered medicinal products may thus be underestimated and clinical monitoring of
safety may be indicated.
INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal products by
therapeutic areas
Recommendations concerning
co-administration
7
Interaction
Geometric mean change (%)
ANTIRETROVIRALS
Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine
400 mg once daily
didanosine AUC ↓ 9%
didanosine C
min
ND
didanosine C
max
↓ 16%
darunavir AUC ↔
darunavir C
min
↔
darunavir C
max
↔
PREZISTA co-administered with
low dose ritonavir and didanosine
can be used without dose
adjustments.
Didanosine is to be administered on
an empty stomach, thus it should be
administered 1 hour before or
2 hours after PREZISTA/ritonavir
given with food.
Tenofovir
300 mg once daily
tenofovir AUC ↑ 22%
tenofovir C
min
↑ 37%
tenofovir C
max
↑ 24%
#
darunavir AUC ↑ 21%
#
Monitoring of renal function may
be indicated when PREZISTA
co-administered with low dose
ritonavir is given in combination
with tenofovir, particularly in
patients with underlying systemic or
renal disease, or in patients taking
nephrotoxic agents.
darunavir C
min
↑ 24%
#
darunavir C
max
↑ 16%(↑ tenofovir from
effect on MDR-1 transport in the renal
tubules)
Abacavir
Emtricitabine
Lamivudine
Stavudine
Zidovudine
Not studied. Based on the different
elimination pathways of the other NRTIs
zidovudine, emtricitabine, stavudine,
lamivudine, that are primarily renally
excreted, and abacavir for which
metabolism is not mediated by CYP450,
no interactions are expected for these
medicinal compounds and PREZISTA
co-administered with low dose ritonavir.
PREZISTA co-administered with
low dose ritonavir can be used with
these NRTIs without dose
adjustment.
Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg once daily
efavirenz AUC ↑ 21%
efavirenz C
min
↑ 17%
efavirenz C
max
↑ 15%
#
Clinical monitoring for central
nervous system toxicity associated
with increased exposure to
efavirenz may be indicated when
PREZISTA co-administered with
low dose ritonavir is given in
combination with efavirenz.
darunavir AUC ↓ 13%
#
darunavir C
min
↓ 31%
#
darunavir C
max
↓ 15%
(↑ efavirenz from CYP3A inhibition)
(↓ darunavir from CYP3A induction)
Efavirenz in combination with
PREZISTA/rtv 800/100 mg once
daily may result in sub-optimal
darunavir C
min
. If efavirenz is to be
used in combination with
PREZISTA/rtv, the PREZISTA/rtv
600/100 mg twice daily regimen
should be used (see section 4.4).
Etravirine
100 mg twice daily
etravirine AUC ↓ 37%
etravirine C
min
↓ 49%
etravirine C
max
↓ 32%
darunavir AUC ↑ 15%
darunavir C
min
↔
darunavir C
max
↔
PREZISTA co-administered with
low dose ritonavir and etravirine
200 mg twice daily
can be used
without dose adjustments.
Nevirapine
200 mg twice daily
nevirapine AUC ↑ 27%
nevirapine C
min
↑ 47%
nevirapine C
max
↑ 18%
#
darunavir: concentrations
were consistent with historical data
(↑ nevirapine from CYP3A inhibition)
PREZISTA co-administered with
low dose ritonavir and nevirapine
can be used without dose
adjustments.
Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir
†
8
Atazanavir
300 mg once daily
atazanavir AUC ↔
atazanavir C
min
↑ 52%
atazanavir C
max
↓ 11%
#
darunavir AUC ↔
#
PREZISTA co-administered with
low dose ritonavir and atazanavir
can be used without dose
adjustments.
darunavir C
min
↔
#
darunavir C
max
↔
Atazanavir: comparison of
atazanavir/ritonavir 300/100 mg once daily
vs. atazanavir 300 mg once daily in
combination with darunavir/ritonavir
400/100 mg twice daily.
Darunavir: comparison of
darunavir/ritonavir 400/100 mg twice daily
vs. darunavir/ritonavir 400/100 mg twice
daily in combination with atazanavir
300 mg once daily.
Indinavir
800 mg twice daily
indinavir AUC ↑ 23%
indinavir C
min
↑ 125%
indinavir C
max
↔
#
When used in combination with
PREZISTA co-administered with
low dose ritonavir, dose adjustment
of indinavir from 800 mg twice
daily to 600 mg twice daily may be
warranted in case of intolerance.
darunavir AUC ↑ 24%
#
darunavir C
min
↑ 44%
#
darunavir C
max
↑ 11%
Indinavir: comparison of
indinavir/ritonavir 800/100 mg twice daily
vs. indinavir/darunavir/ritonavir
800/400/100 mg twice daily.
Darunavir: comparison of
darunavir/ritonavir 400/100 mg twice daily
vs. darunavir/ritonavir 400/100 mg in
combination with indinavir 800 mg twice
daily.
Saquinavir
1,000 mg twice daily
#
darunavir AUC ↓ 26%
It is not recommended to combine
PREZISTA co-administered with
low dose ritonavir with saquinavir.
#
darunavir C
min
↓ 42%
darunavir C
max
↓ 17%
saquinavir AUC ↓ 6%
saquinavir C
min
↓ 18%
saquinavir C
max
↓ 6%
Saquinavir: comparison of
saquinavir/ritonavir 1,000/100 mg twice
daily vs. saquinavir/darunavir/ritonavir
1,000/400/100 mg twice daily
Darunavir: comparison of
darunavir/ritonavir 400/100 mg twice daily
vs. darunavir/ritonavir 400/100 mg in
combination with saquinavir 1,000 mg
twice daily.
Protease inhibitors (PIs) - with co-administration of low dose ritonavir
†
9
#
Lopinavir/ritonavir
400/100 mg twice daily
lopinavir AUC ↑ 9%
lopinavir C
min
↑ 23%
lopinavir C
max
↓ 2%
darunavir AUC ↓ 38%
‡
darunavir C
min
↓ 51%
‡
darunavir C
max
↓ 21%
‡
lopinavir AUC ↔
lopinavir C
min
↑ 13%
lopinavir C
max
↑ 11%
darunavir AUC ↓ 41%
darunavir C
min
↓ 55%
darunavir C
max
↓ 21%
‡
Due to a decrease in the exposure
(AUC) of darunavir by 40%,
appropriate doses of the
combination have not been
established. Hence, concomitant use
of PREZISTA co-administered with
low dose ritonavir and the
combination product
lopinavir/ritonavir is
contraindicated (see section 4.3).
Lopinavir/ritonavir
533/133.3 mg twice
daily
based upon non dose normalised values
CCR5 ANTAGONIST
Maraviroc
150 mg twice daily
maraviroc AUC ↑ 305%
maraviroc C
min
ND
maraviroc C
max
↑ 129%
darunavir, ritonavir concentrations were
consistent with historical data
The maraviroc dose should be
150 mg twice daily when
co-administered with PREZISTA
with low dose ritonavir.
ANTIARRHYTHMIC
Digoxin
0.4 mg single dose
digoxin AUC ↑ 61%
digoxin C
min
ND
digoxin C
max
↑ 29%
(↑ digoxin from probable inhibition of
Pgp)
Given that digoxin has a narrow
therapeutic index, it is
recommended that the lowest
possible dose of digoxin should
initially be prescribed in case
digoxin is given to patients on
darunavir/ritonavir therapy. The
digoxin dose should be carefully
titrated to obtain the desired clinical
effect while assessing the overall
clinical state of the subject.
ANTIBIOTIC
Clarithromycin
500 mg twice daily
clarithromycin AUC ↑ 57%
clarithromycin C
min
↑ 174%
clarithromycin C
max
↑ 26%
#
darunavir AUC ↓ 13%
#
Caution should be exercised when
clarithromycin is combined with
PREZISTA co-administered with
low dose ritonavir.
darunavir C
min
↑ 1%
#
darunavir C
max
↓ 17%
14-OH-clarithromycin concentrations were
not detectable when combined with
PREZISTA/ritonavir.
(↑ clarithromycin from CYP3A inhibition
and possible Pgp inhibition)
ANTICOAGULANT
Warfarin
Not studied. Warfarin concentrations may
be affected when co-administered with
darunavir with low dose ritonavir.
It is recommended that the
international normalised ratio (INR)
be monitored when warfarin is
combined with PREZISTA
co-administered with low dose
ritonavir.
ANTICONVULSANTS
Phenobarbital
Phenytoin
Not studied. Phenobarbital and phenytoin
are expected to decrease plasma
concentrations of darunavir.
(induction of CYP450 enzymes)
PREZISTA co-administered with
low dose ritonavir should not be
used in combination with these
medicines.
10
Carbamazepine
200 mg twice daily
carbamazepine AUC ↑ 45%
carbamazepine C
min
↑ 54%
carbamazepine C
max
↑ 43%
darunavir AUC ↔
darunavir C
min
↓ 15%
darunavir C
max
↔
No dose adjustment for
PREZISTA/ritonavir is
recommended. If there is a need to
combine PREZISTA/ritonavir and
carbamazepine, patients should be
monitored for potential
carbamazepine-related adverse
events. Carbamazepine
concentrations should be monitored
and its dose should be titrated for
adequate response. Based upon the
findings, the carbamazepine dose
may need to be reduced by 25% to
50% in the presence of
PREZISTA/ritonavir.
ANTIFUNGALS
Voriconazole
Not studied. Ritonavir may decrease
plasma concentrations of voriconazole.
(induction of CYP450 enzymes by
ritonavir)
Voriconazole should not be
combined with PREZISTA
co-administered with low dose
ritonavir unless an assessment of
the benefit/risk ratio justifies the use
of voriconazole.
Ketoconazole
200 mg twice daily
ketoconazole AUC ↑ 212%
ketoconazole C
min
↑ 868%
ketoconazole C
max
↑ 111%
#
darunavir AUC ↑ 42%
#
darunavir C
min
↑ 73%
#
Caution is warranted and clinical
monitoring is recommended. When
co-administration is required the
daily dose of ketoconazole should
not exceed 200 mg.
darunavir C
max
↑ 21%
(CYP3A inhibition)
Itraconazole
Not studied. Concomitant systemic use of
itraconazole and darunavir co-administered
with low dose ritonavir may increase
plasma concentrations of darunavir.
Simultaneously, plasma concentrations of
itraconazole may be increased by
darunavir co-administered with low dose
ritonavir.
(CYP3A inhibition)
Caution is warranted and clinical
monitoring is recommended. When
co-administration is required the
daily dose of itraconazole should
not exceed 200 mg.
Clotrimazole
Not studied. Concomitant systemic use of
clotrimazole and darunavir
co-administered with low dose ritonavir
may increase plasma concentrations of
darunavir.
darunavir AUC
24h
↑ 33% (based on
population pharmacokinetic model)
Caution is warranted and clinical
monitoring is recommended, when
co-administration of clotrimazole is
required.
ANTIGOUT MEDICINES
Colchicine
Not studied. Concomitant use of colchicine
and darunavir co-administered with low
dose ritonavir may increase the exposure
to colchicine.
A reduction in colchicine dosage or
an interruption of colchicine
treatment is recommended in
patients with normal renal or
hepatic function if treatment with
PREZISTA co-administered with
low dose ritonavir is required.
Patients with renal or hepatic
impairment should not be given
colchicine with PREZISTA
co-administered with low dose
ritonavir (see section 4.4).
ANTIMYCOBACTERIALS
11
Rifampicin
Not studied. Rifampicin is a strong
CYP3A inducer and has been shown to
cause profound decreases in concentrations
of other protease inhibitors, 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 low dose ritonavir, a high
frequency of liver reactions was seen.
(CYP450 enzyme induction)
The combination of rifampicin and
PREZISTA with concomitant low
dose ritonavir is contraindicated
(see section 4.3).
Rifabutin
150 mg once every
other day
rifabutin AUC
**
↑ 55%
rifabutin C
min
**
↑ ND
rifabutin C
max
**
↔
darunavir AUC ↑ 53%
darunavir C
min
↑ 68%
darunavir C
max
↑ 39%
**
A dosage reduction of rifabutin by
75% of the usual dose of
300 mg/day (i.e. rifabutin 150 mg
once every other day) and increased
monitoring for rifabutin related
adverse events is warranted in
patients receiving the combination.
In case of safety issues, a further
increase of the dosing interval for
rifabutin and/or monitoring of
rifabutin levels should be
considered.
Consideration should be given to
official guidance on the appropriate
treatment of tuberculosis in HIV
infected patients.
Based upon the safety profile of
PREZISTA/ritonavir, the increase
in darunavir exposure in the
presence of rifabutin does not
warrant a dose adjustment for
PREZISTA/ritonavir.
Based on pharmacokinetic
modeling, this dosage reduction of
75% is also applicable if patients
receive rifabutin at doses other than
300 mg/day.
sum of active moieties of rifabutin (parent drug
+ 25-
O-
desacetyl metabolite)
The interaction trial showed a comparable
daily systemic exposure for rifabutin
between treatment at 300 mg once daily
alone and 150 mg once every other day in
combination with PREZISTA/ritonavir
(600/100 mg twice daily) with an about
10-fold increase in the daily exposure to
the active metabolite
25-
O-
desacetylrifabutin. Furthermore,
AUC of the sum of active moieties of
rifabutin (parent drug + 25-
O-
desacetyl
metabolite) was increased 1.6-fold, while
C
max
remained comparable.
Data on comparison with a 150 mg once
daily reference dose is lacking.
(Rifabutin is an inducer and substrate of
CYP3A.) An increase of systemic
exposure to darunavir was observed when
PREZISTA co-administered with 100 mg
ritonavir was co-administered with
rifabutin (150 mg once every other day).
BENZODIAZEPINES
Midazolam
Not studied. Midazolam is extensively
metabolised by CYP3A. Co-administration
with PREZISTA/ritonavir may cause a
large increase in the concentration of this
benzodiazepine.
PREZISTA/ritonavir should not be
co-administered with orally
administered midazolam (see
section 4.3); whereas, caution
should be used with
co-administration of
PREZISTA/ritonavir and parenteral
midazolam.
If PREZISTA/ritonavir is
co-administered with parenteral
midazolam, it should be done in an
intensive care unit (ICU) or similar
setting, which ensures close clinical
monitoring and appropriate medical
management in case of respiratory
depression and/or prolonged
sedation. Dose adjustment for
midazolam should be considered,
especially if more than a single dose
of midazolam is administered.
Based on data for other CYP3A inhibitors,
plasma concentrations of midazolam are
expected to be significantly higher when
midazolam is given orally with
PREZISTA co-administered with low dose
ritonavir.
Co-administration of parenteral midazolam
with PREZISTA/ritonavir may cause a
large increase in the concentration of this
benzodiazepine. Data from concomitant
use of parenteral midazolam with other
protease inhibitors suggest a possible 3-4
fold increase in midazolam plasma levels.
12
CALCIUM CHANNEL BLOCKERS
Felodipine
Nicardipine
Nifedipine
Not studied. PREZISTA co-administered
with low dose ritonavir can be expected to
increase the plasma concentrations of
calcium channel antagonists.
(CYP3A inhibition)
Clinical monitoring of therapeutic
and adverse effects is recommended
when these medicines are
concomitantly administered with
PREZISTA with low dose ritonavir.
CORTICOSTEROIDS
Fluticasone
Budesonide
In a clinical study where ritonavir 100 mg
capsules twice daily were co-administered
with 50 g intranasal fluticasone
propionate (4 times daily) for 7 days in
healthy subjects, fluticasone propionate
plasma concentrations increased
significantly, whereas the intrinsic cortisol
levels decreased by approximately 86%
(90% CI 82-89%). Greater effects may be
expected when fluticasone 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; this
could also occur with other corticosteroids
metabolised via the P4503A pathway, e.g.,
budesonide. The effects of high fluticasone
systemic exposure on ritonavir plasma
levels are unknown.
Concomitant administration of
PREZISTA co-administered with
low dose ritonavir and these
glucocorticoids is not recommended
unless the potential benefit of
treatment outweighs the risk of
systemic corticosteroid effects. A
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 CYP3A (e.g.,
beclomethasone). Moreover, in case
of withdrawal of glucocorticoids,
progressive dose reduction may
have to be performed over a longer
period.
Dexamethasone
(systemic)
Not studied. Dexamethasone may decrease
plasma concentrations of darunavir.
(CYP3A induction)
Systemic dexamethasone should be
used with caution when combined
with PREZISTA co-administered
with low dose ritonavir.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan
Not studied. Concomitant use of bosentan
and darunavir co-administered with low
dose ritonavir may increase plasma
concentrations of bosentan.
When administered concomitantly
with PREZISTA and low dose
ritonavir, the patient’s tolerability of
bosentan should be monitored.
ESTROGEN-BASED CONTRACEPTIVES
Ethinylestradiol
Norethindrone
35 g/1 mg once daily
ethinylestradiol AUC ↓ 44%
ethinylestradiol C
min
↓ 62%
ethinylestradiol C
max
↓ 32%
norethindrone AUC ↓ 14%
norethindrone C
min
↓ 30%
norethindrone C
max
↔
Alternative or additional
contraceptive measures are
recommended when
oestrogen-based contraceptives are
co-administered with PREZISTA
and low dose ritonavir. Patients
using oestrogens as hormone
replacement therapy should be
clinically monitored for signs of
oestrogen deficiency.
HERBAL PRODUCTS
St John's wort
(Hypericum perforatum)
Not studied. St John’s wort is expected to
decrease the plasma concentrations of
darunavir and ritonavir.
(CYP450 induction)
PREZISTA co-administered with
low dose ritonavir must not be used
concomitantly with products
containing St John’s wort
(
Hypericum perforatum
) (see
section 4.3). If a patient is already
taking St John’s wort, stop
St John’s wort and if possible check
viral levels. Darunavir exposure
(and also ritonavir exposure) may
increase on stopping St John’s wort.
The inducing effect may persist for
at least 2 weeks after cessation of
treatment with St John’s wort.
13
HMG CO-A REDUCTASE INHIBITORS
Lovastatin
Simvastatin
Not studied. Lovastatin and simvastatin are
expected to have markedly increased
plasma concentrations when
co-administered with darunavir
co-administered with low dose ritonavir.
(CYP3A inhibition)
Increased plasma concentrations of
lovastatin or simvastatin may cause
myopathy, including
rhabdomyolysis. Concomitant use
of PREZISTA co-administered with
low dose ritonavir with lovastatin
and simvastatin is therefore
contraindicated (see section 4.3).
Atorvastatin
10 mg once daily
atorvastatin AUC ↑ 3-4 fold
atorvastatin C
min
↑
≈
5.5-10 fold
atorvastatin C
max
↑ ≈2 fold
#
darunavir
When administration of atorvastatin
and PREZISTA co-administered
with low dose ritonavir is desired, it
is recommended to start with an
atorvastatin dose of 10 mg once
daily. A gradual dose increase of
atorvastatin may be tailored to the
clinical response.
Pravastatin
40 mg single dose
pravastatin AUC ↑ 81%
¶
pravastatin C
min
ND
pravastatin C
max
↑ 63%
¶
When administration of pravastatin
and PREZISTA co-administered
with low dose ritonavir is required,
it is recommended to start with the
lowest possible dose of pravastatin
and titrate up to the desired clinical
effect while monitoring for safety.
an up to five-fold increase was seen in a limited
subset of subjects
H
2
-RECEPTOR ANTAGONISTS
Ranitidine
150 mg twice daily
#
darunavir AUC ↔
#
darunavir C
min
↔
#
PREZISTA co-administered with
low dose ritonavir can be
co-administered with H
2
-receptor
antagonists without dose
adjustments.
darunavir C
max
↔
IMMUNOSUPPRESSANTS
Cyclosporine
Sirolimus
Tacrolimus
Not studied. Exposure to cyclosporine,
tacrolimus or sirolimus will be increased
when co-administered with PREZISTA
co-administered with low dose ritonavir.
Therapeutic drug monitoring of the
immunosuppressive agent must be
done when co-administration
occurs.
Concomitant use of salmeterol and
PREZISTA co-administered with
low dose ritonavir is not
recommended. The combination
may result in increased risk of
cardiovascular adverse event with
salmeterol, including QT
prolongation, palpitations and sinus
tachycardia.
NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE
Methadone
individual dose ranging
from 55 mg to 150 mg
once daily
Not studied. Concomitant use of
salmeterol and darunavir co-administered
with low dose ritonavir may increase
plasma concentrations of salmeterol.
R(-) methadone AUC ↓ 16%
R(-) methadone C
min
↓ 15%
R(-) methadone C
max
↓ 24%
No adjustment of methadone dosage
is required when initiating
co-administration with
PREZISTA/ritonavir. However,
increased methadone dose may be
necessary when concomitantly
administered for a longer period of
time due to induction of metabolism
by ritonavir. Therefore, clinical
monitoring is recommended, as
maintenance therapy may need to
be adjusted in some patients.
14
INHALED BETA AGONISTS
Salmeterol
Buprenorphine/naloxone
8/2 mg–16/4 mg once
daily
buprenorphine AUC ↓ 11%
buprenorphine C
min
↔
buprenorphine C
max
↓ 8%
norbuprenorphine AUC ↑ 46%
norbuprenorphine C
min
↑ 71%
norbuprenorphine C
max
↑ 36%
naloxone AUC ↔
naloxone C
min
ND
naloxone C
max
↔
The clinical relevance of the
increase in norbuprenorphine
pharmacokinetic parameters has not
been established. Dose adjustment
for buprenorphine may not be
necessary when co-administered
with PREZISTA/ritonavir but a
careful clinical monitoring for signs
of opiate toxicity is recommended.
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of erectile
dysfunction
Sildenafil
Tadalafil
Vardenafil
In an interaction study
#
, a comparable
systemic exposure to sildenafil was
observed for a single intake of 100 mg
sildenafil alone and a single intake of
25 mg sildenafil co-administered with
PREZISTA and low dose ritonavir.
Concomitant use of PDE-5
inhibitors for the treatment of
erectile dysfunction with
PREZISTA co-administered with
low dose ritonavir should be done
with caution. If concomitant use of
PREZISTA co-administered with
low dose ritonavir with sildenafil,
vardenafil or tadalafil is indicated,
sildenafil at a single dose not
exceeding 25 mg in 48 hours,
vardenafil at a single dose not
exceeding 2.5 mg in 72 hours or
tadalafil at a single dose not
exceeding 10 mg in 72 hours is
recommended.
For the treatment of
pulmonary arterial
hypertension
Sildenafil
Tadalafil
Not studied. Concomitant use of sildenafil
or tadalafil for the treatment of pulmonary
arterial hypertension and darunavir
co-administered with low dose ritonavir
may increase plasma concentrations of
sildenafil or tadalafil.
A safe and effective dose of
sildenafil for the treatment of
pulmonary arterial hypertension
co-administered with PREZISTA
and low dose ritonavir has not been
established. There is an increased
potential for sildenafil-associated
adverse events (including visual
disturbances, hypotension,
prolonged erection and syncope).
Therefore, co-administration of
PREZISTA with low dose ritonavir
and sildenafil when used for the
treatment of pulmonary arterial
hypertension is contraindicated (see
section 4.3).
Co-administration of tadalafil for
the treatment of pulmonary arterial
hypertension with PREZISTA and
low dose ritonavir is not
recommended.
PROTON PUMP INHIBITORS
Omeprazole
20 mg once daily
#
darunavir AUC ↔
#
darunavir C
min
↔
#
PREZISTA co-administered with
low dose ritonavir can be
co-administered with proton pump
inhibitors without dose adjustments.
darunavir C
max
↔
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
15
Paroxetine
20 mg once daily
paroxetine AUC ↓ 39%
paroxetine C
min
↓ 37%
paroxetine C
max
↓ 36%
#
darunavir AUC ↔
#
If SSRIs are co-administered with
PREZISTA and low dose ritonavir,
the recommended approach is a
dose titration of the SSRI based on
a clinical assessment of
antidepressant response. In addition,
patients on a stable dose of
sertraline or paroxetine who start
treatment with PREZISTA
co-administered with low dose
ritonavir should be monitored for
antidepressant response.
darunavir C
min
↔
#
darunavir C
max
↔
sertraline AUC ↓ 49%
sertraline C
min
↓ 49%
sertraline C
max
↓ 44%
#
darunavir AUC ↔
#
darunavir C
min
↓ 6%
#
Sertraline
50 mg once daily
darunavir C
max
↔
†
The efficacy and safety of the use of PREZISTA with 100 mg ritonavir and any other PI (e.g. (fos)amprenavir, nelfinavir and tipranavir)
has not been established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is generally not
recommended.
Paediatric population
Interaction studies have only been performed in adults.
Pregnancy
There are no adequate and well controlled studies with darunavir in pregnant women. Studies in
animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal
development, parturition or postnatal development (see section 5.3).
PREZISTA co-administered with low dose ritonavir should be used during pregnancy only if the
potential benefit justifies the potential risk.
Breast-feeding
It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that
darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity. Because of both
the potential for HIV transmission and the potential for adverse reactions in breast-fed infants, mothers
should be instructed not to breast-feed under any circumstances if they are receiving PREZISTA.
Fertility
No human data on the effect of darunavir on fertility are available. There was no effect on mating or
fertility with darunavir treatment in rats (see section 5.3).
PREZISTA in combination with ritonavir has no or negligible influence on the ability to drive and use
machines. However, dizziness has been reported in some patients during treatment with regimens
containing PREZISTA co-administered with low dose ritonavir and should be borne in mind when
considering a patient’s ability to drive or operate machinery (see section 4.8).
The overall safety profile of PREZISTA is based on all available clinical trial and post-marketing data,
and is consistent with the data below.
a. Summary of the safety profile
During the clinical development program (N=1,968 treatment-experienced subjects who initiated
therapy with PREZISTA/rtv 600/100 mg twice daily), 49.5% of subjects experienced at least one
adverse reaction. The total mean treatment duration for subjects was 48.58 weeks. For treatment-naïve
patients, see the information below the table. The most frequent adverse reactions reported in clinical
trials and as spontaneous reports are diarrhoea, immune reconstitution syndrome, nausea, pyrexia and
rash. The most frequent serious reactions are diarrhoea, hepatitis, immune reconstitution syndrome,
pyrexia and rash.
16
b. Tabulated summary of adverse reactions
Adverse reactions are listed by system organ class (SOC) and frequency category. Within each
frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency
categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon
(≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and not known (frequency cannot be estimated
from the available data).
Adverse reactions in clinical trials and post-marketing in adult patients
SOC
Frequency category
Adverse reaction
Infections and infestations
uncommon
herpes simplex
Blood and lymphatic system disorders
uncommon
thrombocytopenia, neutropenia, anaemia,
increased eosinophil count, leukopenia
Immune system disorders
uncommon
immune reconstitution syndrome
1, 2
, (drug)
hypersensitivity
Endocrine disorders
uncommon
hypothyroidism, increased blood thyroid
stimulating hormone
Metabolism and nutrition disorders
common
lipodystrophy (including lipohypertrophy,
lipodystrophy, lipoatrophy)
1, 2
,
hypertriglyceridaemia
1, 2
, hypercholesterolaemia
1,
2
, hyperlipidaemia
1, 2
uncommon
diabetes mellitus
1, 2
, gout, anorexia, decreased
appetite, decreased weight, increased weight,
hyperglycaemia
1, 2
, insulin resistance, decreased
high density lipoprotein, increased appetite,
polydipsia, increased blood lactate
dehydrogenase
Psychiatric disorders
common
insomnia
uncommon
depression, confusional state, disorientation,
anxiety, altered mood, sleep disorder, abnormal
dreams, nightmare, decreased libido, restlessness
Nervous system disorders
common
headache, peripheral neuropathy, dizziness
uncommon
syncope, convulsion, lethargy, paraesthesia,
hypoaesthesia, ageusia, dysgeusia, disturbance in
attention, memory impairment, somnolence,
sleep phase rhythm disturbance
Eye disorders
uncommon
visual disturbance, conjunctival hyperaemia, dry
eye
Ear and labyrinth disorders
uncommon
vertigo
Cardiac disorders
17
uncommon
acute myocardial infarction, myocardial
infarction, angina pectoris, prolonged
electrocardiogram QT, sinus bradycardia,
tachycardia, palpitations
Vascular disorders
uncommon
hypertension, flushing
Respiratory, thoracic and mediastinal disorders
uncommon
dyspnoea, cough, epistaxis, rhinorrhoea, throat
irritation
Gastrointestinal disorders
very common
diarrhoea
common
vomiting, nausea, abdominal pain, increased
blood amylase, dyspepsia, abdominal distension,
flatulence
uncommon
pancreatitis, gastritis, gastrooesophageal reflux
disease, aphthous stomatitis, stomatitis, retching,
haematemesis, dry mouth, abdominal discomfort,
constipation, increased lipase, eructation, oral
dysaesthesia, cheilitis, dry lip, coated tongue
Hepatobiliary disorders
common
increased alanine aminotransferase, increased
aspartate aminotransferase
uncommon
hepatitis
1
, cytolytic hepatitis
1
, hepatic steatosis,
hepatomegaly, increased transaminase, increased
blood bilirubin, increased blood alkaline
phosphatase, increased
gamma-glutamyltransferase
Skin and subcutaneous tissue disorders
common
rash
3
(including macular, maculopapular, papular,
erythematous and pruritic rash)
1, 2
, pruritus
uncommon
angioedema, generalised rash
1, 2
, allergic
dermatitis, urticaria, dermatitis, eczema,
erythema, hyperhidrosis, night sweats, alopecia,
acne, seborrhoeic dermatitis, skin lesion,
xeroderma, dry skin, nail pigmentation
rare
erythema multiforme, Stevens-Johnson
syndrome
1
not known
toxic epidermal necrolysis
1
Musculoskeletal and connective tissue disorders
uncommon
myalgia
2
, osteonecrosis
1, 2
, muscle spasms,
muscular weakness, musculoskeletal stiffness,
arthritis, arthralgia, joint stiffness, pain in
extremity, osteoporosis, increased blood creatine
phosphokinase
2
Renal and urinary disorders
uncommon
acute renal failure, renal failure, nephrolithiasis,
increased blood creatinine, decreased creatinine
renal clearance, proteinuria, bilirubinuria,
dysuria, nocturia, pollakiuria
Reproductive system and breast disorders
uncommon
erectile dysfunction, gynaecomastia
18
General disorders and administration site conditions
common
asthenia, fatigue
uncommon
pyrexia, chest pain, peripheral oedema, malaise,
chills, abnormal feeling, feeling hot, irritability,
pain, xerosis
1
see section 4.4
2
see section 4.8 c)
3
In clinical studies of treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens
containing PREZISTA + raltegravir compared to those containing PREZISTA without raltegravir or raltegravir without PREZISTA.
Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were
10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively.
The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section
4.4).
The safety profile of PREZISTA/rtv 800/100 mg once daily in treatment-naïve subjects is similar to
that seen with PREZISTA/rtv 600/100 mg twice daily in treatment-experienced subjects except for
nausea which was observed more frequently in treatment-naïve subjects. This was driven by mild
intensity nausea.
c.
Description of selected adverse reactions
Rash
In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of
treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in
section 4.4.
Lipodystrophy
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section
4.4).
Metabolic abnormalities
Combination antiretroviral therapy has also been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
Musculoskeletal abnormalities
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of
protease inhibitors, particularly in combination with NRTIs.
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).
Immune reconstitution syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections
may arise (see section 4.4).
Bleeding in haemophiliac patients
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving
antiretroviral protease inhibitors (see section 4.4).
d. Paediatric population
The safety assessment in children and adolescents is based on the safety data from the Phase II trial
DELPHI in which 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years
19
and weighing at least 20 kg received PREZISTA with low dose ritonavir in combination with other
antiretroviral agents (see section 5.1).
Overall, the safety profile in these 80 children and adolescents was similar to that observed in the adult
population.
e. Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virus
Among 1,968 treatment-experienced patients receiving PREZISTA co-administered with ritonavir
600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were
more likely to have baseline and treatment emergent hepatic transaminase elevations than those
without chronic viral hepatitis (see section 4.4).
Human experience of acute overdose with PREZISTA co-administered with low dose ritonavir is
limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the
tablet formulation of darunavir in combination with ritonavir have been administered to healthy
volunteers without untoward symptomatic effects.
There is no specific antidote for overdose with PREZISTA. Treatment of overdose with PREZISTA
consists of general supportive measures including monitoring of vital signs and observation of the
clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved
by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of
unabsorbed active substance. Since darunavir is highly protein bound, dialysis is unlikely to be
beneficial in significant removal of the active substance.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiviral for systemic use, ATC code: J05AE10.
Mechanism of action
Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease
(K
D
of 4.5 x 10
-12
M). It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus
infected cells, thereby preventing the formation of mature infectious virus particles.
Antiviral activity
in vitro
Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory
strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and
human monocytes/macrophages with median EC
50
values ranging from 1.2 to 8.5 nM (0.7 to
5.0 ng/ml). Darunavir demonstrates antiviral activity
in vitro
against a broad panel of HIV-1 group M
(A, B, C, D, E, F, G) and group O primary isolates with EC
50
values ranging from < 0.1 to 4.3 nM.
These EC
50
values are well below the 50% cellular toxicity concentration range of 87 µM to
> 100 µM.
Resistance
In vitro
selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). The
selected viruses were unable to grow in the presence of darunavir concentrations above 400 nM.
Viruses selected in these conditions and showing decreased susceptibility to darunavir (range:
23-50-fold) harboured 2 to 4 amino acid substitutions in the protease gene. Identification of
determinants of decreased susceptibility to darunavir in those viruses is under investigation.
The clinical trial data from ART-experienced patients (TITAN trial and the pooled analysis of the
POWER 1, 2 and 3 and DUET 1 and 2 trials) showed that virologic response to PREZISTA
co-administered with low dose ritonavir was decreased when 3 or more darunavir RAMs (V11I, V32I,
20
L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V) were present at baseline or when these
mutations developed during treatment.
Increasing baseline darunavir fold change in EC
50
(FC) was associated with decreasing virologic
response. A lower and upper clinical cut-off of 10 and 40 were identified. Isolates with baseline FC
≤ 10 are susceptible; isolates with FC > 10 to 40 have decreased susceptibility; isolates with FC
> 40 are resistant (see Clinical results).
Viruses isolated from patients on PREZISTA/rtv 600/100 mg twice daily experiencing virologic
failure by rebound that were susceptible to tipranavir at baseline remained susceptible to tipranavir
after treatment in the vast majority of cases.
The lowest rates of developing resistant HIV virus are observed in ART-naïve patients who are treated
for the first time with darunavir in combination with other ART.
The table below shows the development of mutations and loss of susceptibility to PIs in virologic
failures at endpoint in the ARTEMIS, ODIN and TITAN trials.
ARTEMIS
ODIN
TITAN
PREZISTA/rtv
800/100 mg
once daily
N=343
PREZISTA/rtv
800/100 mg
once daily
N=294
PREZISTA/rtv
600/100 mg
twice daily
N=296
PREZISTA/rtv
600/100 mg
twice daily
N=298
Total number of
virologic failures
a
, n (%)
40 (11.7%)
65 (22.1%)
54 (18.2%)
31 (10.4%)
Rebounders
24 (7.0%)
11 (3.7%)
11 (3.7%)
16 (5.4%)
Never suppressed
subjects
16 (4.7%)
54 (18.4%)
43 (14.5%)
15 (5.0%)
Number of subjects with virologic failure and paired baseline/endpoint genotypes, developing mutations
b
at
endpoint, n/N
Primary (major) PI
mutations
0/10
1/60
0/42
6/28
PI RAMs 3/10 7/60 4/42 10/28
Number of subjects with virologic failure and paired baseline/endpoint phenotypes, showing loss of
susceptibility to PIs at endpoint compared to baseline, n/N
PI
darunavir
0/10
1/58
0/41
3/26
amprenavir
0/10
1/58
0/40
0/22
atazanavir
0/10
2/56
0/40
0/22
indinavir
0/10
2/57
0/40
1/24
lopinavir
0/10
1/58
0/40
0/23
saquinavir
0/10
0/56
0/40
0/22
tipranavir
0/10
0/58
0/41
1/25
a
TLOVR non-VF censored algorithm based on HIV-1 RNA < 50 copies/ml, except for TITAN (HIV-1 RNA < 400 copies/ml)
b
IAS-USA lists
Cross-resistance
Darunavir FC was less than 10 for 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir,
indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to
most PIs remain susceptible to darunavir.
In the virologic failures of the ARTEMIS trial no cross-resistance with other PIs was observed.
Clinical results
Adult patients
For clinical trial results in ART-naïve adult patients, refer to the Summary of Product Characteristics
for PREZISTA 400 mg tablets.
Efficacy of PREZISTA 600 mg twice daily co
-
administered with 100 mg ritonavir twice daily in
ART-experienced patients
21
The evidence of efficacy of PREZISTA co-administered with ritonavir (600/100 mg twice daily) in
ART-experienced patients is based on the 96 weeks analysis of the Phase III trial TITAN in
ART-experienced lopinavir naïve patients, on the 48 week analysis of the Phase III trial ODIN in
ART-experienced patients with no DRV-RAMs, and on the analyses of 96 weeks data from the
Phase IIb trials POWER 1 and 2 in ART-experienced patients with high level of PI resistance.
TITAN
is a randomised, controlled, open-label Phase III trial comparing PREZISTA co-administered
with ritonavir (600/100 mg twice daily) versus lopinavir/ritonavir (400/100 mg twice daily) in
ART-experienced, lopinavir naïve HIV-1 infected adult patients. Both arms used an Optimised
Background Regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).
The table below shows the efficacy data of the 48 week analysis from the TITAN trial.
TITAN
Outcomes
PREZISTA/rtv
600/100 mg twice daily +
OBR
N=298
Lopinavir/ rtv
400/100 mg twice daily +
OBR
N=297
Treatment difference
(95% CI of difference)
HIV-1 RNA
< 50 copies/ml
a
70.8% (211)
60.3% (179)
10.5% (2.9; 18.1)
b
median CD4+ cell
count change from
baseline (x 10
6
/l)
c
88
81
a
Imputations according to the TLOVR algorithm
b
Based on a normal approximation of the difference in % response
c
NC=F
At 48 weeks non-inferiority in virologic response to the PREZISTA/ritonavir treatment, defined as the
percentage of patients with plasma HIV-1 RNA level < 400 and < 50 copies/ml, was demonstrated (at
the pre-defined 12% non-inferiority margin) for both ITT and OP populations. These results were
confirmed in the analysis of data at 96 weeks of treatment in the TITAN trial, with 60.4% of patients
in the PREZISTA/rtv arm having HIV-1 RNA < 50 copies/ml at week 96 compared to 55.2% in the
lopinavir/rtv arm [difference: 5.2%, 95% CI (-2.8–13.1)].
ODIN
is a Phase III, randomised, open-label trial comparing PREZISTA/rtv 800/100 mg once daily
versus PREZISTA/rtv 600/100 mg twice daily in ART-experienced HIV-1 infected patients with
screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V,
I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a screening HIV-1 RNA > 1,000 copies/ml.
Efficacy analysis is based on 48 weeks of treatment (see table below). Both arms used an optimised
background regimen (OBR) of ≥ 2 NRTIs.
ODIN
Outcomes
PREZISTA/rtv
800/100 mg once daily +
OBR
N=294
PREZISTA/rtv
600/100 mg twice daily +
OBR
N=296
Treatment difference
(95% CI of difference)
HIV-1 RNA
< 50 copies/ml
a
72.1% (212)
70.9% (210)
1.2% (-6.1; 8.5)
b
With Baseline HIV-1
RNA (copies/ml)
< 100,000
≥ 100,000
77.6% (198/255)
35.9% (14/39)
73.2% (194/265)
51.6% (16/31)
4.4% (-3.0; 11.9)
-15.7% (-39.2; 7.7)
With Baseline CD4+
cell count (x 10
6
/l)
≥ 100
< 100
75.1% (184/245)
57.1% (28/49)
72.5% (187/258)
60.5% (23/38)
2.6% (-5.1; 10.3)
-3.4% (-24.5; 17.8)
22
With HIV-1 clade
Type B
Type AE
Type C
Other
c
70.4% (126/179)
90.5% (38/42)
72.7% (32/44)
55.2% (16/29)
64.3% (128/199)
91.2% (31/34)
78.8% (26/33)
83.3% (25/30)
6.1% (-3.4; 15.6)
-0.7% (-14.0, 12.6)
-6.1% (-2.6, 13.7)
-28.2% (-51.0, -5.3)
mean CD4+ cell count
change from baseline
(x 10
6
/l)
e
108
112
-5
d
(-25; 16)
a
Imputations according to the TLOVR algorithm
b
Based on a normal approximation of the difference in % response
c
Clades A1, D, F1, G, K, CRF02_AG, CRF12_BF, and CRF06_CPX
d
Difference in means
e
Last Observation Carried Forward imputation
At 48 weeks, virologic response, defined as the percentage of patients with plasma HIV-1 RNA level
< 50 copies/ml, with PREZISTA/ritonavir 800/100 mg once daily treatment was demonstrated to be
non-inferior (at the pre-defined 12% non-inferiority margin) compared to PREZISTA/ritonavir
600/100 mg twice daily for both ITT and OP populations.
PREZISTA/rtv 800/100 mg once daily in ART-experienced patients should not be used in patients
with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA
≥ 100,000 copies/ml or CD4+ cell count < 100 cells x 10
6
/l (see section 4.2 and 4.4). Limited data is
available in patients with HIV-1 clades other than B.
POWER 1
and
POWER 2
are randomised, controlled trials comparing PREZISTA co-administered
with ritonavir (600/100 mg twice daily) with a control group receiving an investigator-selected PI(s)
regimen in HIV-1 infected patients who had previously failed more than 1 PI containing regimen. An
OBR consisting of at least 2 NRTIs with or without enfuvirtide (ENF) was used in both trials.
The table below shows the efficacy data of the 48-week and 96-week analyses from the pooled
POWER 1 and POWER 2 trials.
POWER 1 and POWER 2 pooled data
Week 48
Week 96
Outcomes
PREZISTA/rtv
600/100 mg
twice daily
n=131
Control
n=124
Treatment
difference
PREZISTA/rtv
600/100 mg
twice daily
n=131
Control
n=124
Treatment
difference
HIV RNA
< 50 copies/ml
a
45.0%
(59)
11.3%
(14)
33.7%
(23.4%; 44.1%)
c
38.9%
(51)
8.9%
(11)
30.1%
(20.1; 40.0)
c
CD4+ cell count
mean change from
baseline (x 10
6
/l)
b
103
17
86
(57; 114)
c
133
15
118
(83.9; 153.4)
c
a
Imputations according to the TLOVR algorithm
b
Last Observation Carried Forward imputation
c
95% confidence intervals.
Analyses of data through 96 weeks of treatment in the POWER trials demonstrated sustained
antiretroviral efficacy and immunologic benefit.
Out of the 59 patients who responded with complete viral suppression (< 50 copies/ml) at week 48,
47 patients (80% of the responders at week 48) remained responders at week 96.
Baseline genotype or phenotype and virologic outcome
Baseline genotype and darunavir FC (shift in susceptibility relative to reference) were shown to be a
predictive factor of virologic outcome.
Proportion (%) of patients with response (HIV-1 RNA < 50 copies/ml at week 24) to PREZISTA
co-administered with ritonavir (600/100 mg twice daily) by baseline genotype
a
, and baseline
darunavir FC and by use of enfuvirtide (ENF): As treated analysis of the POWER and DUET trials.
23
Number of baseline mutations
a
Baseline DRV FC
b
Response (HIV-1
RNA < 50 copies/ml
at week 24)
%, n/N
All
ranges
0-2
3
4
All
ranges
10 10-40 > 40
All patients
45%
455/1,014
54%
359/660
39%
67/172
12%
20/171
45%
455/1,014
55%
364/659
29%
59/203
8%
9/118
Patients with
no/non-naïve use of
ENF
c
39%
290/741
50%
238/477
29%
35/120
7%
10/135
39%
290/741
51%
244/477
17%
25/147
5%
5/94
Patients with naïve
use of ENF
d
60%
165/273
66%
121/183
62%
32/52
28%
10/36
60%
165/273
66%
120/182
61%
34/56
17%
4/24
a
Number of mutations from the list of mutations associated with a diminished response to PREZISTA/ritonavir (V11I, V32I, L33F, I47V,
I50V, I54L or M, T74P, L76V, I84V or L89V)
b
fold change in EC
50
c
“Patients with no/non-naïve use of ENF” are patients who did not use ENF or who used ENF but not for the first time
d
“Patients with naïve use of ENF” are patients who used ENF for the first time
Children from the age of 6 years and adolescents
DELPHI is an open-label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and
efficacy of PREZISTA with low dose ritonavir in 80 ART-experienced HIV-1 infected paediatric
patients aged 6 to 17 years and weighing at least 20 kg. These patients received PREZISTA/ritonavir
in combination with other antiretroviral agents (see section 4.2 for dosage recommendations per body
weight). Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least
1.0 log
10
versus baseline.
In the study, patients who were at risk of discontinuing therapy due to intolerance of ritonavir oral
solution (e.g. taste aversion) were allowed to switch to the capsule formulation. Of the 44 patients
taking ritonavir oral solution, 27 switched to the 100 mg capsule formulation and exceeded the
weight-based ritonavir dose without changes in observed safety.
DELPHI
Outcomes at week 48
PREZISTA/ritonavir
N=80
HIV-1 RNA < 50 copies/ml
a
47.5% (38)
CD4+ cell count mean change from baseline
b
147
a
Imputations according to the TLOVR algorithm.
b
Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0.
According to the TLOVR non-virologic failure censored algorithm 24 (30.0%) patients experienced
virological failure, of which 17 (21.3%) patients were rebounders and 7 (8.8%) patients were
non-responders.
The European Medicines Agency has deferred the obligation to submit the results of studies with
PREZISTA in one or more subsets of the paediatric population in Human immunodeficiency virus
infection, as per PIP decision in the granted indication. See section 4.2 for information on paediatric
use.
5.2 Pharmacokinetic properties
The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in
healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1
infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected
patients compared to healthy subjects may be explained by the higher concentrations of alpha-1-acid
glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG
and, therefore, higher plasma concentrations.
Darunavir is primarily metabolised by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the
plasma concentrations of darunavir considerably.
24
Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of
darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.
The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37%
and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overall
pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic
exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with
ritonavir at 100 mg twice daily (see section 4.4).
When administered without food, the relative bioavailability of darunavir in the presence of low dose
ritonavir is 30% lower as compared to intake with food. Therefore, PREZISTA tablets should be taken
with ritonavir and with food. The type of food does not affect exposure to darunavir.
Distribution
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma
alpha-1-acid glycoprotein.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l
(Mean ± SD) and increased to 131 ± 49.9 l (Mean ± SD) in the presence of 100 mg twice-daily
ritonavir.
Metabolism
In vitro
experiments with human liver microsomes (HLMs) indicate that darunavir primarily
undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and
almost exclusively by isozyme CYP3A4. A
14
C-darunavir trial in healthy volunteers showed that a
majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due
to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in
humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild
type HIV.
Elimination
After a 400/100 mg
14
C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the
administered dose of
14
C-darunavir could be retrieved in faeces and urine, respectively. Unchanged
darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine,
respectively. The terminal elimination half-life of darunavir was approximately 15 hours when
combined with ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was
32.8 l/h and 5.9 l/h, respectively.
Special Populations
Paediatric population
The pharmacokinetics of darunavir in combination with ritonavir in 74 treatment-experienced
paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the administered
weight-based doses of PREZISTA/ritonavir resulted in darunavir exposure comparable to that in
adults receiving PREZISTA/ritonavir 600/100 mg twice daily (see section 4.2).
Elderly
Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics
are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients
(n=12, age 65) (see section 4.4). However, only limited data were available in patients above the age
of 65 year.
Gender
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV
infected females compared to males. This difference is not clinically relevant.
Renal impairment
25
Results from a mass balance study with
14
C-darunavir with ritonavir showed that approximately 7.7%
of the administered dose of darunavir is excreted in the urine unchanged.
Although darunavir has not been studied in patients with renal impairment, population
pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly
affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20)
(see sections 4.2 and 4.4).
Hepatic impairment
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with
PREZISTA co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total
plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate
(Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects.
However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and
100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown
therefore, PREZISTA should be used with caution. The effect of severe hepatic impairment on the
pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).
5.3 Preclinical safety data
Animal toxicology studies have been conducted at exposures up to clinical exposure levels with
darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.
In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment
with darunavir. In rodents the target organs identified were the haematopoietic system, the blood
coagulation system, liver and thyroid. A variable but limited decrease in red blood cell-related
parameters was observed, together with increases in activated partial thromboplastin time.
Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and
thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small
increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the
pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity
findings or target organs were identified up to exposures equivalent to clinical exposure at the
recommended dose.
In a study conducted in rats, the number of corpora lutea and implantations were decreased in the
presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir
treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the
clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in
rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The
exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and
postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient
reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening
of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups
that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation.
These effects may be secondary to pup exposure to the active substance via the milk and/or maternal
toxicity. No post weaning functions were affected with darunavir alone or in combination with
ritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with
convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in
adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the
exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to
immaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalities
were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at
500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were
comparable to those observed in adult rats.
Due to uncertainties regarding the rate of development of the human blood brain barrier and liver
enzymes, PREZISTA with low dose ritonavir should not be used in paediatric patients below 3 years
of age.
26
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up
to 104 weeks. Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50,
150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of
hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid
follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a
statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or
rats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limited
relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme
induction and increased thyroid hormone elimination, which predispose rats, but not humans, to
thyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavir
were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans
at the recommended therapeutic doses.
After 2 years administration of darunavir at exposures at or below the human exposure, kidney
changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).
Darunavir was not mutagenic or genotoxic in a battery of
in vitro
and
in vivo
assays including
bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and
in vivo
micronucleus test in mice.
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Colloidal anhydrous silica
Crospovidone
Magnesium stearate
Tablet film-coat
Poly(vinyl alcohol) – partially hydrolyzed
Macrogol 3350
Titanium dioxide (E171)
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 480 tablets, fitted
with polypropylene (PP) child resistant closure.
One bottle
6.6 Special precautions for disposal
No special requirements.
27
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/06/380/005
Date of first authorisation: 12 February 2007
Date of latest renewal: 12 February 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
28
PREZISTA 150 mg film-coated tablets
Each film-coated tablet contains 150 mg of darunavir (as ethanolate).
For a full list of excipients, see section 6.1.
Film-coated tablet.
White oval shaped tablet of 13.7 mm, debossed with “150” on one side and “TMC” on the other side.
PREZISTA, co-administered with low dose ritonavir is indicated in combination with other
antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus
(HIV-1) infection.
PREZISTA 150 mg tablets may be used to provide suitable dose regimens (see section 4.2):
For the treatment of HIV-1 infection in antiretroviral treatment (ART) experienced adult
patients, including those that have been highly pre-treated.
For the treatment of HIV-1 infection in ART-experienced children and adolescents from the age
of 6 years and at least 20 kg body weight.
In deciding to initiate treatment with PREZISTA co-administered with low dose ritonavir careful
consideration should be given to the treatment history of the individual patient and the patterns of
mutations associated with different agents. Genotypic or phenotypic testing (when available) and
treatment history should guide the use of PREZISTA.
Therapy should be initiated by a physician experienced in the management of HIV infection. After
therapy with PREZISTA has been initiated, patients should be advised not to alter the dosage or
discontinue therapy without instruction of their physician.
PREZISTA must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in
combination with other antiretroviral medicinal products. The Summary of Product Characteristics of
ritonavir must therefore be consulted prior to initiation of therapy with PREZISTA.
Patients should be instructed to take PREZISTA with low dose ritonavir within 30 minutes after
completion of a meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5
and 5.2).
Adults
ART-experienced patients
The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily
taken with food. PREZISTA 150 mg tablets can be used to construct the twice daily 600 mg
regimen.
29
The use of 150 mg tablets to achieve the recommended dose is appropriate when there is a
possibility of hypersensitivity to specific colouring agents, or difficulty in swallowing the
300 mg or 600 mg tablets.
For ART-experienced adults with no darunavir resistance associated mutations (DRV-RAMs)*
and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10
6
/l,
a dose regimen of 800 mg once daily with ritonavir 100 mg once daily taken with food may be
used (see the Summary of Product Characteristics for PREZISTA 400 mg tablets).
*
DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V
ART-naïve patients
For dosage recommendations in ART-naïve patients see the Summary of Product Characteristics for
PREZISTA 400 mg tablets.
Paediatric population
ART-experienced paediatric patients (6 to 17 years of age and weighing at least 20 kg)
Recommended dose for treatment-experienced paediatric patients (6 to 17 years of age) for
PREZISTA tablets and ritonavir
Body weight (kg)
Dose
≥ 20 kg–< 30 kg
375 mg PREZISTA/50 mg ritonavir twice daily
≥ 30 kg–< 40 kg
450 mg PREZISTA/60 mg ritonavir twice daily
≥ 40 kg
600 mg PREZISTA/100 mg ritonavir twice daily
The recommended dose of PREZISTA with low dose ritonavir should not exceed the recommended
adult dose (600/100 mg twice daily).
The use of only 75 mg and 150 mg tablets to achieve the recommended dose of PREZISTA could be
appropriate when there is a possibility of hypersensitivity to specific colouring agents.
ART-experienced children less than 6 years of age or less than 20 kg body weight, and ART-naïve
paediatric patients
There are insufficient data on the use of PREZISTA with low dose ritonavir in children less than
6 years of age or less than 20 kg body weight. Hence, PREZISTA is not recommended for use in this
group (see sections 4.4 and 5.3).
Elderly
Limited information is available in this population and therefore PREZISTA should be used with
caution in this age group (see sections 4.4 and 5.2).
Hepatic impairment
Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with
mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, however,
PREZISTA should be used with caution in these patients. No pharmacokinetic data are available in
patients with severe hepatic impairment. Severe hepatic impairment could result in an increase of
darunavir exposure and a worsening of its safety profile. Therefore, PREZISTA must not be used in
patients with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).
Renal impairment
No dose adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).
In case a dose of PREZISTA and/or ritonavir was missed within 6 hours of the time it is usually taken,
patients should be instructed to take the prescribed dose of PREZISTA and ritonavir with food as soon
as possible. If this was noticed later than 6 hours of the time it is usually taken, the missed dose should
not be taken and the patient should resume the usual dosing schedule.
This guidance is based on the 15 hour half-life of darunavir in the presence of ritonavir and the
recommended dosing interval of approximately 12 hours.
30
Hypersensitivity to the active substance or to any of the excipients.
Patients with severe (Child-Pugh Class C) hepatic impairment.
Combination of rifampicin with PREZISTA with concomitant low dose ritonavir is contraindicated
(see section 4.5).
The combination product lopinavir/ritonavir should not be used with PREZISTA because
co-administration causes large decreases in darunavir concentrations, which may in turn significantly
decrease the darunavir therapeutic effect (see section 4.5).
Herbal preparations containing St John’s wort (
Hypericum perforatum
) must not be used while taking
PREZISTA due to the risk of decreased plasma concentrations and reduced clinical effects of
darunavir (see section 4.5).
Co-administration of PREZISTA with low dose ritonavir, with active substances that are highly
dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with
serious and/or life-threatening events is contraindicated. These active substances include e.g.
antiarrhythmics (amiodarone, bepridil, quinidine, systemic lidocaine), alfuzosin, antihistamines
(astemizole, terfenadine), ergot derivatives (e.g. dihydroergotamine, ergonovine, ergotamine,
methylergonovine), gastrointestinal motility agents (cisapride), neuroleptics (pimozide, sertindole),
sedatives/hypnotics [triazolam, midazolam administered orally (for caution on parenterally
administered midazolam, see section 4.5)], sildenafil (when used for the treatment of pulmonary
arterial hypertension) and HMG-CoA reductase inhibitors (simvastatin and lovastatin) (see section
4.5).
Patients should be advised that current antiretroviral therapy does not cure HIV and has not been
proven to prevent the transmission of HIV to others through blood or sexual contact. Appropriate
precautions should continue to be employed.
Regular assessment of virological response is advised. In the setting of lack or loss of virological
response, resistance testing should be performed.
PREZISTA should only be used in combination with low dose ritonavir as a pharmacokinetic
enhancer (see section 5.2).
Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect
darunavir concentrations and is not recommended.
Darunavir binds predominantly to 1-acid glycoprotein. This protein binding is concentration
dependent indicative for saturation of binding. Therefore, protein displacement of medicinal products
highly bound to 1-acid glycoprotein cannot be ruled out (see section 4.5).
ART-experienced patients – once daily dosing
PREZISTA/rtv 800/100 mg once daily in ART-experienced patients should not be used in patients
with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA
≥ 100,000 copies/ml or CD4+ cell count < 100 cells x 10
6
/l (see section 4.2). The efficacy and safety
of PREZISTA/rtv 800/100 mg once daily in combination with optimised background regimen (OBR)
for the treatment of HIV-1 infection in ART-experienced adults with no darunavir resistance
associated mutations (DRV-RAMs) was evaluated in one trial with a duration of 48 weeks.
Combinations with OBRs other than ≥ 2 NRTIs have not been studied in this population. Limited data
is available in patients with HIV-1 clades other than B (see section 5.1).
Paediatric population
31
PREZISTA is not recommended for use in children below 6 years of age or less than 20 kg body
weight (see sections 4.2 and 5.3).
Elderly
As limited information is available on the use of PREZISTA in patients aged 65 and over, caution
should be exercised in the administration of PREZISTA in elderly patients, reflecting the greater
frequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2
and 5.2).
Severe skin reactions
During the clinical development program (N=3,063), severe skin reactions, which may be
accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients.
Stevens-Johnson Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience
toxic epidermal necrolysis has been reported. Discontinue PREZISTA/rtv immediately if signs or
symptoms of severe skin reactions develop. These can include but are not limited to severe rash or
rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions,
conjunctivitis, hepatitis and/or eosinophilia
.
Rash occurred more commonly in treatment-experienced patients receiving regimens containing
PREZISTA + raltegravir compared to patients receiving PREZISTA without raltegravir or raltegravir
without PREZISTA (see section 4.8).
Darunavir contains a sulphonamide moiety. PREZISTA should be used with caution in patients with a
known sulphonamide allergy.
Hepatotoxicity
Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv.
During the clinical development program (N=3,063), hepatitis was reported in 0.5% of patients
receiving combination antiretroviral therapy with PREZISTA/rtv. Patients with pre-existing liver
dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function
abnormalities including severe and potentially fatal hepatic adverse events. In case of concomitant
antiviral therapy for hepatitis B or C, please refer to the relevant product information for these
medicinal products.
Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv and
patients should be monitored during treatment. Increased AST/ALT monitoring should be considered
in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment
elevations of transaminases, especially during the first several months of PREZISTA/rtv treatment.
If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of
liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver
tenderness, hepatomegaly) in patients using PREZISTA/rtv, interruption or discontinuation of
treatment should be considered promptly.
Patients with coexisting conditions
Hepatic impairment
The safety and efficacy of PREZISTA have not been established in patients with severe underlying
liver disorders and PREZISTA is therefore contraindicated in patients with severe hepatic impairment.
Due to an increase in the unbound darunavir plasma concentrations, PREZISTA should be used with
caution in patients with mild or moderate hepatic impairment (see sections 4.2, 4.3 and 5.2).
Renal impairment
No special precautions or dose adjustments are required in patients with renal impairment. As
darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be
significantly removed by haemodialysis or peritoneal dialysis. Therefore, no special precautions or
dose adjustments are required in these patients (see sections 4.2 and 5.2).
32
Haemophiliac patients
There have been reports of increased bleeding, including spontaneous skin haematomas and
haemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additional
factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or
reintroduced if treatment had been discontinued. A causal relationship has been suggested, although
the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made
aware of the possibility of increased bleeding.
Diabetes mellitus/Hyperglycaemia
New onset diabetes mellitus, hyperglycaemia, or exacerbation of existing diabetes mellitus has been
reported in patients receiving antiretroviral therapy, including PIs. In some of these patients 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 and metabolic disorders
Combination antiretroviral therapy has been associated with 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 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 measurement of
fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate
(see section 4.8).
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.
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 weeks or months of initiation of CART. Relevant
examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and
pneumonia caused by
Pneumocystis jirovecii
(formerly known as
Pneumocystis carinii
). Any
inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition,
reactivation of herpes simplex and herpes zoster has been observed in clinical studies with PREZISTA
co-administered with low dose ritonavir.
Interactions with medicinal products
Several of the interaction studies have been performed at lower than recommended doses of darunavir.
The effects on co-administered medicinal products may thus be underestimated and clinical
monitoring of safety may be indicated. For full information on interactions with other medicinal
products see section 4.5.
Efavirenz in combination with PREZISTA/rtv 800/100 mg once daily may result in sub-optimal
darunavir C
min
. If efavirenz is to be used in combination with PREZISTA/rtv, the PREZISTA/rtv
600/100 mg twice daily regimen should be used. See the Summary of Product Characteristics for
PREZISTA 75 mg, 150 mg, 300 mg or 600 mg tablets (see section 4.5).
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and
strong inhibitors of CYP3A and Pgp (see section 4.5).
33
Darunavir and ritonavir are both inhibitors of the CYP3A isoform. Co-administration of darunavir and
ritonavir and medicinal products primarily metabolised by CYP3A may result in increased systemic
exposure to such medicinal products, which could increase or prolong their therapeutic effect and
adverse reactions.
PREZISTA co-administered with low dose ritonavir must not be combined with medicinal products
that are highly dependent on CYP3A for clearance and for which increased systemic exposure is
associated with serious and/or life-threatening events (narrow therapeutic index). These medicinal
products include amiodarone, bepridil, quinidine, systemic lidocaine, astemizole, alfuzosin,
terfenadine, sildenafil (when used for the treatment of pulmonary arterial hypertension), midazolam
administered orally, triazolam, cisapride, pimozide, sertindole, simvastatin, lovastatin and the ergot
alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine) (see section 4.3).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in
the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in
combination with ritonavir at 100 mg twice daily. Therefore, PREZISTA must only be used in
combination with low dose ritonavir as a pharmacokinetic enhancer (see sections 4.4 and 5.2).
A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes
CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and
inhibition of CYP2D6 activity in the presence of PREZISTA/rtv, which may be attributed to the
presence of low dose ritonavir. Co-administration of darunavir and ritonavir and medicinal products
which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result
in increased plasma concentrations of these medicinal products, which could increase or prolong their
therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir and medicinal
products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone)
may result in decreased systemic exposure to such medicinal products, which could decrease or
shorten their therapeutic effect.
Although the effect on CYP2C8 has only been studied
in vitro
, co-administration of darunavir and
ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone,
repaglinide) may result in decreased systemic exposure to such medicinal products, which could
decrease or shorten their therapeutic effect.
Medicinal products that affect darunavir/ritonavir exposure
Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity
would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma
concentrations of darunavir and ritonavir (e.g. rifampicin, St John’s wort, lopinavir).
Co-administration of darunavir and ritonavir and other medicinal products that inhibit CYP3A may
decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of
darunavir and ritonavir (e.g. indinavir, systemic azoles like ketoconazole and clotrimazole). These
interactions are described in the interaction table below.
Interaction table
Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products
are listed in the table below (not determined as “ND”). The direction of the arrow for each
pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being
within (↔), below (↓) or above (↑) the 80-125% range.
Several of the interaction studies (indicated by
#
in the table below) have been performed at lower than
recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The
effects on co-administered medicinal products may thus be underestimated and clinical monitoring of
safety may be indicated.
INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal products by
therapeutic areas
Recommendations concerning
co-administration
34
Interaction
Geometric mean change (%)
ANTIRETROVIRALS
Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine
400 mg once daily
didanosine AUC ↓ 9%
didanosine C
min
ND
didanosine C
max
↓ 16%
darunavir AUC ↔
darunavir C
min
↔
darunavir C
max
↔
PREZISTA co-administered with
low dose ritonavir and didanosine
can be used without dose
adjustments.
Didanosine is to be administered on
an empty stomach, thus it should be
administered 1 hour before or
2 hours after PREZISTA/ritonavir
given with food.
Tenofovir
300 mg once daily
tenofovir AUC ↑ 22%
tenofovir C
min
↑ 37%
tenofovir C
max
↑ 24%
#
darunavir AUC ↑ 21%
#
Monitoring of renal function may
be indicated when PREZISTA
co-administered with low dose
ritonavir is given in combination
with tenofovir, particularly in
patients with underlying systemic or
renal disease, or in patients taking
nephrotoxic agents.
darunavir C
min
↑ 24%
#
darunavir C
max
↑ 16%(↑ tenofovir from
effect on MDR-1 transport in the renal
tubules)
Abacavir
Emtricitabine
Lamivudine
Stavudine
Zidovudine
Not studied. Based on the different
elimination pathways of the other NRTIs
zidovudine, emtricitabine, stavudine,
lamivudine, that are primarily renally
excreted, and abacavir for which
metabolism is not mediated by CYP450,
no interactions are expected for these
medicinal compounds and PREZISTA
co-administered with low dose ritonavir.
PREZISTA co-administered with
low dose ritonavir can be used with
these NRTIs without dose
adjustment.
Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg once daily
efavirenz AUC ↑ 21%
efavirenz C
min
↑ 17%
efavirenz C
max
↑ 15%
#
Clinical monitoring for central
nervous system toxicity associated
with increased exposure to
efavirenz may be indicated when
PREZISTA co-administered with
low dose ritonavir is given in
combination with efavirenz.
darunavir AUC ↓ 13%
#
darunavir C
min
↓ 31%
#
darunavir C
max
↓ 15%
(↑ efavirenz from CYP3A inhibition)
(↓ darunavir from CYP3A induction)
Efavirenz in combination with
PREZISTA/rtv 800/100 mg once
daily may result in sub-optimal
darunavir C
min
. If efavirenz is to be
used in combination with
PREZISTA/rtv, the PREZISTA/rtv
600/100 mg twice daily regimen
should be used (see section 4.4).
Etravirine
100 mg twice daily
etravirine AUC ↓ 37%
etravirine C
min
↓ 49%
etravirine C
max
↓ 32%
darunavir AUC ↑ 15%
darunavir C
min
↔
darunavir C
max
↔
PREZISTA co-administered with
low dose ritonavir and etravirine
200 mg twice daily
can be used
without dose adjustments.
Nevirapine
200 mg twice daily
nevirapine AUC ↑ 27%
nevirapine C
min
↑ 47%
nevirapine C
max
↑ 18%
#
darunavir: concentrations
were consistent with historical data
(↑ nevirapine from CYP3A inhibition)
PREZISTA co-administered with
low dose ritonavir and nevirapine
can be used without dose
adjustments.
Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir
†
35
Atazanavir
300 mg once daily
atazanavir AUC ↔
atazanavir C
min
↑ 52%
atazanavir C
max
↓ 11%
#
darunavir AUC ↔
#
PREZISTA co-administered with
low dose ritonavir and atazanavir
can be used without dose
adjustments.
darunavir C
min
↔
#
darunavir C
max
↔
Atazanavir: comparison of
atazanavir/ritonavir 300/100 mg once daily
vs. atazanavir 300 mg once daily in
combination with darunavir/ritonavir
400/100 mg twice daily.
Darunavir: comparison of
darunavir/ritonavir 400/100 mg twice daily
vs. darunavir/ritonavir 400/100 mg twice
daily in combination with atazanavir
300 mg once daily.
Indinavir
800 mg twice daily
indinavir AUC ↑ 23%
indinavir C
min
↑ 125%
indinavir C
max
↔
#
When used in combination with
PREZISTA co-administered with
low dose ritonavir, dose adjustment
of indinavir from 800 mg twice
daily to 600 mg twice daily may be
warranted in case of intolerance.
darunavir AUC ↑ 24%
#
darunavir C
min
↑ 44%
#
darunavir C
max
↑ 11%
Indinavir: comparison of
indinavir/ritonavir 800/100 mg twice daily
vs. indinavir/darunavir/ritonavir
800/400/100 mg twice daily.
Darunavir: comparison of
darunavir/ritonavir 400/100 mg twice daily
vs. darunavir/ritonavir 400/100 mg in
combination with indinavir 800 mg twice
daily.
Saquinavir
1,000 mg twice daily
#
darunavir AUC ↓ 26%
It is not recommended to combine
PREZISTA co-administered with
low dose ritonavir with saquinavir.
#
darunavir C
min
↓ 42%
darunavir C
max
↓ 17%
saquinavir AUC ↓ 6%
saquinavir C
min
↓ 18%
saquinavir C
max
↓ 6%
Saquinavir: comparison of
saquinavir/ritonavir 1,000/100 mg twice
daily vs. saquinavir/darunavir/ritonavir
1,000/400/100 mg twice daily
Darunavir: comparison of
darunavir/ritonavir 400/100 mg twice daily
vs. darunavir/ritonavir 400/100 mg in
combination with saquinavir 1,000 mg
twice daily.
Protease inhibitors (PIs) - with co-administration of low dose ritonavir
†
36
#
Lopinavir/ritonavir
400/100 mg twice daily
lopinavir AUC ↑ 9%
lopinavir C
min
↑ 23%
lopinavir C
max
↓ 2%
darunavir AUC ↓ 38%
‡
darunavir C
min
↓ 51%
‡
darunavir C
max
↓ 21%
‡
lopinavir AUC ↔
lopinavir C
min
↑ 13%
lopinavir C
max
↑ 11%
darunavir AUC ↓ 41%
darunavir C
min
↓ 55%
darunavir C
max
↓ 21%
‡
Due to a decrease in the exposure
(AUC) of darunavir by 40%,
appropriate doses of the
combination have not been
established. Hence, concomitant use
of PREZISTA co-administered with
low dose ritonavir and the
combination product
lopinavir/ritonavir is
contraindicated (see section 4.3).
Lopinavir/ritonavir
533/133.3 mg twice
daily
based upon non dose normalised values
CCR5 ANTAGONIST
Maraviroc
150 mg twice daily
maraviroc AUC ↑ 305%
maraviroc C
min
ND
maraviroc C
max
↑ 129%
darunavir, ritonavir concentrations were
consistent with historical data
The maraviroc dose should be
150 mg twice daily when
co-administered with PREZISTA
with low dose ritonavir.
ANTIARRHYTHMIC
Digoxin
0.4 mg single dose
digoxin AUC ↑ 61%
digoxin C
min
ND
digoxin C
max
↑ 29%
(↑ digoxin from probable inhibition of
Pgp)
Given that digoxin has a narrow
therapeutic index, it is
recommended that the lowest
possible dose of digoxin should
initially be prescribed in case
digoxin is given to patients on
darunavir/ritonavir therapy. The
digoxin dose should be carefully
titrated to obtain the desired clinical
effect while assessing the overall
clinical state of the subject.
ANTIBIOTIC
Clarithromycin
500 mg twice daily
clarithromycin AUC ↑ 57%
clarithromycin C
min
↑ 174%
clarithromycin C
max
↑ 26%
#
darunavir AUC ↓ 13%
#
Caution should be exercised when
clarithromycin is combined with
PREZISTA co-administered with
low dose ritonavir.
darunavir C
min
↑ 1%
#
darunavir C
max
↓ 17%
14-OH-clarithromycin concentrations were
not detectable when combined with
PREZISTA/ritonavir.
(↑ clarithromycin from CYP3A inhibition
and possible Pgp inhibition)
ANTICOAGULANT
Warfarin
Not studied. Warfarin concentrations may
be affected when co-administered with
darunavir with low dose ritonavir.
It is recommended that the
international normalised ratio (INR)
be monitored when warfarin is
combined with PREZISTA
co-administered with low dose
ritonavir.
ANTICONVULSANTS
Phenobarbital
Phenytoin
Not studied. Phenobarbital and phenytoin
are expected to decrease plasma
concentrations of darunavir.
(induction of CYP450 enzymes)
PREZISTA co-administered with
low dose ritonavir should not be
used in combination with these
medicines.
37
Carbamazepine
200 mg twice daily
carbamazepine AUC ↑ 45%
carbamazepine C
min
↑ 54%
carbamazepine C
max
↑ 43%
darunavir AUC ↔
darunavir C
min
↓ 15%
darunavir C
max
↔
No dose adjustment for
PREZISTA/ritonavir is
recommended. If there is a need to
combine PREZISTA/ritonavir and
carbamazepine, patients should be
monitored for potential
carbamazepine-related adverse
events. Carbamazepine
concentrations should be monitored
and its dose should be titrated for
adequate response. Based upon the
findings, the carbamazepine dose
may need to be reduced by 25% to
50% in the presence of
PREZISTA/ritonavir.
ANTIFUNGALS
Voriconazole
Not studied. Ritonavir may decrease
plasma concentrations of voriconazole.
(induction of CYP450 enzymes by
ritonavir)
Voriconazole should not be
combined with PREZISTA
co-administered with low dose
ritonavir unless an assessment of
the benefit/risk ratio justifies the use
of voriconazole.
Ketoconazole
200 mg twice daily
ketoconazole AUC ↑ 212%
ketoconazole C
min
↑ 868%
ketoconazole C
max
↑ 111%
#
darunavir AUC ↑ 42%
#
darunavir C
min
↑ 73%
#
Caution is warranted and clinical
monitoring is recommended. When
co-administration is required the
daily dose of ketoconazole should
not exceed 200 mg.
darunavir C
max
↑ 21%
(CYP3A inhibition)
Itraconazole
Not studied. Concomitant systemic use of
itraconazole and darunavir co-administered
with low dose ritonavir may increase
plasma concentrations of darunavir.
Simultaneously, plasma concentrations of
itraconazole may be increased by
darunavir co-administered with low dose
ritonavir.
(CYP3A inhibition)
Caution is warranted and clinical
monitoring is recommended. When
co-administration is required the
daily dose of itraconazole should
not exceed 200 mg.
Clotrimazole
Not studied. Concomitant systemic use of
clotrimazole and darunavir
co-administered with low dose ritonavir
may increase plasma concentrations of
darunavir.
darunavir AUC
24h
↑ 33% (based on
population pharmacokinetic model)
Caution is warranted and clinical
monitoring is recommended, when
co-administration of clotrimazole is
required.
ANTIGOUT MEDICINES
Colchicine
Not studied. Concomitant use of colchicine
and darunavir co-administered with low
dose ritonavir may increase the exposure
to colchicine.
A reduction in colchicine dosage or
an interruption of colchicine
treatment is recommended in
patients with normal renal or
hepatic function if treatment with
PREZISTA co-administered with
low dose ritonavir is required.
Patients with renal or hepatic
impairment should not be given
colchicine with PREZISTA
co-administered with low dose
ritonavir (see section 4.4).
ANTIMYCOBACTERIALS
38
Rifampicin
Not studied. Rifampicin is a strong
CYP3A inducer and has been shown to
cause profound decreases in concentrations
of other protease inhibitors, 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 low dose ritonavir, a high
frequency of liver reactions was seen.
(CYP450 enzyme induction)
The combination of rifampicin and
PREZISTA with concomitant low
dose ritonavir is contraindicated
(see section 4.3).
Rifabutin
150 mg once every
other day
rifabutin AUC
**
↑ 55%
rifabutin C
min
**
↑ ND
rifabutin C
max
**
↔
darunavir AUC ↑ 53%
darunavir C
min
↑ 68%
darunavir C
max
↑ 39%
**
A dosage reduction of rifabutin by
75% of the usual dose of
300 mg/day (i.e. rifabutin 150 mg
once every other day) and increased
monitoring for rifabutin related
adverse events is warranted in
patients receiving the combination.
In case of safety issues, a further
increase of the dosing interval for
rifabutin and/or monitoring of
rifabutin levels should be
considered.
Consideration should be given to
official guidance on the appropriate
treatment of tuberculosis in HIV
infected patients.
Based upon the safety profile of
PREZISTA/ritonavir, the increase
in darunavir exposure in the
presence of rifabutin does not
warrant a dose adjustment for
PREZISTA/ritonavir.
Based on pharmacokinetic
modeling, this dosage reduction of
75% is also applicable if patients
receive rifabutin at doses other than
300 mg/day.
sum of active moieties of rifabutin (parent drug
+ 25-
O-
desacetyl metabolite)
The interaction trial showed a comparable
daily systemic exposure for rifabutin
between treatment at 300 mg once daily
alone and 150 mg once every other day in
combination with PREZISTA/ritonavir
(600/100 mg twice daily) with an about
10-fold increase in the daily exposure to
the active metabolite
25-
O-
desacetylrifabutin. Furthermore,
AUC of the sum of active moieties of
rifabutin (parent drug + 25-
O-
desacetyl
metabolite) was increased 1.6-fold, while
C
max
remained comparable.
Data on comparison with a 150 mg once
daily reference dose is lacking.
(Rifabutin is an inducer and substrate of
CYP3A.) An increase of systemic
exposure to darunavir was observed when
PREZISTA co-administered with 100 mg
ritonavir was co-administered with
rifabutin (150 mg once every other day).
BENZODIAZEPINES
Midazolam
Not studied. Midazolam is extensively
metabolised by CYP3A. Co-administration
with PREZISTA/ritonavir may cause a
large increase in the concentration of this
benzodiazepine.
PREZISTA/ritonavir should not be
co-administered with orally
administered midazolam (see
section 4.3); whereas, caution
should be used with
co-administration of
PREZISTA/ritonavir and parenteral
midazolam.
If PREZISTA/ritonavir is
co-administered with parenteral
midazolam, it should be done in an
intensive care unit (ICU) or similar
setting, which ensures close clinical
monitoring and appropriate medical
management in case of respiratory
depression and/or prolonged
sedation. Dose adjustment for
midazolam should be considered,
especially if more than a single dose
of midazolam is administered.
Based on data for other CYP3A inhibitors,
plasma concentrations of midazolam are
expected to be significantly higher when
midazolam is given orally with
PREZISTA co-administered with low dose
ritonavir.
Co-administration of parenteral midazolam
with PREZISTA/ritonavir may cause a
large increase in the concentration of this
benzodiazepine. Data from concomitant
use of parenteral midazolam with other
protease inhibitors suggest a possible 3-4
fold increase in midazolam plasma levels.
39
CALCIUM CHANNEL BLOCKERS
Felodipine
Nicardipine
Nifedipine
Not studied. PREZISTA co-administered
with low dose ritonavir can be expected to
increase the plasma concentrations of
calcium channel antagonists.
(CYP3A inhibition)
Clinical monitoring of therapeutic
and adverse effects is recommended
when these medicines are
concomitantly administered with
PREZISTA with low dose ritonavir.
CORTICOSTEROIDS
Fluticasone
Budesonide
In a clinical study where ritonavir 100 mg
capsules twice daily were co-administered
with 50 g intranasal fluticasone
propionate (4 times daily) for 7 days in
healthy subjects, fluticasone propionate
plasma concentrations increased
significantly, whereas the intrinsic cortisol
levels decreased by approximately 86%
(90% CI 82-89%). Greater effects may be
expected when fluticasone 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; this
could also occur with other corticosteroids
metabolised via the P4503A pathway, e.g.,
budesonide. The effects of high fluticasone
systemic exposure on ritonavir plasma
levels are unknown.
Concomitant administration of
PREZISTA co-administered with
low dose ritonavir and these
glucocorticoids is not recommended
unless the potential benefit of
treatment outweighs the risk of
systemic corticosteroid effects. A
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 CYP3A (e.g.,
beclomethasone). Moreover, in case
of withdrawal of glucocorticoids,
progressive dose reduction may
have to be performed over a longer
period.
Dexamethasone
(systemic)
Not studied. Dexamethasone may decrease
plasma concentrations of darunavir.
(CYP3A induction)
Systemic dexamethasone should be
used with caution when combined
with PREZISTA co-administered
with low dose ritonavir.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan
Not studied. Concomitant use of bosentan
and darunavir co-administered with low
dose ritonavir may increase plasma
concentrations of bosentan.
When administered concomitantly
with PREZISTA and low dose
ritonavir, the patient’s tolerability of
bosentan should be monitored.
ESTROGEN-BASED CONTRACEPTIVES
Ethinylestradiol
Norethindrone
35 g/1 mg once daily
ethinylestradiol AUC ↓ 44%
ethinylestradiol C
min
↓ 62%
ethinylestradiol C
max
↓ 32%
norethindrone AUC ↓ 14%
norethindrone C
min
↓ 30%
norethindrone C
max
↔
Alternative or additional
contraceptive measures are
recommended when
oestrogen-based contraceptives are
co-administered with PREZISTA
and low dose ritonavir. Patients
using oestrogens as hormone
replacement therapy should be
clinically monitored for signs of
oestrogen deficiency.
HERBAL PRODUCTS
St John's wort
(Hypericum perforatum)
Not studied. St John’s wort is expected to
decrease the plasma concentrations of
darunavir and ritonavir.
(CYP450 induction)
PREZISTA co-administered with
low dose ritonavir must not be used
concomitantly with products
containing St John’s wort
(
Hypericum perforatum
) (see
section 4.3). If a patient is already
taking St John’s wort, stop
St John’s wort and if possible check
viral levels. Darunavir exposure
(and also ritonavir exposure) may
increase on stopping St John’s wort.
The inducing effect may persist for
at least 2 weeks after cessation of
treatment with St John’s wort.
40
HMG CO-A REDUCTASE INHIBITORS
Lovastatin
Simvastatin
Not studied. Lovastatin and simvastatin are
expected to have markedly increased
plasma concentrations when
co-administered with darunavir
co-administered with low dose ritonavir.
(CYP3A inhibition)
Increased plasma concentrations of
lovastatin or simvastatin may cause
myopathy, including
rhabdomyolysis. Concomitant use
of PREZISTA co-administered with
low dose ritonavir with lovastatin
and simvastatin is therefore
contraindicated (see section 4.3).
Atorvastatin
10 mg once daily
atorvastatin AUC ↑ 3-4 fold
atorvastatin C
min
↑
≈
5.5-10 fold
atorvastatin C
max
↑ ≈2 fold
#
darunavir
When administration of atorvastatin
and PREZISTA co-administered
with low dose ritonavir is desired, it
is recommended to start with an
atorvastatin dose of 10 mg once
daily. A gradual dose increase of
atorvastatin may be tailored to the
clinical response.
Pravastatin
40 mg single dose
pravastatin AUC ↑ 81%
¶
pravastatin C
min
ND
pravastatin C
max
↑ 63%
¶
When administration of pravastatin
and PREZISTA co-administered
with low dose ritonavir is required,
it is recommended to start with the
lowest possible dose of pravastatin
and titrate up to the desired clinical
effect while monitoring for safety.
an up to five-fold increase was seen in a limited
subset of subjects
H
2
-RECEPTOR ANTAGONISTS
Ranitidine
150 mg twice daily
#
darunavir AUC ↔
#
darunavir C
min
↔
#
PREZISTA co-administered with
low dose ritonavir can be
co-administered with H
2
-receptor
antagonists without dose
adjustments.
darunavir C
max
↔
IMMUNOSUPPRESSANTS
Cyclosporine
Sirolimus
Tacrolimus
Not studied. Exposure to cyclosporine,
tacrolimus or sirolimus will be increased
when co-administered with PREZISTA
co-administered with low dose ritonavir.
Therapeutic drug monitoring of the
immunosuppressive agent must be
done when co-administration
occurs.
Concomitant use of salmeterol and
PREZISTA co-administered with
low dose ritonavir is not
recommended. The combination
may result in increased risk of
cardiovascular adverse event with
salmeterol, including QT
prolongation, palpitations and sinus
tachycardia.
NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE
Methadone
individual dose ranging
from 55 mg to 150 mg
once daily
Not studied. Concomitant use of
salmeterol and darunavir co-administered
with low dose ritonavir may increase
plasma concentrations of salmeterol.
R(-) methadone AUC ↓ 16%
R(-) methadone C
min
↓ 15%
R(-) methadone C
max
↓ 24%
No adjustment of methadone dosage
is required when initiating
co-administration with
PREZISTA/ritonavir. However,
increased methadone dose may be
necessary when concomitantly
administered for a longer period of
time due to induction of metabolism
by ritonavir. Therefore, clinical
monitoring is recommended, as
maintenance therapy may need to
be adjusted in some patients.
41
INHALED BETA AGONISTS
Salmeterol
Buprenorphine/naloxone
8/2 mg–16/4 mg once
daily
buprenorphine AUC ↓ 11%
buprenorphine C
min
↔
buprenorphine C
max
↓ 8%
norbuprenorphine AUC ↑ 46%
norbuprenorphine C
min
↑ 71%
norbuprenorphine C
max
↑ 36%
naloxone AUC ↔
naloxone C
min
ND
naloxone C
max
↔
The clinical relevance of the
increase in norbuprenorphine
pharmacokinetic parameters has not
been established. Dose adjustment
for buprenorphine may not be
necessary when co-administered
with PREZISTA/ritonavir but a
careful clinical monitoring for signs
of opiate toxicity is recommended.
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of erectile
dysfunction
Sildenafil
Tadalafil
Vardenafil
In an interaction study
#
, a comparable
systemic exposure to sildenafil was
observed for a single intake of 100 mg
sildenafil alone and a single intake of
25 mg sildenafil co-administered with
PREZISTA and low dose ritonavir.
Concomitant use of PDE-5
inhibitors for the treatment of
erectile dysfunction with
PREZISTA co-administered with
low dose ritonavir should be done
with caution. If concomitant use of
PREZISTA co-administered with
low dose ritonavir with sildenafil,
vardenafil or tadalafil is indicated,
sildenafil at a single dose not
exceeding 25 mg in 48 hours,
vardenafil at a single dose not
exceeding 2.5 mg in 72 hours or
tadalafil at a single dose not
exceeding 10 mg in 72 hours is
recommended.
For the treatment of
pulmonary arterial
hypertension
Sildenafil
Tadalafil
Not studied. Concomitant use of sildenafil
or tadalafil for the treatment of pulmonary
arterial hypertension and darunavir
co-administered with low dose ritonavir
may increase plasma concentrations of
sildenafil or tadalafil.
A safe and effective dose of
sildenafil for the treatment of
pulmonary arterial hypertension
co-administered with PREZISTA
and low dose ritonavir has not been
established. There is an increased
potential for sildenafil-associated
adverse events (including visual
disturbances, hypotension,
prolonged erection and syncope).
Therefore, co-administration of
PREZISTA with low dose ritonavir
and sildenafil when used for the
treatment of pulmonary arterial
hypertension is contraindicated (see
section 4.3).
Co-administration of tadalafil for
the treatment of pulmonary arterial
hypertension with PREZISTA and
low dose ritonavir is not
recommended.
PROTON PUMP INHIBITORS
Omeprazole
20 mg once daily
#
darunavir AUC ↔
#
darunavir C
min
↔
#
PREZISTA co-administered with
low dose ritonavir can be
co-administered with proton pump
inhibitors without dose adjustments.
darunavir C
max
↔
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
42
Paroxetine
20 mg once daily
paroxetine AUC ↓ 39%
paroxetine C
min
↓ 37%
paroxetine C
max
↓ 36%
#
darunavir AUC ↔
#
If SSRIs are co-administered with
PREZISTA and low dose ritonavir,
the recommended approach is a
dose titration of the SSRI based on
a clinical assessment of
antidepressant response. In addition,
patients on a stable dose of
sertraline or paroxetine who start
treatment with PREZISTA
co-administered with low dose
ritonavir should be monitored for
antidepressant response.
darunavir C
min
↔
#
darunavir C
max
↔
sertraline AUC ↓ 49%
sertraline C
min
↓ 49%
sertraline C
max
↓ 44%
#
darunavir AUC ↔
#
darunavir C
min
↓ 6%
#
Sertraline
50 mg once daily
darunavir C
max
↔
†
The efficacy and safety of the use of PREZISTA with 100 mg ritonavir and any other PI (e.g. (fos)amprenavir, nelfinavir and tipranavir)
has not been established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is generally not
recommended.
Paediatric population
Interaction studies have only been performed in adults.
Pregnancy
There are no adequate and well controlled studies with darunavir in pregnant women. Studies in
animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal
development, parturition or postnatal development (see section 5.3).
PREZISTA co-administered with low dose ritonavir should be used during pregnancy only if the
potential benefit justifies the potential risk.
Breast-feeding
It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that
darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity. Because of both
the potential for HIV transmission and the potential for adverse reactions in breast-fed infants, mothers
should be instructed not to breast-feed under any circumstances if they are receiving PREZISTA.
Fertility
No human data on the effect of darunavir on fertility are available. There was no effect on mating or
fertility with darunavir treatment in rats (see section 5.3).
PREZISTA in combination with ritonavir has no or negligible influence on the ability to drive and use
machines. However, dizziness has been reported in some patients during treatment with regimens
containing PREZISTA co-administered with low dose ritonavir and should be borne in mind when
considering a patient’s ability to drive or operate machinery (see section 4.8).
The overall safety profile of PREZISTA is based on all available clinical trial and post-marketing data,
and is consistent with the data below.
a. Summary of the safety profile
During the clinical development program (N=1,968 treatment-experienced subjects who initiated
therapy with PREZISTA/rtv 600/100 mg twice daily), 49.5% of subjects experienced at least one
adverse reaction. The total mean treatment duration for subjects was 48.58 weeks. For treatment-naïve
patients, see the information below the table. The most frequent adverse reactions reported in clinical
trials and as spontaneous reports are diarrhoea, immune reconstitution syndrome, nausea, pyrexia and
rash. The most frequent serious reactions are diarrhoea, hepatitis, immune reconstitution syndrome,
pyrexia and rash.
43
b. Tabulated summary of adverse reactions
Adverse reactions are listed by system organ class (SOC) and frequency category. Within each
frequency category, adverse reactions are presented in order of decreasing seriousness. Frequency
categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon
(≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and not known (frequency cannot be estimated
from the available data).
Adverse reactions in clinical trials and post-marketing in adult patients
SOC
Frequency category
Adverse reaction
Infections and infestations
uncommon
herpes simplex
Blood and lymphatic system disorders
uncommon
thrombocytopenia, neutropenia, anaemia,
increased eosinophil count, leukopenia
Immune system disorders
uncommon
immune reconstitution syndrome
1, 2
, (drug)
hypersensitivity
Endocrine disorders
uncommon
hypothyroidism, increased blood thyroid
stimulating hormone
Metabolism and nutrition disorders
common
lipodystrophy (including lipohypertrophy,
lipodystrophy, lipoatrophy)
1, 2
,
hypertriglyceridaemia
1, 2
, hypercholesterolaemia
1,
2
, hyperlipidaemia
1, 2
uncommon
diabetes mellitus
1, 2
, gout, anorexia, decreased
appetite, decreased weight, increased weight,
hyperglycaemia
1, 2
, insulin resistance, decreased
high density lipoprotein, increased appetite,
polydipsia, increased blood lactate
dehydrogenase
Psychiatric disorders
common
insomnia
uncommon
depression, confusional state, disorientation,
anxiety, altered mood, sleep disorder, abnormal
dreams, nightmare, decreased libido, restlessness
Nervous system disorders
common
headache, peripheral neuropathy, dizziness
uncommon
syncope, convulsion, lethargy, paraesthesia,
hypoaesthesia, ageusia, dysgeusia, disturbance in
attention, memory impairment, somnolence,
sleep phase rhythm disturbance
Eye disorders
uncommon
visual disturbance, conjunctival hyperaemia, dry
eye
Ear and labyrinth disorders
uncommon
vertigo
Cardiac disorders
44
uncommon
acute myocardial infarction, myocardial
infarction, angina pectoris, prolonged
electrocardiogram QT, sinus bradycardia,
tachycardia, palpitations
Vascular disorders
uncommon
hypertension, flushing
Respiratory, thoracic and mediastinal disorders
uncommon
dyspnoea, cough, epistaxis, rhinorrhoea, throat
irritation
Gastrointestinal disorders
very common
diarrhoea
common
vomiting, nausea, abdominal pain, increased
blood amylase, dyspepsia, abdominal distension,
flatulence
uncommon
pancreatitis, gastritis, gastrooesophageal reflux
disease, aphthous stomatitis, stomatitis, retching,
haematemesis, dry mouth, abdominal discomfort,
constipation, increased lipase, eructation, oral
dysaesthesia, cheilitis, dry lip, coated tongue
Hepatobiliary disorders
common
increased alanine aminotransferase, increased
aspartate aminotransferase
uncommon
hepatitis
1
, cytolytic hepatitis
1
, hepatic steatosis,
hepatomegaly, increased transaminase, increased
blood bilirubin, increased blood alkaline
phosphatase, increased
gamma-glutamyltransferase
Skin and subcutaneous tissue disorders
common
rash
3
(including macular, maculopapular, papular,
erythematous and pruritic rash)
1, 2
, pruritus
uncommon
angioedema, generalised rash
1, 2
, allergic
dermatitis, urticaria, dermatitis, eczema,
erythema, hyperhidrosis, night sweats, alopecia,
acne, seborrhoeic dermatitis, skin lesion,
xeroderma, dry skin, nail pigmentation
rare
erythema multiforme, Stevens-Johnson
syndrome
1
not known
toxic epidermal necrolysis
1
Musculoskeletal and connective tissue disorders
uncommon
myalgia
2
, osteonecrosis
1, 2
, muscle spasms,
muscular weakness, musculoskeletal stiffness,
arthritis, arthralgia, joint stiffness, pain in
extremity, osteoporosis, increased blood creatine
phosphokinase
2
Renal and urinary disorders
uncommon
acute renal failure, renal failure, nephrolithiasis,
increased blood creatinine, decreased creatinine
renal clearance, proteinuria, bilirubinuria,
dysuria, nocturia, pollakiuria
Reproductive system and breast disorders
uncommon
erectile dysfunction, gynaecomastia
45
General disorders and administration site conditions
common
asthenia, fatigue
uncommon
pyrexia, chest pain, peripheral oedema, malaise,
chills, abnormal feeling, feeling hot, irritability,
pain, xerosis
1
see section 4.4
2
see section 4.8 c)
3
In clinical studies of treatment-experienced patients, rash, irrespective of causality, was more commonly observed with regimens
containing PREZISTA + raltegravir compared to those containing PREZISTA without raltegravir or raltegravir without PREZISTA.
Rash considered by the investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were
10.9, 4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR, respectively.
The rashes observed in clinical studies were mild to moderate in severity and did not result in discontinuation of therapy (see section
4.4).
The safety profile of PREZISTA/rtv 800/100 mg once daily in treatment-naïve subjects is similar to
that seen with PREZISTA/rtv 600/100 mg twice daily in treatment-experienced subjects except for
nausea which was observed more frequently in treatment-naïve subjects. This was driven by mild
intensity nausea.
c.
Description of selected adverse reactions
Rash
In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of
treatment and resolving with continued dosing. In cases of severe skin reaction see the warning in
section 4.4.
Lipodystrophy
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section
4.4).
Metabolic abnormalities
Combination antiretroviral therapy has also been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
Musculoskeletal abnormalities
Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of
protease inhibitors, particularly in combination with NRTIs.
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).
Immune reconstitution syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections
may arise (see section 4.4).
Bleeding in haemophiliac patients
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving
antiretroviral protease inhibitors (see section 4.4).
d. Paediatric population
The safety assessment in children and adolescents is based on the safety data from the Phase II trial
DELPHI in which 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years
46
and weighing at least 20 kg received PREZISTA with low dose ritonavir in combination with other
antiretroviral agents (see section 5.1).
Overall, the safety profile in these 80 children and adolescents was similar to that observed in the adult
population.
e. Other special populations
Patients co-infected with hepatitis B and/or hepatitis C virus
Among 1,968 treatment-experienced patients receiving PREZISTA co-administered with ritonavir
600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were
more likely to have baseline and treatment emergent hepatic transaminase elevations than those
without chronic viral hepatitis (see section 4.4).
Human experience of acute overdose with PREZISTA co-administered with low dose ritonavir is
limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the
tablet formulation of darunavir in combination with ritonavir have been administered to healthy
volunteers without untoward symptomatic effects.
There is no specific antidote for overdose with PREZISTA. Treatment of overdose with PREZISTA
consists of general supportive measures including monitoring of vital signs and observation of the
clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved
by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of
unabsorbed active substance. Since darunavir is highly protein bound, dialysis is unlikely to be
beneficial in significant removal of the active substance.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiviral for systemic use, ATC code: J05AE10.
Mechanism of action
Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease
(K
D
of 4.5 x 10
-12
M). It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus
infected cells, thereby preventing the formation of mature infectious virus particles.
Antiviral activity
in vitro
Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory
strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and
human monocytes/macrophages with median EC
50
values ranging from 1.2 to 8.5 nM (0.7 to
5.0 ng/ml). Darunavir demonstrates antiviral activity
in vitro
against a broad panel of HIV-1 group M
(A, B, C, D, E, F, G) and group O primary isolates with EC
50
values ranging from < 0.1 to 4.3 nM.
These EC
50
values are well below the 50% cellular toxicity concentration range of 87 µM to
> 100 µM.
Resistance
In vitro
selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). The
selected viruses were unable to grow in the presence of darunavir concentrations above 400 nM.
Viruses selected in these conditions and showing decreased susceptibility to darunavir (range:
23-50-fold) harboured 2 to 4 amino acid substitutions in the protease gene. Identification of
determinants of decreased susceptibility to darunavir in those viruses is under investigation.
The clinical trial data from ART-experienced patients (TITAN trial and the pooled analysis of the
POWER 1, 2 and 3 and DUET 1 and 2 trials) showed that virologic response to PREZISTA
co-administered with low dose ritonavir was decreased when 3 or more darunavir RAMs (V11I, V32I,
47
L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V) were present at baseline or when these
mutations developed during treatment.
Increasing baseline darunavir fold change in EC
50
(FC) was associated with decreasing virologic
response. A lower and upper clinical cut-off of 10 and 40 were identified. Isolates with baseline FC
≤ 10 are susceptible; isolates with FC > 10 to 40 have decreased susceptibility; isolates with FC
> 40 are resistant (see Clinical results).
Viruses isolated from patients on PREZISTA/rtv 600/100 mg twice daily experiencing virologic
failure by rebound that were susceptible to tipranavir at baseline remained susceptible to tipranavir
after treatment in the vast majority of cases.
The lowest rates of developing resistant HIV virus are observed in ART-naïve patients who are treated
for the first time with darunavir in combination with other ART.
The table below shows the development of mutations and loss of susceptibility to PIs in virologic
failures at endpoint in the ARTEMIS, ODIN and TITAN trials.
ARTEMIS
ODIN
TITAN
PREZISTA/rtv
800/100 mg
once daily
N=343
PREZISTA/rtv
800/100 mg
once daily
N=294
PREZISTA/rtv
600/100 mg
twice daily
N=296
PREZISTA/rtv
600/100 mg
twice daily
N=298
Total number of
virologic failures
a
, n (%)
40 (11.7%)
65 (22.1%)
54 (18.2%)
31 (10.4%)
Rebounders
24 (7.0%)
11 (3.7%)
11 (3.7%)
16 (5.4%)
Never suppressed
subjects
16 (4.7%)
54 (18.4%)
43 (14.5%)
15 (5.0%)
Number of subjects with virologic failure and paired baseline/endpoint genotypes, developing mutations
b
at
endpoint, n/N
Primary (major) PI
mutations
0/10
1/60
0/42
6/28
PI RAMs 3/10 7/60 4/42 10/28
Number of subjects with virologic failure and paired baseline/endpoint phenotypes, showing loss of
susceptibility to PIs at endpoint compared to baseline, n/N
PI
darunavir
0/10
1/58
0/41
3/26
amprenavir
0/10
1/58
0/40
0/22
atazanavir
0/10
2/56
0/40
0/22
indinavir
0/10
2/57
0/40
1/24
lopinavir
0/10
1/58
0/40
0/23
saquinavir
0/10
0/56
0/40
0/22
tipranavir
0/10
0/58
0/41
1/25
a
TLOVR non-VF censored algorithm based on HIV-1 RNA < 50 copies/ml, except for TITAN (HIV-1 RNA < 400 copies/ml)
b
IAS-USA lists
Cross-resistance
Darunavir FC was less than 10 for 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir,
indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to
most PIs remain susceptible to darunavir.
In the virologic failures of the ARTEMIS trial no cross-resistance with other PIs was observed.
Clinical results
Adult patients
For clinical trial results in ART-naïve adult patients, refer to the Summary of Product Characteristics
for PREZISTA 400 mg tablets.
Efficacy of PREZISTA 600 mg twice daily co
-
administered with 100 mg ritonavir twice daily in
ART-experienced patients
48
The evidence of efficacy of PREZISTA co-administered with ritonavir (600/100 mg twice daily) in
ART-experienced patients is based on the 96 weeks analysis of the Phase III trial TITAN in
ART-experienced lopinavir naïve patients, on the 48 week analysis of the Phase III trial ODIN in
ART-experienced patients with no DRV-RAMs, and on the analyses of 96 weeks data from the
Phase IIb trials POWER 1 and 2 in ART-experienced patients with high level of PI resistance.
TITAN
is a randomised, controlled, open-label Phase III trial comparing PREZISTA co-administered
with ritonavir (600/100 mg twice daily) versus lopinavir/ritonavir (400/100 mg twice daily) in
ART-experienced, lopinavir naïve HIV-1 infected adult patients. Both arms used an Optimised
Background Regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).
The table below shows the efficacy data of the 48 week analysis from the TITAN trial.
TITAN
Outcomes
PREZISTA/rtv
600/100 mg twice daily +
OBR
N=298
Lopinavir/ rtv
400/100 mg twice daily +
OBR
N=297
Treatment difference
(95% CI of difference)
HIV-1 RNA
< 50 copies/ml
a
70.8% (211)
60.3% (179)
10.5% (2.9; 18.1)
b
median CD4+ cell
count change from
baseline (x 10
6
/l)
c
88
81
a
Imputations according to the TLOVR algorithm
b
Based on a normal approximation of the difference in % response
c
NC=F
At 48 weeks non-inferiority in virologic response to the PREZISTA/ritonavir treatment, defined as the
percentage of patients with plasma HIV-1 RNA level < 400 and < 50 copies/ml, was demonstrated (at
the pre-defined 12% non-inferiority margin) for both ITT and OP populations. These results were
confirmed in the analysis of data at 96 weeks of treatment in the TITAN trial, with 60.4% of patients
in the PREZISTA/rtv arm having HIV-1 RNA < 50 copies/ml at week 96 compared to 55.2% in the
lopinavir/rtv arm [difference: 5.2%, 95% CI (-2.8–13.1)].
ODIN
is a Phase III, randomised, open-label trial comparing PREZISTA/rtv 800/100 mg once daily
versus PREZISTA/rtv 600/100 mg twice daily in ART-experienced HIV-1 infected patients with
screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V,
I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a screening HIV-1 RNA > 1,000 copies/ml.
Efficacy analysis is based on 48 weeks of treatment (see table below). Both arms used an optimised
background regimen (OBR) of ≥ 2 NRTIs.
ODIN
Outcomes
PREZISTA/rtv
800/100 mg once daily +
OBR
N=294
PREZISTA/rtv
600/100 mg twice daily +
OBR
N=296
Treatment difference
(95% CI of difference)
HIV-1 RNA
< 50 copies/ml
a
72.1% (212)
70.9% (210)
1.2% (-6.1; 8.5)
b
With Baseline HIV-1
RNA (copies/ml)
< 100,000
≥ 100,000
77.6% (198/255)
35.9% (14/39)
73.2% (194/265)
51.6% (16/31)
4.4% (-3.0; 11.9)
-15.7% (-39.2; 7.7)
With Baseline CD4+
cell count (x 10
6
/l)
≥ 100
< 100
75.1% (184/245)
57.1% (28/49)
72.5% (187/258)
60.5% (23/38)
2.6% (-5.1; 10.3)
-3.4% (-24.5; 17.8)
49
With HIV-1 clade
Type B
Type AE
Type C
Other
c
70.4% (126/179)
90.5% (38/42)
72.7% (32/44)
55.2% (16/29)
64.3% (128/199)
91.2% (31/34)
78.8% (26/33)
83.3% (25/30)
6.1% (-3.4; 15.6)
-0.7% (-14.0, 12.6)
-6.1% (-2.6, 13.7)
-28.2% (-51.0, -5.3)
mean CD4+ cell count
change from baseline
(x 10
6
/l)
e
108
112
-5
d
(-25; 16)
a
Imputations according to the TLOVR algorithm
b
Based on a normal approximation of the difference in % response
c
Clades A1, D, F1, G, K, CRF02_AG, CRF12_BF, and CRF06_CPX
d
Difference in means
e
Last Observation Carried Forward imputation
At 48 weeks, virologic response, defined as the percentage of patients with plasma HIV-1 RNA level
< 50 copies/ml, with PREZISTA/ritonavir 800/100 mg once daily treatment was demonstrated to be
non-inferior (at the pre-defined 12% non-inferiority margin) compared to PREZISTA/ritonavir
600/100 mg twice daily for both ITT and OP populations.
PREZISTA/rtv 800/100 mg once daily in ART-experienced patients should not be used in patients
with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA
≥ 100,000 copies/ml or CD4+ cell count < 100 cells x 10
6
/l (see section 4.2 and 4.4). Limited data is
available in patients with HIV-1 clades other than B.
POWER 1
and
POWER 2
are randomised, controlled trials comparing PREZISTA co-administered
with ritonavir (600/100 mg twice daily) with a control group receiving an investigator-selected PI(s)
regimen in HIV-1 infected patients who had previously failed more than 1 PI containing regimen. An
OBR consisting of at least 2 NRTIs with or without enfuvirtide (ENF) was used in both trials.
The table below shows the efficacy data of the 48-week and 96-week analyses from the pooled
POWER 1 and POWER 2 trials.
POWER 1 and POWER 2 pooled data
Week 48
Week 96
Outcomes
PREZISTA/rtv
600/100 mg
twice daily
n=131
Control
n=124
Treatment
difference
PREZISTA/rtv
600/100 mg
twice daily
n=131
Control
n=124
Treatment
difference
HIV RNA
< 50 copies/ml
a
45.0%
(59)
11.3%
(14)
33.7%
(23.4%; 44.1%)
c
38.9%
(51)
8.9%
(11)
30.1%
(20.1; 40.0)
c
CD4+ cell count
mean change from
baseline (x 10
6
/l)
b
103
17
86
(57; 114)
c
133
15
118
(83.9; 153.4)
c
a
Imputations according to the TLOVR algorithm
b
Last Observation Carried Forward imputation
c
95% confidence intervals.
Analyses of data through 96 weeks of treatment in the POWER trials demonstrated sustained
antiretroviral efficacy and immunologic benefit.
Out of the 59 patients who responded with complete viral suppression (< 50 copies/ml) at week 48,
47 patients (80% of the responders at week 48) remained responders at week 96.
Baseline genotype or phenotype and virologic outcome
Baseline genotype and darunavir FC (shift in susceptibility relative to reference) were shown to be a
predictive factor of virologic outcome.
Proportion (%) of patients with response (HIV-1 RNA < 50 copies/ml at week 24) to PREZISTA
co-administered with ritonavir (600/100 mg twice daily) by baseline genotype
a
, and baseline
darunavir FC and by use of enfuvirtide (ENF): As treated analysis of the POWER and DUET trials.
50
Number of baseline mutations
a
Baseline DRV FC
b
Response (HIV-1
RNA < 50 copies/ml
at week 24)
%, n/N
All
ranges
0-2
3
4
All
ranges
10 10-40 > 40
All patients
45%
455/1,014
54%
359/660
39%
67/172
12%
20/171
45%
455/1,014
55%
364/659
29%
59/203
8%
9/118
Patients with
no/non-naïve use of
ENF
c
39%
290/741
50%
238/477
29%
35/120
7%
10/135
39%
290/741
51%
244/477
17%
25/147
5%
5/94
Patients with naïve
use of ENF
d
60%
165/273
66%
121/183
62%
32/52
28%
10/36
60%
165/273
66%
120/182
61%
34/56
17%
4/24
a
Number of mutations from the list of mutations associated with a diminished response to PREZISTA/ritonavir (V11I, V32I, L33F, I47V,
I50V, I54L or M, T74P, L76V, I84V or L89V)
b
fold change in EC
50
c
“Patients with no/non-naïve use of ENF” are patients who did not use ENF or who used ENF but not for the first time
d
“Patients with naïve use of ENF” are patients who used ENF for the first time
Children from the age of 6 years and adolescents
DELPHI is an open-label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and
efficacy of PREZISTA with low dose ritonavir in 80 ART-experienced HIV-1 infected paediatric
patients aged 6 to 17 years and weighing at least 20 kg. These patients received PREZISTA/ritonavir
in combination with other antiretroviral agents (see section 4.2 for dosage recommendations per body
weight). Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least
1.0 log
10
versus baseline.
In the study, patients who were at risk of discontinuing therapy due to intolerance of ritonavir oral
solution (e.g. taste aversion) were allowed to switch to the capsule formulation. Of the 44 patients
taking ritonavir oral solution, 27 switched to the 100 mg capsule formulation and exceeded the
weight-based ritonavir dose without changes in observed safety.
DELPHI
Outcomes at week 48
PREZISTA/ritonavir
N=80
HIV-1 RNA < 50 copies/ml
a
47.5% (38)
CD4+ cell count mean change from baseline
b
147
a
Imputations according to the TLOVR algorithm.
b
Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0.
According to the TLOVR non-virologic failure censored algorithm 24 (30.0%) patients experienced
virological failure, of which 17 (21.3%) patients were rebounders and 7 (8.8%) patients were
non-responders.
The European Medicines Agency has deferred the obligation to submit the results of studies with
PREZISTA in one or more subsets of the paediatric population in Human immunodeficiency virus
infection, as per PIP decision in the granted indication. See section 4.2 for information on paediatric
use.
5.2 Pharmacokinetic properties
The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in
healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1
infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infected
patients compared to healthy subjects may be explained by the higher concentrations of alpha-1-acid
glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG
and, therefore, higher plasma concentrations.
Darunavir is primarily metabolised by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the
plasma concentrations of darunavir considerably.
51
Absorption
Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of
darunavir in the presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.
The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37%
and increased to approximately 82% in the presence of 100 mg twice daily ritonavir. The overall
pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic
exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with
ritonavir at 100 mg twice daily (see section 4.4).
When administered without food, the relative bioavailability of darunavir in the presence of low dose
ritonavir is 30% lower as compared to intake with food. Therefore, PREZISTA tablets should be taken
with ritonavir and with food. The type of food does not affect exposure to darunavir.
Distribution
Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma
alpha-1-acid glycoprotein.
Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l
(Mean ± SD) and increased to 131 ± 49.9 l (Mean ± SD) in the presence of 100 mg twice-daily
ritonavir.
Metabolism
In vitro
experiments with human liver microsomes (HLMs) indicate that darunavir primarily
undergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system and
almost exclusively by isozyme CYP3A4. A
14
C-darunavir trial in healthy volunteers showed that a
majority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was due
to the parent active substance. At least 3 oxidative metabolites of darunavir have been identified in
humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild
type HIV.
Elimination
After a 400/100 mg
14
C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the
administered dose of
14
C-darunavir could be retrieved in faeces and urine, respectively. Unchanged
darunavir accounted for approximately 41.2% and 7.7% of the administered dose in faeces and urine,
respectively. The terminal elimination half-life of darunavir was approximately 15 hours when
combined with ritonavir.
The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was
32.8 l/h and 5.9 l/h, respectively.
Special Populations
Paediatric population
The pharmacokinetics of darunavir in combination with ritonavir in 74 treatment-experienced
paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the administered
weight-based doses of PREZISTA/ritonavir resulted in darunavir exposure comparable to that in
adults receiving PREZISTA/ritonavir 600/100 mg twice daily (see section 4.2).
Elderly
Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics
are not considerably different in the age range (18 to 75 years) evaluated in HIV infected patients
(n=12, age 65) (see section 4.4). However, only limited data were available in patients above the age
of 65 year.
Gender
Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV
infected females compared to males. This difference is not clinically relevant.
Renal impairment
52
Results from a mass balance study with
14
C-darunavir with ritonavir showed that approximately 7.7%
of the administered dose of darunavir is excreted in the urine unchanged.
Although darunavir has not been studied in patients with renal impairment, population
pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly
affected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20)
(see sections 4.2 and 4.4).
Hepatic impairment
Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose study with
PREZISTA co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the total
plasma concentrations of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate
(Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects.
However, unbound darunavir concentrations were approximately 55% (Child-Pugh Class A) and
100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknown
therefore, PREZISTA should be used with caution. The effect of severe hepatic impairment on the
pharmacokinetics of darunavir has not been studied (see sections 4.2, 4.3 and 4.4).
5.3 Preclinical safety data
Animal toxicology studies have been conducted at exposures up to clinical exposure levels with
darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.
In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatment
with darunavir. In rodents the target organs identified were the haematopoietic system, the blood
coagulation system, liver and thyroid. A variable but limited decrease in red blood cell-related
parameters was observed, together with increases in activated partial thromboplastin time.
Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) and
thyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a small
increase in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in the
pancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicity
findings or target organs were identified up to exposures equivalent to clinical exposure at the
recommended dose.
In a study conducted in rats, the number of corpora lutea and implantations were decreased in the
presence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavir
treatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at the
clinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir in
rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The
exposure levels were lower than those with the recommended clinical dose in humans. In a pre- and
postnatal development assessment in rats, darunavir with and without ritonavir, caused a transient
reduction in body weight gain of the offspring pre-weaning and there was a slight delay in the opening
of eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pups
that exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation.
These effects may be secondary to pup exposure to the active substance via the milk and/or maternal
toxicity. No post weaning functions were affected with darunavir alone or in combination with
ritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed with
convulsions in some animals. Exposure in plasma, liver and brain was considerably higher than in
adult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, the
exposure was comparable to that in adult rats. The increased exposure was likely at least partly due to
immaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalities
were noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at
500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile were
comparable to those observed in adult rats.
Due to uncertainties regarding the rate of development of the human blood brain barrier and liver
enzymes, PREZISTA with low dose ritonavir should not be used in paediatric patients below 3 years
of age.
53
Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up
to 104 weeks. Daily doses of 150, 450 and 1,000 mg/kg were administered to mice and doses of 50,
150 and 500 mg/kg were administered to rats. Dose-related increases in the incidences of
hepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroid
follicular cell adenomas were noted in male rats. Administration of darunavir did not cause a
statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or
rats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limited
relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme
induction and increased thyroid hormone elimination, which predispose rats, but not humans, to
thyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavir
were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans
at the recommended therapeutic doses.
After 2 years administration of darunavir at exposures at or below the human exposure, kidney
changes were observed in mice (nephrosis) and rats (chronic progressive nephropathy).
Darunavir was not mutagenic or genotoxic in a battery of
in vitro
and
in vivo
assays including
bacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and
in vivo
micronucleus test in mice.
6.1 List of excipients
Tablet core
Microcrystalline cellulose
Colloidal anhydrous silica
Crospovidone
Magnesium stearate
Tablet film-coat
Poly(vinyl alcohol) – partially hydrolyzed
Macrogol 3350
Titanium dioxide (E171)
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 240 tablets, fitted
with polypropylene (PP) child resistant closure.
One bottle
6.6 Special precautions for disposal
No special requirements.
54
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/06/380/004
Date of first authorisation: 12 February 2007
Date of latest renewal: 12 February 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
55
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
EU/1/06/380/001
Date of first authorisation: 12 February 2007
Date of latest renewal: 12 February 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/
.
82
6. FURTHER INFORMATION
What PREZISTA contains
- The active substance is darunavir. Each tablet contains 600 mg of darunavir as ethanolate.
- The other ingredients are microcrystalline cellulose, colloidal anhydrous silica, crospovidone,
magnesium stearate. The film-coating contains poly(vinyl alcohol) - partially hydrolyzed,
macrogol 3350, titanium dioxide (E171), talc, sunset yellow FCF (E110).
What PREZISTA looks like and contents of the pack
Film-coated, orange, oval shaped tablet, mentioning TMC on one side, 600MG on the other side.
60 tablets in a plastic bottle.
PREZISTA is also available as 75 mg, 150 mg, 300 mg and 400 mg film-coated tablets.
Marketing Authorisation Holder
Janssen-Cilag International NV, Turnhoutseweg 30, 2340 Beerse, Belgium
Manufacturer
Janssen-Cilag SpA, Via C. Janssen, 04010 Borgo San Michele, Latina, Italy
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
TIBOTEC, een divisie van, une division de, eine
Division der JANSSEN-CILAG NV/SA
Antwerpseweg 15-17
B-2340 Beerse
Tél/Tel: +32 14 64 94 11
Luxembourg/Luxemburg
TIBOTEC, une division de, eine Division der
JANSSEN-CILAG NV/SA
Antwerpseweg 15-17
B-2340 Beerse
Belgique/Belgien
Tél/Tel: +32 14 64 94 11
България
Представителство на TIBOTEC, дивизия на
Johnson & Johnson, d.o.o.
ж.к. Младост 4
Бизнес Парк София, сграда 4
София 1715
Тел.: +359 2 489 94 00
Magyarország
TIBOTEC, a JANSSEN-CILAG Kft. divíziója
H-2045 Törökbálint, Tó Park
Tel: +36 23 513 800
Česká republika
TIBOTEC, divize JANSSEN-CILAG s.r.o.
Karla Engliše 3201/06
CZ-150 00 Praha 5 - Smíchov
Tel: +420 227 012 222
Malta
AM MANGION LTD.
Mangion Building, Triq Ġdida fi Triq Valletta
MT-Ħal-Luqa LQA 6000
Tel: +356 2397 6000
193
Danmark
TIBOTEC, en division af JANSSEN-CILAG A/S
Hammerbakken 19
DK-3460 Birkerød
Tlf: +45 45 94 82 82
Nederland
TIBOTEC, een divisie van JANSSEN-CILAG
B.V.
Postbus 90240
NL-5000 LT Tilburg
Tel: +31 13 583 73 73
Deutschland
JANSSEN-CILAG GmbH
Johnson & Johnson Platz 1
D-41470 Neuss
Tel: +49 2137 955-955
Norge
TIBOTEC, en divisjon av JANSSEN-CILAG AS
Drammensveien 288
N-0283 Oslo
Tlf: +47 24 12 65 00
Eesti
TIBOTEC, JANSSEN-CILAG Polska Sp. z o.o.
Eesti filiaal
Lõõtsa 2
EE-11415 Tallinn
Tel: +372 617 7410
Österreich
TIBOTEC, eine Division von JANSSEN-CILAG
Pharma GmbH
Pfarrgasse 75
A-1232 Wien
Tel: +43 1 610 300
Ελλάδα
TIBOTEC, τμήμα της JANSSEN-CILAG
Φαρμακευτική Α.Ε.Β.Ε.
Λεωφόρος Ειρήνης 56
GR-151 21 Πεύκη, Αθήνα
Tηλ: +30 210 80 90 000
Polska
TIBOTEC, oddział JANSSEN-CILAG Polska Sp.
z o.o.
ul. Iłżecka 24
PL-02-135 Warszawa
Tel: +48 22 237 60 00
España
JANSSEN-CILAG, S.A. división TIBOTEC
Paseo de las Doce Estrellas, 5-7
Campo de las Naciones
E-28042 Madrid
Tel: +34 91 722 81 00
Portugal
TIBOTEC, uma divisão da JANSSEN-CILAG
FARMACÊUTICA, LDA.
Estrada Consiglieri Pedroso, 69 A
Queluz de Baixo
PT-2734-503 Barcarena
Tel: +351 21 43 68 835
France
TIBOTEC, une division de JANSSEN-CILAG
1, rue Camille Desmoulins, TSA 91003
F-92787 Issy Les Moulineaux, Cedex 9
Tél: 0 800 25 50 75 / +33 1 55 00 44 44
România
TIBOTEC, subsidiară a Janssen-Cilag, Johnson &
Johnson d.o.o.
Strada Tipografilor nr. 11-15, Clădirea S-Park,
corp A2, etaj 5
013714 Bucureşti
Tel: +40 21 2 071 800
Ireland
TIBOTEC, a division of JANSSEN-CILAG Ltd.
50-100 Holmers Farm Way
High Wycombe
Buckinghamshire HP12 4EG - UK
Tel: +44 1494 567 444
Slovenija
TIBOTEC za Janssen-Cilag, del
Johnson&Johnson d.o.o.
Šmartinska cesta 53
SI-1000 Ljubljana
Tel: +386 1 401 18 30
Ísland
TIBOTEC, deild hjá JANSSEN-CILAG
c/o Vistor hf.
Hörgatún 2
IS-210 Garðabær
Sími: +354 535 7000
Slovenská republika
TIBOTEC, divízia Johnson & Johnson s.r.o.
Plynárenská 7/B
SK-824 78 Bratislava
Tel: +421 233 552 600
194
Italia
TIBOTEC, una divisione di JANSSEN-CILAG
SpA
Via M. Buonarroti, 23
I-20093 Cologno Monzese MI
Tel: +39 02 2510 1
Suomi/Finland
TIBOTEC
JANSSEN-CILAG OY
Vaisalantie/Vaisalavägen 2
FI-02130 Espoo/Esbo
Puh/Tel: +358 207 531 300
Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ,
7 Ανδροκλέους
CY-1060 Λευκωσία
Τηλ: +357 22 755 214
Sverige
TIBOTEC, en division inom JANSSEN-CILAG
AB
Box 7073
S-192 07 Sollentuna
Tel: +46 8 626 50 00
Latvija
TIBOTEC, JANSSEN-CILAG Polska Sp. z o.o.
filiāle Latvijā
Matrožu iela 15
LV-1048, Rīga
Tel: +371 678 93561
United Kingdom
TIBOTEC, a division of JANSSEN-CILAG Ltd.
50-100 Holmers Farm Way
High Wycombe
Buckinghamshire HP12 4EG - UK
Tel: +44 1494 567 444
Lietuva
UAB „Johnson & Johnson”
Geležinio Vilko g. 18A
LT-08104 Vilnius
Tel: +370 5 278 68 88
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
195
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/prezista.html
Copyright © 1995-2021 ITA all rights reserved.