Prezista

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

PREZISTA 100 mg/ml oral suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral suspension contains 100 mg of darunavir (as ethanolate).

Excipient with known effect: sodium methyl parahydroxybenzoate (E219) 3.43 mg/ml.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral suspension

White to off-white opaque suspension

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

PREZISTA, co-administered with low dose ritonavir is indicated in combination with other 
antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) 
infection in adult and paediatric patients from the age of 3 years and at least 15 kg body weight (see 
section 4.2).

PREZISTA, co-administered with cobicistat is indicated in combination with other antiretroviral 
medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult 
patients (see section 4.2).

In deciding to initiate treatment with PREZISTA co-administered with cobicistat or 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 (see sections 4.2, 4.4 and 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a health care provider experienced in the management of HIV 
infection. After therapy with PREZISTA has been initiated, patients should be advised not to alter the 
dosage, dose form or discontinue therapy without discussing with their health care provider.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as 
pharmacokinetic enhancer. Darunavir may therefore have different contraindications and 
recommendations for concomitant medications depending on whether the compound is boosted with 
ritonavir or cobicistat (see sections 4.3, 4.4 and 4.5).

Posology
PREZISTA must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic 
enhancer and in combination with other antiretroviral medicinal products. The Summary of Product 
Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation 
of therapy with PREZISTA. Cobicistat is not indicated for use in twice daily regimens or for use in the 
paediatric population.



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ART-naïve adult patients
The recommended dose regimen is 800 mg once daily with cobicistat 150 mg once daily or ritonavir 
100 mg once daily taken with food.

ART-experienced adult patients
The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken 
with food.

A dose regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg once 
daily taken with food may be used in patients with prior exposure to antiretroviral medicinal products 
but without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1 
RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

If HIV-1 genotype testing is not available, the recommended dose regimen is PREZISTA 600 mg
twice daily taken with ritonavir 100 mg twice daily taken with food.

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 15 kg)
The weight-based dose of PREZISTA and ritonavir in paediatric patients is provided in the table 
below. The dose of cobicistat to be used with PREZISTA in children less than 18 years of age has not 
been established.

Recommended dose for treatment-naïve paediatric patients (3 to 17 years) with PREZISTA 
and ritonavira

Body weight (kg) Dose (once daily with food)
≥ 15 kg to < 30 kg 600 mg (6 ml) PREZISTA/100 mg (1.2 ml) ritonavir once daily
≥ 30 kg to < 40 kg 675 mg (6.8 ml)b PREZISTA/100 mg (1.2 ml) ritonavir once daily
≥ 40 kg 800 mg (8 ml) PREZISTA/100 mg (1.2 ml) ritonavir once daily
a

ritonavir oral solution: 80 mg/ml
b

rounded up for suspension dosing convenience

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 15 kg)
PREZISTA twice daily taken with ritonavir taken with food is usually recommended.

A once daily dose regimen of PREZISTA taken with ritonavir taken with food may be used in patients 
with prior exposure to antiretroviral medicinal products but without darunavir resistance associated 
mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell 
count ≥ 100 cells x 106/l.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The weight-based dose of PREZISTA and ritonavir in paediatric patients is provided in the table 
below. The recommended dose of PREZISTA with low dose ritonavir should not exceed the 
recommended adult dose (600/100 mg twice daily or 800/100 mg once daily). The dose of cobicistat 
to be used with PREZISTA in children less than 18 years of age has not been established.

Recommended dose for treatment-experienced paediatric patients (3 to 17 years) with 
PREZISTA and ritonavira

Body weight (kg) Dose (once daily with food) Dose (twice daily with food)
≥ 15 kg to < 30 kg 600 mg (6 ml) PREZISTA/100 mg 

(1.2 ml) ritonavir once daily
380 mg (3.8 ml) PREZISTA/50 mg 
(0.6 ml) ritonavir twice daily

≥ 30 kg to < 40 kg 675 mg (6.8 ml)b PREZISTA/100 mg 
(1.2 ml) ritonavir once daily

460 mg (4.6 ml) PREZISTA/60 mg 
(0.8 ml) ritonavir twice daily

≥ 40 kg 800 mg (8 ml) PREZISTA/100 mg 
(1.2 ml) ritonavir once daily

600 mg (6 ml) PREZISTA/100 mg 
(1.2 ml) ritonavir twice daily

a
ritonavir oral solution: 80 mg/ml

b
rounded up for suspension dosing convenience



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For ART-experienced paediatric patients HIV genotypic testing is recommended. However, when HIV 
genotypic testing is not feasible, the PREZISTA/ritonavir once daily dosing regimen is recommended 
in HIV protease inhibitor-naïve paediatric patients and the twice daily dosing regimen is 
recommended in HIV protease inhibitor-experienced patients.

PREZISTA oral suspension can be used in patients unable to swallow PREZISTA tablets. PREZISTA 
is also available as 75 mg, 150 mg, 400 mg, 600 mg and 800 mg film-coated tablets.

Advice on missed doses
The following guidance is based on the half-life of darunavir in the presence of cobicistat or ritonavir 
and the recommended dosing interval of approximately 12 hours (twice daily regimen) or 
approximately 24 hours (once daily regimen).

 If using the twice daily regimen: in case a dose of PREZISTA and/or ritonavir is 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 is noticed later than 6 hours 
after the time it is usually taken, the missed dose should not be taken and the patient should 
resume the usual dosing schedule.

 If using the once daily regimen: in case a dose of PREZISTA and/or cobicistat or ritonavir is
missed within 12 hours of the time it is usually taken, patients should be instructed to take the 
prescribed dose of PREZISTA and cobicistat or ritonavir with food as soon as possible. If this is
noticed later than 12 hours after the time it is usually taken, the missed dose should not be taken 
and the patient should resume the usual dosing schedule.

Special populations

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 for darunavir/ritonavir in patients with renal impairment (see sections 
4.4 and 5.2). Cobicistat has not been studied in patients receiving dialysis, and, therefore, no 
recommendation can be made for the use of darunavir/cobicistat in these patients.

Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum 
creatinine and modest declines in creatinine clearance. Hence, the use of creatinine clearance as an 
estimate of renal elimination capacity may be misleading. Cobicistat as a pharmacokinetic enhancer of 
darunavir should, therefore, not be initiated in patients with creatine clearance less than 70 ml/min if 
any co-administered agent requires dose adjustment based on creatinine clearance: e.g. emtricitabine, 
lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate) or adefovir dipovoxil.

For information on cobicistat, consult the cobicistat Summary of Product Characteristics.

Paediatric population
PREZISTA should not be used in children
- below 3 years of age, because of safety concerns (see sections 4.4 and 5.3), or,
- less than 15 kg body weight, as the dose for this population has not been established in a 

sufficient number of patients (see section 5.1).



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The weight-based dose regimen for PREZISTA and ritonavir is provided in the tables above. The dose 
of cobicistat to be used with PREZISTA has not been established in this patient population.

Pregnancy and postpartum
No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. 
PREZISTA/ritonavir should be used during pregnancy only if the potential benefit justifies the 
potential risk (see sections 4.4, 4.6 and 5.2).

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure 
(see sections 4.4 and 5.2). Therefore, therapy with PREZISTA/cobicistat should not be initiated during 
pregnancy, and women who become pregnant during therapy with PREZISTA/cobicistat should be 
switched to an alternative regimen, (see sections 4.4 and 4.6). PREZISTA/ritonavir may be considered 
as an alternative.

Method of administration
Patients should be instructed to take PREZISTA with cobicistat or 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).

PREZISTA suspension is administered orally. Shake the bottle vigorously prior to each dose. The 
supplied oral dosing pipette should not be used for any other medicinal products.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with severe (Child-Pugh Class C) hepatic impairment.

Concomitant treatment with any of the following medicinal products given the expected decrease in 
plasma concentrations of darunavir, ritonavir and cobicistat and the potential for loss of therapeutic 
effect (see sections 4.4 and 4.5).

Applicable to darunavir boosted with either ritonavir or cobicistat:
- The combination product lopinavir/ritonavir (see section 4.5).
- The strong CYP3A inducers rifampicin and herbal preparations containing St John’s wort 

(Hypericum perforatum). Co-administration is expected to reduce plasma concentrations of 
darunavir, ritonavir and cobicistat, which could lead to loss of therapeutic effect and possible 
development of resistance (see sections 4.4 and 4.5).

Applicable to darunavir boosted with cobicistat, not when boosted with ritonavir:
- Darunavir boosted with cobicistat is more sensitive for CYP3A induction than darunavir 

boosted with ritonavir. Concomitant use with strong CYP3A inducers is contraindicated, since 
these may reduce the exposure to cobicistat and darunavir leading to loss of therapeutic effect. 
Strong CYP3A inducers include e.g. carbamazepine, phenobarbital and phenytoin (see sections 
4.4 and 4.5).

Darunavir boosted with either ritonavir or cobicistat inhibits the elimination of active substances that 
are highly dependent on CYP3A for clearance, which results in increased exposure to the 
co-administered medicinal product. Therefore, concomitant treatment with such medicinal products 
for which elevated plasma concentrations are associated with serious and/or life-threatening events is 
contraindicated (applies to darunavir boosted with either ritonavir or cobicistat). These active 
substances include e.g.:
- alfuzosin
- amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
- astemizole, terfenadine
- colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)



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- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
- elbasvir/grazoprevir
- cisapride
- dapoxetine
- domperidone
- naloxegol
- lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
- triazolam, midazolam administered orally (for caution on parenterally administered midazolam, 

see section 4.5)
- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil
- simvastatin, lovastatin, lomitapide (see section 4.5)
- dabigatran, ticagrelor (see section 4.5).

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission 
should be taken in accordance with national guidelines.

Regular assessment of virological response is advised. In the setting of lack or loss of virological 
response, resistance testing should be performed.

PREZISTA must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic 
enhancer and in combination with other antiretroviral medicinal products (see section 5.2). The 
Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore be 
consulted prior to initiation of therapy with PREZISTA.

Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect 
darunavir concentrations. It is not recommended to alter the dose of cobicistat or ritonavir.

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 used in combination with cobicistat or low dose ritonavir 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 106/l (see section 
4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs have not been 
studied in this population. Limited data are available in patients with HIV-1 clades other than B (see 
section 5.1).

Paediatric population
PREZISTA is not recommended for use in paediatric patients below 3 years of age or less than 15 kg 
body weight (see sections 4.2 and 5.3).

Pregnancy
PREZISTA/ritonavir should be used during pregnancy only if the potential benefit justifies the 
potential risk. Caution should be used in pregnant women with concomitant medications which may 
further decrease darunavir exposure (see sections 4.5 and 5.2).

Treatment with darunavir/cobicistat 800/150 mg once daily during the second and third trimester has 
been shown to result in low darunavir exposure, with a reduction of around 90% in Cmin levels (see 
section 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantial 
reduction in darunavir exposure may result in virological failure and an increased risk of mother to 
child transmission of HIV infection. Therefore, therapy with PREZISTA/cobicistat should not be 
initiated during pregnancy, and women who become pregnant during therapy with 



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PREZISTA/cobicistat should be switched to an alternative regimen (see sections 4.2 and 4.6). 
PREZISTA given with low dose ritonavir may be considered as an alternative.

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 darunavir/ritonavir 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. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson 
Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal 
necrolysis and acute generalised exanthematous pustulosis have been reported. PREZISTA should be 
discontinued immediately if signs or symptoms of severe skin reactions develop. These can include,
but are not limited to, severe rash or rash accompanied by 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/ritonavir + raltegravir compared to patients receiving PREZISTA/ritonavir 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. 
During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 
0.5% of patients receiving combination antiretroviral therapy with PREZISTA/ritonavir. 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 reactions. 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 used in 
combination with cobicistat or low dose ritonavir 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 used in combination with cobicistat or low dose ritonavir 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 used in combination with cobicistat or low 
dose ritonavir, 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 for darunavir/ritonavir are required in patients with renal 
impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they 



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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). Cobicistat has 
not been studied in patients receiving dialysis, therefore, no recommendation can be made for the use 
of darunavir/cobicistat in these patients (see section 4.2).

Cobicistat decreases the estimated creatinine clearance due to inhibition of tubular secretion of 
creatinine. This should be taken into consideration if darunavir with cobicistat is administered to 
patients in whom the estimated creatinine clearance is used to adjust doses of co-administered 
medicinal products (see section 4.2 and cobicistat SmPC).

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil and 
cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that 
include tenofovir disoproxil without cobicistat.

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.

Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported particularly in patients with advanced HIV disease and/or long-term exposure to combination 
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience 
joint aches and pain, joint stiffness or difficulty in movement.

Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
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.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment (see section 4.8).

Interactions with medicinal products
Several of the interaction studies have been performed with darunavir at lower than recommended 
doses. 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.



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Pharmacokinetic enhancer and concomitant medications
Darunavir has different interaction profiles depending on whether the compound is boosted with 
ritonavir or cobicistat:
- Darunavir boosted with cobicistat is more sensitive for CYP3A induction: concomitant use of

darunavir/cobicistat and strong CYP3A inducers is therefore contraindicated (see section 4.3), 
and concomitant use with weak to moderate CYP3A inducers is not recommended (see section
4.5). Concomitant use of darunavir/ritonavir and darunavir/cobicistat with lopinavir/ritonavir, 
rifampicin and herbal products containing St John’s wort, Hypericum perforatum, is 
contraindicated (see section 4.5).

- Unlike ritonavir, cobicistat does not have inducing effects on enzymes or transport proteins (see 
section 4.5). If switching the pharmacoenhancer from ritonavir to cobicistat, caution is required 
during the first two weeks of treatment with darunavir/cobicistat, particularly if doses of any 
concomitantly administered medicinal products have been titrated or adjusted during use of 
ritonavir as a pharmacoenhancer. A dose reduction of the co-administered drug may be needed 
in these cases.

Efavirenz in combination with boosted PREZISTA may result in sub-optimal darunavir Cmin. If 
efavirenz is to be used in combination with PREZISTA, the PREZISTA/ritonavir 600/100 mg twice 
daily regimen should be used. See the Summary of Product Characteristics for PREZISTA 75 mg, 
150 mg and 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 P-glycoprotein (P-gp; see sections 4.3 and 4.5).

PREZISTA oral suspension contains sodium methyl parahydroxybenzoate (E219) which may cause 
allergic reactions (possibly delayed).

4.5 Interaction with other medicinal products and other forms of interaction

The interaction profile of darunavir may differ depending on whether ritonavir or cobicistat is used as 
pharmacoenhancer. The recommendations given for concomitant use of darunavir and other medicinal 
products may therefore differ depending on whether darunavir is boosted with ritonavir or cobicistat 
(see sections 4.3 and 4.4), and caution is also required during the first time of treatment if switching 
the pharmacoenhancer from ritonavir to cobicistat (see section 4.4).

Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer)
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 these compounds and consequently that of darunavir, leading to loss of therapeutic 
effect and possible development of resistance (see sections 4.3 and 4.4). CYP3A inducers that are 
contraindicated include rifampicin, St John’s wort and lopinavir.

Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may 
decrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrations 
of darunavir and ritonavir. Co-administration with strong CYP3A4 inhibitors is not recommended and 
caution is warranted, these interactions are described in the interaction table below (e.g. indinavir, 
azole antifungals such as clotrimazole).

Medicinal products that affect darunavir exposure (cobicistat as pharmacoenhancer)
Darunavir and cobicistat are metabolised by CYP3A, and co-administration with CYP3A inducers 
may therefore result in subtherapeutic plasma exposure to darunavir. Darunavir boosted with 
cobicistat is more sensitive to CYP3A induction than ritonavir-boosted darunavir: co-administration of 
darunavir/cobicistat with medicinal products that are strong inducers of CYP3A (e.g. St John’s wort, 
rifampicin, carbamazepine, phenobarbital, and phenytoin) is contraindicated (see section 4.3). 
Co-administration of darunavir/cobicistat with weak to moderate CYP3A inducers (e.g. efavirenz, 
etravirine, nevirapine, boceprevir, fluticasone, and bosentan) is not recommended (see interaction 
table below).



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For co-administration with strong CYP3A4 inhibitors, the same recommendations apply independent 
of whether darunavir is boosted with ritonavir or with cobicistat (see section above).

Medicinal products that may be affected by darunavir boosted with ritonavir
Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of 
darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or 
transported by P-gp may result in increased systemic exposure to such medicinal products, which 
could increase or prolong their therapeutic effect and adverse reactions.

Darunavir 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) (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, darunavir must only be used in 
combination with 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 darunavir/ritonavir, which may be attributed to the 
presence of low dose ritonavir. Co-administration of darunavir and ritonavir with 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 with 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.

Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration 
with substrates of these transporters can result in increased plasma concentrations of these compounds 
(e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).

Medicinal products that may be affected by darunavir boosted with cobicistat
The recommendations for darunavir boosted with ritonavir are adequate also for darunavir boosted 
with cobicistat with regard to substrates of CYP3A4, CYP2D6, P-glycoprotein, OATP1B1 and 
OATP1B3 (see contraindications and recommendations presented in the section above). Cobicistat 
150 mg given with darunavir 800 mg once daily enhances darunavir pharmacokinetic parameters in a 
comparable way to ritonavir (see section 5.2).

Unlike ritonavir, cobicistat does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or 
UGT1A1. For further information on cobicistat, consult the cobicistat Summary of Product 
Characteristics.

Interaction table
Interaction studies have only been performed in adults.

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.



11

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as 
pharmacokinetic enhancer. Darunavir may therefore have different recommendations for concomitant 
medications depending on whether the compound is boosted with ritonavir or cobicistat. The same 
recommendations apply, unless specifically indicated. For further information on cobicistat, consult 
the cobicistat Summary of Product Characteristics.

Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products 
are listed in the table below. 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 (not determined as “ND”).

In the table below the specific pharmacokinetic enhancer is specified when recommendations differ. 
When the recommendation is the same for PREZISTA when co-administered with a low dose ritonavir 
or cobicistat, the term “boosted PREZISTA” is used.

The below list of examples of drug drug interactions is not comprehensive and therefore the label of 
each drug that is co-administered with PREZISTA should be consulted for information related to the 
route of metabolism, interaction pathways, potential risks, and specific actions to be taken with 
regards to co-administration.

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal products by 
therapeutic areas

Interaction
Geometric mean change (%)

Recommendations concerning 
co-administration

HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors

Dolutegravir dolutegravir AUC ↓ 22%
dolutegravir C24h ↓ 38%
dolutegravir Cmax ↓ 11%
darunavir ↔*
* Using cross-study comparisons to historical 
pharmacokinetic data

Boosted PREZISTA and 
dolutegravir can be used without 
dose adjustment.

Raltegravir Some clinical studies suggest raltegravir 
may cause a modest decrease in 
darunavir plasma concentrations.

At present the effect of raltegravir 
on darunavir plasma 
concentrations does not appear to 
be clinically relevant. Boosted 
PREZISTA and raltegravir can be 
used without dose adjustments.

Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine
400 mg once daily

didanosine AUC ↓ 9%
didanosine Cmin ND
didanosine Cmax ↓ 16%
darunavir AUC ↔
darunavir Cmin ↔
darunavir Cmax ↔

Boosted PREZISTA 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 boosted 
PREZISTA given with food.



12

Tenofovir disoproxil
245 mg once daily

‡
tenofovir AUC ↑ 22%
tenofovir Cmin ↑ 37%
tenofovir Cmax ↑ 24%
#
darunavir AUC ↑ 21%

#
darunavir Cmin ↑ 24%

#
darunavir Cmax ↑ 16%

(↑ tenofovir from effect on MDR-1 
transport in the renal tubules)

Monitoring of renal function may 
be indicated when boosted 
PREZISTA is given in 
combination with tenofovir
disoproxil, particularly in patients 
with underlying systemic or renal 
disease, or in patients taking 
nephrotoxic agents.

PREZISTA co-administered with 
cobicistat lowers the creatinine 
clearance. Refer to section 4.4 if 
creatinine clearance is used for 
dose adjustment of tenofovir
disoproxil.

Emtricitabine/tenofovir 
alafenamide

Tenofovir alafenamide ↔
Tenofovir ↑

The recommended dose of 
emtricitabine/tenofovir 
alafenamide is 200/10 mg once 
daily when used with boosted 
PREZISTA.

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 boosted
PREZISTA.

Boosted PREZISTA can be used 
with these NRTIs without dose 
adjustment.

PREZISTA co-administered with 
cobicistat lowers the creatinine 
clearance. Refer to section 4.4 if 
creatinine clearance is used for 
dose adjustment of emtricitabine or 
lamivudine.

Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg once daily

efavirenz AUC ↑ 21%
efavirenz Cmin ↑ 17%
efavirenz Cmax ↑ 15%
#
darunavir AUC ↓ 13%

#
darunavir Cmin ↓ 31%

#
darunavir Cmax ↓ 15%

(↑ efavirenz from CYP3A inhibition)
(↓ darunavir from CYP3A induction)

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.

Efavirenz in combination with 
PREZISTA/ritonavir 800/100 mg 
once daily may result in 
sub-optimal darunavir Cmin. If 
efavirenz is to be used in 
combination with 
PREZISTA/ritonavir, the 
PREZISTA/ritonavir 600/100 mg 
twice daily regimen should be used 
(see section 4.4).

Co-administration with 
PREZISTA co-administered with 
cobicistat is not recommended (see 
section 4.4).

Etravirine
100 mg twice daily

etravirine AUC ↓ 37%
etravirine Cmin ↓ 49%
etravirine Cmax ↓ 32%
darunavir AUC ↑ 15%
darunavir Cmin ↔
darunavir Cmax ↔

PREZISTA co-administered with 
low dose ritonavir and etravirine 
200 mg twice daily can be used
without dose adjustments.

Co-administration with 
PREZISTA co-administered with 
cobicistat is not recommended (see 
section 4.4).



13

Nevirapine
200 mg twice daily

nevirapine AUC ↑ 27%
nevirapine Cmin ↑ 47%
nevirapine Cmax ↑ 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.

Co-administration with 
PREZISTA co-administered with 
cobicistat is not recommended (see 
section 4.4).

Rilpivirine
150 mg once daily

rilpivirine AUC ↑ 130%
rilpivirine Cmin ↑ 178%
rilpivirine Cmax ↑ 79%
darunavir AUC ↔
darunavir Cmin ↓ 11%
darunavir Cmax ↔

Boosted PREZISTA and rilpivirine 
can be used without dose 
adjustments.

HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir
†

Atazanavir
300 mg once daily

atazanavir AUC ↔
atazanavir Cmin ↑ 52%
atazanavir Cmax ↓ 11%
#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

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.

PREZISTA co-administered with 
low dose ritonavir and atazanavir 
can be used without dose 
adjustments.

PREZISTA co-administered with 
cobicistat should not be used in 
combination with another 
antiretroviral agent that requires 
pharmacoenhancement by means 
of co-administration with an 
inhibitor of CYP3A4 (see section 
4.5).

Indinavir
800 mg twice daily

indinavir AUC ↑ 23%
indinavir Cmin ↑ 125%
indinavir Cmax ↔
#
darunavir AUC ↑ 24%

#
darunavir Cmin ↑ 44%

#
darunavir Cmax ↑ 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.

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.

PREZISTA co-administered with
cobicistat should not be used in 
combination with another 
antiretroviral agent that requires 
pharmacoenhancement by means 
of co-administration with an 
inhibitor of CYP3A4 (see section 
4.5).



14

Saquinavir
1,000 mg twice daily

#
darunavir AUC ↓ 26%

#
darunavir Cmin ↓ 42%

#
darunavir Cmax ↓ 17%

saquinavir AUC ↓ 6%
saquinavir Cmin ↓ 18%
saquinavir Cmax ↓ 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.

It is not recommended to combine 
PREZISTA co-administered with 
low dose ritonavir with saquinavir.

PREZISTA co-administered with 
cobicistat should not be used in 
combination with another 
antiretroviral agent that requires 
pharmacoenhancement by means 
of co-administration with an 
inhibitor of CYP3A4 (see section 
4.5).

HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavir
†

Lopinavir/ritonavir
400/100 mg twice daily

Lopinavir/ritonavir
533/133.3 mg twice daily

lopinavir AUC ↑ 9%
lopinavir Cmin ↑ 23%
lopinavir Cmax ↓ 2%

darunavir AUC ↓ 38%
‡

darunavir Cmin ↓ 51%
‡

darunavir Cmax ↓ 21%
‡

lopinavir AUC ↔
lopinavir Cmin ↑ 13%
lopinavir Cmax ↑ 11%
darunavir AUC ↓ 41%
darunavir Cmin ↓ 55%
darunavir Cmax ↓ 21%
‡

based upon non dose normalised values

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 boosted PREZISTA and the 
combination product 
lopinavir/ritonavir is 
contraindicated (see section 4.3).

CCR5 ANTAGONIST
Maraviroc
150 mg twice daily

maraviroc AUC ↑ 305%
maraviroc Cmin ND
maraviroc Cmax ↑ 129%
darunavir, ritonavir concentrations were 
consistent with historical data

The maraviroc dose should be 
150 mg twice daily when 
co-administered with boosted 
PREZISTA.

α1-ADRENORECEPTOR ANTAGONIST
Alfuzosin Based on theoretical considerations 

PREZISTA is expected to increase 
alfuzosin plasma concentrations.
(CYP3A inhibition)

Co-administration of boosted 
PREZISTA and alfuzosin is 
contraindicated (see section 4.3).

ANAESTHETIC
Alfentanil Not studied. The metabolism of alfentanil 

is mediated via CYP3A, and may as such 
be inhibited by boosted PREZISTA.

The concomitant use with boosted 
PREZISTA may require to lower 
the dose of alfentanil and requires 
monitoring for risks of prolonged 
or delayed respiratory depression.



15

ANTIANGINA/ANTIARRHYTHMIC
Disopyramide
Flecainide
Lidocaine (systemic)
Mexiletine
Propafenone

Amiodarone
Bepridil
Dronedarone
Ivabradine
Quinidine
Ranolazine

Not studied. Boosted PREZISTA is 
expected to increase these antiarrhythmic
plasma concentrations.
(CYP3A and/or CYP2D6 inhibition)

Caution is warranted and 
therapeutic concentration 
monitoring, if available, is 
recommended for these 
antiarrhythmics when 
co-administered with boosted 
PREZISTA.

Co-administration of boosted 
PREZISTA and amiodarone, 
bepridil, dronedarone, ivabradine,
quinidine, or ranolazine is 
contraindicated (see section 4.3).

Digoxin
0.4 mg single dose

digoxin AUC ↑ 61%
digoxin Cmin ND
digoxin Cmax ↑ 29%
(↑ digoxin from probable inhibition of 
P-gp)

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 
boosted PREZISTA 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 Cmin ↑ 174%
clarithromycin Cmax ↑ 26%
#
darunavir AUC ↓ 13%

#
darunavir Cmin ↑ 1%

#
darunavir Cmax ↓ 17%

14-OH-clarithromycin concentrations 
were not detectable when combined with 
PREZISTA/ritonavir.
(↑ clarithromycin from CYP3A inhibition 
and possible P-gp inhibition)

Caution should be exercised when 
clarithromycin is combined with 
boosted PREZISTA.

For patients with renal impairment 
the Summary of Product 
Characteristics for clarithromycin 
should be consulted for the 
recommended dose.

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban
Edoxaban
Rivaroxaban

Not studied. Co-administration of 
boosted PREZISTA with these 
anticoagulants may increase 
concentrations of the anticoagulant, 
which may lead to an increased bleeding 
risk.
(CYP3A and/or P-gp inhibition)

The use of boosted PREZISTA 
and these anticoagulants is not 
recommended.

Dabigatran
Ticagrelor

Not studied. Co-administration with 
boosted PREZISTA may lead to a 
substantial increase in exposure to 
dabigatran or ticagrelor.

Concomitant administration of 
boosted PREZISTA with 
dabigatran or ticagrelor is 
contraindicated (see section 4.3).

Use of other antiplatelets not 
affected by CYP inhibition or 
induction (e.g. prasugrel) is 
recommended.

Warfarin Not studied. Warfarin concentrations may 
be affected when co-administered with 
boosted PREZISTA.

It is recommended that the 
international normalised ratio 
(INR) be monitored when warfarin 
is combined with boosted 
PREZISTA.



16

ANTICONVULSANTS
Phenobarbital
Phenytoin

Not studied. Phenobarbital and phenytoin 
are expected to decrease plasma 
concentrations of darunavir and its 
pharmacoenhancer.
(induction of CYP450 enzymes)

PREZISTA co-administered with 
low dose ritonavir should not be 
used in combination with these 
medicines.

The use of these medicines with
PREZISTA/cobicistat is 
contraindicated (see section 4.3).

Carbamazepine
200 mg twice daily

carbamazepine AUC ↑ 45%
carbamazepine Cmin ↑ 54%
carbamazepine Cmax ↑ 43%
darunavir AUC ↔
darunavir Cmin ↓ 15%
darunavir Cmax ↔

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.

The use of carbamazepine with
PREZISTA co-administered with 
cobicistat is contraindicated (see 
section 4.3).

Clonazepam Not studied. Co-administration of 
boosted PREZISTA with clonazepam 
may increase concentrations of 
clonazepam. (CYP3A inhibition)

Clinical monitoring is 
recommended when 
co-administering boosted 
PREZISTA and clonazepam.

ANTIDEPRESSANTS
Paroxetine
20 mg once daily

Sertraline
50 mg once daily

Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone

paroxetine AUC ↓ 39%
paroxetine Cmin ↓ 37%
paroxetine Cmax ↓ 36%
#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

sertraline AUC ↓ 49%
sertraline Cmin ↓ 49%
sertraline Cmax ↓ 44%
#
darunavir AUC ↔

#
darunavir Cmin ↓ 6%

#
darunavir Cmax ↔

In contrast to these data with 
PREZISTA/ritonavir, 
PREZISTA/cobicistat may increase these 
antidepressant plasma concentrations 
(CYP2D6 and/or CYP3A inhibition).

Concomitant use of boosted PREZISTA 
and these antidepressants may increase 
concentrations of the antidepressant.
(CYP2D6 and/or CYP3A inhibition)

If antidepressants are 
co-administered with boosted 
PREZISTA, the recommended 
approach is a dose titration of the 
antidepressant based on a clinical 
assessment of antidepressant 
response. In addition, patients on a 
stable dose of these antidepressants 
who start treatment with boosted 
PREZISTA should be monitored 
for antidepressant response.

Clinical monitoring is 
recommended when 
co-administering boosted 
PREZISTA with these 
antidepressants and a dose 
adjustment of the antidepressant 
may be needed.



17

ANTI-DIABETICS
Metformin Not studied. Based on theoretical 

considerations PREZISTA 
co-administered with cobicistat is 
expected to increase metformin plasma 
concentrations.
(MATE1 inhibition)

Careful patient monitoring and 
dose adjustment of metformin is 
recommended in patients who are 
taking PREZISTA co-administered 
with cobicistat.
(not applicable for PREZISTA 
co-administered with ritonavir)

ANTIEMETICS
Domperidone Not studied. Co-administration of domperidone 

with boosted PREZISTA is 
contraindicated. 

ANTIFUNGALS
Voriconazole Not studied. Ritonavir may decrease 

plasma concentrations of voriconazole.
(induction of CYP450 enzymes)

Concentrations of voriconazole may 
increase or decrease when 
co-administered with PREZISTA 
co-administered with cobicistat.
(inhibition of CYP450 enzymes)

Voriconazole should not be 
combined with boosted 
PREZISTA unless an assessment 
of the benefit/risk ratio justifies the 
use of voriconazole.

Fluconazole
Isavuconazole
Itraconazole
Posaconazole

Clotrimazole

Not studied. Boosted PREZISTA may 
increase antifungal plasma concentrations 
and posaconazole, isavuconazole, 
itraconazole or fluconazole may increase 
darunavir concentrations.
(CYP3A and/or P-gp inhibition)

Not Studied. Concomitant systemic use 
of clotrimazole and boosted PREZISTA
may increase plasma concentrations of 
darunavir and/or clotrimazole.
darunavir AUC24h ↑ 33% (based on 
population pharmacokinetic model)

Caution is warranted and clinical 
monitoring is recommended. When 
co-administration is required the 
daily dose of itraconazole should 
not exceed 200 mg.

ANTIGOUT MEDICINES
Colchicine Not studied. Concomitant use of 

colchicine and boosted PREZISTA may 
increase the exposure to colchicine.
(CYP3A and/ or P-gp inhibition)

A reduction in colchicine dosage 
or an interruption of colchicine 
treatment is recommended in 
patients with normal renal or 
hepatic function if treatment with 
boosted PREZISTA is required. 
For patients with renal or hepatic 
impairment colchicine with 
boosted PREZISTA is
contraindicated (see sections 4.3
and 4.4).

ANTIMALARIALS
Artemether/Lumefantrine
80/480 mg, 6 doses at 0, 
8, 24, 36, 48, and 
60 hours

artemether AUC ↓ 16%
artemether Cmin ↔
artemether Cmax ↓ 18%
dihydroartemisinin AUC ↓ 18%
dihydroartemisinin Cmin ↔
dihydroartemisinin Cmax ↓ 18%
lumefantrine AUC ↑ 175%
lumefantrine Cmin ↑ 126%
lumefantrine Cmax ↑ 65%
darunavir AUC ↔
darunavir Cmin ↓ 13%
darunavir Cmax ↔

The combination of boosted 
PREZISTA and 
artemether/lumefantrine can be 
used without dose adjustments;
however, due to the increase in 
lumefantrine exposure, the 
combination should be used with 
caution.



18

ANTIMYCOBACTERIALS
Rifampicin
Rifapentine

Not studied. Rifapentine and rifampicin 
are strong CYP3A inducers and have 
been shown to cause profound decreases 
in concentrations of other protease 
inhibitors, which can result in virological 
failure and resistance development 
(CYP450 enzyme induction). 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 with rifampicin.

The combination of rifapentine and 
boosted PREZISTA is not 
recommended.

The combination of rifampicin and 
boosted PREZISTA is 
contraindicated (see section 4.3).

Rifabutin
150 mg once every other 
day

rifabutin AUC
**

↑ 55%

rifabutin Cmin
**

↑ ND

rifabutin Cmax
**

↔
darunavir AUC ↑ 53%
darunavir Cmin ↑ 68%
darunavir Cmax ↑ 39%
**

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 Cmax 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).

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 with PREZISTA 
co-administered with ritonavir. 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.

Co-administration of PREZISTA 
co-administered with cobicistat 
and rifabutin is not recommended.

ANTINEOPLASTICS
Dasatinib
Nilotinib
Vinblastine
Vincristine

Everolimus
Irinotecan

Not studied. Boosted PREZISTA is 
expected to increase these antineoplastic 
plasma concentrations.
(CYP3A inhibition)

Concentrations of these medicinal 
products may be increased when 
co-administered with boosted 
PREZISTA resulting in the 
potential for increased adverse 
events usually associated with 
these agents.
Caution should be exercised when 
combining one of these 
antineoplastic agents with boosted 
PREZISTA.

Concominant use of everolimus or 
irinotecan and boosted PREZISTA 
is not recommended.



19

ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine Not studied. Boosted PREZISTA is 

expected to increase these antipsychotic 
plasma concentrations.
(CYP3A inhibition)

Concomitant administration of 
boosted PREZISTA and quetiapine 
is contraindicated as it may 
increase quetiapine-related 
toxicity. Increased concentrations 
of quetiapine may lead to coma
(see section 4.3).

Perphenazine
Risperidone
Thioridazine

Lurasidone
Pimozide
Sertindole

Not studied. Boosted PREZISTA is 
expected to increase these antipsychotic 
plasma concentrations.
(CYP3A, CYP2D6 and/or P-gp
inhibition)

A dose decrease may be needed for 
these drugs when co-administered 
with boosted PREZISTA.

Concominant administration of 
boosted PREZISTA and 
lurasidone, pimozide or sertindole 
is contraindicated (see section 4.3).

β-BLOCKERS
Carvedilol
Metoprolol
Timolol

Not studied. Boosted PREZISTA is 
expected to increase these β-blocker 
plasma concentrations.
(CYP2D6 inhibition)

Clinical monitoring is 
recommended when 
co-administering boosted 
PREZISTA with β-blockers. A 
lower dose of the β-blocker should 
be considered.

CALCIUM CHANNEL BLOCKERS
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil

Not studied. Boosted PREZISTA can be 
expected to increase the plasma 
concentrations of calcium channel 
blockers.
(CYP3A and/or CYP2D6 inhibition)

Clinical monitoring of therapeutic 
and adverse effects is 
recommended when these 
medicines are concomitantly 
administered with boosted 
PREZISTA.

CORTICOSTEROIDS
Corticosteroids primarily 
metabolised by CYP3A 
(including 
betamethasone, 
budesonide, fluticasone, 
mometasone, prednisone, 
triamcinolone)

Fluticasone: 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. The 
effects of high fluticasone systemic 
exposure on ritonavir plasma levels are 
unknown.

Other corticosteroids: interaction not 
studied. Plasma concentrations of these 
medicinal products may be increased 
when co-administered with boosted 
PREZISTA, resulting in reduced serum 
cortisol concentrations.

Concomitant use of boosted 
PREZISTA and corticosteroids 
that are metabolised by CYP3A 
(e.g. fluticasone propionate or 
other inhaled or nasal 
corticosteroids) may increase the 
risk of development of systemic 
corticosteroid effects, including 
Cushing’s syndrome and adrenal 
suppression.
Co-administration with CYP3A-
metabolised corticosteroids is not 
recommended unless the potential 
benefit to the patient outweighs the 
risk, in which case patients should 
be monitored for systemic 
corticosteroid effects.
Alternative corticosteroids which 
are less dependent on CYP3A
metabolism e.g. beclomethasone 
for intranasal or inhalational use 
should be considered, particularly 
for long term use.

Dexamethasone
(systemic)

Not studied. Dexamethasone may 
decrease plasma concentrations of 
darunavir.
(CYP3A induction)

Systemic dexamethasone should 
be used with caution when 
combined with boosted 
PREZISTA.



20

ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan Not studied. Concomitant use of bosentan 

and boosted PREZISTA may increase 
plasma concentrations of bosentan.

Bosentan is expected to decrease plasma 
concentrations of darunavir and/or its 
pharmacoenhancer.
(CYP3A induction)

When administered concomitantly 
with PREZISTA and low dose 
ritonavir, the patient’s tolerability 
of bosentan should be monitored.

Co-administration of PREZISTA 
co-administered with cobicistat 
and bosentan is not recommended.

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A protease inhibitors

Elbasvir/grazoprevir Boosted PREZISTA may increase the 
exposure to grazoprevir.
(CYP3A and OATP1B inhibition)

Concomitant use of boosted 
PREZISTA and
elbasvir/grazoprevir is 
contraindicated (see section 4.3).

Boceprevir
800 mg three times daily

boceprevir AUC ↓ 32%
boceprevir Cmin ↓ 35%
boceprevir Cmax ↓ 25%
darunavir AUC ↓ 44%
darunavir Cmin ↓ 59%
darunavir Cmax ↓ 36%

It is not recommended to 
co-administer boosted PREZISTA 
and boceprevir.

Glecaprevir/pibrentasvir Based on theoretical considerations 
boosted PREZISTA may increase the 
exposure to glecaprevir and pibrentasvir.
(P-gp, BCRP and/or OATP1B1/3 
inhibition)

It is not recommended to 
co-administer boosted PREZISTA 
with glecaprevir/pibrentasvir.

Simeprevir simeprevir AUC ↑ 159%
simeprevir Cmin ↑ 358%
simeprevir Cmax ↑ 79%
darunavir AUC ↑ 18%
darunavir Cmin ↑ 31%
darunavir Cmax 

The dose of simeprevir in this interaction 
study was 50 mg when co-administered 
in combination with darunavir/ritonavir, 
compared to 150 mg in the simeprevir 
alone treatment group.

It is not recommended to 
co-administer boosted PREZISTA 
and simeprevir.

HERBAL PRODUCTS
St John's wort
(Hypericum perforatum)

Not studied. St John’s wort is expected to 
decrease the plasma concentrations of 
darunavir or its pharmacoenhancers.
(CYP450 induction)

Boosted PREZISTA 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.

HMG CO-A REDUCTASE INHIBITORS
Lovastatin
Simvastatin

Not studied. Lovastatin and simvastatin 
are expected to have markedly increased 
plasma concentrations when 
co-administered with boosted
PREZISTA.
(CYP3A inhibition)

Increased plasma concentrations of 
lovastatin or simvastatin may 
cause myopathy, including 
rhabdomyolysis. Concomitant use 
of boosted PREZISTA with 
lovastatin and simvastatin is 
therefore contraindicated (see 
section 4.3).



21

Atorvastatin
10 mg once daily

atorvastatin AUC ↑ 3-4 fold
atorvastatin Cmin ↑ ≈5.5-10 fold
atorvastatin Cmax ↑ ≈2 fold
#

darunavir/ritonavir

atorvastatin AUC ↑ 290%
Ω

atorvastatin Cmax ↑ 319%
Ω

atorvastatin Cmin ND
Ω

Ω
with darunavir/cobicistat 800/150 mg

When administration of 
atorvastatin and boosted
PREZISTA 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 Cmin ND
pravastatin Cmax ↑ 63%
¶

an up to five-fold increase was seen in a 
limited subset of subjects

When administration of pravastatin 
and boosted PREZISTA 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.

Rosuvastatin
10 mg once daily

rosuvastatin AUC ↑ 48%
║

rosuvastatin Cmax ↑ 144%
║

║
based on published data with 

darunavir/ritonavir

rosuvastatin AUC ↑ 93%
§

rosuvastatin Cmax ↑ 277%
§

rosuvastatin Cmin ND
§

§
with darunavir/cobicistat 800/150 mg

When administration of 
rosuvastatin and boosted
PREZISTA is required, it is 
recommended to start with the 
lowest possible dose of 
rosuvastatin and titrate up to the 
desired clinical effect while 
monitoring for safety.

OTHER LIPID MODIFYING AGENTS
Lomitapide Based on theoretical considerations 

boosted PREZISTA is expected to 
increase the exposure of lomitapide when 
co-administered.
(CYP3A inhibition)

Co-administration is 
contraindicated (see section 4.3)

H2-RECEPTOR ANTAGONISTS
Ranitidine
150 mg twice daily

#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

Boosted PREZISTA can be 
co-administered with H2-receptor 
antagonists without dose 
adjustments.

IMMUNOSUPPRESSANTS
Ciclosporin
Sirolimus
Tacrolimus

Everolimus

Not studied. Exposure to these 
immunosuppressants will be increased 
when co-administered with boosted 
PREZISTA.
(CYP3A inhibition)

Therapeutic drug monitoring of the 
immunosuppressive agent must be 
done when co-administration 
occurs.

Concomitant use of everolimus 
and boosted PREZISTA is not 
recommended.

INHALED BETA AGONISTS
Salmeterol Not studied. Concomitant use of 

salmeterol and boosted darunavir may 
increase plasma concentrations of 
salmeterol.

Concomitant use of salmeterol and 
boosted PREZISTA is not 
recommended. The combination 
may result in increased risk of 
cardiovascular adverse event with 
salmeterol, including QT 
prolongation, palpitations and 
sinus tachycardia.



22

NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE
Methadone
individual dose ranging 
from 55 mg to 150 mg 
once daily

R(-) methadone AUC ↓ 16%
R(-) methadone Cmin ↓ 15%
R(-) methadone Cmax ↓ 24%

PREZISTA/cobicistat may, in contrast, 
increase methadone plasma 
concentrations (see cobicistat SmPC).

No adjustment of methadone 
dosage is required when initiating 
co-administration with boosted
PREZISTA. However, adjustment 
of the methadone dose may be 
necessary when concomitantly 
administered for a longer period of 
time. Therefore, clinical 
monitoring is recommended, as 
maintenance therapy may need to 
be adjusted in some patients.

Buprenorphine/naloxone
8/2 mg–16/4 mg once 
daily

buprenorphine AUC ↓ 11%
buprenorphine Cmin ↔
buprenorphine Cmax ↓ 8%
norbuprenorphine AUC ↑ 46%
norbuprenorphine Cmin ↑ 71%
norbuprenorphine Cmax ↑ 36%
naloxone AUC ↔
naloxone Cmin ND
naloxone Cmax ↔

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 boosted 
PREZISTA but a careful clinical 
monitoring for signs of opiate 
toxicity is recommended.

Fentanyl
Oxycodone
Tramadol

Based on theoretical considerations 
boosted PREZISTA may increase plasma 
concentrations of these analgesics.
(CYP2D6 and/or CYP3A inhibition)

Clinical monitoring is 
recommended when 
co-administering boosted 
PREZISTA with these analgesics.

OESTROGEN-BASED CONTRACEPTIVES
Drospirenone 
Ethinylestradiol 
(3 mg/0.02 mg once 
daily)

Ethinylestradiol
Norethindrone
35 g/1 mg once daily

drospirenone AUC ↑ 58%
€

drospirenone Cmin ND
€

drospirenone Cmax ↑ 15%
€

ethinylestradiol AUC  30%
€

ethinylestradiol Cmin ND
€

ethinylestradiol Cmax  14%
€

€
with darunavir/cobicistat

ethinylestradiol AUC ↓ 44%
β

ethinylestradiol Cmin ↓ 62%
β

ethinylestradiol Cmax ↓ 32%
β

norethindrone AUC ↓ 14%
β

norethindrone Cmin ↓ 30%
β

norethindrone Cmax ↔
β

β
with darunavir/ritonavir

Alternative or additional 
contraceptive measures are 
recommended when 
oestrogen-based contraceptives are 
co-administered with boosted 
PREZISTA. Patients using 
oestrogens as hormone 
replacement therapy should be 
clinically monitored for signs of 
oestrogen deficiency.

When PREZISTA is co-
administered with a drospirenone-
containing product, clinical 
monitoring is recommended due to 
the potential for hyperkalaemia.

OPIOID ANTAGONIST
Naloxegol Not studied. Co-administration of boosted 

PREZISTA and naloxegol is 
contraindicated.



23

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of 
erectile dysfunction

Avanafil
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.

The combination of avanafil and 
boosted PREZISTA is 
contraindicated (see section 4.3).
Concomitant use of other PDE-5 
inhibitors for the treatment of 
erectile dysfunction with boosted 
PREZISTA should be done with 
caution. If concomitant use of 
boosted PREZISTA 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 
boosted PREZISTA may increase plasma 
concentrations of sildenafil or tadalafil.
(CYP3A inhibition)

A safe and effective dose of 
sildenafil for the treatment of 
pulmonary arterial hypertension 
co-administered with boosted 
PREZISTA 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 
boosted PREZISTA 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 boosted 
PREZISTA is not recommended.

PROTON PUMP INHIBITORS
Omeprazole
20 mg once daily

#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

Boosted PREZISTA can be 
co-administered with proton pump 
inhibitors without dose 
adjustments.



24

SEDATIVES/HYPNOTICS
Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zolpidem

Midazolam (oral)
Triazolam

Not studied. Sedative/hypnotics are 
extensively metabolised by CYP3A. 
Co-administration with boosted 
PREZISTA may cause a large increase in 
the concentration of these medicines.

If parenteral midazolam is 
co-administered with boosted PREZISTA 
it 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.

Clinical monitoring is 
recommended when 
co-administering boosted 
PREZISTA with these 
sedatives/hypnotics and a lower 
dose of the sedatives/hypnotics 
should be considered.

If parenteral midazolam is 
co-administered with boosted 
PREZISTA, 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.

Boosted PREZISTA with 
triazolam or oral midazolam is 
contraindicated (see section 4.3)

TREATMENT FOR PREMATURE EJACULATION
Dapoxetine Not studied. Co-administration of boosted 

PREZISTA with dapoxetine is 
contraindicated.

UROLOGICAL DRUGS
Fesoterodine
Solifenacin

Not studied. Use with caution. Monitor for 
fesoterodine or solifenacin adverse 
reactions, dose reduction of 
fesoterodine or solifenacin may be 
necessary.

#
Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see 
section 4.2 Posology).

†
The efficacy and safety of the use of PREZISTA with 100 mg ritonavir and any other HIV 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.

‡
Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.

4.6 Fertility, pregnancy and lactation

Pregnancy
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in 
pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 
the animal data as well as the clinical experience in pregnant women should be taken into account.

There are no adequate and well controlled studies on pregnancy outcome 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.

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure 
(see section 5.2), which may be associated with an increased risk of treatment failure and an increased 
risk of HIV transmission to the child. Therapy with PREZISTA/cobicistat should not be initiated 



25

during pregnancy, and women who become pregnant during therapy with PREZISTA/cobicistat 
should be switched to an alternative regimen (see sections 4.2 and 4.4).

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).

4.7 Effects on ability to drive and use machines

PREZISTA in combination with cobicistat or 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 cobicistat or low dose ritonavir and should be 
borne in mind when considering a patient’s ability to drive or operate machinery (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile
During the clinical development program (N=2,613 treatment-experienced subjects who initiated 
therapy with PREZISTA/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one 
adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent 
adverse reactions reported in clinical trials and as spontaneous reports are diarrhoea, nausea, rash, 
headache and vomiting. The most frequent serious reactions are acute renal failure, myocardial 
infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, 
diarrhoea, hepatitis and pyrexia.

In the 96 week analysis, the safety profile of PREZISTA/ritonavir 800/100 mg once daily in 
treatment-naïve subjects was similar to that seen with PREZISTA/ritonavir 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. No new safety findings were 
identified in the 192 week analysis of the treatment-naïve subjects in which the mean treatment 
duration of PREZISTA/ritonavir 800/100 mg once daily was 162.5 weeks.

During the Phase III clinical trial GS-US-216-130 with darunavir/cobicistat (N=313 treatment-naïve 
and treatment-experienced subjects), 66.5% of subjects experienced at least one adverse reaction. The 
mean treatment duration was 58.4 weeks. The most frequent adverse reactions reported were diarrhoea 
(28%), nausea (23%), and rash (16%). Serious adverse reactions are diabetes mellitus, (drug) 
hypersensitivity, immune reconstitution inflammatory syndrome, rash and vomiting.

For information on cobicistat, consult the cobicistat Summary of Product Characteristics.

Tabulated list 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).



26

Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing

MedDRA system organ class
Frequency category

Adverse reaction

Infections and infestations
uncommon herpes simplex
Blood and lymphatic system disorders
uncommon thrombocytopenia, neutropenia, anaemia, 

leukopenia

rare increased eosinophil count
Immune system disorders
uncommon immune reconstitution inflammatory syndrome, 

(drug) hypersensitivity
Endocrine disorders
uncommon hypothyroidism, increased blood thyroid 

stimulating hormone
Metabolism and nutrition disorders
common diabetes mellitus, hypertriglyceridaemia, 

hypercholesterolaemia, hyperlipidaemia

uncommon gout, anorexia, decreased appetite, decreased 
weight, increased weight, hyperglycaemia, 
insulin resistance, decreased high density 
lipoprotein, increased appetite, polydipsia, 
increased blood lactate dehydrogenase

Psychiatric disorders
common insomnia

uncommon depression, disorientation, anxiety, sleep 
disorder, abnormal dreams, nightmare, 
decreased libido

rare confusional state, altered mood, restlessness
Nervous system disorders
common headache, peripheral neuropathy, dizziness

uncommon lethargy, paraesthesia, hypoaesthesia, dysgeusia, 
disturbance in attention, memory impairment, 
somnolence

rare syncope, convulsion, ageusia, sleep phase 
rhythm disturbance

Eye disorders
uncommon conjunctival hyperaemia, dry eye

rare visual disturbance
Ear and labyrinth disorders
uncommon vertigo
Cardiac disorders
uncommon myocardial infarction, angina pectoris, 

prolonged electrocardiogram QT, tachycardia

rare acute myocardial infarction, sinus bradycardia, 
palpitations



27

Vascular disorders
uncommon hypertension, flushing
Respiratory, thoracic and mediastinal disorders
uncommon dyspnoea, cough, epistaxis, throat irritation

rare rhinorrhoea
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, retching, dry 
mouth, abdominal discomfort, constipation, 
increased lipase, eructation, oral dysaesthesia

rare stomatitis, haematemesis, cheilitis, dry lip, 
coated tongue

Hepatobiliary disorders
common increased alanine aminotransferase

uncommon hepatitis, cytolytic hepatitis, hepatic steatosis, 
hepatomegaly, increased transaminase, increased 
aspartate aminotransferase, increased blood 
bilirubin, increased blood alkaline phosphatase, 
increased gamma-glutamyltransferase

Skin and subcutaneous tissue disorders
common rash (including macular, maculopapular, 

papular, erythematous and pruritic rash), pruritus

uncommon angioedema, generalised rash, allergic 
dermatitis, urticaria, eczema, erythema, 
hyperhidrosis, night sweats, alopecia, acne, dry 
skin, nail pigmentation

rare DRESS, Stevens-Johnson syndrome, erythema 
multiforme, dermatitis, seborrhoeic dermatitis, 
skin lesion, xeroderma

not known toxic epidermal necrolysis, acute generalised 
exanthematous pustulosis

Musculoskeletal and connective tissue disorders
uncommon myalgia, osteonecrosis, muscle spasms, 

muscular weakness, arthralgia, pain in 
extremity, osteoporosis, increased blood creatine 
phosphokinase

rare musculoskeletal stiffness, arthritis, joint stiffness
Renal and urinary disorders
uncommon acute renal failure, renal failure, nephrolithiasis, 

increased blood creatinine, proteinuria,
bilirubinuria, dysuria, nocturia, pollakiuria

rare decreased creatinine renal clearance



28

Reproductive system and breast disorders
uncommon erectile dysfunction, gynaecomastia
General disorders and administration site conditions
common asthenia, fatigue

uncommon pyrexia, chest pain, peripheral oedema, malaise, 
feeling hot, irritability, pain

rare chills, abnormal feeling, xerosis

Adverse reactions observed with darunavir/cobicistat in adult patients

MedDRA system organ class
Frequency category

Adverse reaction

Immune system disorders
common (drug) hypersensitivity

uncommon immune reconstitution inflammatory syndrome
Metabolism and nutrition disorders
common anorexia, diabetes mellitus, 

hypercholesterolaemia, hypertriglyceridaemia, 
hyperlipidaemia

Psychiatric disorders
common abnormal dreams
Nervous system disorders
very common headache
Gastrointestinal disorders
very common diarrhoea, nausea

common vomiting, abdominal pain, abdominal distension, 
dyspepsia, flatulence, pancreatic enzymes 
increased

uncommon pancreatitis acute
Hepatobiliary disorders
common hepatic enzyme increased

uncommon hepatitis*, cytolytic hepatitis*
Skin and subcutaneous tissue disorders
very common rash (including macular, maculopapular, 

papular, erythematous, pruritic rash, generalised 
rash, and allergic dermatitis)

common angioedema, pruritus, urticaria

rare drug reaction with eosinophilia and systemic 
symptoms*, Stevens-Johnson syndrome*

not known toxic epidermal necrolysis*, acute generalised 
exanthematous pustulosis*

Musculoskeletal and connective tissue disorders
common myalgia

uncommon osteonecrosis*
Reproductive system and breast disorders
uncommon gynaecomastia*



29

General disorders and administration site conditions
common fatigue

uncommon asthenia
Investigations
common increased blood creatinine
* these adverse drug reactions have not been reported in clinical trial experience with darunavir/cobicistat but have been 

noted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.

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. In a single arm trial investigating darunavir 800 mg once daily in combination with 
cobicistat 150 mg once daily and other antiretrovirals 2.2% of patients discontinued treatment due to 
rash.

During the clinical development program of raltegravir in treatment-experienced patients, rash, 
irrespective of causality, was more commonly observed with regimens containing 
PREZISTA/ritonavir + raltegravir compared to those containing PREZISTA/ritonavir without 
raltegravir or raltegravir without PREZISTA/ritonavir. 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).

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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 inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (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).

Paediatric population
The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three 
Phase II trials. The following patient populations were evaluated (see section 5.1):
 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at 

least 20 kg who received PREZISTA tablets with low dose ritonavir twice daily in combination 
with other antiretroviral agents.



30

 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 
10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received PREZISTA oral 
suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.

 12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 
40 kg who received PREZISTA tablets with low dose ritonavir once daily in combination with 
other antiretroviral agents (see section 5.1).

Overall, the safety profile in these paediatric patients was similar to that observed in the adult 
population.

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).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

Human experience of acute overdose with PREZISTA co-administered with cobicistat or 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. Since darunavir is highly protein bound, dialysis is unlikely to be 
beneficial in significant removal of the active substance.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitors, ATC code: J05AE10.

Mechanism of action
Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease 
(KD of 4.5 x 10

-12M). 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 EC50 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 EC50 values ranging from < 0.1 to 4.3 nM.

These EC50 values are well below the 50% cellular toxicity concentration range of 87 µM to 
> 100 µM.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


31

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. The decreased 
susceptibility to darunavir of the emerging viruses in the selection experiment could not be explained 
by the emergence of these protease mutations.

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, 
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 EC50 (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/ritonavir 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 HIV-1 protease mutations and loss of susceptibility to PIs 
in virologic failures at endpoint in the ARTEMIS, ODIN and TITAN trials.

ARTEMIS
Week 192

ODIN
Week 48

TITAN
Week 48

PREZISTA/ 
ritonavir

800/100 mg
once daily

N=343

PREZISTA/ 
ritonavir

800/100 mg
once daily

N=294

PREZISTA/ 
ritonavir

600/100 mg
twice daily

N=296

PREZISTA/ 
ritonavir

600/100 mg
twice daily

N=298
Total number of 
virologic failures

a
, n 

(%)

55 (16.0%) 65 (22.1%) 54 (18.2%) 31 (10.4%)

Rebounders 39 (11.4%) 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

0/43 1/60 0/42 6/28

PI RAMs 4/43 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 0/39 1/58 0/41 3/26
amprenavir 0/39 1/58 0/40 0/22
atazanavir 0/39 2/56 0/40 0/22
indinavir 0/39 2/57 0/40 1/24
lopinavir 0/39 1/58 0/40 0/23
saquinavir 0/39 0/56 0/40 0/22
tipranavir 0/39 0/58 0/41 1/25



32

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

Low rates of developing resistant HIV-1 virus were observed in ART-naïve patients who are treated 
for the first time with darunavir/cobicistat once daily in combination with other ART, and in 
ART-experienced patients with no darunavir RAMs receiving darunavir/cobicistat in combination 
with other ART. The table below shows the development of HIV-1 protease mutations and resistance 
to PIs in virologic failures at endpoint in the GS-US-216-130 trial.

GS-US-216-130
Week 48

Treatment-naïve
darunavir/cobicistat 800/150 mg

once daily
N=295

Treatment-experienced
darunavir/cobicistat 800/150 mg

once daily
N=18

Number of subjects with virologic failure
a

and genotype data that develop mutations
b

at endpoint, n/N
Primary (major) PI 
mutations

0/8 1/7

PI RAMs 2/8 1/7

Number of subjects with virologic failure
a

and phenotype data that show resistance to PIs at endpoint
c
, n/N

HIV PI
darunavir 0/8 0/7
amprenavir 0/8 0/7
atazanavir 0/8 0/7
indinavir 0/8 0/7
lopinavir 0/8 0/7
saquinavir 0/8 0/7
tipranavir 0/8 0/7

a
Virogic failures were defined as: never suppressed: confirmed HIV-1 RNA < 1 log10 reduction from baseline and 
≥ 50 copies/ml at the week-8; rebound: HIV-1 RNA < 50 copies/ml followed by confirmed HIV-1 RNA to 
≥ 400 copies/ml or confirmed > 1 log10 HIV-1 RNA increase from the nadir; discontinuations with HIV-1 RNA 
≥ 400 copies/ml at last visit

b
IAS-USA lists

c
In GS-US216-130 baseline phenotype was not available

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.
In the virologic failures of the GS-US-216-130 trial no cross-resistance with other HIV PIs was 
observed.

Clinical results

The pharmacokinetic enhancing effect of cobicistat on darunavir was evaluated in a Phase I study in 
healthy subjects that were administered darunavir 800 mg with either cobicistat at 150 mg or ritonavir 
at 100 mg once daily. The steady-state pharmacokinetic parameters of darunavir were comparable 
when boosted with cobicistat versus ritonavir. For information on cobicistat, consult the cobicistat 
Summary of Product Characteristics.

Adult patients

Efficacy of darunavir 800 mg once daily co-administered with 150 mg cobicistat once daily in 
ART-naïve and ART-experienced patients
GS-US-216-130 is a single arm, open-label, Phase III trial evaluating the pharmacokinetics, safety, 
tolerability, and efficacy of darunavir with cobicistat in 313 HIV-1 infected adult patients 



33

(295 treatment-naïve and 18 treatment-experienced). These patients received darunavir 800 mg once 
daily in combination with cobicistat 150 mg once daily with an investigator selected background 
regimen consisting of 2 active NRTIs.

HIV-1 infected patients who were eligible for this trial had a screening genotype showing no darunavir 
RAMs and plasma HIV-1 RNA ≥ 1,000 copies/ml. The table below shows the efficacy data of the 
48 week analyses from the GS-US-216-130 trial:

GS-US-216-130

Outcomes at Week 48

Treatment-naïve
darunavir/cobicistat 

800/150 mg once
daily+ OBR

N=295

Treatment-experienced
darunavir/cobicistat 

800/150 mg once daily
+ OBR
N=18

All subjects
darunavir/cobicistat 

800/150 mg once daily
+ OBR
N=313

HIV-1 RNA < 50 copies/ml
a 245 (83.1%) 8 (44.4%) 253 (80.8%)

mean HIV-1 RNA log change 
from baseline 
(log10 copies/ml)

-3.01 -2.39 -2.97

CD4+ cell count mean 
change from baselineb

+174 +102 +170

a
Imputations according to the TLOVR algorithm

b
Last Observation Carried Forward imputation

Efficacy of PREZISTA 800 mg once daily co-administered with 100 mg ritonavir once daily in 
ART-naïve patients
The evidence of efficacy of PREZISTA/ritonavir 800/100 mg once daily is based on the analyses of 
192 week data from the randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviral 
treatment-naïve HIV-1 infected patients comparing PREZISTA/ritonavir 800/100 mg once daily with 
lopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both arms 
used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily and 
emtricitabine 200 mg once daily.

The table below shows the efficacy data of the 48 week and 96 week analyses from the ARTEMIS
trial:

ARTEMIS

Week 48
a

Week 96
b

Outcomes PREZISTA/ 
ritonavir

800/100 mg 
once daily

N=343

Lopinavir/ 
ritonavir

800/200 mg 
per day
N=346

Treatment 
difference 
(95% CI of 
difference)

PREZISTA/ 
ritonavir

800/100 mg 
once daily

N=343

Lopinavir/ 
ritonavir

800/200 m
g per day
N=346

Treatment 
difference 
(95% CI of 
difference)

HIV-1 RNA 
< 50 copies/ml

c

All patients 83.7%
(287)

78.3%
(271)

5.3%

(-0.5; 11.2)
d

79.0%
(271)

70.8%
(245)

8.2%

(1.7; 14.7)
d

With baseline 
HIV-RNA 
< 100,000

85.8%
(194/226)

84.5%
(191/226)

1.3%

(-5.2; 7.9)
d

80.5%
(182/226)

75.2%
(170/226)

5.3%

(-2.3; 13.0)
d

With baseline 
HIV-RNA 
≥ 100,000

79.5%
(93/117)

66.7%
(80/120)

12.8%

(1.6; 24.1)
d

76.1%
(89/117)

62.5%
(75/120)

13.6%

(1.9; 25.3)
d

With baseline 
CD4+ cell 
count < 200

79.4%
(112/141)

70.3%
(104/148)

9.2%

(-0.8; 19.2)
d

78.7%
(111/141)

64.9%
(96/148)

13.9%

(3.5; 24.2)
d

With baseline 
CD4+ cell 
count ≥ 200

86.6%
(175/202)

84.3%
(167/198)

2.3%

(-4.6; 9.2)
d

79.2%
(160/202)

75.3%
(149/198)

4.0%

(-4.3; 12.2)
d



34

median 
CD4+ cell count 
change from 

baseline (x 10
6
/l)

e

137 141 171 188

a
Data based on analyses at week 48

b
Data based on analyses at week 96

c
Imputations according to the TLOVR algorithm

d
Based on normal approximation to the difference in % response

e
Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0

Non-inferiority in virologic response to the PREZISTA/ritonavir treatment, defined as the percentage 
of patients with plasma HIV-1 RNA level < 50 copies/ml, was demonstrated (at the pre-defined 12% 
non-inferiority margin) for both Intent-To-Treat (ITT) and On Protocol (OP) populations in the 
48 week analysis. These results were confirmed in the analyses of data at 96 weeks of treatment in the 
ARTEMIS trial. These results were sustained up to 192 weeks of treatment in the ARTEMIS trial.

Efficacy of PREZISTA 600 mg twice daily co-administered with 100 mg ritonavir twice daily in 
ART-experienced patients
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/ritonavir

600/100 mg twice daily + 
OBR

N=298

Lopinavir/ritonavir
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/ritonavir arm having HIV-1 RNA < 50 copies/ml at week 96 compared to 55.2% in the 
lopinavir/ritonavir arm [difference: 5.2%, 95% CI (-2.8; 13.1)].

ODIN is a Phase III, randomised, open-label trial comparing PREZISTA/ritonavir 800/100 mg once 
daily versus PREZISTA/ritonavir 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 



35

> 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/ritonavir 

800/100 mg once daily + 
OBR

N=294

PREZISTA/ritonavir 
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)

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/ritonavir 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 106/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.



36

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/ 
ritonavir 

600/100 mg 
twice daily 

n=131

Control 
n=124

Treatment 
difference

PREZISTA/ 
ritonavir 

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 genotypea, and baseline 
darunavir FC and by use of enfuvirtide (ENF): As treated analysis of the POWER and DUET trials.

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%

455/1,01
4

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 EC50

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

Paediatric patients

ART-experienced paediatric patients from the age of 6 to < 18 years, and weighing at least 20 kg
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 



37

patients aged 6 to 17 years and weighing at least 20 kg. These patients received PREZISTA/ritonavir 
twice daily 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 log10 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/mla 47.5% (38)
CD4+ cell count mean change from baselineb 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.

ART-experienced paediatric patients from the age of 3 to < 6 years
The pharmacokinetics, safety, tolerability and efficacy of PREZISTA/ritonavir twice daily in 
combination with other antiretroviral agents in 21 ART-experienced HIV-1 infected paediatric patients 
aged 3 to < 6 years and weighing 10 kg to < 20 kg was evaluated in an open-label, Phase II trial, 
ARIEL. Patients received a weight-based twice daily treatment regimen, patients weighing 10 kg to 
< 15 kg received darunavir/ritonavir 25/3 mg/kg twice daily, and patients weighing 15 kg to < 20 kg 
received darunavir/ritonavir 375/50 mg twice daily. At week 48, the virologic response, defined as the 
percentage of patients with confirmed plasma viral load < 50 HIV-1 RNA copies/ml, was evaluated in 
16 paediatric patients 15 kg to < 20 kg and 5 paediatric patients 10 kg to < 15 kg receiving 
PREZISTA/ritonavir in combination with other antiretroviral agents (see section 4.2 for dosage 
recommendations per body weight).

ARIEL
Outcomes at week 48 PREZISTA/ritonavir

10 kg to < 15 kg
N=5

15 kg to < 20 kg
N=16

HIV-1 RNA < 50 copies/mla 80.0% (4) 81.3% (13)
CD4+ percent change from baselineb 4 4
CD4+ cell count mean change from 
baselineb

16 241

a
Imputations according to the TLOVR algorithm.

b
NC=F

Limited efficacy data are available in paediatric patients below 15 kg and no recommendation on a 
posology can be made.

ART-naïve paediatric patients from the age of 12 years to < 18 years, and weighing at least 40 kg
DIONE is an open-label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and 
efficacy of PREZISTA with low dose ritonavir in 12 ART-naïve HIV-1 infected paediatric patients 
aged 12 to less than 18 years and weighing at least 40 kg. These patients received 
PREZISTA/ritonavir 800/100 mg once daily in combination with other antiretroviral agents. Virologic 
response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1.0 log10 versus 
baseline.



38

DIONE

Outcomes at week 48
PREZISTA/ritonavir

N=12
HIV-1 RNA < 50 copies/mla 83.3% (10)
CD4+ percent change from baselineb 14
CD4+ cell count mean change from baselineb 221
≥ 1.0 log10 decrease from baseline in plasma viral load 100%
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.

Pregnancy and postpartum
Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a 
background regimen was evaluated in a clinical trial of 36 pregnant women (18 in each arm) during 
the second and third trimesters, and postpartum. Virologic response was preserved throughout the 
study period in both arms. No mother to child transmission occurred in the infants born to the 
31 subjects who stayed on the antiretroviral treatment through delivery. There were no new clinically 
relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1 
infected adults (see sections 4.2, 4.4 and 5.2).

5.2 Pharmacokinetic properties

The pharmacokinetic properties of darunavir, co-administered with cobicistat or 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 
α1-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. Cobicistat and ritonavir inhibit CYP3A, thereby 
increasing the plasma concentrations of darunavir considerably.

For information on cobicistat pharmacokinetic properties, consult the cobicistat Summary of Product 
Characteristics.

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 cobicistat 
or low dose ritonavir is lower as compared to intake with food. Therefore, PREZISTA tablets should 
be taken with cobicistat or 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 α1-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.



39

Biotransformation
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 14C-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 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the 
administered dose of 14C-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 taken twice daily 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).

The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 
14 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to 
< 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that 
achieved in adults receiving PREZISTA/ritonavir 600/100 mg twice daily (see section 4.2).

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naïve 
paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that 
PREZISTA/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that 
achieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily. Therefore the same once 
daily dosage may be used in treatment-experienced adolescents aged 12 to < 18 years and weighing at 
least 40 kg without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma 
HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 
10 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to 
< 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that 
achieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily (see section 4.2). In addition, 
pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages 
of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed 
the identification of weight-based PREZISTA/ritonavir once daily dosing regimens for paediatric 
patients weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patients 
without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count 
≥ 100 cells x 106/l (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

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.



40

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
Results from a mass balance study with 14C-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).

Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice 
daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally 
lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the 
pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an 
increase in the unbound fraction of darunavir during pregnancy compared to postpartum.

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 
600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of 

pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of 
total darunavir
(mean ± SD)

Second trimester of 
pregnancy

(n=12)a

Third trimester of 
pregnancy

(n=12)

Postpartum 
(6-12 weeks)

(n=12)
Cmax, ng/ml 4,668 ± 1,097 5,328 ± 1,631 6,659 ± 2,364
AUC12h, ng.h/ml 39,370 ± 9,597 45,880 ± 17,360 56,890 ± 26,340
Cmin, ng/ml 1,922 ± 825 2,661 ± 1,269 2,851 ± 2,216
a

n=11 for AUC12h

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 
800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of 

pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of 
total darunavir
(mean ± SD)

Second trimester of 
pregnancy

(n=17)

Third Trimester of 
pregnancy

(n=15)

Postpartum 
(6-12 weeks)

(n=16)
Cmax, ng/ml 4,964 ± 1,505 5,132 ± 1,198 7,310 ± 1,704
AUC24h, ng.h/ml 62,289 ± 16,234 61,112 ± 13,790 92,116 ± 29,241
Cmin, ng/ml 1,248 ± 542 1,075 ± 594 1,473 ± 1,141

In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of 
pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 
26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total 
darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as 
compared with postpartum.



41

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of 
pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 
30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total 
darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared 
with postpartum.

Treatment with darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavir 
exposure. In women receiving darunavir/cobicistat during the second trimester of pregnancy, mean 
intra-individual values for total darunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower, 
respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir 
Cmax, AUC24h and Cmin values were 37%, 50% and 89% lower, respectively, as compared with 
postpartum. The unbound fraction was also substantially reduced, including around 90% reductions of 
Cmin levels. The main cause of these low exposures is a marked reduction in cobicistat exposure as a 
consequence of pregnancy-associated enzyme induction (see below).

Pharmacokinetic results of total darunavir after administration of darunavir/cobicistat 
800/150 mg once daily as part of an antiretroviral regimen, during the second trimester of 

pregnancy, the third trimester of pregnancy, and postpartum
Pharmacokinetics of 
total darunavir
(mean ± SD)

Second trimester 
of pregnancy

(n=7)

Third trimester 
of pregnancy

(n=6)

Postpartum 
(6-12 weeks)

(n=6)
Cmax, ng/mL 4,340 ± 1,616 4,910 ± 970 7,918 ± 2,199
AUC24h, ng.h/mL 47,293 ± 19,058 47,991 ± 9,879 99,613 ± 34,862
Cmin, ng/mL 168 ± 149 184 ± 99 1,538 ± 1,344

The exposure to cobicistat was lower during pregnancy, potentially leading to suboptimal boosting of 
darunavir. During the second trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin were 50%, 
63%, and 83% lower, respectively, as compared with postpartum. During the third trimester of 
pregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, as 
compared with postpartum.

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 



42

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.

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. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hydroxypropylcellulose
Microcrystalline cellulose
Carmellose sodium
Citric acid monohydrate
Sucralose
Strawberry cream flavour
Masking flavour
Sodium methyl parahydroxybenzoate (E219)
Hydrocholoric acid (for pH adjustment)
Purified water

6.2 Incompatibilities

Not applicable.



43

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 30°C.
Do not refrigerate or freeze. Avoid exposure to excessive heat.
Store in the original container.

6.5 Nature and contents of container

Amber-coloured multiple-dose glass bottle for 200 ml suspension with a polypropylene closure with 
LDPE liner packaged with a 6 ml oral dosing pipette with 0.2 ml gradations. The bottle neck is filled 
with a low density polyethylene (LDPE) insert that accommodates the dosing pipette.

PREZISTA oral suspension is available in packs of one bottle.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Shake the bottle vigorously prior to each dose. The supplied oral dosing pipette should not be used for 
any other medicinal products.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/380/006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 February 2007
Date of latest renewal: 19 September 2013

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.europa.eu/


44

1. NAME OF THE MEDICINAL PRODUCT

PREZISTA 75 mg film-coated tablets
PREZISTA 150 mg film-coated tablets
PREZISTA 600 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

PREZISTA 75 mg film-coated tablets
Each film-coated tablet contains 75 mg of darunavir (as ethanolate).

PREZISTA 150 mg film-coated tablets
Each film-coated tablet contains 150 mg of darunavir (as ethanolate).

PREZISTA 600 mg film-coated tablets
Each film-coated tablet contains 600 mg of darunavir (as ethanolate).
Excipient with known effect: Each tablet contains a maximum of 2.750 mg sunset yellow FCF (E110).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

PREZISTA 75 mg film-coated tablets
Film-coated tablet.
White caplet shaped tablet of 9.2 mm, debossed with “75” on one side and “TMC” on the other side.

PREZISTA 150 mg film-coated tablets
Film-coated tablet.
White oval shaped tablet of 13.7 mm, debossed with “150” on one side and “TMC” on the other side.

PREZISTA 600 mg film-coated tablets
Film-coated tablet.
Orange oval shaped tablet of 21.1 mm, debossed with “600MG” on one side and “TMC” on the other 
side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 (see section 4.2).

PREZISTA 75 mg, 150 mg, and 600 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 paediatric patients from the age of 3 years and at least 

15 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 (see sections 4.2, 4.4 and 5.1).



45

4.2 Posology and method of administration

Therapy should be initiated by a health care provider experienced in the management of HIV 
infection. After therapy with PREZISTA has been initiated, patients should be advised not to alter the 
dosage, dose form or discontinue therapy without discussing with their health care provider.

Posology
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.

PREZISTA is also available as an oral suspension for use in patients who are unable to swallow 
PREZISTA tablets (please refer to the Summary of Product Characteristics for PREZISTA oral 
suspension).

ART-experienced adult patients
The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken 
with food. PREZISTA 75 mg, 150 mg, and 600 mg tablets can be used to construct the twice daily 
600 mg regimen.

The use of 75 mg and 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 600 mg 
tablets.

ART-naïve adult patients
For dosage recommendations in ART-naïve patients see the Summary of Product Characteristics for 
PREZISTA 400 mg and 800 mg tablets.

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 15 kg)
The weight-based dose of PREZISTA and ritonavir in paediatric patients is provided in the table 
below.

Recommended dose for treatment-naïve paediatric patients (3 to 17 years) with PREZISTA 
tablets and ritonavira

Body weight (kg) Dose (once daily with food)
≥ 15 kg to < 30 kg 600 mg PREZISTA/100 mg ritonavir once daily
≥ 30 kg to < 40 kg 675 mg PREZISTA/100 mg ritonavir once daily
≥ 40 kg 800 mg PREZISTA/100 mg ritonavir once daily
a

ritonavir oral solution: 80 mg/ml

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 15 kg)
PREZISTA twice daily taken with ritonavir taken with food is usually recommended.

A once daily dose regimen of PREZISTA taken with ritonavir taken with food may be used in patients 
with prior exposure to antiretroviral medicinal products but without darunavir resistance associated 
mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell 
count ≥ 100 cells x 106/l.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The weight-based dose of PREZISTA and ritonavir in paediatric patients is provided in the table 
below. The recommended dose of PREZISTA with low dose ritonavir should not exceed the 
recommended adult dose (600/100 mg twice daily or 800/100 mg once daily).



46

Recommended dose for treatment-experienced paediatric patients (3 to 17 years) with
PREZISTA tablets and ritonavira

Body weight (kg) Dose (once daily with food) Dose (twice daily with food)
≥ 15 kg–< 30 kg 600 mg PREZISTA/100 mg ritonavir 

once daily
375 mg PREZISTA/50 mg ritonavir 
twice daily

≥ 30 kg–< 40 kg 675 mg PREZISTA/100 mg ritonavir 
once daily

450 mg PREZISTA/60 mg ritonavir 
twice daily

≥ 40 kg 800 mg PREZISTA/100 mg ritonavir 
once daily

600 mg PREZISTA/100 mg ritonavir 
twice daily

a
ritonavir oral solution: 80 mg/ml

For ART-experienced paediatric patients HIV genotypic testing is recommended. However, when HIV 
genotypic testing is not feasible, the PREZISTA/ritonavir once daily dosing regimen is recommended 
in HIV protease inhibitor-naïve paediatric patients and the twice daily dosing regimen is 
recommended in HIV protease inhibitor-experienced patients.

The use of only 75 mg and 150 mg tablets or the 100 mg/ml oral suspension to achieve the 
recommended dose of PREZISTA could be appropriate when there is a possibility of hypersensitivity 
to specific colouring agents.

Advice on missed doses
In case a dose of PREZISTA and/or ritonavir is 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 is noticed later than 6 hours after 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.

Special populations

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).

Paediatric population
PREZISTA/ritonavir should not be used in children with a body weight of less than 15 kg as the dose 
for this population has not been established in a sufficient number of patients (see section 5.1). 
PREZISTA/ritonavir should not be used in children below 3 years of age because of safety concerns 
(see sections 4.4 and 5.3).

The weight-based dose regimen for PREZISTA and ritonavir is provided in the tables above.



47

Pregnancy and postpartum
No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. 
PREZISTA/ritonavir should be used during pregnancy only if the potential benefit justifies the 
potential risk (see sections 4.4, 4.6 and 5.2).

Method of administration
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).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with severe (Child-Pugh Class C) hepatic impairment.

Combination of rifampicin with PREZISTA with concomitant low dose ritonavir (see section 4.5).

Co-administration with the combination product lopinavir/ritonavir (see section 4.5).

Co-administration with herbal preparations containing St John’s wort (Hypericum perforatum) (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. These active substances include e.g.:
- alfuzosin
- amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
- astemizole, terfenadine
- colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)
- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
- elbasvir/grazoprevir
- cisapride
- dapoxetine
- domperidone
- naloxegol
- lurasidone, pimozide, quetiapine, sertindole (see section 4.5)
- triazolam, midazolam administered orally (for caution on parenterally administered midazolam, 

see section 4.5)
- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil
- simvastatin, lovastatin and lomitapide (see section 4.5)
- dabigatran, ticagrelor (see section 4.5).

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission 
should be taken in accordance with national guidelines.

Regular assessment of virological response is advised. In the setting of lack or loss of virological 
response, resistance testing should be performed.

PREZISTA must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in 
combination with other antiretroviral medicinal products (see section 5.2). The Summary of Product 
Characteristics of ritonavir as appropriate, must therefore be consulted prior to initiation of therapy 
with PREZISTA.



48

Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect 
darunavir concentrations It is not recommended to alter the dose of ritonavir.

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 used in combination with cobicistat or low dose ritonavir 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 106/l (see section 
4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs have not been 
studied in this population. Limited data are available in patients with HIV-1 clades other than B (see 
section 5.1).

Paediatric population
PREZISTA is not recommended for use in paediatric patients below 3 years of age or less than 15 kg 
body weight (see sections 4.2 and 5.3).

Pregnancy
PREZISTA/ritonavir should be used during pregnancy only if the potential benefit justifies the 
potential risk. Caution should be used in pregnant women with concomitant medications which may 
further decrease darunavir exposure (see sections 4.5 and 5.2).

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 darunavir/ritonavir 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. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson 
Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal 
necrolysis and acute generalised exanthematous pustulosis have been reported. PREZISTA should be 
discontinued immediately if signs or symptoms of severe skin reactions develop. These can include,
but are not limited to, severe rash or rash accompanied by 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/ritonavir + raltegravir compared to patients receiving PREZISTA/ritonavir 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. 
During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 
0.5% of patients receiving combination antiretroviral therapy with PREZISTA/ritonavir. 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 reactions. In case of
concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for 
these medicinal products.



49

Appropriate laboratory testing should be conducted prior to initiating therapy with 
PREZISTA/ritonavir 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/ritonavir 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/ritonavir, 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 for darunavir/ritonavir 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).

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.

Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported particularly in patients with advanced HIV disease and/or long-term exposure to combination 
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience 
joint aches and pain, joint stiffness or difficulty in movement.

Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
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.



50

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment (see section 4.8).

Interactions with medicinal products
Several of the interaction studies have been performed with darunavir at lower than recommended 
doses. 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 boosted PREZISTA once daily may result in sub-optimal darunavir 
Cmin. If efavirenz is to be used in combination with PREZISTA, the PREZISTA/ritonavir 600/100 mg 
twice daily regimen should be used (see section 4.5).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and 
strong inhibitors of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).

PREZISTA 600 mg tablets contain sunset yellow FCF (E110) which may cause an allergic reaction.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Medicinal products that may be affected by darunavir boosted with ritonavir
Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of 
darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or 
transported by P-gp 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) (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 darunavir/ritonavir, which may be attributed to the 
presence of low dose ritonavir. Co-administration of darunavir and ritonavir with 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 with 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.



51

Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration 
with substrates of these transporters can result in increased plasma concentrations of these compounds 
(e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).

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, azole antifungals like clotrimazole). These interactions are 
described in the interaction table below.

Interaction table
Interactions between PREZISTA/ritonavir and antiretroviral and non-antiretroviral medicinal products 
are listed in the table below. 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 (not determined as “ND”).

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.

The below list of examples of drug drug interactions is not comprehensive and therefore the label of 
each drug that is co-administered with PREZISTA should be consulted for information related to the 
route of metabolism, interaction pathways, potential risks, and specific actions to be taken with 
regards to co-administration.

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal products by 
therapeutic areas

Interaction
Geometric mean change (%)

Recommendations concerning 
co-administration

HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors

Dolutegravir dolutegravir AUC ↓ 22%
dolutegravir C24h ↓ 38%
dolutegravir Cmax ↓ 11%
darunavir ↔*
* Using cross-study comparisons to historical 
pharmacokinetic data

PREZISTA co-administered with 
low dose ritonavir and dolutegravir 
can be used without dose 
adjustment.

Raltegravir Some clinical studies suggest raltegravir 
may cause a modest decrease in 
darunavir plasma concentrations.

At present the effect of raltegravir 
on darunavir plasma 
concentrations does not appear to 
be clinically relevant. PREZISTA 
co-administered with low dose
ritonavir and raltegravir can be 
used without dose adjustments.

Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine
400 mg once daily

didanosine AUC ↓ 9%
didanosine Cmin ND
didanosine Cmax ↓ 16%
darunavir AUC ↔
darunavir Cmin ↔
darunavir Cmax ↔

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.



52

Tenofovir disoproxil
245 mg once daily

‡
tenofovir AUC ↑ 22%
tenofovir Cmin ↑ 37%
tenofovir Cmax ↑ 24%
#
darunavir AUC ↑ 21%

#
darunavir Cmin ↑ 24%

#
darunavir Cmax ↑ 16%

(↑ tenofovir from effect on MDR-1 
transport in the renal tubules)

Monitoring of renal function may 
be indicated when PREZISTA 
co-administered with low dose 
ritonavir is given in combination 
with tenofovir disoproxil, 
particularly in patients with 
underlying systemic or renal 
disease, or in patients taking 
nephrotoxic agents.

Emtricitabine/tenofovir 
alafenamide

Tenofovir alafenamide ↔
Tenofovir ↑

The recommended dose of 
emtricitabine/tenofovir 
alafenamide is 200/10 mg once 
daily when used with PREZISTA
with low dose ritonavir.

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 Cmin ↑ 17%
efavirenz Cmax ↑ 15%
#
darunavir AUC ↓ 13%

#
darunavir Cmin ↓ 31%

#
darunavir Cmax ↓ 15%

(↑ efavirenz from CYP3A inhibition)
(↓ darunavir from CYP3A induction)

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.

Efavirenz in combination with 
PREZISTA/ritonavir 800/100 mg 
once daily may result in 
sub-optimal darunavir Cmin. If 
efavirenz is to be used in 
combination with 
PREZISTA/ritonavir, the 
PREZISTA/ritonavir 600/100 mg 
twice daily regimen should be used 
(see section 4.4).

Etravirine
100 mg twice daily

etravirine AUC ↓ 37%
etravirine Cmin ↓ 49%
etravirine Cmax ↓ 32%
darunavir AUC ↑ 15%
darunavir Cmin ↔
darunavir Cmax ↔

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 Cmin ↑ 47%
nevirapine Cmax ↑ 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.

Rilpivirine
150 mg once daily

rilpivirine AUC ↑ 130%
rilpivirine Cmin ↑ 178%
rilpivirine Cmax ↑ 79%
darunavir AUC ↔
darunavir Cmin ↓ 11%
darunavir Cmax ↔

PREZISTA co-administered with 
low dose ritonavir and rilpivirine 
can be used without dose 
adjustments.



53

HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir
†

Atazanavir
300 mg once daily

atazanavir AUC ↔
atazanavir Cmin ↑ 52%
atazanavir Cmax ↓ 11%
#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

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.

PREZISTA co-administered with 
low dose ritonavir and atazanavir 
can be used without dose 
adjustments.

Indinavir
800 mg twice daily

indinavir AUC ↑ 23%
indinavir Cmin ↑ 125%
indinavir Cmax ↔
#
darunavir AUC ↑ 24%

#
darunavir Cmin ↑ 44%

#
darunavir Cmax ↑ 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.

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.

Saquinavir
1,000 mg twice daily

#
darunavir AUC ↓ 26%

#
darunavir Cmin ↓ 42%

#
darunavir Cmax ↓ 17%

saquinavir AUC ↓ 6%
saquinavir Cmin ↓ 18%
saquinavir Cmax ↓ 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.

It is not recommended to combine 
PREZISTA co-administered with 
low dose ritonavir with saquinavir.



54

HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavir
†

Lopinavir/ritonavir
400/100 mg twice daily

Lopinavir/ritonavir
533/133.3 mg twice daily

lopinavir AUC ↑ 9%
lopinavir Cmin ↑ 23%
lopinavir Cmax ↓ 2%

darunavir AUC ↓ 38%
‡

darunavir Cmin ↓ 51%
‡

darunavir Cmax ↓ 21%
‡

lopinavir AUC ↔
lopinavir Cmin ↑ 13%
lopinavir Cmax ↑ 11%
darunavir AUC ↓ 41%
darunavir Cmin ↓ 55%
darunavir Cmax ↓ 21%
‡

based upon non dose normalised values

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).

CCR5 ANTAGONIST
Maraviroc
150 mg twice daily

maraviroc AUC ↑ 305%
maraviroc Cmin ND
maraviroc Cmax ↑ 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.

α1-ADRENORECEPTOR ANTAGONIST
Alfuzosin Based on theoretical considerations 

PREZISTA is expected to increase 
alfuzosin plasma concentrations.
(CYP3A inhibition)

Co-administration of PREZISTA
with low dose ritonavir and
alfuzosin is contraindicated (see 
section 4.3).

ANAESTHETIC
Alfentanil Not studied. The metabolism of alfentanil 

is mediated via CYP3A, and may as such 
be inhibited by PREZISTA 
co-administered with low dose ritonavir.

The concomitant use with 
PREZISTA and low dose ritonavir 
may require to lower the dose of 
alfentanil and requires monitoring 
for risks of prolonged or delayed 
respiratory depression.

ANTIANGINA/ANTIARRHYTHMIC
Disopyramide
Flecainide
Lidocaine (systemic)
Mexiletine
Propafenone

Amiodarone
Bepridil
Dronedarone
Ivabradine 
Quinidine
Ranolazine

Not studied. PREZISTA is expected to 
increase these antiarrhythmic plasma 
concentrations.
(CYP3A and/or CYP2D6 inhibition)

Caution is warranted and 
therapeutic concentration 
monitoring, if available, is 
recommended for these 
antiarrhythmics when 
co-administered with PREZISTA 
with low dose ritonavir.

PREZISTA co-administered with 
low dose ritonavir and 
amiodarone, bepridil, dronedarone, 
ivabradine, quinidine, or 
ranolazine is contraindicated (see 
section 4.3).

Digoxin
0.4 mg single dose

digoxin AUC ↑ 61%
digoxin Cmin ND
digoxin Cmax ↑ 29%
(↑ digoxin from probable inhibition of 
P-gp)

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.



55

ANTIBIOTIC
Clarithromycin
500 mg twice daily

clarithromycin AUC ↑ 57%
clarithromycin Cmin ↑ 174%
clarithromycin Cmax ↑ 26%
#
darunavir AUC ↓ 13%

#
darunavir Cmin ↑ 1%

#
darunavir Cmax ↓ 17%

14-OH-clarithromycin concentrations 
were not detectable when combined with 
PREZISTA/ritonavir.
(↑ clarithromycin from CYP3A inhibition 
and possible P-gp inhibition)

Caution should be exercised when 
clarithromycin is combined with 
PREZISTA co-administered with 
low dose ritonavir.

For patients with renal impairment 
the Summary of Product 
Characteristics for clarithromycin 
should be consulted for the 
recommended dose.

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban
Edoxaban
Rivaroxaban

Not studied. Co-administration of 
PREZISTA with these anticoagulants 
may increase concentrations of the 
anticoagulant, which may lead to an 
increased bleeding risk.
(CYP3A and/or P-gp inhibition)

The use of PREZISTA 
co-administered with low dose 
ritonavir and these anticoagulants 
is not recommended.

Dabigatran
Ticagrelor

Not studied. Co-administration with 
boosted PREZISTA may lead to a 
substantial increase in exposure to 
dabigatran or ticagrelor.

Concomitant administration of 
boosted PREZISTA with 
dabigatran or ticagrelor is 
contraindicated (see section 4.3).

Use of other antiplatelets not 
affected by CYP inhibition or 
induction (e.g. prasugrel) is 
recommended.

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 and its 
pharmacoenhancer.
(induction of CYP450 enzymes)

PREZISTA co-administered with 
low dose ritonavir should not be 
used in combination with these 
medicines.

Carbamazepine
200 mg twice daily

carbamazepine AUC ↑ 45%
carbamazepine Cmin ↑ 54%
carbamazepine Cmax ↑ 43%
darunavir AUC ↔
darunavir Cmin ↓ 15%
darunavir Cmax ↔

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.

Clonazepam Not studied. Co-administration of 
boosted PREZISTA with clonazepam 
may increase concentrations of 
clonazepam. (CYP3A inhibition)

Clinical monitoring is 
recommended when 
co-administering PREZISTA with 
low dose ritonavir and
clonazepam.



56

ANTIDEPRESSANTS
Paroxetine
20 mg once daily

Sertraline
50 mg once daily

Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone

paroxetine AUC ↓ 39%
paroxetine Cmin ↓ 37%
paroxetine Cmax ↓ 36%
#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

sertraline AUC ↓ 49%
sertraline Cmin ↓ 49%
sertraline Cmax ↓ 44%
#
darunavir AUC ↔

#
darunavir Cmin ↓ 6%

#
darunavir Cmax ↔

Concomitant use of PREZISTA 
co-administered with low dose ritonavir 
and these antidepressants may increase 
concentrations of the antidepressant.
(CYP2D6 and/or CYP3A inhibition)

If antidepressants are 
co-administered with PREZISTA 
with low dose ritonavir, the 
recommended approach is a dose 
titration of the antidepressant 
based on a clinical assessment of 
antidepressant response. In 
addition, patients on a stable dose 
of these antidepressants who start 
treatment with PREZISTA with 
low dose ritonavir should be 
monitored for antidepressant 
response.

Clinical monitoring is 
recommended when 
co-administering PREZISTA with 
low dose ritonavir with these 
antidepressants and a dose 
adjustment of the antidepressant 
may be needed.

ANTIEMETICS
Domperidone Not studied. Co-administration of domperidone 

with boosted PREZISTA is 
contraindicated.

ANTIFUNGALS
Voriconazole Not studied. Ritonavir may decrease 

plasma concentrations of voriconazole.
(induction of CYP450 enzymes)

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.

Fluconazole
Isavuconazole
Itraconazole
Posaconazole

Clotrimazole

Not studied. PREZISTA may increase 
antifungal plasma concentrations and 
posaconazole, isavuconazole,
itraconazole, or fluconazole may increase 
darunavir concentrations.
(CYP3A and/or P-gp inhibition)

Not studied. Concomitant systemic use of 
clotrimazole and darunavir 
co-administered with low dose ritonavir 
may increase plasma concentrations of 
darunavir and/or clotrimazole.
darunavir AUC24h ↑ 33% (based on 
population pharmacokinetic model)

Caution is warranted and clinical 
monitoring is recommended. When 
co-administration is required the 
daily dose of itraconazole should 
not exceed 200 mg.



57

ANTIGOUT MEDICINES
Colchicine Not studied. Concomitant use of 

colchicine and darunavir co-administered 
with low dose ritonavir may increase the 
exposure to colchicine.
(CYP3A and/ or P-gp inhibition)

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. For 
patients with renal or hepatic 
impairment colchicine with 
PREZISTA co-administered with 
low dose ritonavir is 
contraindicated (see sections 4.3 
and 4.4).

ANTIMALARIALS
Artemether/Lumefantrine
80/480 mg, 6 doses at 0, 
8, 24, 36, 48, and 
60 hours

artemether AUC ↓ 16%
artemether Cmin ↔
artemether Cmax ↓ 18%
dihydroartemisinin AUC ↓ 18%
dihydroartemisinin Cmin ↔
dihydroartemisinin Cmax ↓ 18%
lumefantrine AUC ↑ 175%
lumefantrine Cmin ↑ 126%
lumefantrine Cmax ↑ 65%
darunavir AUC ↔
darunavir Cmin ↓ 13%
darunavir Cmax ↔

The combination of PREZISTA 
and artemether/lumefantrine can 
be used without dose adjustments; 
however, due to the increase in 
lumefantrine exposure, the 
combination should be used with 
caution.

ANTIMYCOBACTERIALS
Rifampicin
Rifapentine

Not studied. Rifapentine and rifampicin 
are strong CYP3A inducers and have 
been shown to cause profound decreases 
in concentrations of other protease 
inhibitors, which can result in virological 
failure and resistance development 
(CYP450 enzyme induction). 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 with rifampicin.

The combination of rifapentine and 
PREZISTA with concomitant low 
dose ritonavir is not recommended.

The combination of rifampicin and 
PREZISTA with concomitant low
dose ritonavir is contraindicated 
(see section 4.3).



58

Rifabutin
150 mg once every other 
day

rifabutin AUC
**

↑ 55%

rifabutin Cmin
**

↑ ND

rifabutin Cmax
**

↔
darunavir AUC ↑ 53%
darunavir Cmin ↑ 68%
darunavir Cmax ↑ 39%
**

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 Cmax 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).

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 with PREZISTA 
co-administered with ritonavir. 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.

ANTINEOPLASTICS
Dasatinib
Nilotinib
Vinblastine
Vincristine

Everolimus
Irinotecan

Not studied. PREZISTA is expected to 
increase these antineoplastic plasma 
concentrations.
(CYP3A inhibition)

Concentrations of these medicinal 
products may be increased when 
co-administered with PREZISTA 
with low dose ritonavir resulting in 
the potential for increased adverse 
events usually associated with 
these agents.
Caution should be exercised when 
combining one of these 
antineoplastic agents with 
PREZISTA with low dose 
ritonavir.

Concominant use of everolimus or 
irinotecan and PREZISTA 
co-administered with low dose 
ritonavir is not recommended.

ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine Not studied. PREZISTA is expected to

increase these antipsychotic plasma 
concentrations.
(CYP3A inhibition)

Concomitant administration of 
PREZISTA with low dose 
ritonavir and quetiapine is 
contraindicated as it may increase 
quetiapine-related toxicity. 
Increased concentrations of 
quetiapine may lead to coma (see 
section 4.3).



59

Perphenazine
Risperidone
Thioridazine

Lurasidone
Pimozide
Sertindole

Not studied. PREZISTA is expected to 
increase these antipsychotic plasma 
concentrations.
(CYP3A, CYP2D6 and/or P-gp
inhibition)

A dose decrease may be needed for 
these drugs when co-administered 
with PREZISTA co-administered 
with low dose ritonavir.

Concominant administration of 
PREZISTA with low dose 
ritonavir and lurasidone, pimozide 
or sertindole is contraindicated
(see section 4.3).

β-BLOCKERS
Carvedilol
Metoprolol
Timolol

Not studied. PREZISTA is expected to 
increase these β-blocker plasma 
concentrations.
(CYP2D6 inhibition)

Clinical monitoring is 
recommended when 
co-administering PREZISTA with 
β-blockers. A lower dose of the 
β-blocker should be considered.

CALCIUM CHANNEL BLOCKERS
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil

Not studied. PREZISTA co-administered 
with low dose ritonavir can be expected 
to increase the plasma concentrations of 
calcium channel blockers.
(CYP3A and/or CYP2D6 inhibition)

Clinical monitoring of therapeutic 
and adverse effects is 
recommended when these 
medicines are concomitantly 
administered with PREZISTA with 
low dose ritonavir.

CORTICOSTEROIDS
Corticosteroids primarily 
metabolised by CYP3A 
(including 
betamethasone, 
budesonide, fluticasone, 
mometasone, prednisone, 
triamcinolone)

Fluticasone: 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. The 
effects of high fluticasone systemic 
exposure on ritonavir plasma levels are 
unknown.

Other corticosteroids: interaction not 
studied. Plasma concentrations of these 
medicinal products may be increased 
when co-administered with PREZISTA
with low dose ritonavir, resulting in 
reduced serum cortisol concentrations.

Concomitant use of PREZISTA 
with low dose ritonavir and 
corticosteroids that are 
metabolised by CYP3A (e.g. 
fluticasone propionate or other 
inhaled or nasal corticosteroids) 
may increase the risk of 
development of systemic 
corticosteroid effects, including 
Cushing’s syndrome and adrenal 
suppression.
Co-administration with CYP3A-
metabolised corticosteroids is not 
recommended unless the potential 
benefit to the patient outweighs the 
risk, in which case patients should 
be monitored for systemic 
corticosteroid effects.
Alternative corticosteroids which 
are less dependent on CYP3A 
metabolism e.g. beclomethasone 
for intranasal or inhalational use 
should be considered, particularly 
for long term use.

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.



60

ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan Not studied. Concomitant use of bosentan 

and PREZISTA co-administered with 
low dose ritonavir may increase plasma 
concentrations of bosentan.
Bosentan is expected to decrease plasma 
concentrations of darunavir and/or its 
pharmacoenhancer.
(CYP3A induction)

When administered concomitantly 
with PREZISTA and low dose 
ritonavir, the patient’s tolerability 
of bosentan should be monitored.

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A protease inhibitors

Elbasvir/grazoprevir PREZISTA with low dose ritonavir may 
increase the exposure to grazoprevir.
(CYP3A and OATP1B inhibition)

Concomitant use of PREZISTA 
with low dose ritonavir and
elbasvir/grazoprevir is 
contraindicated (see section 4.3).

Boceprevir
800 mg three times daily

boceprevir AUC ↓ 32%
boceprevir Cmin ↓ 35%
boceprevir Cmax ↓ 25%
darunavir AUC ↓ 44%
darunavir Cmin ↓ 59%
darunavir Cmax ↓ 36%

It is not recommended to 
co-administer PREZISTA with 
low dose ritonavir and boceprevir.

Glecaprevir/pibrentasvir Based on theoretical considerations 
boosted PREZISTA may increase the 
exposure to glecaprevir and pibrentasvir.
(P-gp, BCRP and/or OATP1B1/3 
inhibition)

It is not recommended to 
co-administer boosted PREZISTA 
with glecaprevir/pibrentasvir.

Simeprevir simeprevir AUC ↑ 159%
simeprevir Cmin ↑ 358%
simeprevir Cmax ↑ 79%
darunavir AUC ↑ 18%
darunavir Cmin ↑ 31%
darunavir Cmax 

The dose of simeprevir in this interaction 
study was 50 mg when co-administered 
in combination with darunavir/ritonavir, 
compared to 150 mg in the simeprevir 
alone treatment group.

It is not recommended to 
co-administer PREZISTA with 
low dose ritonavir and simeprevir.

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.



61

HMG CO-A REDUCTASE INHIBITORS
Lovastatin
Simvastatin

Not studied. Lovastatin and simvastatin 
are expected to have markedly increased 
plasma concentrations when 
co-administered with 
PREZISTAco-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 Cmin ↑ ≈5.5-10 fold
atorvastatin Cmax ↑ ≈2 fold
#
darunavir/ritonavir

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 Cmin ND
pravastatin Cmax ↑ 63%
¶

an up to five-fold increase was seen in a 
limited subset of subjects

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.

Rosuvastatin
10 mg once daily

rosuvastatin AUC ↑ 48%
║

rosuvastatin Cmax ↑ 144%
║

║
based on published data with 

darunavir/ritonavir

When administration of 
rosuvastatin and PREZISTA 
co-administered with low dose 
ritonavir is required, it is 
recommended to start with the 
lowest possible dose of 
rosuvastatin and titrate up to the 
desired clinical effect while 
monitoring for safety.

OTHER LIPID MODIFYING AGENTS
Lomitapide Based on theoretical considerations 

boosted PREZISTA is expected to 
increase the exposure of lomitapide when 
co-administered.
(CYP3A inhibition)

Co-administration is 
contraindicated (see section 4.3)

H2-RECEPTOR ANTAGONISTS
Ranitidine
150 mg twice daily

#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

PREZISTA co-administered with 
low dose ritonavir can be 
co-administered with H2-receptor 
antagonists without dose 
adjustments.

IMMUNOSUPPRESSANTS
Ciclosporin
Sirolimus
Tacrolimus

Everolimus

Not studied. Exposure to these 
immunosuppressants will be increased 
when co-administered with PREZISTA 
co-administered with low dose ritonavir.
(CYP3A inhibition)

Therapeutic drug monitoring of the 
immunosuppressive agent must be 
done when co-administration 
occurs.

Concomitant use of everolimus 
and PREZISTA co-administered 
with low dose ritonavir is not 
recommended.



62

INHALED BETA AGONISTS
Salmeterol Not studied. Concomitant use of 

salmeterol and darunavir co-administered 
with low dose ritonavir may increase 
plasma concentrations of salmeterol.

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

R(-) methadone AUC ↓ 16%
R(-) methadone Cmin ↓ 15%
R(-) methadone Cmax ↓ 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.

Buprenorphine/naloxone
8/2 mg–16/4 mg once 
daily

buprenorphine AUC ↓ 11%
buprenorphine Cmin ↔
buprenorphine Cmax ↓ 8%
norbuprenorphine AUC ↑ 46%
norbuprenorphine Cmin ↑ 71%
norbuprenorphine Cmax ↑ 36%
naloxone AUC ↔
naloxone Cmin ND
naloxone Cmax ↔

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.

Fentanyl
Oxycodone
Tramadol

Based on theoretical considerations 
boosted PREZISTA may increase plasma 
concentrations of these analgesics.
(CYP2D6 and/or CYP3A inhibition)

Clinical monitoring is 
recommended when 
co-administering PREZISTA with 
low dose ritonavir with these 
analgesics.

OESTROGEN-BASED CONTRACEPTIVES
Drospirenone 
Ethinylestradiol 
(3 mg/0.02 mg once 
daily)

Ethinylestradiol
Norethindrone
35 g/1 mg once daily

Not studied with darunavir/ritonavir.

ethinylestradiol AUC ↓ 44%
β

ethinylestradiol Cmin ↓ 62%
β

ethinylestradiol Cmax ↓ 32%
β

norethindrone AUC ↓ 14%
β

norethindrone Cmin ↓ 30%
β

norethindrone Cmax ↔
β

β
with darunavir/ritonavir

When PREZISTA is co-
administered with a drospirenone-
containing product, clinical 
monitoring is recommended due to 
the potential for hyperkalaemia.

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.

OPIOID ANTAGONIST
Naloxegol Not studied. Co-administration of boosted 

PREZISTA and naloxegol is 
contraindicated.



63

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of 
erectile dysfunction

Avanafil
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.

The combination of avanafil and 
PREZISTA with low dose 
ritonavir is contraindicated (see 
section 4.3). Concomitant use of 
other 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.
(CYP3A inhibition)

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 Cmin ↔

#
darunavir Cmax ↔

PREZISTA co-administered with 
low dose ritonavir can be 
co-administered with proton pump 
inhibitors without dose 
adjustments.



64

SEDATIVES/HYPNOTICS
Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zolpidem

Midazolam (oral)
Triazolam

Not studied. Sedative/hypnotics are 
extensively metabolised by CYP3A. 
Co-administration with 
PREZISTA/ritonavir may cause a large 
increase in the concentration of these 
medicines.

If parenteral midazolam is 
co-administered with PREZISTA 
co-administered with low dose ritonavir it 
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.

Clinical monitoring is 
recommended when 
co-administering PREZISTA with 
these sedatives/hypnotics and a 
lower dose of the 
sedatives/hypnotics should be 
considered.

If parenteral midazolam is 
co-administered with PREZISTA 
with low dose ritonavir, 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.

PREZISTA with low dose 
ritonavir with triazolam or oral 
midazolam is contraindicated (see 
section 4.3)

TREATMENT FOR PREMATURE EJACULATION
Dapoxetine Not studied. Co-administration of boosted 

PREZISTA with dapoxetine is 
contraindicated.

UROLOGICAL DRUGS
Fesoterodine
Solifenacin

Not studied. Use with caution. Monitor for 
fesoterodine or solifenacin adverse 
reactions, dose reduction of
fesoterodine or solifenacin may be 
necessary.

#
Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see 
section 4.2 Posology).

†
The efficacy and safety of the use of PREZISTA with 100 mg ritonavir and any other HIV 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.

‡
Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.

4.6 Fertility, pregnancy and lactation

Pregnancy
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in 
pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 
the animal data as well as the clinical experience in pregnant women should be taken into account.

There are no adequate and well controlled studies on pregnancy outcome 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.



65

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).

4.7 Effects on ability to drive and use machines

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).

4.8 Undesirable effects

Summary of the safety profile
During the clinical development program (N=2,613 treatment-experienced subjects who initiated 
therapy with PREZISTA/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one 
adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent 
adverse reactions reported in clinical trials and as spontaneous reports are diarrhoea, nausea, rash, 
headache and vomiting. The most frequent serious reactions are acute renal failure, myocardial 
infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, 
diarrhoea, hepatitis and pyrexia.

In the 96 week analysis, the safety profile of PREZISTA/ritonavir 800/100 mg once daily in 
treatment-naïve subjects was similar to that seen with PREZISTA/ritonavir 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. No new safety findings were 
identified in the 192 week analysis of the treatment-naïve subjects in which the mean treatment 
duration of PREZISTA/ritonavir 800/100 mg once daily was 162.5 weeks.

Tabulated list 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 observed with darunavir/ritonavir in clinical trials and post-marketing

MedDRA system organ class
Frequency category

Adverse reaction

Infections and infestations
Uncommon herpes simplex
Blood and lymphatic system disorders
Uncommon thrombocytopenia, neutropenia, anaemia, 

leukopenia

Rare increased eosinophil count
Immune system disorders
Uncommon immune reconstitution inflammatory syndrome, 

(drug) hypersensitivity



66

Endocrine disorders
Uncommon hypothyroidism, increased blood thyroid 

stimulating hormone
Metabolism and nutrition disorders
Common diabetes mellitus, hypertriglyceridaemia, 

hypercholesterolaemia, hyperlipidaemia

Uncommon gout, anorexia, decreased appetite, decreased 
weight, increased weight, hyperglycaemia, 
insulin resistance, decreased high density 
lipoprotein, increased appetite, polydipsia, 
increased blood lactate dehydrogenase

Psychiatric disorders
Common insomnia

uncommon depression, disorientation, anxiety, sleep 
disorder, abnormal dreams, nightmare, 
decreased libido

Rare confusional state, altered mood, restlessness
Nervous system disorders
Common headache, peripheral neuropathy, dizziness

Uncommon lethargy, paraesthesia, hypoaesthesia, dysgeusia, 
disturbance in attention, memory impairment, 
somnolence

Rare syncope, convulsion, ageusia, sleep phase 
rhythm disturbance

Eye disorders
Uncommon conjunctival hyperaemia, dry eye

Rare visual disturbance
Ear and labyrinth disorders
Uncommon vertigo
Cardiac disorders
Uncommon myocardial infarction, angina pectoris, 

prolonged electrocardiogram QT, tachycardia

Rare acute myocardial infarction, sinus bradycardia, 
palpitations

Vascular disorders
Uncommon hypertension, flushing
Respiratory, thoracic and mediastinal disorders
Uncommon dyspnoea, cough, epistaxis, throat irritation

Rare rhinorrhoea
Gastrointestinal disorders
very common diarrhoea

Common vomiting, nausea, abdominal pain, increased 
blood amylase, dyspepsia, abdominal distension, 
flatulence



67

Uncommon pancreatitis, gastritis, gastrooesophageal reflux 
disease, aphthous stomatitis, retching, dry 
mouth, abdominal discomfort, constipation, 
increased lipase, eructation, oral dysaesthesia

Rare stomatitis, haematemesis, cheilitis, dry lip, 
coated tongue

Hepatobiliary disorders
Common increased alanine aminotransferase

Uncommon hepatitis, cytolytic hepatitis, hepatic steatosis,
hepatomegaly, increased transaminase, increased 
aspartate aminotransferase, increased blood 
bilirubin, increased blood alkaline phosphatase, 
increased gamma-glutamyltransferase

Skin and subcutaneous tissue disorders
Common rash (including macular, maculopapular, 

papular, erythematous and pruritic rash), pruritus

Uncommon angioedema, generalised rash, allergic 
dermatitis, urticaria, eczema, erythema, 
hyperhidrosis, night sweats, alopecia, acne, dry 
skin, nail pigmentation

Rare DRESS, Stevens-Johnson syndrome, erythema 
multiforme, dermatitis, seborrhoeic dermatitis, 
skin lesion, xeroderma

not known toxic epidermal necrolysis, acute generalised 
exanthematous pustulosis

Musculoskeletal and connective tissue disorders
Uncommon myalgia, osteonecrosis, muscle spasms, 

muscular weakness, arthralgia, pain in 
extremity, osteoporosis, increased blood creatine 
phosphokinase

Rare musculoskeletal stiffness, arthritis, joint stiffness
Renal and urinary disorders
Uncommon acute renal failure, renal failure, nephrolithiasis, 

increased blood creatinine, proteinuria,
bilirubinuria, dysuria, nocturia, pollakiuria

Rare decreased creatinine renal clearance
Reproductive system and breast disorders
Uncommon erectile dysfunction, gynaecomastia
General disorders and administration site conditions
Common asthenia, fatigue

Uncommon pyrexia, chest pain, peripheral oedema, malaise, 
feeling hot, irritability, pain

Rare chills, abnormal feeling, xerosis



68

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.

During the clinical development program of raltegravir in treatment-experienced patients, rash, 
irrespective of causality, was more commonly observed with regimens containing 
PREZISTA/ritonavir + raltegravir compared to those containing PREZISTA/ritonavir without 
raltegravir or raltegravir without PREZISTA/ritonavir. 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).

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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 inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (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).

Paediatric population
The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three 
Phase II trials. The following patient populations were evaluated (see section 5.1):
 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at 

least 20 kg who received PREZISTA tablets with low dose ritonavir twice daily in combination 
with other antiretroviral agents.

 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 
10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received PREZISTA oral 
suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.

 12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 
40 kg who received PREZISTA tablets with low dose ritonavir once daily in combination with 
other antiretroviral agents (see section 5.1).

Overall, the safety profile in these paediatric patients was similar to that observed in the adult 
population.



69

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).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

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. Since darunavir is highly protein bound, dialysis is unlikely to be 
beneficial in significant removal of the active substance.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitors, ATC code: J05AE10.

Mechanism of action
Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease
(KD of 4.5 x 10

-12M). 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 EC50 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 EC50 values ranging from < 0.1 to 4.3 nM.

These EC50 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. The decreased 
susceptibility to darunavir of the emerging viruses in the selection experiment could not be explained 
by the emergence of these protease mutations.

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

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


70

co-administered with low dose ritonavir was decreased when 3 or more darunavir RAMs (V11I, V32I, 
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 EC50 (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/ritonavir 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 HIV-1 protease mutations and loss of susceptibility to PIs 
in virologic failures at endpoint in the ARTEMIS, ODIN and TITAN trials.

ARTEMIS
Week 192

ODIN
Week 48

TITAN
Week 48

PREZISTA/
ritonavir

800/100 mg
once daily

N=343

PREZISTA/
ritonavir

800/100 mg
once daily

N=294

PREZISTA/
ritonavir

600/100 mg
twice daily

N=296

PREZISTA/
ritonavir

600/100 mg
twice daily

N=298
Total number of 
virologic failures

a
, n 

(%)

55 (16.0%) 65 (22.1%) 54 (18.2%) 31 (10.4%)

Rebounders 39 (11.4%) 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

0/43 1/60 0/42 6/28

PI RAMs 4/43 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 0/39 1/58 0/41 3/26
amprenavir 0/39 1/58 0/40 0/22
atazanavir 0/39 2/56 0/40 0/22
indinavir 0/39 2/57 0/40 1/24
lopinavir 0/39 1/58 0/40 0/23
saquinavir 0/39 0/56 0/40 0/22
tipranavir 0/39 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.



71

Clinical results

Adult patients
For clinical trial results in ART-naïve adult patients, refer to the Summary of Product Characteristics 
for PREZISTA 400 mg and 800 mg tablets or 100 mg/ml oral suspension.

Efficacy of PREZISTA 600 mg twice daily co-administered with 100 mg ritonavir twice daily in 
ART-experienced patients
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/ritonavir

600/100 mg twice daily + 
OBR

N=298

Lopinavir/ritonavir
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/ritonavir arm having HIV-1 RNA < 50 copies/ml at week 96 compared to 55.2% in the 
lopinavir/ritonavir arm [difference: 5.2%, 95% CI (-2.8; 13.1)].

ODIN is a Phase III, randomised, open-label trial comparing PREZISTA/ritonavir 800/100 mg once 
daily versus PREZISTA/ritonavir 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.



72

ODIN
Outcomes PREZISTA/ritonavir 

800/100 mg once daily + 
OBR

N=294

PREZISTA/ritonavir 
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)

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/ritonavir 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 106/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/ 
ritonavir 

600/100 mg 
twice daily 

n=131

Control 
n=124

Treatment 
difference

PREZISTA/ 
ritonavir 

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



73

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 genotypea, and baseline 
darunavir FC and by use of enfuvirtide (ENF): As treated analysis of the POWER and DUET trials.

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%

455/1,01
4

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 EC50

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

Paediatric patients
For clinical trial results in ART-naïve paediatric patients aged 12 to 17 years, refer to the Summary of 
Product Characteristics for PREZISTA 400 mg and 800 mg tablets or PREZISTA 100 mg/ml oral 
suspension.

ART-experienced paediatric patients from the age of 6 to < 18 years, and weighing at least 20 kg
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 
twice daily 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 log10 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.



74

DELPHI

Outcomes at week 48
PREZISTA/ritonavir

N=80
HIV-1 RNA < 50 copies/mla 47.5% (38)
CD4+ cell count mean change from baselineb 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.

ART-experienced paediatric patients from the age of 3 to < 6 years
The pharmacokinetics, safety, tolerability and efficacy of PREZISTA/ritonavir twice daily in 
combination with other antiretroviral agents in 21 ART-experienced HIV-1 infected paediatric patients 
aged 3 to < 6 years and weighing 10 kg to < 20 kg was evaluated in an open-label, Phase II trial, 
ARIEL. Patients received a weight-based twice daily treatment regimen, patients weighing 10 kg to 
< 15 kg received darunavir/ritonavir 25/3 mg/kg twice daily, and patients weighing 15 kg to < 20 kg
received darunavir/ritonavir 375/50 mg twice daily. At week 48, the virologic response, defined as the 
percentage of patients with confirmed plasma viral load < 50 HIV-1 RNA copies/ml, was evaluated in 
16 paediatric patients 15 kg to < 20 kg and 5 paediatric patients 10 kg to < 15 kg receiving 
PREZISTA/ritonavir in combination with other antiretroviral agents (see section 4.2 for dosage 
recommendations per body weight).

ARIEL
Outcomes at week 48 PREZISTA/ritonavir

10 kg to < 15 kg
N=5

15 kg to < 20 kg
N=16

HIV-1 RNA < 50 copies/mla 80.0% (4) 81.3% (13)
CD4+ percent change from baselineb 4 4
CD4+ cell count mean change from baselineb 16 241
a

Imputations according to the TLOVR algorithm.
b

NC=F

Limited efficacy data are available in paediatric patients below 15 kg and no recommendation on a 
posology can be made.

Pregnancy and postpartum
Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a 
background regimen was evaluated in a clinical trial of 36 pregnant women (18 in each arm) during 
the second and third trimesters, and postpartum. Virologic response was preserved throughout the 
study period in both arms. No mother to child transmission occurred in the infants born to the 
31 subjects who stayed on the antiretroviral treatment through delivery. There were no new clinically 
relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1 
infected adults (see sections 4.2, 4.4 and 5.2).

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 α1-acid 
glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAG 
and, therefore, higher plasma concentrations.



75

Darunavir is primarily metabolised by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the 
plasma concentrations of darunavir considerably.

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 α1-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.

Biotransformation
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 14C-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 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the 
administered dose of 14C-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 taken twice daily 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).

The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in
14 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to 
< 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that 
achieved in adults receiving PREZISTA/ritonavir 600/100 mg twice daily (see section 4.2).



76

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naïve 
paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that 
PREZISTA/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that 
achieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily. Therefore the same once 
daily dosage may be used in treatment-experienced adolescents aged 12 to < 18 years and weighing at 
least 40 kg without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma 
HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 
10 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to 
< 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that 
achieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily (see section 4.2). In addition, 
pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages 
of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed 
the identification of weight-based PREZISTA/ritonavir once daily dosing regimens for paediatric 
patients weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patients 
without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count 
≥ 100 cells x 106/l (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

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
Results from a mass balance study with 14C-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).

Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice 
daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally 
lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the 
pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an 
increase in the unbound fraction of darunavir during pregnancy compared to postpartum.



77

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 
600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of 

pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of 
total darunavir
(mean ± SD)

Second trimester of 
pregnancy

(n=12)a

Third trimester of 
pregnancy

(n=12)

Postpartum 
(6-12 weeks)

(n=12)
Cmax, ng/ml 4,668 ± 1,097 5,328 ± 1,631 6,659 ± 2,364
AUC12h, ng.h/ml 39,370 ± 9,597 45,880 ± 17,360 56,890 ± 26,340
Cmin, ng/ml 1,922 ± 825 2,661 ± 1,269 2,851 ± 2,216
a

n=11 for AUC12h

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 
800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of 

pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of 
total darunavir
(mean ± SD)

Second trimester of 
pregnancy

(n=17)

Third Trimester of 
pregnancy

(n=15)

Postpartum 
(6-12 weeks)

(n=16)
Cmax, ng/ml 4,964 ± 1,505 5,132 ± 1,198 7,310 ± 1,704
AUC24h, ng.h/ml 62,289 ± 16,234 61,112 ± 13,790 92,116 ± 29,241
Cmin, ng/ml 1,248 ± 542 1,075 ± 594 1,473 ± 1,141

In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of 
pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 
26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total 
darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as 
compared with postpartum.

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of 
pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 
30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total 
darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared 
with postpartum.

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 



78

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.

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. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

PREZISTA 75 mg film-coated tablets
Tablet core
Microcrystalline cellulose
Colloidal anhydrous silica
Crospovidone
Magnesium stearate

Tablet film-coat
Poly(vinyl alcohol) – partially hydrolysed
Macrogol 3350
Titanium dioxide (E171)
Talc



79

PREZISTA 150 mg film-coated tablets
Tablet core
Microcrystalline cellulose
Colloidal anhydrous silica
Crospovidone
Magnesium stearate

Tablet film-coat
Poly(vinyl alcohol) – partially hydrolysed
Macrogol 3350
Titanium dioxide (E171)
Talc

PREZISTA 600 mg film-coated tablets
Tablet core
Microcrystalline cellulose
Colloidal anhydrous silica
Crospovidone
Magnesium stearate

Tablet film-coat
Poly(vinyl alcohol) – partially hydrolysed
Macrogol 3350
Titanium dioxide (E171)
Talc
Sunset yellow FCF (E110)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PREZISTA 75 mg film-coated tablets
Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 480 tablets, fitted 
with polypropylene (PP) child resistant closure.
Pack size of one bottle.

PREZISTA 150 mg film-coated tablets
Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 240 tablets, fitted 
with polypropylene (PP) child resistant closure.
Pack size of one bottle.

PREZISTA 600 mg film-coated tablets
Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 60 tablets, fitted 
with polypropylene (PP) child resistant closure.
Pack size of one bottle.



80

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

PREZISTA 75 mg film-coated tablets
EU/1/06/380/005

PREZISTA 150 mg film-coated tablets
EU/1/06/380/004

PREZISTA 600 mg film-coated tablets
EU/1/06/380/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 February 2007
Date of latest renewal: 19 September 2013

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.europa.eu/


81

1. NAME OF THE MEDICINAL PRODUCT

PREZISTA 400 mg film-coated tablets
PREZISTA 800 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

PREZISTA 400 mg film-coated tablets
Each film-coated tablet contains 400 mg of darunavir (as ethanolate).
Excipient with known effect: Each tablet contains 0.834 mg sunset yellow FCF (E110).

PREZISTA 800 mg film-coated tablets
Each film-coated tablet contains 800 mg of darunavir (as ethanolate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

PREZISTA 400 mg film-coated tablets
Film-coated tablet.
Light orange oval shaped tablet of 19.1 mm, debossed with “400MG” on one side and “TMC” on the 
other side.

PREZISTA 800 mg film-coated tablets
Film-coated tablet.
Dark red oval shaped tablet of 20.0 mm, debossed with “800” on one side and “T” on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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, co-administered with cobicistat is indicated in combination with other antiretroviral 
medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adult 
patients (see section 4.2).

PREZISTA 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the 
treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg 
body weight who are:
 antiretroviral therapy (ART)-naïve (see section 4.2).
 ART-experienced 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 106/l. In 
deciding to initiate treatment with PREZISTA in such ART-experienced patients, genotypic 
testing should guide the use of PREZISTA (see sections 4.2, 4.3, 4.4 and 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a health care provider experienced in the management of HIV 
infection. After therapy with PREZISTA has been initiated, patients should be advised not to alter the 
dosage, dose form or discontinue therapy without discussing with their health care provider.



82

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as 
pharmacokinetic enhancer. Darunavir may therefore have different contraindications and 
recommendations for concomitant medications depending on whether the compound is boosted with 
ritonavir or cobicistat (see sections 4.3, 4.4 and 4.5).

Posology
PREZISTA must always be given orally with cobicistat or low dose ritonavir as a pharmacokinetic 
enhancer and in combination with other antiretroviral medicinal products. The Summary of Product 
Characteristics of cobicistat or ritonavir as appropriate, must therefore be consulted prior to initiation 
of therapy with PREZISTA. Cobicistat is not indicated for use in twice daily regimens or for use in the 
paediatric population.

PREZISTA is also available as an oral suspension for use in patients who are unable to swallow 
PREZISTA tablets (please refer to the Summary of Product Characteristics for PREZISTA oral 
suspension).

ART-naïve adult patients
The recommended dose regimen is 800 mg once daily with cobicistat 150 mg once daily or ritonavir 
100 mg once daily taken with food. PREZISTA 400 mg and 800 mg tablets can be used to construct 
the once daily 800 mg regimen.

ART-experienced adult patients
The recommended dose regimens are as follows:
 In ART-experienced patients 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 106/l
(see section 4.1) a regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 
100 mg once daily taken with food may be used. PREZISTA 400 mg and 800 mg tablets can be 
used to construct the once daily 800 mg regimen.

 In all other ART-experienced patients or if HIV-1 genotype testing is not available, the 
recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken 
with food. See the Summary of Product Characteristics for PREZISTA 100 mg/ml oral 
suspension, 75 mg, 150 mg or 600 mg tablets.

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with 
food. The dose of cobicistat to be used with PREZISTA in children less than 18 years of age has not 
been established.

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The dose of cobicistat to be used with PREZISTA in children less than 18 years of age has not been 
established.

The recommended dose regimens are as follows:
 In ART-experienced patients without DRV-RAMs* and who have plasma HIV-1 RNA 

< 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l (see section 4.1) a regimen of 
800 mg once daily with ritonavir 100 mg once daily taken with food may be used. PREZISTA 
400 mg and 800 mg tablets can be used to construct the once daily 800 mg regimen.

 In all other ART-experienced patients or if HIV-1 genotype testing is not available, the 
recommended dose regimen is described in the Summary of Product Characteristics for 
PREZISTA 100 mg/ml oral suspension,75 mg, 150 mg and 600 mg tablets.

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

Advice on missed doses
If a once daily dose of PREZISTA and/or cobicistat or ritonavir is missed within 12 hours of the time 
it is usually taken, patients should be instructed to take the prescribed dose of PREZISTA and 
cobicistat or ritonavir with food as soon as possible. If this is noticed later than 12 hours after the time 



83

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 half-life of darunavir in the presence of cobicistat or ritonavir and the 
recommended dosing interval of approximately 24 hours.

Special populations

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 for darunavir/ritonavir in patients with renal impairment (see sections 
4.4 and 5.2). Cobicistat has not been studied in patients receiving dialysis, and, therefore, no 
recommendation can be made for the use of darunavir/cobicistat in these patients.

Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum 
creatinine and modest declines in creatinine clearance. Hence, the use of creatinine clearance as an 
estimate of renal elimination capacity may be misleading. Cobicistat as a pharmacokinetic enhancer of 
darunavir should, therefore, not be initiated in patients with creatine clearance less than 70 ml/min if 
any co-administered agent requires dose adjustment based on creatinine clearance: e.g. emtricitabine, 
lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate) or adefovir dipovoxil.
For information on cobicistat, consult the cobicistat Summary of Product Characteristics.

Paediatric population
PREZISTA should not be used in paediatric patients below 3 years of age or less than 15 kg body 
weight (see sections 4.4 and 5.3).

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg)
The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with 
food.

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)
In ART-experienced patients without DRV-RAMs* and who have plasma HIV-1 RNA 
< 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l, a regimen of 800 mg once daily with 
ritonavir 100 mg once daily taken with food may be used.
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

Paediatric patients (3 to 17 years of age and weighing less than 40 kg)
The 400 and 800 mg tablets are not suitable for this patient population. Other formulations are 
available, see the Summary of Product Characteristics for PREZISTA 75 mg, 150 mg, 600 mg tablets 
and 100 mg/ml oral suspension.

The dose of cobicistat to be used with PREZISTA has not been established in this patient population.



84

Pregnancy and postpartum
No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. 
PREZISTA/ritonavir should be used during pregnancy only if the potential benefit justifies the 
potential risk (see sections 4.4, 4.6 and 5.2).

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure 
(see sections 4.4 and 5.2). Therefore, therapy with PREZISTA/cobicistat should not be initiated during 
pregnancy, and women who become pregnant during therapy with PREZISTA/cobicistat should be 
switched to an alternative regimen (see sections 4.4 and 4.6). PREZISTA/ritonavir may be considered 
as an alternative.

Method of administration
Patients should be instructed to take PREZISTA with cobicistat or 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).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with severe (Child-Pugh Class C) hepatic impairment.

Concomitant treatment with any of the following medicinal products given the expected decrease in 
plasma concentrations of darunavir, ritonavir and cobicistat and the potential for loss of therapeutic 
effect (see sections 4.4 and 4.5).

Applicable to darunavir boosted with either ritonavir or cobicistat:
- The combination product lopinavir/ritonavir (see section 4.5).
- The strong CYP3A inducers rifampicin and herbal preparations containing St John’s wort 

(Hypericum perforatum). Co-administration is expected to reduce plasma concentrations of 
darunavir, ritonavir and cobicistat, which could lead to loss of therapeutic effect and possible 
development of resistance (see sections 4.4 and 4.5).

Applicable to darunavir boosted with cobicistat, not when boosted with ritonavir:
- Darunavir boosted with cobicistat is more sensitive for CYP3A induction than darunavir 

boosted with ritonavir. Concomitant use with strong CYP3A inducers is contraindicated, since 
these may reduce the exposure to cobicistat and darunavir leading to loss of therapeutic effect. 
Strong CYP3A inducers include e.g. carbamazepine, phenobarbital and phenytoin (see sections 
4.4 and 4.5).

Darunavir boosted with either ritonavir or cobicistat inhibits the elimination of active substances that 
are highly dependent on CYP3A for clearance, which results in increased exposure to the 
co-administered medicinal product. Therefore, concomitant treatment with such medicinal products 
for which elevated plasma concentrations are associated with serious and/or life-threatening events is 
contraindicated (applies to darunavir boosted with either ritonavir or cobicistat). These active 
substances include e.g.:
- alfuzosin
- amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine
- astemizole, terfenadine
- colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)
- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)
- elbasvir/grazoprevir
- cisapride
- dapoxetine
- domperidone
- naloxegol
- lurasidone, pimozide, quetiapine, sertindole (see section 4.5)



85

- triazolam, midazolam administered orally (for caution on parenterally administered midazolam, 
see section 4.5)

- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil
- simvastatin, lovastatin and lomitapide (see section 4.5)
- dabigatran, ticagrelor (see section 4.5).

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission
should be taken in accordance with national guidelines.

Regular assessment of virological response is advised. In the setting of lack or loss of virological 
response, resistance testing should be performed.

PREZISTA 400 mg or 800 mg must always be given orally with cobicistat or low dose ritonavir as a 
pharmacokinetic enhancer and in combination with other antiretroviral medicinal products (see section 
5.2). The Summary of Product Characteristics of cobicistat or ritonavir as appropriate, must therefore 
be consulted prior to initiation of therapy with PREZISTA.

Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect 
darunavir concentrations. It is not recommended to alter the dose of cobicistat or ritonavir.

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 used in combination with cobicistat or low dose ritonavir 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 106/l (see section 
4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs have not been 
studied in this population. Limited data are available in patients with HIV-1 clades other than B (see 
section 5.1).

Paediatric population
PREZISTA is not recommended for use in paediatric patients below 3 years of age or less than 15 kg 
body weight (see sections 4.2 and 5.3).

Pregnancy
PREZISTA/ritonavir should be used during pregnancy only if the potential benefit justifies the 
potential risk. Caution should be used in pregnant women with concomitant medications which may 
further decrease darunavir exposure (see sections 4.5 and 5.2).

Treatment with darunavir/cobicistat 800/150 mg once daily during the second and third trimester has 
been shown to result in low darunavir exposure, with a reduction of around 90% in Cmin levels (see 
section 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantial 
reduction in darunavir exposure may result in virological failure and an increased risk of mother to 
child transmission of HIV infection. Therefore, therapy with PREZISTA/cobicistat should not be 
initiated during pregnancy, and women who become pregnant during therapy with 
PREZISTA/cobicistat should be switched to an alternative regimen (see sections 4.2 and 4.6). 
PREZISTA given with low dose ritonavir may be considered as an alternative.

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 



86

frequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2 
and 5.2).

Severe skin reactions
During the darunavir/ritonavir 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. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson 
Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal 
necrolysis and acute generalised exanthematous pustulosis have been reported. PREZISTA should be 
discontinued immediately if signs or symptoms of severe skin reactions develop. These can include,
but are not limited to, severe rash or rash accompanied by 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/ritonavir + raltegravir compared to patients receiving PREZISTA/ritonavir 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. 
During the darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 
0.5% of patients receiving combination antiretroviral therapy with PREZISTA/ritonavir. 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 reactions. 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 used in 
combination with cobicistat or low dose ritonavir 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 used in combination with cobicistat or low dose ritonavir 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 used in combination with cobicistat or low 
dose ritonavir, 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 for darunavir/ritonavir 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). Cobicistat has 
not been studied in patients receiving dialysis, therefore, no recommendation can be made for the use 
of darunavir/cobicistat in these patients (see section 4.2).



87

Cobicistat decreases the estimated creatinine clearance due to inhibition of tubular secretion of 
creatinine. This should be taken into consideration if darunavir with cobicistat is administered to 
patients in whom the estimated creatinine clearance is used to adjust doses of co-administered 
medicinal products (see section 4.2 and cobicistat SmPC).

There are currently inadequate data to determine whether co-administration of tenofovir disoproxil and 
cobicistat is associated with a greater risk of renal adverse reactions compared with regimens that 
include tenofovir disoproxil without cobicistat.

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.

Weight and metabolic parameters
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment. For monitoring of blood lipids and glucose reference is made to 
established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported particularly in patients with advanced HIV disease and/or long-term exposure to combination 
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience 
joint aches and pain, joint stiffness or difficulty in movement.

Immune reconstitution inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
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.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reactivation; however, the reported time to onset is more variable and 
these events can occur many months after initiation of treatment (see section 4.8).

Interactions with medicinal products
Several of the interaction studies have been performed with darunavir at lower than recommended 
doses. 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.

Pharmacokinetic enhancer and concomitant medications
Darunavir has different interaction profiles depending on whether the compound is boosted with 
ritonavir or cobicistat:
- Darunavir boosted with cobicistat is more sensitive for CYP3A induction: concomitant use of 

darunavir/cobicistat and strong CYP3A inducers is therefore contraindicated (see section 4.3), 



88

and concomitant use with weak to moderate CYP3A inducers is not recommended (see section 
4.5). Concomitant use of darunavir/ritonavir and darunavir/cobicistat with lopinavir/ritonavir, 
rifampicin and herbal products containing St John’s wort, Hypericum perforatum, is 
contraindicated (see section 4.5).

- Unlike ritonavir, cobicistat does not have inducing effects on enzymes or transport proteins (see 
section 4.5). If switching the pharmacoenhancer from ritonavir to cobicistat, caution is required 
during the first two weeks of treatment with darunavir/cobicistat, particularly if doses of any 
concomitantly administered medicinal products have been titrated or adjusted during use of 
ritonavir as a pharmacoenhancer. A dose reduction of the co-administered drug may be needed 
in these cases.

Efavirenz in combination with PREZISTA may result in sub-optimal darunavir Cmin. If efavirenz is to 
be used in combination with PREZISTA, the PREZISTA/ritonavir 600/100 mg twice daily regimen 
should be used. See the Summary of Product Characteristics for PREZISTA 75 mg, 150 mg and
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 P-glycoprotein (P-gp; see sections 4.3 and 4.5).

PREZISTA 400 mg tablets contain sunset yellow FCF (E110) which may cause an allergic reaction.

4.5 Interaction with other medicinal products and other forms of interaction

The interaction profile of darunavir may differ depending on whether ritonavir or cobicistat is used as 
pharmacoenhancer. The recommendations given for concomitant use of darunavir and other medicinal 
products may therefore differ depending on whether darunavir is boosted with ritonavir or cobicistat 
(see sections 4.3 and 4.4), and caution is also required during the first time of treatment if switching 
the pharmacoenhancer from ritonavir to cobicistat (see section 4.4).

Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer)
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 these compounds and consequently that of darunavir, leading to loss of therapeutic 
effect and possible development of resistance (see sections 4.3 and 4.4). CYP3A inducers that are 
contraindicated include rifampicin, St John’s wort and lopinavir.

Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may 
decrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrations 
of darunavir and ritonavir. Co-administration with strong CYP3A4 inhibitors is not recommended and 
caution is warranted, these interactions are described in the interaction table below (e.g. indinavir, 
azole antifungals like clotrimazole).

Medicinal products that affect darunavir exposure (cobicistat as pharmacoenhancer)
Darunavir and cobicistat are metabolised by CYP3A, and co-administration with CYP3A inducers 
may therefore result in subtherapeutic plasma exposure to darunavir. Darunavir boosted with 
cobicistat is more sensitive to CYP3A induction than ritonavir-boosted darunavir: co-administration of 
darunavir/cobicistat with medicinal products that are strong inducers of CYP3A (e.g. St John’s wort, 
rifampicin, carbamazepine, phenobarbital, and phenytoin) is contraindicated (see section 4.3). 
Co-administration of darunavir/cobicistat with weak to moderate CYP3A inducers (e.g. efavirenz, 
etravirine, nevirapine, boceprevir, fluticasone, and bosentan) is not recommended (see interaction 
table below).

For co-administration with strong CYP3A4 inhibitors, the same recommendations apply independent 
of whether darunavir is boosted with ritonavir or with cobicistat (see section above).



89

Medicinal products that may be affected by darunavir boosted with ritonavir
Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of 
darunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or 
transported by P-gp may result in increased systemic exposure to such medicinal products, which 
could increase or prolong their therapeutic effect and adverse reactions.

Darunavir 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) (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, darunavir must only be used in 
combination with 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 darunavir/ritonavir, which may be attributed to the 
presence of low dose ritonavir. Co-administration of darunavir and ritonavir with 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.

Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration 
with substrates of these transporters can result in increased plasma concentrations of these compounds 
(e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).

Medicinal products that may be affected by darunavir boosted with cobicistat
The recommendations for darunavir boosted with ritonavir are adequate also for darunavir boosted 
with cobicistat with regard to substrates of CYP3A4, CYP2D6, P-glycoprotein, OATP1B1 and 
OATP1B3 (see contraindications and recommendations presented in the section above). Cobicistat 
150 mg given with darunavir 800 mg once daily enhances darunavir pharmacokinetic parameters in a 
comparable way to ritonavir (see section 5.2).

Unlike ritonavir, cobicistat does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or 
UGT1A1. For further information on cobicistat, consult the cobicistat Summary of Product 
Characteristics.

Interaction table
Interaction studies have only been performed in adults.

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.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as 
pharmacokinetic enhancer. Darunavir may therefore have different recommendations for concomitant 
medications depending on whether the compound is boosted with ritonavir or cobicistat. No 



90

interaction studies presented in the table have been performed with darunavir boosted with cobicistat. 
The same recommendations apply, unless specifically indicated. For further information on cobicistat, 
consult the cobicistat Summary of Product Characteristics.

Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products 
are listed in the table below. 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 (not determined as “ND”).

In the table below the specific pharmacokinetic enhancer is specified when recommendations differ. 
When the recommendation is the same for PREZISTA when co-administered with a low dose ritonavir 
or cobicistat, the term “boosted PREZISTA” is used.

The below list of examples of drug drug interactions is not comprehensive and therefore the label of 
each drug that is co-administered with PREZISTA should be consulted for information related to the 
route of metabolism, interaction pathways, potential risks, and specific actions to be taken with 
regards to co-administration.

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS
Medicinal products by 
therapeutic areas

Interaction
Geometric mean change (%)

Recommendations concerning 
co-administration

HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors

Dolutegravir dolutegravir AUC ↓ 22%
dolutegravir C24h ↓ 38%
dolutegravir Cmax ↓ 11%
darunavir ↔*
* Using cross-study comparisons to historical 
pharmacokinetic data

Boosted PREZISTA and 
dolutegravir can be used without 
dose adjustment.

Raltegravir Some clinical studies suggest raltegravir 
may cause a modest decrease in 
darunavir plasma concentrations.

At present the effect of raltegravir 
on darunavir plasma 
concentrations does not appear to 
be clinically relevant. Boosted 
PREZISTA and raltegravir can be 
used without dose adjustments.

Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine
400 mg once daily

didanosine AUC ↓ 9%
didanosine Cmin ND
didanosine Cmax ↓ 16%
darunavir AUC ↔
darunavir Cmin ↔
darunavir Cmax ↔

Boosted PREZISTA 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 boosted 
PREZISTA given with food.

Tenofovir disoproxil

245 mg once daily
‡

tenofovir AUC ↑ 22%
tenofovir Cmin ↑ 37%
tenofovir Cmax ↑ 24%
#
darunavir AUC ↑ 21%

#
darunavir Cmin ↑ 24%

#
darunavir Cmax ↑ 16%

(↑ tenofovir from effect on MDR-1 
transport in the renal tubules)

Monitoring of renal function may 
be indicated when boosted
PREZISTA is given in 
combination with tenofovir
disoproxil, particularly in patients 
with underlying systemic or renal 
disease, or in patients taking 
nephrotoxic agents.

PREZISTA co-administered with 
cobicistat lowers the creatinine 
clearance. Refer to section 4.4 if 
creatinine clearance is used for 
dose adjustment of tenofovir
disoproxil.



91

Emtricitabine/tenofovir 
alafenamide 

Tenofovir alafenamide ↔
Tenofovir ↑

The recommended dose of 
emtricitabine/tenofovir 
alafenamide is 200/10 mg once 
daily when used with boosted 
PREZISTA. 

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 boosted
PREZISTA.

Boosted PREZISTA can be used 
with these NRTIs without dose 
adjustment.

PREZISTA co-administered with 
cobicistat lowers the creatinine 
clearance. Refer to section 4.4 if 
creatinine clearance is used for 
dose adjustment of emtricitabine or 
lamivudine.

Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg once daily

efavirenz AUC ↑ 21%
efavirenz Cmin ↑ 17%
efavirenz Cmax ↑ 15%
#
darunavir AUC ↓ 13%

#
darunavir Cmin ↓ 31%

#
darunavir Cmax ↓ 15%

(↑ efavirenz from CYP3A inhibition)
(↓ darunavir from CYP3A induction)

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.

Efavirenz in combination with 
PREZISTA/ritonavir 800/100 mg 
once daily may result in 
sub-optimal darunavir Cmin. If 
efavirenz is to be used in 
combination with 
PREZISTA/ritonavir, the 
PREZISTA/ritonavir 600/100 mg 
twice daily regimen should be used 
(see section 4.4).

Co-administration with 
PREZISTA co-administered with 
cobicistat is not recommended (see 
section 4.4).

Etravirine
100 mg twice daily

etravirine AUC ↓ 37%
etravirine Cmin ↓ 49%
etravirine Cmax ↓ 32%
darunavir AUC ↑ 15%
darunavir Cmin ↔
darunavir Cmax ↔

PREZISTA co-administered with 
low dose ritonavir and etravirine 
200 mg twice daily can be used
without dose adjustments.

Co-administration with 
PREZISTA co-administered with 
cobicistat is not recommended (see 
section 4.4).

Nevirapine
200 mg twice daily

nevirapine AUC ↑ 27%
nevirapine Cmin ↑ 47%
nevirapine Cmax ↑ 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.

Co-administration with 
PREZISTA co-administered with 
cobicistat is not recommended (see 
section 4.4).

Rilpivirine
150 mg once daily

rilpivirine AUC ↑ 130%
rilpivirine Cmin ↑ 178%
rilpivirine Cmax ↑ 79%
darunavir AUC ↔
darunavir Cmin ↓ 11%
darunavir Cmax ↔

Boosted PREZISTA and rilpivirine 
can be used without dose 
adjustments.



92

HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir
†

Atazanavir
300 mg once daily

atazanavir AUC ↔
atazanavir Cmin ↑ 52%
atazanavir Cmax ↓ 11%
#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

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.

PREZISTA co-administered with 
low dose ritonavir and atazanavir 
can be used without dose 
adjustments.

PREZISTA co-administered with 
cobicistat should not be used in 
combination with another 
antiretroviral agent that requires 
pharmacoenhancement by means 
of co-administration with an 
inhibitor of CYP3A4 (see section 
4.5).

Indinavir
800 mg twice daily

indinavir AUC ↑ 23%
indinavir Cmin ↑ 125%
indinavir Cmax ↔
#
darunavir AUC ↑ 24%

#
darunavir Cmin ↑ 44%

#
darunavir Cmax ↑ 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.

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.

PREZISTA co-administered with
cobicistat should not be used in 
combination with another 
antiretroviral agent that requires 
pharmacoenhancement by means 
of co-administration with an 
inhibitor of CYP3A4 (see section 
4.5).

Saquinavir
1,000 mg twice daily

#
darunavir AUC ↓ 26%

#
darunavir Cmin ↓ 42%

#
darunavir Cmax ↓ 17%

saquinavir AUC ↓ 6%
saquinavir Cmin ↓ 18%
saquinavir Cmax ↓ 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.

It is not recommended to combine 
PREZISTA co-administered with 
low dose ritonavir with saquinavir.

PREZISTA co-administered with 
cobicistat should not be used in 
combination with another 
antiretroviral agent that requires 
pharmacoenhancement by means 
of co-administration with an 
inhibitor of CYP3A4 (see section 
4.5).



93

HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavir
†

Lopinavir/ritonavir
400/100 mg twice daily

Lopinavir/ritonavir
533/133.3 mg twice daily

lopinavir AUC ↑ 9%
lopinavir Cmin ↑ 23%
lopinavir Cmax ↓ 2%

darunavir AUC ↓ 38%
‡

darunavir Cmin ↓ 51%
‡

darunavir Cmax ↓ 21%
‡

lopinavir AUC ↔
lopinavir Cmin ↑ 13%
lopinavir Cmax ↑ 11%
darunavir AUC ↓ 41%
darunavir Cmin ↓ 55%
darunavir Cmax ↓ 21%
‡

based upon non dose normalised values

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 boosted PREZISTA and the 
combination product 
lopinavir/ritonavir is 
contraindicated (see section 4.3).

CCR5 ANTAGONIST
Maraviroc
150 mg twice daily

maraviroc AUC ↑ 305%
maraviroc Cmin ND
maraviroc Cmax ↑ 129%
darunavir, ritonavir concentrations were 
consistent with historical data

The maraviroc dose should be 
150 mg twice daily when 
co-administered with boosted 
PREZISTA.

α1-ADRENORECEPTOR ANTAGONIST
Alfuzosin Based on theoretical considerations 

PREZISTA is expected to increase 
alfuzosin plasma concentrations.
(CYP3A inhibition)

Co-administration of boosted 
PREZISTA and alfuzosin is 
contraindicated (see section 4.3).

ANAESTHETIC
Alfentanil Not studied. The metabolism of alfentanil 

is mediated via CYP3A, and may as such 
be inhibited by boosted PREZISTA.

The concomitant use with boosted 
PREZISTA may require to lower 
the dose of alfentanil and requires 
monitoring for risks of prolonged 
or delayed respiratory depression.

ANTIANGINA/ANTIARRHYTHMIC
Disopyramide
Flecainide
Lidocaine (systemic)
Mexiletine
Propafenone

Amiodarone
Bepridil
Dronedarone
Ivabradine 
Quinidine
Ranolazine

Not studied. Boosted PREZISTA is 
expected to increase these antiarrhythmic
plasma concentrations.
(CYP3A and/or CYP2D6 inhibition)

Caution is warranted and 
therapeutic concentration 
monitoring, if available, is 
recommended for these 
antiarrhythmics when 
co-administered with boosted 
PREZISTA.

Co-administration of boosted 
PREZISTA and amiodarone, 
bepridil, dronedarone, ivabradine,
quinidine, or ranolazine is 
contraindicated (see section 4.3).

Digoxin
0.4 mg single dose

digoxin AUC ↑ 61%
digoxin Cmin ND
digoxin Cmax ↑ 29%
(↑ digoxin from probable inhibition of 
P-gp)

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 
boosted PREZISTA therapy. The 
digoxin dose should be carefully 
titrated to obtain the desired 
clinical effect while assessing the 
overall clinical state of the subject.



94

ANTIBIOTIC
Clarithromycin
500 mg twice daily

clarithromycin AUC ↑ 57%
clarithromycin Cmin ↑ 174%
clarithromycin Cmax ↑ 26%
#
darunavir AUC ↓ 13%

#
darunavir Cmin ↑ 1%

#
darunavir Cmax ↓ 17%

14-OH-clarithromycin concentrations 
were not detectable when combined with 
PREZISTA/ritonavir.
(↑ clarithromycin from CYP3A inhibition 
and possible P-gp inhibition)

Caution should be exercised when 
clarithromycin is combined with 
boosted PREZISTA.

For patients with renal impairment 
the Summary of Product 
Characteristics for clarithromycin 
should be consulted for the 
recommended dose.

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban
Edoxaban
Rivaroxaban

Not studied. Co-administration of 
boosted PREZISTA with these 
anticoagulants may increase 
concentrations of the anticoagulant, 
which may lead to an increased bleeding 
risk.
(CYP3A and/or P-gp inhibition)

The use of boosted PREZISTA 
and these anticoagulants is not 
recommended.

Dabigatran
Ticagrelor

Not studied. Co-administration with 
boosted PREZISTA may lead to a 
substantial increase in exposure to 
dabigatran or ticagrelor.

Concomitant administration of 
boosted PREZISTA with 
dabigatran or ticagrelor is 
contraindicated (see section 4.3).

Use of other antiplatelets not 
affected by CYP inhibition or 
induction (e.g. prasugrel) is 
recommended.

Warfarin Not studied. Warfarin concentrations may 
be affected when co-administered with 
boosted PREZISTA.

It is recommended that the 
international normalised ratio 
(INR) be monitored when warfarin 
is combined with boosted 
PREZISTA.

ANTICONVULSANTS
Phenobarbital
Phenytoin

Not studied. Phenobarbital and phenytoin 
are expected to decrease plasma 
concentrations of darunavir and its 
pharmacoenhancer.
(induction of CYP450 enzymes)

PREZISTA co-administered with 
low dose ritonavir should not be 
used in combination with these 
medicines.

The use of these medicines with
PREZISTA/cobicistat is 
contraindicated (see section 4.3).



95

Carbamazepine
200 mg twice daily

carbamazepine AUC ↑ 45%
carbamazepine Cmin ↑ 54%
carbamazepine Cmax ↑ 43%
darunavir AUC ↔
darunavir Cmin ↓ 15%
darunavir Cmax ↔

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.

The use of carbamazepine with
PREZISTA co-administered with 
cobicistat is contraindicated (see 
section 4.3).

Clonazepam Not studied. Co-administration of 
boosted PREZISTA with clonazepam 
may increase concentrations of 
clonazepam. (CYP3A inhibition)

Clinical monitoring is 
recommended when 
co-administering boosted 
PREZISTA and clonazepam.

ANTIDEPRESSANTS
Paroxetine
20 mg once daily

Sertraline
50 mg once daily

Amitriptyline
Desipramine
Imipramine
Nortriptyline
Trazodone

paroxetine AUC ↓ 39%
paroxetine Cmin ↓ 37%
paroxetine Cmax ↓ 36%
#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

sertraline AUC ↓ 49%
sertraline Cmin ↓ 49%
sertraline Cmax ↓ 44%
#
darunavir AUC ↔

#
darunavir Cmin ↓ 6%

#
darunavir Cmax ↔

In contrast to these data with 
PREZISTA/ritonavir, 
PREZISTA/cobicistat may increase these 
antidepressant plasma concentrations 
(CYP2D6 and/or CYP3A inhibition).

Concomitant use of boosted PREZISTA 
and these antidepressants may increase 
concentrations of the antidepressant.
(CYP2D6 and/or CYP3A inhibition)

If antidepressants are 
co-administered with boosted 
PREZISTA, the recommended 
approach is a dose titration of the 
antidepressant based on a clinical 
assessment of antidepressant 
response. In addition, patients on a 
stable dose of these antidepressants 
who start treatment with boosted 
PREZISTA should be monitored 
for antidepressant response.

Clinical monitoring is 
recommended when 
co-administering boosted 
PREZISTA with these 
antidepressants and a dose 
adjustment of the antidepressant 
may be needed.

ANTI-DIABETICS
Metformin Not studied. Based on theoretical 

considerations PREZISTA 
co-administered with cobicistat is 
expected to increase metformin plasma 
concentrations.
(MATE1 inhibition)

Careful patient monitoring and 
dose adjustment of metformin is 
recommended in patients who are 
taking PREZISTA co-administered 
with cobicistat.
(not applicable for PREZISTA 
co-administered with ritonavir)



96

ANTIEMETICS
Domperidone Not studied. Co-administration of domperidone 

with boosted PREZISTA is 
contraindicated.

ANTIFUNGALS
Voriconazole Not studied. Ritonavir may decrease 

plasma concentrations of voriconazole.
(induction of CYP450 enzymes)

Concentrations of voriconazole may 
increase or decrease when 
co-administered with PREZISTA 
co-administered with cobicistat.
(inhibition of CYP450 enzymes)

Voriconazole should not be 
combined with boosted 
PREZISTA unless an assessment 
of the benefit/risk ratio justifies the 
use of voriconazole.

Fluconazole
Isavuconazole
Itraconazole
Posaconazole

Clotrimazole

Not studied. Boosted PREZISTA may 
increase antifungal plasma concentrations 
and posaconazole, isavuconazole, 
itraconazole or fluconazole may increase 
darunavir concentrations.
(CYP3A and/or P-gp inhibition)

Not studied. Concomitant systemic use of 
clotrimazole and boosted PREZISTA
may increase plasma concentrations of 
darunavir and/or clotrimazole.
darunavir AUC24h ↑ 33% (based on 
population pharmacokinetic model)

Caution is warranted and clinical 
monitoring is recommended.
When co-administration is 

required the daily dose of 
itraconazole should not exceed 
200 mg.

ANTIGOUT MEDICINES
Colchicine Not studied. Concomitant use of 

colchicine and boosted PREZISTA may 
increase the exposure to colchicine.
(CYP3A and/ or P-gp inhibition)

A reduction in colchicine dosage 
or an interruption of colchicine 
treatment is recommended in 
patients with normal renal or 
hepatic function if treatment with 
boosted PREZISTA is required. 
For patients with renal or hepatic 
impairment colchicine with 
boosted PREZISTA is 
contraindicated (see sections 4.3
and 4.4).

ANTIMALARIALS
Artemether/Lumefantrine
80/480 mg, 6 doses at 0, 
8, 24, 36, 48, and 
60 hours

artemether AUC ↓ 16%
artemether Cmin ↔
artemether Cmax ↓ 18%
dihydroartemisinin AUC ↓ 18%
dihydroartemisinin Cmin ↔
dihydroartemisinin Cmax ↓ 18%
lumefantrine AUC ↑ 175%
lumefantrine Cmin ↑ 126%
lumefantrine Cmax ↑ 65%
darunavir AUC ↔
darunavir Cmin ↓ 13%
darunavir Cmax ↔

The combination of boosted 
PREZISTA and 
artemether/lumefantrine can be 
used without dose adjustments; 
however, due to the increase in 
lumefantrine exposure, the 
combination should be used with 
caution.



97

ANTIMYCOBACTERIALS
Rifampicin
Rifapentine

Not studied. Rifapentine and rifampicin 
are strong CYP3A inducers and have 
been shown to cause profound decreases
in concentrations of other protease 
inhibitors, which can result in virological 
failure and resistance development 
(CYP450 enzyme induction). 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 with rifampicin.

The combination of rifapentine and 
boosted PREZISTA is not 
recommended.

The combination of rifampicin and 
boosted PREZISTA is 
contraindicated (see section 4.3).

Rifabutin
150 mg once every other 
day

rifabutin AUC
**

↑ 55%

rifabutin Cmin
**

↑ ND

rifabutin Cmax
**

↔
darunavir AUC ↑ 53%
darunavir Cmin ↑ 68%
darunavir Cmax ↑ 39%
**

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 Cmax 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).

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 with PREZISTA 
co-administered with ritonavir. 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.

Co-administration of PREZISTA 
co-administered with cobicistat 
and rifabutin is not recommended.

ANTINEOPLASTICS
Dasatinib
Nilotinib
Vinblastine
Vincristine

Everolimus
Irinotecan

Not studied. Boosted PREZISTA is 
expected to increase these antineoplastic 
plasma concentrations.
(CYP3A inhibition)

Concentrations of these medicinal 
products may be increased when 
co-administered with boosted 
PREZISTA resulting in the 
potential for increased adverse 
events usually associated with 
these agents.
Caution should be exercised when 
combining one of these 
antineoplastic agents with boosted 
PREZISTA.

Concominant use of everolimus or
irinotecan and boosted PREZISTA 
is not recommended.



98

ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine Not studied. Boosted PREZISTA is 

expected to increase these antipsychotic 
plasma concentrations.
(CYP3A inhibition)

Concomitant administration of 
boosted PREZISTA and quetiapine 
is contraindicated as it may 
increase quetiapine-related 
toxicity. Increased concentrations 
of quetiapine may lead to coma
(see section 4.3).

Perphenazine
Risperidone
Thioridazine

Lurasidone
Pimozide
Sertindole

Not studied. Boosted PREZISTA is 
expected to increase these antipsychotic 
plasma concentrations.
(CYP3A, CYP2D6 and/or P-gp
inhibition)

A dose decrease may be needed for 
these drugs when co-administered 
with boosted PREZISTA.

Concominant administration of 
boosted PREZISTA and 
lurasidone, pimozide or sertindole 
is contraindicated (see section 4.3).

β-BLOCKERS
Carvedilol
Metoprolol
Timolol

Not studied. Boosted PREZISTA is 
expected to increase these β-blocker 
plasma concentrations.
(CYP2D6 inhibition)

Clinical monitoring is 
recommended when 
co-administering boosted 
PREZISTA with β-blockers. A 
lower dose of the β-blocker should 
be considered.

CALCIUM CHANNEL BLOCKERS
Amlodipine
Diltiazem
Felodipine
Nicardipine
Nifedipine
Verapamil

Not studied. Boosted PREZISTA can be 
expected to increase the plasma 
concentrations of calcium channel 
blockers.
(CYP3A and/or CYP2D6 inhibition)

Clinical monitoring of therapeutic 
and adverse effects is 
recommended when these 
medicines are concomitantly 
administered with boosted 
PREZISTA.

CORTICOSTEROIDS
Corticosteroids primarily 
metabolised by CYP3A 
(including 
betamethasone, 
budesonide, fluticasone, 
mometasone, prednisone, 
triamcinolone)

Fluticasone: 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. The 
effects of high fluticasone systemic 
exposure on ritonavir plasma levels are 
unknown.

Other corticosteroids: interaction not 
studied. Plasma concentrations of these 
medicinal products may be increased 
when co-administered with boosted 
PREZISTA, resulting in reduced serum 
cortisol concentrations.

Concomitant use of boosted 
PREZISTA and corticosteroids 
that are metabolised by CYP3A 
(e.g. fluticasone propionate or 
other inhaled or nasal 
corticosteroids) may increase the 
risk of development of systemic 
corticosteroid effects, including 
Cushing’s syndrome and adrenal 
suppression.
Co-administration with CYP3A-
metabolised corticosteroids is not 
recommended unless the potential 
benefit to the patient outweighs the 
risk, in which case patients should 
be monitored for systemic 
corticosteroid effects.
Alternative corticosteroids which 
are less dependent on CYP3A 
metabolism e.g. beclomethasone 
for intranasal or inhalational use 
should be considered, particularly 
for long term use.

Dexamethasone
(systemic)

Not studied. Dexamethasone may 
decrease plasma concentrations of 
darunavir.
(CYP3A induction)

Systemic dexamethasone should 
be used with caution when 
combined with boosted 
PREZISTA.



99

ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan Not studied. Concomitant use of bosentan 

and boosted PREZISTA may increase 
plasma concentrations of bosentan.
Bosentan is expected to decrease plasma 
concentrations of darunavir and/or its 
pharmacoenhancer.
(CYP3A induction)

When administered concomitantly 
with PREZISTA and low dose 
ritonavir, the patient’s tolerability 
of bosentan should be monitored.

Co-administration of PREZISTA 
co-administered with cobicistat 
and bosentan is not recommended.

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A protease inhibitors

Elbasvir/grazoprevir Boosted PREZISTA may increase the 
exposure to grazoprevir.
(CYP3A and OATP1B inhibition)

Concomitant use of boosted 
PREZISTA and
elbasvir/grazoprevir is 
contraindicated (see section 4.3).

Boceprevir
800 mg three times daily

boceprevir AUC ↓ 32%
boceprevir Cmin ↓ 35%
boceprevir Cmax ↓ 25%
darunavir AUC ↓ 44%
darunavir Cmin ↓ 59%
darunavir Cmax ↓ 36%

It is not recommended to 
co-administer boosted PREZISTA 
and boceprevir.

Glecaprevir/pibrentasvir Based on theoretical considerations 
boosted PREZISTA may increase the 
exposure to glecaprevir and pibrentasvir.
(P-gp, BCRP and/or OATP1B1/3 
inhibition)

It is not recommended to 
co-administer boosted PREZISTA 
with glecaprevir/pibrentasvir.

Simeprevir simeprevir AUC ↑ 159%
simeprevir Cmin ↑ 358%
simeprevir Cmax ↑ 79%
darunavir AUC ↑ 18%
darunavir Cmin ↑ 31%
darunavir Cmax 

The dose of simeprevir in this interaction 
study was 50 mg when co-administered 
in combination with darunavir/ritonavir, 
compared to 150 mg in the simeprevir 
alone treatment group.

It is not recommended to 
co-administer boosted PREZISTA 
and simeprevir.

HERBAL PRODUCTS
St John's wort
(Hypericum perforatum)

Not studied. St John’s wort is expected to 
decrease the plasma concentrations of 
darunavir or its pharmacoenhancers.
(CYP450 induction)

Boosted PREZISTA 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.

HMG CO-A REDUCTASE INHIBITORS
Lovastatin
Simvastatin

Not studied. Lovastatin and simvastatin 
are expected to have markedly increased 
plasma concentrations when 
co-administered with boosted
PREZISTA.
(CYP3A inhibition)

Increased plasma concentrations of 
lovastatin or simvastatin may 
cause myopathy, including 
rhabdomyolysis. Concomitant use 
of boosted PREZISTA with 
lovastatin and simvastatin is 
therefore contraindicated (see 
section 4.3).



100

Atorvastatin
10 mg once daily

atorvastatin AUC ↑ 3-4 fold
atorvastatin Cmin ↑ ≈5.5-10 fold
atorvastatin Cmax ↑ ≈2 fold
#

darunavir/ritonavir

atorvastatin AUC ↑ 290%
Ω

atorvastatin Cmax ↑ 319%
Ω

atorvastatin Cmin ND
Ω

Ω
with darunavir/cobicistat 800/150 mg

When administration of 
atorvastatin and boosted
PREZISTA 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 Cmin ND
pravastatin Cmax ↑ 63%
¶

an up to five-fold increase was seen in a 
limited subset of subjects

When administration of pravastatin 
and boosted PREZISTA 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.

Rosuvastatin
10 mg once daily

rosuvastatin AUC ↑ 48%
║

rosuvastatin Cmax ↑ 144%
║

║
based on published data with 

darunavir/ritonavir

rosuvastatin AUC ↑ 93%
§

rosuvastatin Cmax ↑ 277%
§

rosuvastatin Cmin ND
§

§
with darunavir/cobicistat 800/150 mg

When administration of 
rosuvastatin and boosted
PREZISTA is required, it is 
recommended to start with the 
lowest possible dose of 
rosuvastatin and titrate up to the 
desired clinical effect while 
monitoring for safety.

OTHER LIPID MODIFYING AGENTS
Lomitapide Based on theoretical considerations 

boosted PREZISTA is expected to 
increase the exposure of lomitapide when 
co-administered.
(CYP3A inhibition)

Co-administration is 
contraindicated (see section 4.3)

H2-RECEPTOR ANTAGONISTS
Ranitidine
150 mg twice daily

#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

Boosted PREZISTA can be 
co-administered with H2-receptor 
antagonists without dose 
adjustments.

IMMUNOSUPPRESSANTS
Ciclosporin
Sirolimus
Tacrolimus

Everolimus

Not studied. Exposure to these 
immunosuppressants will be increased 
when co-administered with boosted 
PREZISTA.
(CYP3A inhibition)

Therapeutic drug monitoring of the 
immunosuppressive agent must be 
done when co-administration 
occurs.

Concomitant use of everolimus 
and boosted PREZISTA is not 
recommended.

INHALED BETA AGONISTS
Salmeterol Not studied. Concomitant use of 

salmeterol and boosted darunavir may 
increase plasma concentrations of 
salmeterol.

Concomitant use of salmeterol and 
boosted PREZISTA is not 
recommended. The combination 
may result in increased risk of 
cardiovascular adverse event with 
salmeterol, including QT 
prolongation, palpitations and 
sinus tachycardia.



101

NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE
Methadone
individual dose ranging 
from 55 mg to 150 mg 
once daily

R(-) methadone AUC ↓ 16%
R(-) methadone Cmin ↓ 15%
R(-) methadone Cmax ↓ 24%

PREZISTA/cobicistat may, in contrast, 
increase methadone plasma 
concentrations (see cobicistat SmPC).

No adjustment of methadone 
dosage is required when initiating 
co-administration with boosted
PREZISTA. However, adjustment 
of the methadone dose may be 
necessary when concomitantly 
administered for a longer period of 
time. Therefore, clinical 
monitoring is recommended, as 
maintenance therapy may need to 
be adjusted in some patients.

Buprenorphine/naloxone
8/2 mg–16/4 mg once 
daily

buprenorphine AUC ↓ 11%
buprenorphine Cmin ↔
buprenorphine Cmax ↓ 8%
norbuprenorphine AUC ↑ 46%
norbuprenorphine Cmin ↑ 71%
norbuprenorphine Cmax ↑ 36%
naloxone AUC ↔
naloxone Cmin ND
naloxone Cmax ↔

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 boosted 
PREZISTA but a careful clinical 
monitoring for signs of opiate 
toxicity is recommended.

Fentanyl
Oxycodone
Tramadol

Based on theoretical considerations 
boosted PREZISTA may increase plasma 
concentrations of these analgesics.
(CYP2D6 and/or CYP3A inhibition)

Clinical monitoring is 
recommended when 
co-administering boosted 
PREZISTA with these analgesics.

OESTROGEN-BASED CONTRACEPTIVES
Drospirenone 
Ethinylestradiol 
(3 mg/0.02 mg once 
daily)

Ethinylestradiol
Norethindrone
35 g/1 mg once daily

drospirenone AUC ↑ 58%
€

drospirenone Cmin ND
€

drospirenone Cmax ↑ 15%
€

ethinylestradiol AUC  30%
€

ethinylestradiol Cmin ND
€

ethinylestradiol Cmax  14%
€

€
with darunavir/cobicistat

ethinylestradiol AUC ↓ 44%
β

ethinylestradiol Cmin ↓ 62%
β

ethinylestradiol Cmax ↓ 32%
β

norethindrone AUC ↓ 14%
β

norethindrone Cmin ↓ 30%
β

norethindrone Cmax ↔
β

β
with darunavir/ritonavir

When PREZISTA is co-
administered with a drospirenone-
containing product, clinical 
monitoring is recommended due to 
the potential for hyperkalaemia.

Alternative or additional 
contraceptive measures are 
recommended when 
oestrogen-based contraceptives are 
co-administered with boosted 
PREZISTA. Patients using 
oestrogens as hormone 
replacement therapy should be 
clinically monitored for signs of 
oestrogen deficiency.

OPIOID ANTAGONIST
Naloxegol Not studied. Co-administration of boosted 

PREZISTA and naloxegol is 
contraindicated.



102

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of 
erectile dysfunction

Avanafil
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.

The combination of avanafil and 
boosted PREZISTA is 
contraindicated (see section 4.3).
Concomitant use of other PDE-5 
inhibitors for the treatment of 
erectile dysfunction with boosted 
PREZISTA should be done with 
caution. If concomitant use of 
boosted PREZISTA 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 
boosted PREZISTA may increase plasma 
concentrations of sildenafil or tadalafil.
(CYP3A inhibition)

A safe and effective dose of 
sildenafil for the treatment of 
pulmonary arterial hypertension 
co-administered with boosted 
PREZISTA 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 
boosted PREZISTA 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 boosted 
PREZISTA is not recommended.

PROTON PUMP INHIBITORS
Omeprazole
20 mg once daily

#
darunavir AUC ↔

#
darunavir Cmin ↔

#
darunavir Cmax ↔

Boosted PREZISTA can be 
co-administered with proton pump 
inhibitors without dose 
adjustments.



103

SEDATIVES/HYPNOTICS
Buspirone
Clorazepate
Diazepam
Estazolam
Flurazepam
Midazolam (parenteral)
Zolpidem

Midazolam (oral)
Triazolam

Not studied. Sedative/hypnotics are 
extensively metabolised by CYP3A. 
Co-administration with boosted 
PREZISTA may cause a large increase in 
the concentration of these medicines.

If parenteral midazolam is 
co-administered with boosted PREZISTA 
it 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.

Clinical monitoring is 
recommended when 
co-administering boosted 
PREZISTA with these 
sedatives/hypnotics and a lower 
dose of the sedatives/hypnotics 
should be considered.

If parenteral midazolam is 
co-administered with boosted 
PREZISTA, 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.

Boosted PREZISTA with 
triazolam or oral midazolam is 
contraindicated (see section 4.3)

TREATMENT FOR PREMATURE EJACULATION
Dapoxetime Not studied. Co-administration of boosted 

PREZISTA with dapoxetine is 
contraindicated.

UROLOGICAL DRUGS
Fesoterodine
Solifenacin

Not studied. Use with caution. Monitor for 
fesoterodine or solifenacin adverse 
reactions, dose reduction of 
fesoterodine or solifenacin may be 
necessary.

#
Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see 
section 4.2 Posology).

†
The efficacy and safety of the use of PREZISTA with 100 mg ritonavir and any other HIV 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.

‡
Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.

4.6 Fertility, pregnancy and lactation

Pregnancy
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in 
pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 
the animal data as well as the clinical experience in pregnant women should be taken into account.

There are no adequate and well controlled studies on pregnancy outcome 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.

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure 
(see section 5.2), which may be associated with an increased risk of treatment failure and an increased 
risk of HIV transmission to the child. Therapy with PREZISTA/cobicistat should not be initiated 



104

during pregnancy, and women who become pregnant during therapy with PREZISTA/cobicistat 
should be switched to an alternative regimen (see sections 4.2 and 4.4).

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).

4.7 Effects on ability to drive and use machines

PREZISTA in combination with cobicistat or 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 cobicistat or low dose ritonavir and should be 
borne in mind when considering a patient’s ability to drive or operate machinery (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile
During the clinical development program (N=2,613 treatment-experienced subjects who initiated 
therapy with PREZISTA/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one 
adverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequent 
adverse reactions reported in clinical trials and as spontaneous reports are diarrhoea, nausea, rash, 
headache and vomiting. The most frequent serious reactions are acute renal failure, myocardial 
infarction, immune reconstitution inflammatory syndrome, thrombocytopenia, osteonecrosis, 
diarrhoea, hepatitis and pyrexia.

In the 96 week analysis, the safety profile of PREZISTA/ritonavir 800/100 mg once daily in 
treatment-naïve subjects was similar to that seen with PREZISTA/ritonavir 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. No new safety findings were 
identified in the 192 week analysis of the treatment-naïve subjects in which the mean treatment 
duration of PREZISTA/ritonavir 800/100 mg once daily was 162.5 weeks.

During the Phase III clinical trial GS-US-216-130 with darunavir/cobicistat (N=313 treatment-naïve 
and treatment-experienced subjects), 66.5% of subjects experienced at least one adverse reaction. The 
mean treatment duration was 58.4 weeks. The most frequent adverse reactions reported were diarrhoea 
(28%), nausea (23%), and rash (16%). Serious adverse reactions are diabetes mellitus, (drug) 
hypersensitivity, immune reconstitution inflammatory syndrome, rash and vomiting.

For information on cobicistat, consult the cobicistat Summary of Product Characteristics.

Tabulated list 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).



105

Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing

MedDRA system organ class
Frequency category

Adverse reaction

Infections and infestations
uncommon herpes simplex
Blood and lymphatic system disorders
uncommon thrombocytopenia, neutropenia, anaemia, 

leukopenia

rare increased eosinophil count
Immune system disorders
uncommon immune reconstitution inflammatory syndrome, 

(drug) hypersensitivity
Endocrine disorders
uncommon hypothyroidism, increased blood thyroid 

stimulating hormone
Metabolism and nutrition disorders
common diabetes mellitus, hypertriglyceridaemia, 

hypercholesterolaemia, hyperlipidaemia

uncommon gout, anorexia, decreased appetite, decreased 
weight, increased weight, hyperglycaemia, 
insulin resistance, decreased high density 
lipoprotein, increased appetite, polydipsia, 
increased blood lactate dehydrogenase

Psychiatric disorders
common insomnia

uncommon depression, disorientation, anxiety, sleep 
disorder, abnormal dreams, nightmare, 
decreased libido

rare confusional state, altered mood, restlessness
Nervous system disorders
common headache, peripheral neuropathy, dizziness

uncommon lethargy, paraesthesia, hypoaesthesia, dysgeusia, 
disturbance in attention, memory impairment, 
somnolence

rare syncope, convulsion, ageusia, sleep phase 
rhythm disturbance

Eye disorders
uncommon conjunctival hyperaemia, dry eye

rare visual disturbance
Ear and labyrinth disorders
uncommon vertigo
Cardiac disorders
uncommon myocardial infarction, angina pectoris, 

prolonged electrocardiogram QT, tachycardia

rare acute myocardial infarction, sinus bradycardia, 
palpitations



106

Vascular disorders
uncommon hypertension, flushing
Respiratory, thoracic and mediastinal disorders
uncommon dyspnoea, cough, epistaxis, throat irritation

rare rhinorrhoea
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, retching, dry 
mouth, abdominal discomfort, constipation, 
increased lipase, eructation, oral dysaesthesia

rare stomatitis, haematemesis, cheilitis, dry lip, 
coated tongue

Hepatobiliary disorders
common increased alanine aminotransferase

uncommon hepatitis, cytolytic hepatitis, hepatic steatosis, 
hepatomegaly, increased transaminase, increased 
aspartate aminotransferase, increased blood 
bilirubin, increased blood alkaline phosphatase, 
increased gamma-glutamyltransferase

Skin and subcutaneous tissue disorders
common rash (including macular, maculopapular, 

papular, erythematous and pruritic rash), pruritus

uncommon angioedema, generalised rash, allergic 
dermatitis, urticaria, eczema, erythema, 
hyperhidrosis, night sweats, alopecia, acne, dry 
skin, nail pigmentation

rare DRESS, Stevens-Johnson syndrome, erythema 
multiforme, dermatitis, seborrhoeic dermatitis, 
skin lesion, xeroderma

not known toxic epidermal necrolysis, acute generalised 
exanthematous pustulosis

Musculoskeletal and connective tissue disorders
uncommon myalgia, osteonecrosis, muscle spasms, 

muscular weakness, arthralgia, pain in
extremity, osteoporosis, increased blood creatine 
phosphokinase

rare musculoskeletal stiffness, arthritis, joint stiffness
Renal and urinary disorders
uncommon acute renal failure, renal failure, nephrolithiasis, 

increased blood creatinine, proteinuria, 
bilirubinuria, dysuria, nocturia, pollakiuria

rare decreased creatinine renal clearance



107

Reproductive system and breast disorders
uncommon erectile dysfunction, gynaecomastia
General disorders and administration site conditions
common asthenia, fatigue

uncommon pyrexia, chest pain, peripheral oedema, malaise, 
feeling hot, irritability, pain

rare chills, abnormal feeling, xerosis

Adverse reactions observed with darunavir/cobicistat in adult patients

MedDRA system organ class
Frequency category

Adverse reaction

Immune system disorders
common (drug) hypersensitivity

uncommon immune reconstitution inflammatory syndrome
Metabolism and nutrition disorders
common anorexia, diabetes mellitus, 

hypercholesterolaemia, hypertriglyceridaemia, 
hyperlipidaemia

Psychiatric disorders
common abnormal dreams
Nervous system disorders
very common headache
Gastrointestinal disorders
very common diarrhoea, nausea

common vomiting, abdominal pain, abdominal distension, 
dyspepsia, flatulence, pancreatic enzymes 
increased

uncommon pancreatitis acute
Hepatobiliary disorders
common hepatic enzyme increased

uncommon hepatitis*, cytolytic hepatitis*
Skin and subcutaneous tissue disorders
very common rash (including macular, maculopapular, 

papular, erythematous, pruritic rash, generalised 
rash, and allergic dermatitis)

common angioedema, pruritus, urticaria

rare drug reaction with eosinophilia and systemic 
symptoms*, Stevens-Johnson syndrome*

not known toxic epidermal necrolysis*, acute generalised 
exanthematous pustulosis*

Musculoskeletal and connective tissue disorders
common myalgia

uncommon osteonecrosis*
Reproductive system and breast disorders
uncommon gynaecomastia*



108

General disorders and administration site conditions
common fatigue

uncommon asthenia
Investigations
common increased blood creatinine
* these adverse drug reactions have not been reported in clinical trial experience with darunavir/cobicistat but have been 

noted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.

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. In a single arm trial investigating darunavir 800 mg once daily in combination with 
cobicistat 150 mg once daily and other antiretrovirals 2.2% of patients discontinued treatment due to 
rash.

During the clinical development program of raltegravir in treatment-experienced patients, rash, 
irrespective of causality, was more commonly observed with regimens containing 
PREZISTA/ritonavir + raltegravir compared to those containing PREZISTA/ritonavir without 
raltegravir or raltegravir without PREZISTA/ritonavir. 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).

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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 inflammatory syndrome
In HIV infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and these events can occur 
many months after initiation of treatment (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).

Paediatric population
The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three 
Phase II trials. The following patient populations were evaluated (see section 5.1):
 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at 

least 20 kg who received PREZISTA tablets with low dose ritonavir twice daily in combination 
with other antiretroviral agents.



109

 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 
10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received PREZISTA oral 
suspension with low dose ritonavir twice daily in combination with other antiretroviral agents.

 12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 
40 kg who received PREZISTA tablets with low dose ritonavir once daily in combination with 
other antiretroviral agents (see section 5.1).

Overall, the safety profile in these paediatric patients was similar to that observed in the adult 
population.

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).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

Human experience of acute overdose with PREZISTA co-administered with cobicistat or 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. Since darunavir is highly protein bound, dialysis is unlikely to be 
beneficial in significant removal of the active substance.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitors, ATC code: J05AE10.

Mechanism of action
Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease 
(KD of 4.5 x 10

-12M). 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 EC50 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 EC50 values ranging from < 0.1 to 4.3 nM.

These EC50 values are well below the 50% cellular toxicity concentration range of 87 µM to 
> 100 µM.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


110

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. The decreased 
susceptibility to darunavir of the emerging viruses in the selection experiment could not be explained 
by the emergence of these protease mutations.

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, 
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 EC50 (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/ritonavir 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 HIV-1 protease mutations and loss of susceptibility to PIs 
in virologic failures at endpoint in the ARTEMIS, ODIN and TITAN trials.

ARTEMIS
Week 192

ODIN
Week 48

TITAN
Week 48

PREZISTA/ 
ritonavir

800/100 mg
once daily

N=343

PREZISTA/ 
ritonavir

800/100 mg
once daily

N=294

PREZISTA/ 
ritonavir

600/100 mg
twice daily

N=296

PREZISTA/ 
ritonavir

600/100 mg
twice daily

N=298
Total number of 
virologic failures

a
, n 

(%)

55 (16.0%) 65 (22.1%) 54 (18.2%) 31 (10.4%)

Rebounders 39 (11.4%) 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

0/43 1/60 0/42 6/28

PI RAMs 4/43 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 0/39 1/58 0/41 3/26
amprenavir 0/39 1/58 0/40 0/22
atazanavir 0/39 2/56 0/40 0/22
indinavir 0/39 2/57 0/40 1/24
lopinavir 0/39 1/58 0/40 0/23
saquinavir 0/39 0/56 0/40 0/22
tipranavir 0/39 0/58 0/41 1/25



111

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

Low rates of developing resistant HIV-1 virus were observed in ART-naïve patients who are treated 
for the first time with darunavir/cobicistat once daily in combination with other ART, and in 
ART-experienced patients with no darunavir RAMs receiving darunavir/cobicistat in combination 
with other ART. The table below shows the development of HIV-1 protease mutations and resistance 
to PIs in virologic failures at endpoint in the GS-US-216-130 trial.

GS-US-216-130
Week 48

Treatment-naïve
darunavir/cobicistat 800/150 mg

once daily
N=295

Treatment-experienced
darunavir/cobicistat 800/150 mg

once daily
N=18

Number of subjects with virologic failure
a

and genotype data that develop mutations
b

at endpoint, n/N
Primary (major) PI 
mutations

0/8 1/7

PI RAMs 2/8 1/7

Number of subjects with virologic failure
a

and phenotype data that show resistance to PIs at endpoint
c
, n/N

HIV PI
darunavir 0/8 0/7
amprenavir 0/8 0/7
atazanavir 0/8 0/7
indinavir 0/8 0/7
lopinavir 0/8 0/7
saquinavir 0/8 0/7
tipranavir 0/8 0/7

a
Virologic failures were defined as: never suppressed: confirmed HIV-1 RNA < 1 log10 reduction from baseline and 
≥ 50 copies/ml at the week-8; rebound: HIV-1 RNA < 50 copies/ml followed by confirmed HIV-1 RNA to 
≥ 400 copies/ml or confirmed > 1 log10 HIV-1 RNA increase from the nadir; discontinuations with HIV-1 RNA 
≥ 400 copies/ml at last visit

b
IAS-USA lists

c
In GS-US216-130 baseline phenotype was not available

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.
In the virologic failures of the GS-US-216-130 trial no cross-resistance with other HIV PIs was 
observed.

Clinical results
The pharmacokinetic enhancing effect of cobicistat on darunavir was evaluated in a Phase I study in 
healthy subjects that were administered darunavir 800 mg with either cobicistat at 150 mg or ritonavir 
at 100 mg once daily. The steady-state pharmacokinetic parameters of darunavir were comparable 
when boosted with cobicistat versus ritonavir. For information on cobicistat, consult the cobicistat 
Summary of Product Characteristics.

Adult patients

Efficacy of darunavir 800 mg once daily co-administered with 150 mg cobicistat once daily in 
ART-naïve and ART-experienced patients
GS-US-216-130 is a single arm, open-label, Phase III trial evaluating the pharmacokinetics, safety, 
tolerability, and efficacy of darunavir with cobicistat in 313 HIV-1 infected adult patients 
(295 treatment-naïve and 18 treatment-experienced). These patients received darunavir 800 mg once 



112

daily in combination with cobicistat 150 mg once daily with an investigator selected background 
regimen consisting of 2 active NRTIs.

HIV-1 infected patients who were eligible for this trial had a screening genotype showing no darunavir 
RAMs and plasma HIV-1 RNA ≥ 1,000 copies/ml. The table below shows the efficacy data of the 
48 week analyses from the GS-US-216-130 trial:

GS-US-216-130

Outcomes at Week 48

Treatment-naïve
darunavir/cobicistat 

800/150 mg once daily
+ OBR
N=295

Treatment-experienced
darunavir/cobicistat 

800/150 mg once daily
+ OBR
N=18

All subjects
darunavir/cobicistat 

800/150 mg once daily
+ OBR
N=313

HIV-1 RNA < 50 copies/ml
a 245 (83.1%) 8 (44.4%) 253 (80.8%)

mean HIV-1 RNA log change 
from baseline 
(log10 copies/ml)

-3.01 -2.39 -2.97

CD4+ cell count mean 

change from baseline
b

+174 +102 +170

a
Imputations according to the TLOVR algorithm

b
Last Observation Carried Forward imputation

Efficacy of PREZISTA 800 mg once daily co-administered with 100 mg ritonavir once daily in 
ART-naïve patients
The evidence of efficacy of PREZISTA/ritonavir 800/100 mg once daily is based on the analyses of 
192 week data from the randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviral 
treatment-naïve HIV-1 infected patients comparing PREZISTA/ritonavir 800/100 mg once daily with 
lopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both arms 
used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily and 
emtricitabine 200 mg once daily.

The table below shows the efficacy data of the 48 week and 96 week analyses from the ARTEMIS
trial:

ARTEMIS

Week 48
a

Week 96
b

Outcomes PREZISTA/ 
ritonavir

800/100 mg 
once daily

N=343

Lopinavir/ 
ritonavir

800/200 mg 
per day
N=346

Treatment 
difference 
(95% CI of 
difference)

PREZISTA/ 
ritonavir

800/100 mg 
once daily

N=343

Lopinavir/ 
ritonavir

800/200 m
g per day
N=346

Treatment 
difference 
(95% CI of 
difference)

HIV-1 RNA 
< 50 copies/ml

c

All patients 83.7%
(287)

78.3%
(271)

5.3%

(-0.5; 11.2)
d

79.0%
(271)

70.8%
(245)

8.2%

(1.7; 14.7)
d

With baseline 
HIV-RNA 
< 100,000

85.8%
(194/226)

84.5%
(191/226)

1.3%

(-5.2; 7.9)
d

80.5%
(182/226)

75.2%
(170/226)

5.3%

(-2.3; 13.0)
d

With baseline 
HIV-RNA 
≥ 100,000

79.5%
(93/117)

66.7%
(80/120)

12.8%

(1.6; 24.1)
d

76.1%
(89/117)

62.5%
(75/120)

13.6%

(1.9; 25.3)
d

With baseline 
CD4+ cell 
count < 200

79.4%
(112/141)

70.3%
(104/148)

9.2%

(-0.8; 19.2)
d

78.7%
(111/141)

64.9%
(96/148)

13.9%

(3.5; 24.2)
d

With baseline 
CD4+ cell 
count ≥ 200

86.6%
(175/202)

84.3%
(167/198)

2.3%

(-4.6; 9.2)
d

79.2%
(160/202)

75.3%
(149/198)

4.0%

(-4.3; 12.2)
d



113

median 
CD4+ cell count 
change from 

baseline (x 10
6
/l)

e

137 141 171 188

a
Data based on analyses at week 48

b
Data based on analyses at week 96

c
Imputations according to the TLOVR algorithm

d
Based on normal approximation to the difference in % response

e
Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0

Non-inferiority in virologic response to the PREZISTA/ritonavir treatment, defined as the percentage 
of patients with plasma HIV-1 RNA level < 50 copies/ml, was demonstrated (at the pre-defined 12% 
non-inferiority margin) for both Intent-To-Treat (ITT) and On Protocol (OP) populations in the 
48 week analysis. These results were confirmed in the analyses of data at 96 weeks of treatment in the 
ARTEMIS trial. These results were sustained up to 192 weeks of treatment in the ARTEMIS trial.

Efficacy of PREZISTA 800 mg once daily co-administered with 100 mg ritonavir once daily in 
ART-experienced patients
ODIN is a Phase III, randomised, open-label trial comparing PREZISTA/ritonavir 800/100 mg once 
daily versus PREZISTA/ritonavir 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/ritonavir 

800/100 mg once daily + 
OBR

N=294

PREZISTA/ritonavir 
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)

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.



114

PREZISTA/ritonavir 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 106/l (see section 4.2 and 4.4). Limited data is 
available in patients with HIV-1 clades other than B.

Paediatric patients

ART-naïve paediatric patients from the age of 12 years to < 18 years, and weighing at least 40 kg
DIONE is an open-label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and 
efficacy of PREZISTA with low dose ritonavir in 12 ART-naïve HIV-1 infected paediatric patients 
aged 12 to less than 18 years and weighing at least 40 kg. These patients received 
PREZISTA/ritonavir 800/100 mg once daily in combination with other antiretroviral agents. Virologic 
response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1.0 log10 versus 
baseline.

DIONE

Outcomes at week 48
PREZISTA/ritonavir

N=12
HIV-1 RNA < 50 copies/mla 83.3% (10)
CD4+ percent change from baselineb 14
CD4+ cell count mean change from baselineb 221
≥ 1.0 log10 decrease from baseline in plasma viral load 100%
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.

For additional clinical study results in ART-experienced adults and paediatric patients, refer to the 
Summary of Product Characteristics for PREZISTA 75 mg, 150 mg or 600 mg tablets and 100 mg/ml 
oral suspension.

Pregnancy and postpartum
Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a 
background regimen was evaluated in a clinical trial of 36 pregnant women (18 in each arm) during 
the second and third trimesters, and postpartum. Virologic response was preserved throughout the 
study period in both arms. No mother to child transmission occurred in the infants born to the 
31 subjects who stayed on the antiretroviral treatment through delivery. There were no new clinically 
relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1 
infected adults (see sections 4.2, 4.4 and 5.2).

5.2 Pharmacokinetic properties

The pharmacokinetic properties of darunavir, co-administered with cobicistat or 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 
α1-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. Cobicistat and ritonavir inhibit CYP3A, thereby 
increasing the plasma concentrations of darunavir considerably.

For information on cobicistat pharmacokinetic properties, consult the cobicistat Summary of Product 
Characteristics.

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.



115

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 cobicistat 
or low dose ritonavir is lower as compared to intake with food. Therefore, PREZISTA tablets should 
be taken with cobicistat or 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 α1-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.

Biotransformation
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 14C-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 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the 
administered dose of 14C-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 taken twice daily 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).

The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 
14 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to 
< 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that 
achieved in adults receiving PREZISTA/ritonavir 600/100 mg twice daily (see section 4.2).

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naïve 
paediatric patients, aged 12 to < 18 years and weighing at least 40 kg, showed that 
PREZISTA/ritonavir 800/100 mg once daily results in darunavir exposure that was comparable to that 
achieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily. Therefore the same once 
daily dosage may be used in treatment-experienced adolescents aged 12 to < 18 years and weighing at 
least 40 kg without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma 
HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l (see section 4.2).



116

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 
10 treatment-experienced paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to 
< 20 kg, showed that weight-based dosages resulted in darunavir exposure that was comparable to that 
achieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily (see section 4.2). In addition, 
pharmacokinetic modeling and simulation of darunavir exposures in paediatric patients across the ages 
of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowed 
the identification of weight-based PREZISTA/ritonavir once daily dosing regimens for paediatric 
patients weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patients 
without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count 
≥ 100 cells x 106/l (see section 4.2).
* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

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
Results from a mass balance study with 14C-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).

Pregnancy and postpartum
The exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice 
daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally 
lower during pregnancy compared with postpartum. However, for unbound (i.e. active) darunavir, the 
pharmacokinetic parameters were less reduced during pregnancy compared to postpartum, due to an 
increase in the unbound fraction of darunavir during pregnancy compared to postpartum.

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 
600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester of 

pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of 
total darunavir
(mean ± SD)

Second trimester of 
pregnancy

(n=12)a

Third trimester of 
pregnancy

(n=12)

Postpartum 
(6-12 weeks)

(n=12)
Cmax, ng/ml 4,668 ± 1,097 5,328 ± 1,631 6,659 ± 2,364



117

AUC12h, ng.h/ml 39,370 ± 9,597 45,880 ± 17,360 56,890 ± 26,340
Cmin, ng/ml 1,922 ± 825 2,661 ± 1,269 2,851 ± 2,216
a

n=11 for AUC12h

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at 
800/100 mg once daily as part of an antiretroviral regimen, during the second trimester of 

pregnancy, the third trimester of pregnancy and postpartum
Pharmacokinetics of 
total darunavir
(mean ± SD)

Second trimester of 
pregnancy

(n=17)

Third Trimester of 
pregnancy

(n=15)

Postpartum 
(6-12 weeks)

(n=16)
Cmax, ng/ml 4,964 ± 1,505 5,132 ± 1,198 7,310 ± 1,704
AUC24h, ng.h/ml 62,289 ± 16,234 61,112 ± 13,790 92,116 ± 29,241
Cmin, ng/ml 1,248 ± 542 1,075 ± 594 1,473 ± 1,141

In women receiving darunavir/ritonavir 600/100 mg twice daily during the second trimester of 
pregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and 
26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total 
darunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, as 
compared with postpartum.

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester of 
pregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and 
30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, total 
darunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as compared 
with postpartum.

Treatment with darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavir 
exposure. In women receiving darunavir/cobicistat during the second trimester of pregnancy, mean 
intra-individual values for total darunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower, 
respectively, as compared with postpartum; during the third trimester of pregnancy, total darunavir 
Cmax, AUC24h and Cmin values were 37%, 50% and 89% lower, respectively, as compared with 
postpartum. The unbound fraction was also substantially reduced, including around 90% reductions of 
Cmin levels. The main cause of these low exposures is a marked reduction in cobicistat exposure as a 
consequence of pregnancy-associated enzyme induction (see below).

Pharmacokinetic results of total darunavir after administration of darunavir/cobicistat 
800/150 mg once daily as part of an antiretroviral regimen, during the second trimester of 

pregnancy, the third trimester of pregnancy, and postpartum
Pharmacokinetics of 
total darunavir
(mean ± SD)

Second trimester 
of pregnancy

(n=7)

Third trimester 
of pregnancy

(n=6)

Postpartum 
(6-12 weeks)

(n=6)
Cmax, ng/mL 4,340 ± 1,616 4,910 ± 970 7,918 ± 2,199
AUC24h, ng.h/mL 47,293 ± 19,058 47,991 ± 9,879 99,613 ± 34,862
Cmin, ng/mL 168 ± 149 184 ± 99 1,538 ± 1,344

The exposure to cobicistat was lower during pregnancy, potentially leading to suboptimal boosting of 
darunavir. During the second trimester of pregnancy, cobicistat Cmax, AUC24h, and Cmin were 50%, 
63%, and 83% lower, respectively, as compared with postpartum. During the third trimester of 
pregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, as 
compared with postpartum.

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.



118

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.

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.



119

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

PREZISTA 400 mg film-coated tablets
Tablet core
Microcrystalline cellulose
Colloidal anhydrous silica
Crospovidone
Magnesium stearate

Tablet film-coat
Poly(vinyl alcohol) – partially hydrolysed
Macrogol 3350
Titanium dioxide (E171)
Talc
Sunset yellow FCF (E110)

PREZISTA 800 mg film-coated tablets
Tablet core
Microcrystalline cellulose
Colloidal anhydrous silica
Crospovidone
Magnesium stearate
Hypromellose

Tablet film-coat
Poly(vinyl alcohol) – partially hydrolysed
Macrogol 3350
Titanium dioxide (E171)
Talc
Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PREZISTA 400 mg film-coated tablets
Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 60 tablets, fitted 
with polypropylene (PP) child resistant closure.
Pack size of one bottle.

PREZISTA 800 mg film-coated tablets
Opaque, white, high density polyethylene (HDPE) plastic, 75 ml bottle containing 30 tablets, fitted 
with polypropylene (PP) child resistant closure.
Pack size of one bottle or three bottles per carton.



120

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

8. MARKETING AUTHORISATION NUMBER(S)

PREZISTA 400 mg film-coated tablets
EU/1/06/380/003

PREZISTA 800 mg film-coated tablets
EU/1/06/380/007 - 30 film-coated tablets
EU/1/06/380/008 - 90 film-coated tablets (3 x 30)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 February 2007
Date of latest renewal: 19 September 2013

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.europa.eu/


121

ANNEX II

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



122

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

PREZISTA oral suspension
Janssen Pharmaceutica NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

PREZISTA tablets
Janssen-Cilag SpA
Via C. Janssen
Borgo San Michele
04100 Latina
Italy

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.



123

ANNEX III

LABELLING AND PACKAGE LEAFLET



124

A. LABELLING



125

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON FOR ORAL SUSPENSION

1. NAME OF THE MEDICINAL PRODUCT

PREZISTA 100 mg/ml oral suspension
darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each ml of suspension contains 100 mg darunavir (as ethanolate).

3. LIST OF EXCIPIENTS

Contains sodium methyl parahydroxybenzoate (E219).
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Oral suspension
200 ml bottle
Pack includes a 6 ml dosing pipette with 0.2 ml gradations.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Shake bottle vigorously before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.
Do not refrigerate or freeze. Avoid exposure to excessive heat.



126

Store in the original container.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/380/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

prezista 100 mg/ml

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



127

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL FOR ORAL SUSPENSION

1. NAME OF THE MEDICINAL PRODUCT

PREZISTA 100 mg/ml oral suspension
darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each ml of suspension contains 100 mg darunavir (as ethanolate).

3. LIST OF EXCIPIENTS

Contains sodium methyl parahydroxybenzoate (E219).
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Oral suspension
200 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use
Shake bottle vigorously before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.
Do not refrigerate or freeze. Avoid exposure to excessive heat.
Store in the original container.



128

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/380/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE



129

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

OUTER CARTON / BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

PREZISTA 75 mg film-coated tablets
darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 75 mg darunavir (as ethanolate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

480 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



130

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/380/005

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

prezista 75 mg (this is only applicable to the outer pack)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



131

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

OUTER CARTON / BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

PREZISTA 150 mg film-coated tablets
darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 150 mg darunavir (as ethanolate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

240 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



132

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/380/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

prezista 150 mg (this is only applicable to the outer pack)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



133

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

OUTER CARTON / BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

PREZISTA 400 mg film-coated tablets
darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 400 mg darunavir (as ethanolate).

3. LIST OF EXCIPIENTS

Also contains sunset yellow FCF (E110).

4. PHARMACEUTICAL FORM AND CONTENTS

60 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



134

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/380/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

prezista 400 mg (this is only applicable to the outer pack)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



135

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

OUTER CARTON / BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

PREZISTA 600 mg film-coated tablets
darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 600 mg darunavir (as ethanolate).

3. LIST OF EXCIPIENTS

Also contains sunset yellow FCF (E110).

4. PHARMACEUTICAL FORM AND CONTENTS

60 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



136

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/380/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

prezista 600 mg (this is only applicable to the outer pack)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



137

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

OUTER CARTON / BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

PREZISTA 800 mg film-coated tablets
darunavir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each film-coated tablet contains 800 mg darunavir (as ethanolate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 film-coated tablets
90 film-coated tablets (3 bottles containing 30 tablets each)
The bottles are not to be distributed individually.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



138

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/06/380/007 - 30 film-coated tablets
EU/1/06/380/008 - 90 film-coated tablets (3 x 30)

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

prezista 800 mg (this is only applicable to the outer pack)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



139

B. PACKAGE LEAFLET



140

Package leaflet: Information for the user

PREZISTA 100 mg/ml oral suspension
darunavir

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What PREZISTA is and what it is used for
2. What you need to know before you take PREZISTA
3. How to take PREZISTA
4. Possible side effects
5. How to store PREZISTA
6. Contents of the pack and other information

1. What PREZISTA is and what it is used for

What is PREZISTA?
PREZISTA contains the active substance darunavir. PREZISTA is an antiretroviral medicine used in 
the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of medicines 
called protease inhibitors. PREZISTA works by reducing the amount of HIV in your body. This will 
improve your immune system and reduces the risk of developing illnesses linked to HIV infection.

What it is used for?
PREZISTA is used to treat HIV infected adults as well as HIV infected children of 3 years of age and 
above, and at least 15 kilogram body weight (see How to take PREZISTA).

PREZISTA must be taken in combination with a low dose of cobicistat or ritonavir and other anti-HIV 
medicines. Your doctor will discuss with you which combination of medicines is best for you.

2. What you need to know before you take PREZISTA

Do not take PREZISTA
- if you are allergic to darunavir or any of the other ingredients of this medicine (listed in section

6) or to cobicistat or ritonavir.
- if you have severe liver problems. Ask your doctor if you are unsure about the severity of your 

liver disease. Some additional tests might be necessary.

Do not combine PREZISTA with any of the following medicines
If you are taking any of these, ask your doctor about switching to another medicine.

Medicine Purpose of the medicine
Avanafil to treat erectile dysfunction 
Astemizole or terfenadine to treat allergy symptoms
Triazolam and oral (taken by mouth) midazolam to help you sleep and/or relieve anxiety
Cisapride to treat some stomach conditions
Colchicine (if you have kidney and/or liver
problems)

to treat gout or familial Mediterranean fever



141

Lurasidone, pimozide, quetiapine or sertindole to treat psychiatric conditions
Ergot alkaloids like ergotamine, 
dihydroergotamine, ergometrine and 
methylergonovine

to treat migraine headaches

Amiodarone, bepridil, dronedarone, ivabradine,
quinidine, ranolazine 

to treat certain heart disorders e.g. abnormal 
heart beat

Lovastatin, simvastatin and lomitapide to lower cholesterol levels
Rifampicin to treat some infections such as tuberculosis
The combination product lopinavir/ritonavir this anti-HIV medicine belongs to the same class 

as PREZISTA
Elbasvir/grazoprevir to treat hepatitis C infection
Alfuzosin to treat enlarged prostate
Sildenafil to treat high blood pressure in the pulmonary 

circulation
Dabigatran, ticagrelor to help stop the clumping of platelets in the 

treatment of patients with a history of a heart 
attack

Naloxegol to treat opioid induced constipation
Dapoxetine to treat premature ejaculation
Domperidone to treat nausea and vomiting

Do not combine PREZISTA with products that contain St John’s wort (Hypericum perforatum).

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking PREZISTA.

PREZISTA is not a cure for HIV infection. You can still pass on HIV when taking this medicine, 
although the risk is lowered by effective antiretroviral therapy. Discuss with your physician the 
precautions needed to avoid infecting other people.

People taking PREZISTA may still develop infections or other illnesses associated with HIV infection. 
You must keep in regular contact with your doctor.

People taking PREZISTA may develop a skin rash. Infrequently a rash may become severe or 
potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking PREZISTA and raltegravir (for HIV infection), rashes (generally mild or moderate) 
may occur more frequently than in patients taking either medicine separately.

Tell your doctor about your situation BEFORE and DURING your treatment
Make sure that you check the following points and tell your doctor if any of these apply to you.
- Tell your doctor if you have had problems with your liver before, including hepatitis B or C

infection. Your doctor may evaluate how severe your liver disease is before deciding if you can 
take PREZISTA.

- Tell your doctor if you have diabetes. PREZISTA might increase sugar levels in the blood.
- Tell your doctor immediately if you notice any symptoms of infection (for example enlarged 

lymph nodes and fever). In some patients with advanced HIV infection and a history of 
opportunistic infection, signs and symptoms of inflammation from previous infections may 
occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an 
improvement in the body’s immune response, enabling the body to fight infections that may 
have been present with no obvious symptoms.

- In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection. Autoimmune disorders may occur many months after 
the start of treatment. If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 



142

the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment.

- Tell your doctor if you have haemophilia. PREZISTA might increase the risk of bleeding.
- Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).
- Tell your doctor if you notice any musculoskeletal problems. Some patients taking 

combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of 
bone tissue caused by loss of blood supply to the bone). The length of combination 
antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, 
higher body mass index, among others, may be some of the many risk factors for developing 
this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, 
knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor.

Elderly
PREZISTA has only been used in limited numbers of patients 65 years or older. If you belong to this 
age group, please discuss with your doctor if you can use PREZISTA.

Children
PREZISTA is not for use in children younger than 3 years of age or weighing less than 15 kilograms.

Other medicines and PREZISTA
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

There are some medicines that you must not combine with PREZISTA. These are mentioned above 
under the heading ‘Do not combine PREZISTA with any of the following medicines:’

In most cases, PREZISTA can be combined with anti-HIV medicines belonging to another class [e.g. 
NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase 
inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. PREZISTA with cobicistat or ritonavir has 
not been tested with all PIs (protease inhibitors) and must not be used with other HIV PIs. In some 
cases dosage of other medicines might need to be changed. Therefore always tell your doctor if you 
take other anti-HIV medicines and follow your doctor’s instruction carefully on which medicines can 
be combined.

The effects of PREZISTA might be reduced if you take any of the following products. Tell your 
doctor if you take:
- Phenobarbital, phenytoin (to prevent seizures)
- Dexamethasone (corticosteroid)
- Efavirenz (HIV infection)
- Boceprevir (hepatitis C infection)
- Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis)
- Saquinavir (HIV infection).

The effects of other medicines might be influenced if you take PREZISTA. Tell your doctor if you 
take:
- Amlodipine, diltiazem, disopyramide, carvedilol, felodipine, flecainide, lidocaine, metoprolol,

mexiletine, nifedipine, nicardipine, propafenone, timolol, verapamil (for heart disease) as the 
therapeutic effect or side effects of these medicines may be increased.

- Apixaban, edoxaban, rivaroxaban, warfarin (to reduce clotting of the blood) as their therapeutic 
effect or side effects may be altered; your doctor may have to check your blood.

- Oestrogen-based hormonal contraceptives and hormonal replacement therapy. PREZISTA 
might reduce its effectiveness. When used for birth control, alternative methods of 
non-hormonal contraception are recommended.

- Ethinylestradiol/drospirenone. PREZISTA might increase the risk for elevated potassium levels 
by drospirenone.



143

- Atorvastatin, pravastatin, rosuvastatin (to lower cholesterol levels). The risk of muscle damage
might be increased. Your doctor will evaluate which cholesterol lowering regimen is best for 
your specific situation.

- Clarithromycin (antibiotic)
- Ciclosporin, everolimus, tacrolimus, sirolimus (for dampening down your immune system) as 

the therapeutic effect or side effects of these medicines might be increased. Your doctor might 
want to do some additional tests.

- Corticosteroids including betamethasone, budesonide, fluticasone, mometasone, prednisone, 
triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel 
diseases, inflammatory conditions of the eyes, joints and muscles and other inflammatory 
conditions. If alternatives cannot be used, its use should only take place after medical evaluation 
and under close monitoring by your doctor for corticosteroid side effects.

- Buprenorphine/naloxone (medicines to treat opioid dependence)
- Salmeterol (medicine to treat asthma)
- Artemether/lumefantrine (a combination medicine to treat malaria)
- Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer)
- Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder 

called pulmonary arterial hypertension)
- Glecaprevir/pibrentasvir, simeprevir (to treat hepatitis C infection)
- Fentanyl, oxycodone, tramadol (to treat pain)
- Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or PREZISTA’s 
therapeutic effect or side effects may be influenced when combined.
Tell your doctor if you take:
- Alfentanil (injectable strong and short-acting painkiller that is used for surgical procedures)
- Digoxin (to treat certain heart disorders)
- Clarithromycin (antibiotic)
- Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal 

infections). Voriconazole should only be taken after medical evaluation.
- Rifabutin (against bacterial infections)
- Sildenafil, vardenafil, tadalafil (for erectile dysfunction or high blood pressure in the pulmonary 

circulation)
- Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat 

depression and anxiety)
- Maraviroc (to treat HIV infection)
- Methadone (to treat opiate dependance)
- Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain)
- Colchicine (to treat gout or familial Mediterranean fever)
- Bosentan (to treat high blood pressure in the pulmonary circulation)
- Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, 

zolpidem (sedative agents)
- Perphenazine, risperidone, thioridazine (to treat psychiatric conditions)
- Metformin (to treat type 2 diabetes).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are 
taking.

PREZISTA with food and drink
See section 3 ‘How to take PREZISTA.’

Pregnancy and breast-feeding
Tell your doctor immediately if you are pregnant, planning to become pregnant or if you are 
breast-feeding. Pregnant or breast-feeding mothers should not take PREZISTA with ritonavir unless 
specifically directed by the doctor. Pregnant or breast-feeding mothers should not take PREZISTA 
with cobicistat.



144

It is recommended that HIV infected women must not breast-feed their infants because of both the 
possibility of your baby becoming infected with HIV through your breast milk and because of the 
unknown effects of the medicine on your baby.

Driving and using machines
Do not operate machines or drive if you feel dizzy after taking PREZISTA.

PREZISTA oral suspension contains sodium methyl parahydroxybenzoate. This ingredient may
cause allergic reactions (sometimes delayed).

3. How to take PREZISTA

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has 
told you. Check with your doctor, pharmacist or nurse if you are not sure.
Even if you feel better, do not stop taking PREZISTA and cobicistat or ritonavir without talking to 
your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be 
stopped without instruction of the doctor.

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have not taken 
antiretroviral medicines before (your child’s doctor will determine this)
The doctor will work out the right once daily dose based on the weight of the child (see table below). 
This dose must not exceed the recommended adult dose, which is 800 milligram PREZISTA together 
with 100 milligram ritonavir once a day.
The doctor will inform you on how much PREZISTA oral suspension and how much ritonavir 
(capsules, tablets or solution) the child must take.

Weight One PREZISTA dose is One ritonavira dose is
between 15 and 30 kilograms 600 milligram (6 milliliter) 100 milligram (1.2 milliliter)
between 30 and 40 kilograms 675 milligram (6.8 milliliter) 100 milligram (1.2 milliliter)
more than 40 kilograms 800 milligram (8 milliliter) 100 milligram (1.2 milliliter)
a

ritonavir oral solution: 80 milligram per milliliter

The child must take PREZISTA every day and always in combination with 100 milligram of ritonavir 
and with food. PREZISTA cannot work properly without ritonavir and food. The child must eat a meal 
or a snack within 30 minutes prior to taking PREZISTA and ritonavir. The type of food is not 
important.

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have taken 
antiretroviral medicines before (your child’s doctor will determine this)
The doctor will work out the right dose based on the weight of the child (see table below). The doctor
will determine if once daily dosing or twice daily dosing is appropriate for the child. This dose must 
not exceed the recommended adult dose, which is 600 milligram PREZISTA together with 
100 milligram ritonavir two times per day or 800 milligram PREZISTA together with 100 milligram 
ritonavir once a day.
The doctor will inform you on how much PREZISTA oral suspension and how much ritonavir 
(capsules, tablets or solution) the child must take.

Twice daily dosing
Weight One PREZISTA dose is One ritonavira dose is

between 15 and 30 kilograms 380 milligram (3.8 milliliter) 50 milligram (0.6 milliliter)
between 30 and 40 kilograms 460 milligram (4.6 milliliter) 60 milligram (0.8 milliliter)
more than 40 kilograms 600 milligram (6 milliliter) 100 milligram (1.2 milliliter)
a

ritonavir oral solution: 80 milligram per milliliter



145

Once daily dosing
Weight One PREZISTA dose is One ritonavira dose is

between 15 and 30 kilograms 600 milligram (6 milliliter) 100 milligram (1.2 milliliter)
between 30 and 40 kilograms 675 milligram (6.8 milliliter) 100 milligram (1.2 milliliter)
more than 40 kilograms 800 milligram (8 milliliter) 100 milligram (1.2 milliliter)
a

ritonavir oral solution: 80 milligram per milliliter

Instructions for children
- The child must take PREZISTA always together with ritonavir. PREZISTA cannot work 

properly without ritonavir.
- The child must take the appropriate doses of PREZISTA and ritonavir two times per day or once 

a day. If prescribed PREZISTA twice daily the child must take one dose in the morning, and 
one dose in the evening. Your child’s doctor will determine the appropriate dosing regimen for 
your child.

- The child must take PREZISTA with food. PREZISTA cannot work properly without food. The 
type of food is not important.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine 
this)
The usual dose of PREZISTA is 800 milligram once daily.
You must take PREZISTA every day and always in combination with 150 milligram of cobicistat or 
100 milligram of ritonavir and with food. PREZISTA cannot work properly without cobicistat or 
ritonavir and food. You must eat a meal or a snack within 30 minutes prior to taking your PREZISTA 
and cobicistat or ritonavir. The type of food is not important. Even if you feel better, do not stop taking 
PREZISTA and cobicistat or ritonavir without talking to your doctor.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this)
The dose is either:
- 600 milligram PREZISTA together with 100 milligram ritonavir twice daily.

OR
- 800 milligram PREZISTA together with 150 milligram cobicistat or 100 milligram ritonavir 

once daily.

Please discuss with your doctor which dose is right for you.

Instructions for adults
- Take PREZISTA always together with cobicistat or ritonavir. PREZISTA cannot work properly 

without cobicistat or ritonavir.
- Take PREZISTA with food. PREZISTA cannot work properly without food. The type of food is 

not important.

Instructions for use
Use the dosing pipette supplied with the pack to measure your dose accurately:
1. Shake the bottle well before each use.
2. Open the bottle of PREZISTA oral suspension by pushing downward on the cap and twisting it 

counter-clockwise.
3. Insert the supplied oral dosing pipette all the way into the 

bottle.



146

4. Pull the plunger until the top of the barrel meets the line that matches the dose prescribed by 
your health care provider.

5. Take the dose of PREZISTA. Place the tip of the oral dosing pipette in the mouth. Press on the 
plunger of the pipette towards the mouth, then swallow.

6. Close the bottle with the cap after use, and store PREZISTA oral suspension as directed in 
section 5 below.

7. Remove the plunger from the barrel of the pipette, rinse both with water and allow to air dry 
after each use.

8. Put the oral dosing pipette back together after air drying and store with the PREZISTA bottle.

Do not use the dosing pipette for any other medicines.

If you take more PREZISTA than you should
Contact your doctor, pharmacist or nurse immediately.

If you forget to take PREZISTA
If you take PREZISTA two times a day and if you notice within 6 hours, you must take the oral 
suspension immediately. Always take with ritonavir and food. If you notice after 6 hours, then skip 
the intake and take the next doses as usual. Do not take a double dose to make up for a forgotten dose.

If you take PREZISTA once a day and if you notice within 12 hours, you must take the oral 
suspension immediately. Always take with cobicistat or ritonavir and food. If you notice after 
12 hours, then skip the intake and take the next doses as usual. Do not take a double dose to make up 
for a forgotten dose.

Do not stop taking PREZISTA without talking to your doctor first
Anti-HIV medicines may make you feel better. Even when you feel better, do not stop taking 
PREZISTA. Talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor if you develop any of the following side effects.

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests 
before you start PREZISTA. If you have chronic hepatitis B or C infection, your doctor should check 
your blood tests more often because you have an increased chance of developing liver problems. Talk 
to your doctor about the signs and symptoms of liver problems. These may include yellowing of your 
skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), 
nausea, vomiting, loss of appetite, or pain, aching, or pain and discomfort on your right side below 
your ribs.

Skin rash (more often when used in combination with raltegravir), itching. The rash is usually mild to 
moderate. A skin rash might also be a symptom of a rare severe situation. It is important to talk to your 
doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms or whether 
PREZISTA must be stopped.

Other severe side effects were diabetes (common) and inflammation of the pancreas (uncommon).



147

Very common side effects (may affect more than 1 in 10 people)
- diarrhoea.

Common side effects (may affect up to 1 in 10 people)
- vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence
- headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of 

strength, difficulty falling asleep.

Uncommon side effects (may affect up to 1 in 100 people)
- chest pain, changes in electrocardiogram, rapid heart beating
- decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory, 

problems with your balance
- difficulty breathing, cough, nosebleed, throat irritation
- inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the 

abdomen, constipation, belching
- kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of

urine, sometimes at night
- urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, 

excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails
- muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis
- slowing down of the thyroid gland function. This can be seen in a blood test.
- high blood pressure, flushing
- red or dry eyes
- fever, swelling of lower limbs due to fluids, malaise, irritability, pain
- symptoms of infection, herpes simplex
- erectile dysfunction, enlargement of breasts
- sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive

Rare side effects (may affect up to 1 in 1,000 people)
- a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of 

the face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver, 
kidney or lung]

- heart attack, slow heart beating, palpitations
- visual disturbance
- chills, feeling abnormal
- a feeling of confusion or disorientation, altered mood, restlessness
- fainting, epileptic fits, changes or loss of taste
- mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue
- running nose
- skin lesions, dry skin
- stiffness of muscles or joints, joint pain with or without inflammation
- changes in some values of your blood cells or chemistry. These can be seen in the results of 

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some 
white blood cells.

Some side effects are typical for anti-HIV medicines in the same family as PREZISTA. These are:
- muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been 

serious.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


148

5. How to store PREZISTA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the bottle after 
EXP. The expiry date refers to the last day of that month.

Do not store above 30°C.
Do not refrigerate or freeze. Avoid exposure to excessive heat.
Store in the original container.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away any medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What PREZISTA contains
- The active substance is darunavir. Each milliliter contains 100 milligram of darunavir (as 

ethanolate).
- The other ingredients are hydroxypropylcellulose, microcrystalline cellulose and carmellose 

sodium, citric acid monohydrate, sucralose, strawberry cream flavour, masking flavour, sodium 
methyl parahydroxybenzoate (E219), hydrocholoric acid (for pH adjustment), purified water.

- This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially ‘sodium-free’.

What PREZISTA looks like and contents of the pack
White to off-white opaque oral suspension. Provided in a 200 ml amber glass bottle with 
polypropylene child resistant closure and a 6 ml low density polyethylene (LDPE) oral dosing pipette 
with 0.2 ml gradations. The bottle neck is filled with a low density polyethylene (LDPE) insert that 
accommodates the dosing pipette. Do not use the oral dosing pipette for any other medicines.
PREZISTA is also available as 75 milligram, 150 milligram, 400 milligram, 600 milligram and 
800 milligram film-coated tablets.

Marketing Authorisation Holder
Janssen-Cilag International NV, Turnhoutseweg 30, 2340 Beerse, Belgium

Manufacturer
Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: +32 14 64 94 11
janssen@jacbe.jnj.com

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00
jjsafety@its.jnj.com

Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: +32 14 64 94 11
janssen@jacbe.jnj.com



149

Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858
janssenhu@its.jnj.com

Danmark
Janssen-Cilag A/S
Tlf: +45 4594 8282
jacdk@its.jnj.com

Malta
AM MANGION LTD
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955 955
jancil@its.jnj.com

Nederland
Janssen-Cilag B.V.
Tel: +31 76 711 1111
janssen@jacnl.jnj.com

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00
jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00
contacto@its.jnj.com

Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.: +48 22 237 60 00

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800

Ireland
Janssen Sciences Ireland UC
Tel: +353 1 800 709 122

Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com

Ísland
Janssen-Cilag AB
c/o Vistor hf.
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Tel: 800.688.777 / +39 02 2510 1
janssenita@its.jnj.com

Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300
jacfi@its.jnj.com

mailto:janssenita@its.jnj.com


150

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Tfn: +46 8 626 50 00
jacse@its.jnj.com

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Janssen-Cilag Ltd.
Tel: +44 1 494 567 444

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

http://www.ema.europa.eu/


151

Package leaflet: Information for the user

PREZISTA 75 mg film-coated tablets
darunavir

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What PREZISTA is and what it is used for
2. What you need to know before you take PREZISTA
3. How to take PREZISTA
4. Possible side effects
5. How to store PREZISTA
6. Contents of the pack and other information

1. What PREZISTA is and what it is used for

What is PREZISTA?
PREZISTA contains the active substance darunavir. PREZISTA is an antiretroviral medicine used in 
the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of medicines 
called protease inhibitors. PREZISTA works by reducing the amount of HIV in your body. This will 
improve your immune system and reduces the risk of developing illnesses linked to HIV infection.

What it is used for?
PREZISTA is used to treat adults and children of 3 years of age and above, and at least 15 kilogram 
body weight who are infected by HIV and who have already used other antiretroviral medicines.

PREZISTA must be taken in combination with a low dose of ritonavir and other anti-HIV medicines. 
Your doctor will discuss with you which combination of medicines is best for you.

2. What you need to know before you take PREZISTA

Do not take PREZISTA
- if you are allergic to darunavir or any of the other ingredients of this medicine (listed in section 

6) or to ritonavir.
- if you have severe liver problems. Ask your doctor if you are unsure about the severity of your 

liver disease. Some additional tests might be necessary.

Do not combine PREZISTA with any of the following medicines
If you are taking any of these, ask your doctor about switching to another medicine.

Medicine Purpose of the medicine
Avanafil to treat erectile dysfunction 
Astemizole or terfenadine to treat allergy symptoms
Triazolam and oral (taken by mouth) midazolam to help you sleep and/or relieve anxiety
Cisapride to treat some stomach conditions
Colchicine (if you have kidney and/or liver 
problems)

to treat gout or familial Mediterranean fever



152

Lurasidone, pimozide, quetiapine or sertindole to treat psychiatric conditions
Ergot alkaloids like ergotamine, 
dihydroergotamine, ergometrine and 
methylergonovine

to treat migraine headaches

Amiodarone, bepridil, dronedarone, ivabradine,
quinidine, ranolazine 

to treat certain heart disorders e.g. abnormal 
heart beat

Lovastatin, simvastatin and lomitapide to lower cholesterol levels
Rifampicin to treat some infections such as tuberculosis
The combination product lopinavir/ritonavir this anti-HIV medicine belongs to the same class 

as PREZISTA
Elbasvir/grazoprevir to treat hepatitis C infection
Alfuzosin to treat enlarged prostate
Sildenafil to treat high blood pressure in the pulmonary 

circulation
Dabigatran, ticagrelor to help stop the clumping of platelets in the 

treatment of patients with a history of a heart 
attack

Naloxegol to treat opioid induced constipation
Dapoxetine to treat premature ejaculation
Domperidone to treat nausea and vomiting

Do not combine PREZISTA with products that contain St John’s wort (Hypericum perforatum).

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking PREZISTA.

PREZISTA is not a cure for HIV infection. You can still pass on HIV when taking this medicine, 
although the risk is lowered by effective antiretroviral therapy. Discuss with your physician the 
precautions needed to avoid infecting other people.

People taking PREZISTA may still develop infections or other illnesses associated with HIV infection. 
You must keep in regular contact with your doctor.

People taking PREZISTA may develop a skin rash. Infrequently a rash may become severe or 
potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking PREZISTA and raltegravir (for HIV infection), rashes (generally mild or moderate) 
may occur more frequently than in patients taking either medicine separately.

Tell your doctor about your situation BEFORE and DURING your treatment
Make sure that you check the following points and tell your doctor if any of these apply to you.
- Tell your doctor if you have had problems with your liver before, including hepatitis B or C

infection. Your doctor may evaluate how severe your liver disease is before deciding if you can 
take PREZISTA.

- Tell your doctor if you have diabetes. PREZISTA might increase sugar levels in the blood.
- Tell your doctor immediately if you notice any symptoms of infection (for example enlarged 

lymph nodes and fever). In some patients with advanced HIV infection and a history of 
opportunistic infection, signs and symptoms of inflammation from previous infections may 
occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an 
improvement in the body’s immune response, enabling the body to fight infections that may 
have been present with no obvious symptoms.

- In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection. Autoimmune disorders may occur many months after 
the start of treatment. If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 



153

the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment.

- Tell your doctor if you have haemophilia. PREZISTA might increase the risk of bleeding.
- Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).
- Tell your doctor if you notice any musculoskeletal problems. Some patients taking 

combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of 
bone tissue caused by loss of blood supply to the bone). The length of combination 
antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, 
higher body mass index, among others, may be some of the many risk factors for developing 
this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, 
knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor.

Elderly
PREZISTA has only been used in limited numbers of patients 65 years or older. If you belong to this 
age group, please discuss with your doctor if you can use PREZISTA.

Children
PREZISTA is not for use in children younger than 3 years of age or weighing less than 15 kilograms.

Other medicines and PREZISTA
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

There are some medicines that you must not combine with PREZISTA. These are mentioned above 
under the heading ‘Do not combine PREZISTA with any of the following medicines:’

In most cases, PREZISTA can be combined with anti-HIV medicines belonging to another class [e.g. 
NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase 
inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. PREZISTA with ritonavir has not been 
tested with all PIs (protease inhibitors) and must not be used with other HIV PIs. In some cases dosage 
of other medicines might need to be changed. Therefore always tell your doctor if you take other 
anti-HIV medicines and follow your doctor’s instruction carefully on which medicines can be 
combined.

The effects of PREZISTA might be reduced if you take any of the following products. Tell your 
doctor if you take:
- Phenobarbital, phenytoin (to prevent seizures)
- Dexamethasone (corticosteroid)
- Efavirenz (HIV infection)
- Boceprevir (hepatitis C infection)
- Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis)
- Saquinavir (HIV infection).

The effects of other medicines might be influenced if you take PREZISTA. Tell your doctor if you 
take:
- Amlodipine, diltiazem, disopyramide, carvedilol, felodipine, flecainide, lidocaine, metoprolol,

mexiletine, nifedipine, nicardipine, propafenone, timolol, verapamil (for heart disease) as the 
therapeutic effect or side effects of these medicines may be increased.

- Apixaban, edoxaban, rivaroxaban, warfarin (to reduce clotting of the blood) as their therapeutic 
effect or side effects may be altered; your doctor may have to check your blood.

- Oestrogen-based hormonal contraceptives and hormonal replacement therapy. PREZISTA 
might reduce its effectiveness. When used for birth control, alternative methods of 
non-hormonal contraception are recommended.

- Ethinylestradiol/drospirenone. PREZISTA might increase the risk for elevated potassium levels 
by drospirenone.



154

- Atorvastatin, pravastatin, rosuvastatin (to lower cholesterol levels). The risk of muscle damage
might be increased. Your doctor will evaluate which cholesterol lowering regimen is best for 
your specific situation.

- Clarithromycin (antibiotic)
- Ciclosporin, everolimus, tacrolimus, sirolimus (for dampening down your immune system) as 

the therapeutic effect or side effects of these medicines might be increased. Your doctor might 
want to do some additional tests.

- Corticosteroids including betamethasone, budesonide, fluticasone, mometasone, prednisone, 
triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel 
diseases, inflammatory conditions of the eyes, joints and muscles and other inflammatory 
conditions. If alternatives cannot be used, its use should only take place after medical evaluation 
and under close monitoring by your doctor for corticosteroid side effects.

- Buprenorphine/naloxone (medicines to treat opioid dependence)
- Salmeterol (medicine to treat asthma)
- Artemether/lumefantrine (a combination medicine to treat malaria)
- Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer)
- Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder 

called pulmonary arterial hypertension)
- Glecaprevir/pibrentasvir, simeprevir (to treat hepatitis C infection)
- Fentanyl, oxycodone, tramadol (to treat pain)
- Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or PREZISTA’s 
therapeutic effect or side effects may be influenced when combined.
Tell your doctor if you take:
- Alfentanil (injectable strong and short-acting painkiller that is used for surgical procedures)
- Digoxin (to treat certain heart disorders)
- Clarithromycin (antibiotic)
- Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal 

infections). Voriconazole should only be taken after medical evaluation.
- Rifabutin (against bacterial infections)
- Sildenafil, vardenafil, tadalafil (for erectile dysfunction or high blood pressure in the pulmonary 

circulation)
- Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat 

depression and anxiety)
- Maraviroc (to treat HIV infection)
- Methadone (to treat opiate dependance)
- Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain)
- Colchicine (to treat gout or familial Mediterranean fever)
- Bosentan (to treat high blood pressure in the pulmonary circulation)
- Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, 

zolpidem (sedative agents)
- Perphenazine, risperidone, thioridazine (to treat psychiatric conditions).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are 
taking.

PREZISTA with food and drink
See section 3 ‘How to take PREZISTA.’

Pregnancy and breast-feeding
Tell your doctor immediately if you are pregnant, planning to become pregnant or if you are 
breast-feeding. Pregnant or breast-feeding mothers should not take PREZISTA with ritonavir unless 
specifically directed by the doctor. Pregnant or breast-feeding mothers should not take PREZISTA 
with cobicistat.



155

It is recommended that HIV infected women must not breast-feed their infants because of both the 
possibility of your baby becoming infected with HIV through your breast milk and because of the 
unknown effects of the medicine on your baby.

Driving and using machines
Do not operate machines or drive if you feel dizzy after taking PREZISTA.

3. How to take PREZISTA

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has 
told you. Check with your doctor, pharmacist or nurse if you are not sure.
Even if you feel better, do not stop taking PREZISTA and ritonavir without talking to your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be 
stopped without instruction of the doctor.

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have not taken 
antiretroviral medicines before (your child’s doctor will determine this)
The doctor will work out the right once daily dose based on the weight of the child (see table below). 
This dose must not exceed the recommended adult dose, which is 800 milligram PREZISTA together 
with 100 milligram ritonavir once a day.
The doctor will inform you on how much PREZISTA tablets and how much ritonavir (capsules, 
tablets or solution) the child must take.

Weight One PREZISTA dose is One ritonavira dose is
between 15 and 30 kilograms 600 milligram 100 milligram
between 30 and 40 kilograms 675 milligram 100 milligram
more than 40 kilograms 800 milligram 100 milligram
a

ritonavir oral solution: 80 milligram per milliliter

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have taken 
antiretroviral medicines before (your child’s doctor will determine this)
The doctor will work out the right dose based on the weight of the child (see table below). The doctor 
will determine if once daily dosing or twice daily dosing is appropriate for the child. This dose must 
not exceed the recommended adult dose, which is 600 milligram PREZISTA together with
100 milligram ritonavir two times per day or 800 milligram PREZISTA together with 100 milligram 
ritonavir once a day.
The doctor will inform you on how many PREZISTA tablets and how much ritonavir (capsules, 
tablets or solution) the child must take. Tablets of other strengths are available and your doctor may 
have prescribed a certain combination of tablets to construct the appropriate dosing regimen.
PREZISTA oral suspension is also available. Your doctor will determine whether PREZISTA tablets 
or oral suspension is right for the child.

Twice daily dosing
Weight One dose is

between 15 and 30 kilograms 375 milligram PREZISTA + 50 milligram ritonavir twice a day
between 30 and 40 kilograms 450 milligram PREZISTA + 60 milligram ritonavir twice a day
more than 40 kilograms* 600 milligram PREZISTA + 100 milligram ritonavir twice a day
* For children aged 12 or more and weighing at least 40 kilograms, your child’s doctor will determine if PREZISTA 

800 milligram once daily dosing may be used. This cannot be administered with these 75 milligram tablets. Other 
strengths of PREZISTA are available.

Once daily dosing
Weight One PREZISTA dose is One ritonavira dose is

between 15 and 30 kilograms 600 milligram 100 milligram
between 30 and 40 kilograms 675 milligram 100 milligram



156

more than 40 kilograms 800 milligram 100 milligram
a

ritonavir oral solution: 80 milligram per milliliter

Instructions for children
- The child must take PREZISTA always together with ritonavir. PREZISTA cannot work 

properly without ritonavir.
- The child must take the appropriate doses of PREZISTA and ritonavir two times per day or once 

a day. If prescribed PREZISTA twice daily the child must take one dose in the morning, and 
one dose in the evening. Your child’s doctor will determine the appropriate dosing regimen for 
your child.

- The child must take PREZISTA with food. PREZISTA cannot work properly without food. The 
type of food is not important.

- The child must swallow the tablets with a drink such as water or milk.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine 
this)
You will require a different dose of PREZISTA which cannot be administered with these 75 milligram 
tablets. Other strengths of PREZISTA are available.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this)
The dose is either:
- 600 milligram PREZISTA together with 100 milligram ritonavir twice daily.

OR
- 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet 

containing 800 milligram of PREZISTA) together with 100 milligram ritonavir once daily. 
PREZISTA 400 milligram and 800 milligram tablets are only to be used to construct the once 
daily 800 milligram regimen.

Please discuss with your doctor which dose is right for you.

Instructions for adults
- Take PREZISTA always together with ritonavir. PREZISTA cannot work properly without 

ritonavir.
- In the morning, take 600 milligram PREZISTA together with 100 milligram ritonavir.
- In the evening, take 600 milligram PREZISTA together with 100 milligram ritonavir.
- Take PREZISTA with food. PREZISTA cannot work properly without food. The type of food is 

not important.
- Swallow the tablets with a drink such as water or milk.
- PREZISTA 75 milligram and 150 milligram tablets and 100 milligram per milliliter oral 

suspension have been developed for use in children, but can also be used in adults in some 
cases.

Removing the child resistant cap
The plastic bottle comes with a child resistant cap and must be opened as 
follows:
- Push the plastic screw cap down while turning it counter clockwise.
- Remove the unscrewed cap.

If you take more PREZISTA than you should
Contact your doctor, pharmacist or nurse immediately.

If you forget to take PREZISTA
If you notice within 6 hours, you must take the tablets immediately. Always take with ritonavir and 
food. If you notice after 6 hours, then skip the intake and take the next doses as usual. Do not take a 
double dose to make up for a forgotten dose.



157

Do not stop taking PREZISTA without talking to your doctor first
Anti-HIV medicines may make you feel better. Even when you feel better, do not stop taking 
PREZISTA. Talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor if you develop any of the following side effects.

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests 
before you start PREZISTA. If you have chronic hepatitis B or C infection, your doctor should check 
your blood tests more often because you have an increased chance of developing liver problems. Talk 
to your doctor about the signs and symptoms of liver problems. These may include yellowing of your 
skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), 
nausea, vomiting, loss of appetite, or pain, aching, or pain and discomfort on your right side below 
your ribs.

Skin rash (more often when used in combination with raltegravir), itching. The rash is usually mild to 
moderate. A skin rash might also be a symptom of a rare severe situation. It is therefore important to
talk to your doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms 
or whether PREZISTA must be stopped.

Other severe side effects were diabetes (common) and inflammation of the pancreas (uncommon).

Very common side effects (may affect more than 1 in 10 people)
- diarrhoea.

Common side effects (may affect up to 1 in 10 people)
- vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence
- headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of 

strength, difficulty falling asleep.

Uncommon side effects (may affect up to 1 in 100 people)
- chest pain, changes in electrocardiogram, rapid heart beating
- decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory, 

problems with your balance
- difficulty breathing, cough, nosebleed, throat irritation
- inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the 

abdomen, constipation, belching
- kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of 

urine, sometimes at night
- urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, 

excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails
- muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis
- slowing down of the thyroid gland function. This can be seen in a blood test.
- high blood pressure, flushing
- red or dry eyes
- fever, swelling of lower limbs due to fluids, malaise, irritability, pain
- symptoms of infection, herpes simplex



158

- erectile dysfunction, enlargement of breasts
- sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive

Rare side effects (may affect up to 1 in 1,000 people)
- a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of 

the face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver, 
kidney or lung]

- heart attack, slow heart beating, palpitations
- visual disturbance
- chills, feeling abnormal
- a feeling of confusion or disorientation, altered mood, restlessness
- fainting, epileptic fits, changes or loss of taste
- mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue
- running nose
- skin lesions, dry skin
- stiffness of muscles or joints, joint pain with or without inflammation
- changes in some values of your blood cells or chemistry. These can be seen in the results of 

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some 
white blood cells.

Some side effects are typical for anti-HIV medicines in the same family as PREZISTA. These are:
- muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been 

serious.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store PREZISTA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the bottle after 
EXP. The expiry date refers to the last day of that month.

PREZISTA does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away any medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What PREZISTA contains
- The active substance is darunavir. Each tablet contains 75 milligram of darunavir (as 

ethanolate).
- The other ingredients are microcrystalline cellulose, colloidal anhydrous silica, crospovidone, 

magnesium stearate. The film-coating contains poly(vinyl alcohol) - partially hydrolysed, 
macrogol 3350, titanium dioxide (E171), talc.

- This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially ‘sodium-free’.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


159

What PREZISTA looks like and contents of the pack
Film-coated, white, caplet shaped tablet, mentioning TMC on one side, 75 on the other side. 
480 tablets in a plastic bottle.
PREZISTA is also available as 150 milligram, 400 milligram, 600 milligram and 800 milligram 
film-coated tablets and 100 milligram per milliliter oral suspension.

Marketing Authorisation Holder
Janssen-Cilag International NV, Turnhoutseweg 30, 2340 Beerse, Belgium

Manufacturer
Janssen-Cilag SpA, Via C. Janssen, Borgo San Michele, 04100 Latina, Italy

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: +32 14 64 94 11
janssen@jacbe.jnj.com

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00
jjsafety@its.jnj.com

Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: +32 14 64 94 11
janssen@jacbe.jnj.com

Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858
janssenhu@its.jnj.com

Danmark
Janssen-Cilag A/S
Tlf: +45 4594 8282
jacdk@its.jnj.com

Malta
AM MANGION LTD
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955 955
jancil@its.jnj.com

Nederland
Janssen-Cilag B.V.
Tel: +31 76 711 1111
janssen@jacnl.jnj.com

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00
jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00
contacto@its.jnj.com

Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.: +48 22 237 60 00



160

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800

Ireland
Janssen Sciences Ireland UC
Tel: +353 1 800 709 122

Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com

Ísland
Janssen-Cilag AB
c/o Vistor hf.
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Tel: 800.688.777 / +39 02 2510 1
janssenita@its.jnj.com

Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300
jacfi@its.jnj.com

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Tfn: +46 8 626 50 00
jacse@its.jnj.com

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Janssen-Cilag Ltd.
Tel: +44 1 494 567 444

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

http://www.ema.europa.eu/
mailto:janssenita@its.jnj.com


161

Package leaflet: Information for the user

PREZISTA 150 mg film-coated tablets
darunavir

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What PREZISTA is and what it is used for
2. What you need to know before you take PREZISTA
3. How to take PREZISTA
4. Possible side effects
5. How to store PREZISTA
6. Contents of the pack and other information

1. What PREZISTA is and what it is used for

What is PREZISTA?
PREZISTA contains the active substance darunavir. PREZISTA is an antiretroviral medicine used in 
the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of medicines 
called protease inhibitors. PREZISTA works by reducing the amount of HIV in your body. This will 
improve your immune system and reduces the risk of developing illnesses linked to HIV infection.

What it is used for?
PREZISTA is used to treat adults and children of 3 years of age and above, and at least 15 kilogram 
body weight who are infected by HIV and who have already used other antiretroviral medicines.

PREZISTA must be taken in combination with a low dose of ritonavir and other anti-HIV medicines. 
Your doctor will discuss with you which combination of medicines is best for you.

2. What you need to know before you take PREZISTA

Do not take PREZISTA
- if you are allergic to darunavir or any of the other ingredients of this medicine (listed in section 

6) or to ritonavir.
- if you have severe liver problems. Ask your doctor if you are unsure about the severity of your 

liver disease. Some additional tests might be necessary.

Do not combine PREZISTA with any of the following medicines
If you are taking any of these, ask your doctor about switching to another medicine.

Medicine Purpose of the medicine
Avanafil to treat erectile dysfunction 
Astemizole or terfenadine to treat allergy symptoms
Triazolam and oral (taken by mouth) midazolam to help you sleep and/or relieve anxiety
Cisapride to treat some stomach conditions
Colchicine (if you have kidney and/or liver 
problems)

to treat gout or familial Mediterranean fever



162

Lurasidone, pimozide, quetiapine or sertindole to treat psychiatric conditions
Ergot alkaloids like ergotamine, 
dihydroergotamine, ergometrine and 
methylergonovine

to treat migraine headaches

Amiodarone, bepridil, dronedarone, ivabradine,
quinidine, ranolazine 

to treat certain heart disorders e.g. abnormal 
heart beat

Lovastatin, simvastatin and lomitapide to lower cholesterol levels
Rifampicin to treat some infections such as tuberculosis
The combination product lopinavir/ritonavir this anti-HIV medicine belongs to the same class 

as PREZISTA
Elbasvir/grazoprevir to treat hepatitis C infection
Alfuzosin to treat enlarged prostate
Sildenafil to treat high blood pressure in the pulmonary 

circulation
Dabigatran, ticagrelor to help stop the clumping of platelets in the 

treatment of patients with a history of a heart 
attack

Naloxegol to treat opioid induced constipation
Dapoxetine to treat premature ejaculation
Domperidone to treat nausea and vomiting

Do not combine PREZISTA with products that contain St John’s wort (Hypericum perforatum).

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking PREZISTA.

PREZISTA is not a cure for HIV infection. You can still pass on HIV when taking this medicine, 
although the risk is lowered by effective antiretroviral therapy. Discuss with your physician the 
precautions needed to avoid infecting other people.

People taking PREZISTA may still develop infections or other illnesses associated with HIV infection. 
You must keep in regular contact with your doctor.

People taking PREZISTA may develop a skin rash. Infrequently a rash may become severe or 
potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking PREZISTA and raltegravir (for HIV infection), rashes (generally mild or moderate) 
may occur more frequently than in patients taking either medicine separately.

Tell your doctor about your situation BEFORE and DURING your treatment
Make sure that you check the following points and tell your doctor if any of these apply to you.
- Tell your doctor if you have had problems with your liver before, including hepatitis B or C

infection. Your doctor may evaluate how severe your liver disease is before deciding if you can 
take PREZISTA.

- Tell your doctor if you have diabetes. PREZISTA might increase sugar levels in the blood.
- Tell your doctor immediately if you notice any symptoms of infection (for example enlarged 

lymph nodes and fever). In some patients with advanced HIV infection and a history of 
opportunistic infection, signs and symptoms of inflammation from previous infections may 
occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an 
improvement in the body’s immune response, enabling the body to fight infections that may 
have been present with no obvious symptoms.

- In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection. Autoimmune disorders may occur many months after 
the start of treatment. If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 



163

the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment.

- Tell your doctor if you have haemophilia. PREZISTA might increase the risk of bleeding.
- Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).
- Tell your doctor if you notice any musculoskeletal problems. Some patients taking 

combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of 
bone tissue caused by loss of blood supply to the bone). The length of combination 
antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, 
higher body mass index, among others, may be some of the many risk factors for developing 
this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, 
knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor.

Elderly
PREZISTA has only been used in limited numbers of patients 65 years or older. If you belong to this 
age group, please discuss with your doctor if you can use PREZISTA.

Children
PREZISTA is not for use in children younger than 3 years of age or weighing less than 15 kilograms.

Other medicines and PREZISTA
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

There are some medicines that you must not combine with PREZISTA. These are mentioned above 
under the heading ‘Do not combine PREZISTA with any of the following medicines:’

In most cases, PREZISTA can be combined with anti-HIV medicines belonging to another class [e.g. 
NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase 
inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. PREZISTA with ritonavir has not been 
tested with all PIs (protease inhibitors) and must not be used with other HIV PIs. In some cases dosage 
of other medicines might need to be changed. Therefore always tell your doctor if you take other 
anti-HIV medicines and follow your doctor’s instruction carefully on which medicines can be 
combined.

The effects of PREZISTA might be reduced if you take any of the following products. Tell your 
doctor if you take:
- Phenobarbital, phenytoin (to prevent seizures)
- Dexamethasone (corticosteroid)
- Efavirenz (HIV infection)
- Boceprevir (hepatitis C infection)
- Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis)
- Saquinavir (HIV infection).

The effects of other medicines might be influenced if you take PREZISTA. Tell your doctor if you 
take:
- Amlodipine, diltiazem, disopyramide, carvedilol, felodipine, flecainide, lidocaine, metoprolol,

mexiletine, nifedipine, nicardipine, propafenone, timolol, verapamil (for heart disease) as the 
therapeutic effect or side effects of these medicines may be increased.

- Apixaban, edoxaban, rivaroxaban, warfarin (to reduce clotting of the blood) as their therapeutic 
effect or side effects may be altered; your doctor may have to check your blood.

- Oestrogen-based hormonal contraceptives and hormonal replacement therapy. PREZISTA 
might reduce its effectiveness. When used for birth control, alternative methods of 
non-hormonal contraception are recommended.

- Ethinylestradiol/drospirenone. PREZISTA might increase the risk for elevated potassium levels 
by drospirenone.



164

- Atorvastatin, pravastatin, rosuvastatin (to lower cholesterol levels). The risk of muscle damage
might be increased. Your doctor will evaluate which cholesterol lowering regimen is best for 
your specific situation.

- Clarithromycin (antibiotic)
- Ciclosporin, everolimus, tacrolimus, sirolimus (for dampening down your immune system) as 

the therapeutic effect or side effects of these medicines might be increased. Your doctor might 
want to do some additional tests.

- Corticosteroids including betamethasone, budesonide, fluticasone, mometasone, prednisone, 
triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel 
diseases, inflammatory conditions of the eyes, joints and muscles and other inflammatory 
conditions. If alternatives cannot be used, its use should only take place after medical evaluation 
and under close monitoring by your doctor for corticosteroid side effects.

- Buprenorphine/naloxone (medicines to treat opioid dependence)
- Salmeterol (medicine to treat asthma)
- Artemether/lumefantrine (a combination medicine to treat malaria)
- Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer)
- Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder 

called pulmonary arterial hypertension)
- Glecaprevir/pibrentasvir, simeprevir (to treat hepatitis C infection)
- Fentanyl, oxycodone, tramadol (to treat pain)
- Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or PREZISTA’s 
therapeutic effect or side effects may be influenced when combined.
Tell your doctor if you take:
- Alfentanil (injectable strong and short-acting painkiller that is used for surgical procedures)
- Digoxin (to treat certain heart disorders)
- Clarithromycin (antibiotic)
- Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal 

infections). Voriconazole should only be taken after medical evaluation.
- Rifabutin (against bacterial infections)
- Sildenafil, vardenafil, tadalafil (for erectile dysfunction or high blood pressure in the pulmonary 

circulation)
- Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat 

depression and anxiety)
- Maraviroc (to treat HIV infection)
- Methadone (to treat opiate dependance)
- Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain)
- Colchicine (to treat gout or familial Mediterranean fever)
- Bosentan (to treat high blood pressure in the pulmonary circulation)
- Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, 

zolpidem (sedative agents)
- Perphenazine, risperidone, thioridazine (to treat psychiatric conditions).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are 
taking.

PREZISTA with food and drink
See section 3 ‘How to take PREZISTA.’

Pregnancy and breast-feeding
Tell your doctor immediately if you are pregnant, planning to become pregnant or if you are 
breast-feeding. Pregnant or breast-feeding mothers should not take PREZISTA with ritonavir unless 
specifically directed by the doctor. Pregnant or breast-feeding mothers should not take PREZISTA 
with cobicistat.



165

It is recommended that HIV infected women must not breast-feed their infants because of both the 
possibility of your baby becoming infected with HIV through your breast milk and because of the 
unknown effects of the medicine on your baby.

Driving and using machines
Do not operate machines or drive if you feel dizzy after taking PREZISTA.

3. How to take PREZISTA

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has 
told you. Check with your doctor, pharmacist or nurse if you are not sure.
Even if you feel better, do not stop taking PREZISTA and ritonavir without talking to your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be 
stopped without instruction of the doctor.

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have not taken 
antiretroviral medicines before (your child’s doctor will determine this)
The doctor will work out the right once daily dose based on the weight of the child (see table below). 
This dose must not exceed the recommended adult dose, which is 800 milligram PREZISTA together 
with 100 milligram ritonavir once a day.
The doctor will inform you on how much PREZISTA tablets and how much ritonavir (capsules, 
tablets or solution) the child must take.

Weight One PREZISTA dose is One ritonavira dose is
between 15 and 30 kilograms 600 milligram 100 milligram
between 30 and 40 kilograms 675 milligram 100 milligram
more than 40 kilograms 800 milligram 100 milligram
a

ritonavir oral solution: 80 milligram per milliliter

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have taken 
antiretroviral medicines before (your child’s doctor will determine this)
The doctor will work out the right dose based on the weight of the child (see table below). The doctor 
will determine if once daily dosing or twice daily dosing is appropriate for the child. This dose must 
not exceed the recommended adult dose, which is 600 milligram PREZISTA together with
100 milligram ritonavir two times per day or 800 milligram PREZISTA together with 100 milligram 
ritonavir once a day.
The doctor will inform you on how many PREZISTA tablets and how much ritonavir (capsules, 
tablets or solution) the child must take. Tablets of other strengths are available and your doctor may 
have prescribed a certain combination of tablets to construct the appropriate dosing regimen.
PREZISTA oral suspension is also available. Your doctor will determine whether PREZISTA tablets 
or oral suspension is right for the child.

Twice daily dosing
Weight One dose is

between 15 and 30 kilograms 375 milligram PREZISTA + 50 milligram ritonavir twice a day
between 30 and 40 kilograms 450 milligram PREZISTA + 60 milligram ritonavir twice a day
more than 40 kilograms* 600 milligram PREZISTA + 100 milligram ritonavir twice a day
* For children aged 12 or more and weighing at least 40 kilograms, your child’s doctor will determine if PREZISTA 

800 milligram once daily dosing may be used. This cannot be administered with these 150 milligram tablets. Other 
strengths of PREZISTA are available.

Once daily dosing
Weight One PREZISTA dose is One ritonavira dose is

between 15 and 30 kilograms 600 milligram 100 milligram
between 30 and 40 kilograms 675 milligram 100 milligram



166

more than 40 kilograms 800 milligram 100 milligram
a

ritonavir oral solution: 80 milligram per milliliter

Instructions for children
- The child must take PREZISTA always together with ritonavir. PREZISTA cannot work 

properly without ritonavir.
- The child must take the appropriate doses of PREZISTA and ritonavir two times per day or once 

a day. If prescribed PREZISTA twice daily the child must take one dose in the morning, and 
one dose in the evening. Your child’s doctor will determine the appropriate dosing regimen for 
your child.

- The child must take PREZISTA with food. PREZISTA cannot work properly without food. The 
type of food is not important.

- The child must swallow the tablets with a drink such as water or milk.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine 
this)
You will require a different dose of PREZISTA which cannot be administered with these
150 milligram tablets. Other strengths of PREZISTA are available.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this)
The dose is either:
- 600 milligram PREZISTA together with 100 milligram ritonavir twice daily.

OR
- 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet 

containing 800 milligram of PREZISTA) together with 100 milligram ritonavir once daily. 
PREZISTA 400 milligram and 800 milligram tablets are only to be used to construct the once 
daily 800 milligram regimen.

Please discuss with your doctor which dose is right for you.

Instructions for adults
- Take PREZISTA always together with ritonavir. PREZISTA cannot work properly without 

ritonavir.
- In the morning, take 600 milligram PREZISTA together with 100 milligram ritonavir.
- In the evening, take 600 milligram PREZISTA together with 100 milligram ritonavir.
- Take PREZISTA with food. PREZISTA cannot work properly without food. The type of food is 

not important.
- Swallow the tablets with a drink such as water or milk.
- PREZISTA 75 milligram and 150 milligram tablets and 100 milligram per milliliter oral 

suspension have been developed for use in children, but can also be used in adults in some 
cases.

Removing the child resistant cap
The plastic bottle comes with a child resistant cap and must be opened as 
follows:
- Push the plastic screw cap down while turning it counter clockwise.
- Remove the unscrewed cap.

If you take more PREZISTA than you should
Contact your doctor, pharmacist or nurse immediately.

If you forget to take PREZISTA
If you notice within 6 hours, you must take the tablets immediately. Always take with ritonavir and 
food. If you notice after 6 hours, then skip the intake and take the next doses as usual. Do not take a 
double dose to make up for a forgotten dose.



167

Do not stop taking PREZISTA without talking to your doctor first
Anti-HIV medicines may make you feel better. Even when you feel better, do not stop taking 
PREZISTA. Talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor if you develop any of the following side effects.

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests 
before you start PREZISTA. If you have chronic hepatitis B or C infection, your doctor should check 
your blood tests more often because you have an increased chance of developing liver problems. Talk 
to your doctor about the signs and symptoms of liver problems. These may include yellowing of your 
skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), 
nausea, vomiting, loss of appetite, or pain, aching, or pain and discomfort on your right side below 
your ribs.

Skin rash (more often when used in combination with raltegravir), itching. The rash is usually mild to 
moderate. A skin rash might also be a symptom of a rare severe situation. It is therefore important to 
talk to your doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms 
or whether PREZISTA must be stopped.

Other severe side effects were diabetes (common) and inflammation of the pancreas (uncommon).

Very common side effects (may affect more than 1 in 10 people)
- diarrhoea.

Common side effects (may affect up to 1 in 10 people)
- vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence
- headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of 

strength, difficulty falling asleep.

Uncommon side effects (may affect up to 1 in 100 people)
- chest pain, changes in electrocardiogram, rapid heart beating
- decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory, 

problems with your balance
- difficulty breathing, cough, nosebleed, throat irritation
- inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the 

abdomen, constipation, belching
- kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of 

urine, sometimes at night
- urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, 

excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails
- muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis
- slowing down of the thyroid gland function. This can be seen in a blood test.
- high blood pressure, flushing
- red or dry eyes
- fever, swelling of lower limbs due to fluids, malaise, irritability, pain
- symptoms of infection, herpes simplex



168

- erectile dysfunction, enlargement of breasts
- sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive

Rare side effects (may affect up to 1 in 1,000 people)
- a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of 

the face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver, 
kidney or lung]

- heart attack, slow heart beating, palpitations
- visual disturbance
- chills, feeling abnormal
- a feeling of confusion or disorientation, altered mood, restlessness
- fainting, epileptic fits, changes or loss of taste
- mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue
- running nose
- skin lesions, dry skin
- stiffness of muscles or joints, joint pain with or without inflammation
- changes in some values of your blood cells or chemistry. These can be seen in the results of 

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some 
white blood cells.

Some side effects are typical for anti-HIV medicines in the same family as PREZISTA. These are:
- muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been 

serious.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store PREZISTA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the bottle after 
EXP. The expiry date refers to the last day of that month.

PREZISTA does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away any medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What PREZISTA contains
- The active substance is darunavir. Each tablet contains 150 milligram of darunavir (as 

ethanolate).
- The other ingredients are microcrystalline cellulose, colloidal anhydrous silica, crospovidone, 

magnesium stearate. The film-coating contains poly(vinyl alcohol) - partially hydrolysed, 
macrogol 3350, titanium dioxide (E171), talc.

- This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially ‘sodium-free’. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


169

What PREZISTA looks like and contents of the pack
Film-coated, white, oval shaped tablet, mentioning TMC on one side, 150 on the other side. 
240 tablets in a plastic bottle.
PREZISTA is also available as 75 milligram, 400 milligram, 600 milligram and 800 milligram 
film-coated tablets and 100 milligram per milliliter oral suspension.

Marketing Authorisation Holder
Janssen-Cilag International NV, Turnhoutseweg 30, 2340 Beerse, Belgium

Manufacturer
Janssen-Cilag SpA, Via C. Janssen, Borgo San Michele, 04100 Latina, Italy

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: +32 14 64 94 11
janssen@jacbe.jnj.com

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00
jjsafety@its.jnj.com

Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: +32 14 64 94 11
janssen@jacbe.jnj.com

Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858
janssenhu@its.jnj.com

Danmark
Janssen-Cilag A/S
Tlf: +45 4594 8282
jacdk@its.jnj.com

Malta
AM MANGION LTD
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955 955
jancil@its.jnj.com

Nederland
Janssen-Cilag B.V.
Tel: +31 76 711 1111
janssen@jacnl.jnj.com

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00
jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00
contacto@its.jnj.com

Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.: +48 22 237 60 00



170

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800

Ireland
Janssen Sciences Ireland UC
Tel: +353 1 800 709 122

Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com

Ísland
Janssen-Cilag AB
c/o Vistor hf.
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Tel: 800.688.777 / +39 02 2510 1
janssenita@its.jnj.com

Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300
jacfi@its.jnj.com

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Tfn: +46 8 626 50 00
jacse@its.jnj.com

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Janssen-Cilag Ltd.
Tel: +44 1 494 567 444

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

http://www.ema.europa.eu/
mailto:janssenita@its.jnj.com


171

Package leaflet: Information for the user

PREZISTA 400 mg film-coated tablets
darunavir

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What PREZISTA is and what it is used for
2. What you need to know before you take PREZISTA
3. How to take PREZISTA
4. Possible side effects
5. How to store PREZISTA
6. Contents of the pack and other information

1. What PREZISTA is and what it is used for

What is PREZISTA?
PREZISTA contains the active substance darunavir. PREZISTA is an antiretroviral medicine used in 
the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of medicines 
called protease inhibitors. PREZISTA works by reducing the amount of HIV in your body. This will 
improve your immune system and reduces the risk of developing illnesses linked to HIV infection.

What it is used for?
The PREZISTA 400 milligram tablet is used to treat adults and children (3 years of age and above, at 
least 40 kilograms body weight) who are infected by HIV and
- who have not used antiretroviral medicines before.
- in certain patients who have used antiretroviral medicines before (your doctor will determine 

this).

PREZISTA must be taken in combination with a low dose of cobicistat or ritonavir and other anti-HIV 
medicines. Your doctor will discuss with you which combination of medicines is best for you.

2. What you need to know before you take PREZISTA

Do not take PREZISTA
- if you are allergic to darunavir or any of the other ingredients of this medicine (listed in section 

6) or to cobicistat or ritonavir.
- if you have severe liver problems. Ask your doctor if you are unsure about the severity of your 

liver disease. Some additional tests might be necessary.

Do not combine PREZISTA with any of the following medicines
If you are taking any of these, ask your doctor about switching to another medicine.

Medicine Purpose of the medicine
Avanafil to treat erectile dysfunction 
Astemizole or terfenadine to treat allergy symptoms



172

Triazolam and oral (taken by mouth) midazolam to help you sleep and/or relieve anxiety
Cisapride to treat some stomach conditions
Colchicine (if you have kidney and/or liver 
problems)

to treat gout or familial Mediterranean fever

Lurasidone, pimozide, quetiapine or sertindole to treat psychiatric conditions
Ergot alkaloids like ergotamine, 
dihydroergotamine, ergometrine and 
methylergonovine

to treat migraine headaches

Amiodarone, bepridil, dronedarone, ivabradine,
quinidine, ranolazine 

to treat certain heart disorders e.g. abnormal 
heart beat

Lovastatin, simvastatin and lomitapide to lower cholesterol levels
Rifampicin to treat some infections such as tuberculosis
The combination product lopinavir/ritonavir this anti-HIV medicine belongs to the same class 

as PREZISTA
Elbasvir/grazoprevir to treat hepatitis C infection
Alfuzosin to treat enlarged prostate
Sildenafil to treat high blood pressure in the pulmonary 

circulation
Dabigatran, ticagrelor to help stop the clumping of platelets in the 

treatment of patients with a history of a heart 
attack

Naloxegol to treat opioid induced constipation
Dapoxetine to treat premature ejaculation
Domperidone to treat nausea and vomiting

Do not combine PREZISTA with products that contain St John’s wort (Hypericum perforatum).

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking PREZISTA.

PREZISTA is not a cure for HIV infection. You can still pass on HIV when taking this medicine, 
although the risk is lowered by effective antiretroviral therapy. Discuss with your physician the 
precautions needed to avoid infecting other people.

People taking PREZISTA may still develop infections or other illnesses associated with HIV infection. 
You must keep in regular contact with your doctor.

People taking PREZISTA may develop a skin rash. Infrequently a rash may become severe or 
potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking PREZISTA and raltegravir (for HIV infection), rashes (generally mild or moderate) 
may occur more frequently than in patients taking either medicine separately.

Tell your doctor about your situation BEFORE and DURING your treatment
Make sure that you check the following points and tell your doctor if any of these apply to you.
- Tell your doctor if you have had problems with your liver before, including hepatitis B or C

infection. Your doctor may evaluate how severe your liver disease is before deciding if you can 
take PREZISTA.

- Tell your doctor if you have diabetes. PREZISTA might increase sugar levels in the blood.
- Tell your doctor immediately if you notice any symptoms of infection (for example enlarged 

lymph nodes and fever). In some patients with advanced HIV infection and a history of 
opportunistic infection, signs and symptoms of inflammation from previous infections may 
occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an 
improvement in the body’s immune response, enabling the body to fight infections that may 
have been present with no obvious symptoms.



173

- In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection. Autoimmune disorders may occur many months after 
the start of treatment. If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 
the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek
necessary treatment.

- Tell your doctor if you have haemophilia. PREZISTA might increase the risk of bleeding.
- Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).
- Tell your doctor if you notice any musculoskeletal problems. Some patients taking 

combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of 
bone tissue caused by loss of blood supply to the bone). The length of combination 
antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, 
higher body mass index, among others, may be some of the many risk factors for developing 
this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, 
knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor.

Elderly
PREZISTA has only been used in limited numbers of patients 65 years or older. If you belong to this 
age group, please discuss with your doctor if you can use PREZISTA.

Children and adolescents
The PREZISTA 400 milligram tablet is not for use in children younger than 3 years of age or 
weighing less than 40 kilograms.

Other medicines and PREZISTA
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

There are some medicines that you must not combine with PREZISTA. These are mentioned above 
under the heading ‘Do not combine PREZISTA with any of the following medicines:’

In most cases, PREZISTA can be combined with anti-HIV medicines belonging to another class [e.g. 
NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase 
inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. PREZISTA with cobicistat or ritonavir has 
not been tested with all PIs (protease inhibitors) and must not be used with other HIV PIs. In some 
cases dosage of other medicines might need to be changed. Therefore always tell your doctor if you 
take other anti-HIV medicines and follow your doctor’s instruction carefully on which medicines can 
be combined.

The effects of PREZISTA might be reduced if you take any of the following products. Tell your 
doctor if you take:
- Phenobarbital, phenytoin (to prevent seizures)
- Dexamethasone (corticosteroid)
- Efavirenz (HIV infection)
- Boceprevir (hepatitis C infection)
- Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis)
- Saquinavir (HIV infection).

The effects of other medicines might be influenced if you take PREZISTA. Tell your doctor if you 
take:
- Amlodipine, diltiazem, disopyramide, carvedilol, felodipine, flecainide, lidocaine, metoprolol,

mexiletine, nifedipine, nicardipine, propafenone, timolol, verapamil (for heart disease) as the 
therapeutic effect or side effects of these medicines may be increased.

- Apixaban, edoxaban, rivaroxaban, warfarin (to reduce clotting of the blood) as their therapeutic 
effect or side effects may be altered; your doctor may have to check your blood.



174

- Oestrogen-based hormonal contraceptives and hormonal replacement therapy. PREZISTA 
might reduce its effectiveness. When used for birth control, alternative methods of 
non-hormonal contraception are recommended.

- Ethinylestradiol/drospirenone. PREZISTA might increase the risk for elevated potassium levels 
by drospirenone.

- Atorvastatin, pravastatin, rosuvastatin (to lower cholesterol levels). The risk of muscle damage
might be increased. Your doctor will evaluate which cholesterol lowering regimen is best for 
your specific situation.

- Clarithromycin (antibiotic)
- Ciclosporin, everolimus, tacrolimus, sirolimus (for dampening down your immune system) as 

the therapeutic effect or side effects of these medicines might be increased. Your doctor might 
want to do some additional tests.

- Corticosteroids including betamethasone, budesonide, fluticasone, mometasone, prednisone, 
triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel 
diseases, inflammatory conditions of the eyes, joints and muscles and other inflammatory 
conditions. If alternatives cannot be used, its use should only take place after medical evaluation 
and under close monitoring by your doctor for corticosteroid side effects.

- Buprenorphine/naloxone (medicines to treat opioid dependence)
- Salmeterol (medicine to treat asthma)
- Artemether/lumefantrine (a combination medicine to treat malaria)
- Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer)
- Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder 

called pulmonary arterial hypertension)
- Glecaprevir/pibrentasvir, simeprevir (to treat hepatitis C infection)
- Fentanyl, oxycodone, tramadol (to treat pain)
- Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or PREZISTA’s 
therapeutic effect or side effects may be influenced when combined.
Tell your doctor if you take:
- Alfentanil (injectable strong and short-acting painkiller that is used for surgical procedures)
- Digoxin (to treat certain heart disorders)
- Clarithromycin (antibiotic)
- Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal 

infections). Voriconazole should only be taken after medical evaluation.
- Rifabutin (against bacterial infections)
- Sildenafil, vardenafil, tadalafil (for erectile dysfunction or high blood pressure in the pulmonary 

circulation)
- Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat 

depression and anxiety)
- Maraviroc (to treat HIV infection)
- Methadone (to treat opiate dependance)
- Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain)
- Colchicine (to treat gout or familial Mediterranean fever)
- Bosentan (to treat high blood pressure in the pulmonary circulation)
- Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, 

zolpidem (sedative agents)
- Perphenazine, risperidone, thioridazine (to treat psychiatric conditions)
- Metformin (to treat type 2 diabetes).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are 
taking.

PREZISTA with food and drink
See section 3 ‘How to take PREZISTA.’



175

Pregnancy and breast-feeding
Tell your doctor immediately if you are pregnant, planning to become pregnant or if you are 
breast-feeding. Pregnant or breast-feeding mothers should not take PREZISTA with ritonavir unless 
specifically directed by the doctor. Pregnant or breast-feeding mothers should not take PREZISTA 
with cobicistat.

It is recommended that HIV infected women must not breast-feed their infants because of both the 
possibility of your baby becoming infected with HIV through your breast milk and because of the 
unknown effects of the medicine on your baby.

Driving and using machines
Do not operate machines or drive if you feel dizzy after taking PREZISTA.

PREZISTA tablets contain sunset yellow FCF (E110) which may cause allergic reactions.

3. How to take PREZISTA

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has 
told you. Check with your doctor, pharmacist or nurse if you are not sure.
Even if you feel better, do not stop taking PREZISTA and cobicistat or ritonavir without talking to 
your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be 
stopped without instruction of the doctor.

PREZISTA 400 milligram tablets are only to be used to construct the once daily 800 milligram 
regimen.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine 
this)
The usual dose of PREZISTA is 800 milligram (2 tablets containing 400 milligram of PREZISTA or 
1 tablet containing 800 milligram of PREZISTA) once daily.
You must take PREZISTA every day and always in combination with 150 milligram of cobicistat or
100 milligram of ritonavir and with food. PREZISTA cannot work properly without cobicistat or 
ritonavir and food. You must eat a meal or a snack within 30 minutes prior to taking your PREZISTA 
and cobicistat or ritonavir. The type of food is not important. Even if you feel better, do not stop taking 
PREZISTA and cobicistat or ritonavir without talking to your doctor.

Instructions for adults
- Take two 400 milligram tablets at the same time, once a day, every day.
- Take PREZISTA always together with 150 milligram of cobicistat or 100 milligram of ritonavir.
- Take PREZISTA with food.
- Swallow the tablets with a drink such as water or milk.
- Take your other HIV medicines used in combination with PREZISTA and cobicistat or ritonavir 

as recommended by your doctor.
- PREZISTA 100 milligram per milliliter oral suspension has been developed for use in children, 

but can also be used in adults in some cases.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this)
The dose is either:
- 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet 

containing 800 milligram of PREZISTA) together with 150 milligram cobicistat or 
100 milligram ritonavir once daily.
OR

- 600 milligram PREZISTA together with 100 milligram ritonavir twice daily.



176

Please discuss with your doctor which dose is right for you.

Dose for children 3 years of age and above, weighing more than 40 kilograms who have not 
taken antiretroviral medicines before (your child’s doctor will determine this)
- The usual dose of PREZISTA is 800 milligram (2 tablets containing 400 milligram of 

PREZISTA or 1 tablet containing 800 milligram of PREZISTA) together with 100 milligram 
ritonavir once daily.

Dose for children 3 years of age and above, weighing more than 40 kilograms who have taken 
antiretroviral medicines before (your child’s doctor will determine this)
The dose is either:
- 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet 

containing 800 milligram of PREZISTA) together with 100 milligram ritonavir once daily.
OR

- 600 milligram PREZISTA together with 100 milligram ritonavir twice daily.

Please discuss with your doctor which dose is right for you.

Instructions for children 3 years of age and above, weighing more than 40 kilograms
- Take 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet 

containing 800 milligram of PREZISTA) at the same time, once a day, every day.
- Take PREZISTA always together with 100 milligram of ritonavir.
- Take PREZISTA with food.
- Swallow the tablets with a drink such as water or milk.
- Take your other HIV medicines used in combination with PREZISTA and ritonavir as 

recommended by your doctor.

Removing the child resistant cap
The plastic bottle comes with a child resistant cap and must be opened as 
follows:
- Push the plastic screw cap down while turning it counter clockwise.
- Remove the unscrewed cap.

If you take more PREZISTA than you should
Contact your doctor, pharmacist or nurse immediately.

If you forget to take PREZISTA
If you notice within 12 hours, you must take the tablets immediately. Always take with cobicistat or 
ritonavir and food. If you notice after 12 hours, then skip the intake and take the next doses as usual. 
Do not take a double dose to make up for a forgotten dose.

Do not stop taking PREZISTA without talking to your doctor first
Anti-HIV medicines may make you feel better. Even when you feel better, do not stop taking 
PREZISTA. Talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.



177

Tell your doctor if you develop any of the following side effects.

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests 
before you start PREZISTA. If you have chronic hepatitis B or C infection, your doctor should check 
your blood tests more often because you have an increased chance of developing liver problems. Talk 
to your doctor about the signs and symptoms of liver problems. These may include yellowing of your 
skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), 
nausea, vomiting, loss of appetite, or pain, aching, or pain and discomfort on your right side below 
your ribs.

Skin rash (more often when used in combination with raltegravir), itching. The rash is usually mild to 
moderate. A skin rash might also be a symptom of a rare severe situation. It is important to talk to your 
doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms or whether 
PREZISTA must be stopped.

Other severe side effects were diabetes (common) and inflammation of the pancreas (uncommon).

Very common side effects (may affect more than 1 in 10 people)
- diarrhoea.

Common side effects (may affect up to 1 in 10 people)
- vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence
- headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of 

strength, difficulty falling asleep.

Uncommon side effects (may affect up to 1 in 100 people)
- chest pain, changes in electrocardiogram, rapid heart beating
- decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory, 

problems with your balance
- difficulty breathing, cough, nosebleed, throat irritation
- inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the 

abdomen, constipation, belching
- kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of 

urine, sometimes at night
- urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, 

excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails
- muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis
- slowing down of the thyroid gland function. This can be seen in a blood test.
- high blood pressure, flushing
- red or dry eyes
- fever, swelling of lower limbs due to fluids, malaise, irritability, pain
- symptoms of infection, herpes simplex
- erectile dysfunction, enlargement of breasts
- sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive

Rare side effects (may affect up to 1 in 1,000 people)
- a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of 

the face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver, 
kidney or lung]

- heart attack, slow heart beating, palpitations
- visual disturbance
- chills, feeling abnormal
- a feeling of confusion or disorientation, altered mood, restlessness
- fainting, epileptic fits, changes or loss of taste
- mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue
- running nose
- skin lesions, dry skin



178

- stiffness of muscles or joints, joint pain with or without inflammation
- changes in some values of your blood cells or chemistry. These can be seen in the results of 

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some 
white blood cells.

Some side effects are typical for anti-HIV medicines in the same family as PREZISTA. These are:
- muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been 

serious.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store PREZISTA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the bottle after 
EXP. The expiry date refers to the last day of that month.

PREZISTA does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away any medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What PREZISTA contains
- The active substance is darunavir. Each tablet contains 400 milligram of darunavir (as 

ethanolate).
- The other ingredients are microcrystalline cellulose, colloidal anhydrous silica, crospovidone, 

magnesium stearate. The film-coating contains poly(vinyl alcohol) - partially hydrolysed, 
macrogol 3350, titanium dioxide (E171), talc, sunset yellow FCF (E110).

- This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially ‘sodium-free’.

What PREZISTA looks like and contents of the pack
Film-coated, light orange, oval shaped tablet, mentioning TMC on one side, 400MG on the other side. 
60 tablets in a plastic bottle.
PREZISTA is also available as 75 milligram, 150 milligram, 600 milligram and 800 milligram 
film-coated tablets and 100 milligram per milliliter oral suspension.

Marketing Authorisation Holder
Janssen-Cilag International NV, Turnhoutseweg 30, 2340 Beerse, Belgium

Manufacturer
Janssen-Cilag SpA, Via C. Janssen, Borgo San Michele, 04100 Latina, Italy

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


179

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: +32 14 64 94 11
janssen@jacbe.jnj.com

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00
jjsafety@its.jnj.com

Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: +32 14 64 94 11
janssen@jacbe.jnj.com

Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858
janssenhu@its.jnj.com

Danmark
Janssen-Cilag A/S
Tlf: +45 4594 8282
jacdk@its.jnj.com

Malta
AM MANGION LTD
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955 955
jancil@its.jnj.com

Nederland
Janssen-Cilag B.V.
Tel: +31 76 711 1111
janssen@jacnl.jnj.com

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00
jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00
contacto@its.jnj.com

Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.: +48 22 237 60 00

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800

Ireland
Janssen Sciences Ireland UC
Tel: +353 1 800 709 122

Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com



180

Ísland
Janssen-Cilag AB
c/o Vistor hf.
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Tel: 800.688.777 / +39 02 2510 1
janssenita@its.jnj.com

Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300
jacfi@its.jnj.com

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Tfn: +46 8 626 50 00
jacse@its.jnj.com

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Janssen-Cilag Ltd.
Tel: +44 1 494 567 444

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

http://www.ema.europa.eu/
mailto:janssenita@its.jnj.com


181

Package leaflet: Information for the user

PREZISTA 600 mg film-coated tablets
darunavir

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What PREZISTA is and what it is used for
2. What you need to know before you take PREZISTA
3. How to take PREZISTA
4. Possible side effects
5. How to store PREZISTA
6. Contents of the pack and other information

1. What PREZISTA is and what it is used for

What is PREZISTA?
PREZISTA contains the active substance darunavir. PREZISTA is an antiretroviral medicine used in 
the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of medicines 
called protease inhibitors. PREZISTA works by reducing the amount of HIV in your body. This will 
improve your immune system and reduces the risk of developing illnesses linked to HIV infection.

What it is used for?
PREZISTA is used to treat adults and children of 3 years of age and above, and at least 15 kilogram 
body weight who are infected by HIV and who have already used other antiretroviral medicines.

PREZISTA must be taken in combination with a low dose of ritonavir and other anti-HIV medicines. 
Your doctor will discuss with you which combination of medicines is best for you.

2. What you need to know before you take PREZISTA

Do not take PREZISTA
- if you are allergic to darunavir or any of the other ingredients of this medicine (listed in section 

6) or to ritonavir.
- if you have severe liver problems. Ask your doctor if you are unsure about the severity of your 

liver disease. Some additional tests might be necessary.

Do not combine PREZISTA with any of the following medicines
If you are taking any of these, ask your doctor about switching to another medicine.

Medicine Purpose of the medicine
Avanafil to treat erectile dysfunction 
Astemizole or terfenadine to treat allergy symptoms
Triazolam and oral (taken by mouth) midazolam to help you sleep and/or relieve anxiety
Cisapride to treat some stomach conditions
Colchicine (if you have kidney and/or liver 
problems)

to treat gout or familial Mediterranean fever



182

Lurasidone, pimozide, quetiapine or sertindole to treat psychiatric conditions
Ergot alkaloids like ergotamine, 
dihydroergotamine, ergometrine and 
methylergonovine

to treat migraine headaches

Amiodarone, bepridil, dronedarone, ivabradine,
quinidine, ranolazine

to treat certain heart disorders e.g. abnormal 
heart beat

Lovastatin, simvastatin and lomitapide to lower cholesterol levels
Rifampicin to treat some infections such as tuberculosis
The combination product lopinavir/ritonavir this anti-HIV medicine belongs to the same class 

as PREZISTA
Elbasvir/grazoprevir to treat hepatitis C infection
Alfuzosin to treat enlarged prostate
Sildenafil to treat high blood pressure in the pulmonary 

circulation
Dabigatran, ticagrelor to help stop the clumping of platelets in the 

treatment of patients with a history of a heart 
attack

Naloxegol to treat opioid induced constipation
Dapoxetine to treat premature ejaculation
Domperidone to treat nausea and vomiting

Do not combine PREZISTA with products that contain St John’s wort (Hypericum perforatum).

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking PREZISTA.

PREZISTA is not a cure for HIV infection. You can still pass on HIV when taking this medicine, 
although the risk is lowered by effective antiretroviral therapy. Discuss with your physician the 
precautions needed to avoid infecting other people.

People taking PREZISTA may still develop infections or other illnesses associated with HIV infection. 
You must keep in regular contact with your doctor.

People taking PREZISTA may develop a skin rash. Infrequently a rash may become severe or 
potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking PREZISTA and raltegravir (for HIV infection), rashes (generally mild or moderate) 
may occur more frequently than in patients taking either medicine separately.

Tell your doctor about your situation BEFORE and DURING your treatment
Make sure that you check the following points and tell your doctor if any of these apply to you.
- Tell your doctor if you have had problems with your liver before, including hepatitis B or C

infection. Your doctor may evaluate how severe your liver disease is before deciding if you can 
take PREZISTA.

- Tell your doctor if you have diabetes. PREZISTA might increase sugar levels in the blood.
- Tell your doctor immediately if you notice any symptoms of infection (for example enlarged

lymph nodes and fever). In some patients with advanced HIV infection and a history of 
opportunistic infection, signs and symptoms of inflammation from previous infections may 
occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an 
improvement in the body’s immune response, enabling the body to fight infections that may 
have been present with no obvious symptoms.

- In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection. Autoimmune disorders may occur many months after 
the start of treatment. If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 



183

the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment.

- Tell your doctor if you have haemophilia. PREZISTA might increase the risk of bleeding.
- Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).
- Tell your doctor if you notice any musculoskeletal problems. Some patients taking 

combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of 
bone tissue caused by loss of blood supply to the bone). The length of combination 
antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, 
higher body mass index, among others, may be some of the many risk factors for developing 
this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, 
knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor.

Elderly
PREZISTA has only been used in limited numbers of patients 65 years or older. If you belong to this 
age group, please discuss with your doctor if you can use PREZISTA.

Children
PREZISTA is not for use in children younger than 3 years of age or weighing less than 15 kilograms.

Other medicines and PREZISTA
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

There are some medicines that you must not combine with PREZISTA. These are mentioned above 
under the heading ‘Do not combine PREZISTA with any of the following medicines:’

In most cases, PREZISTA can be combined with anti-HIV medicines belonging to another class [e.g. 
NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase 
inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. PREZISTA with ritonavir has not been 
tested with all PIs (protease inhibitors) and must not be used with other HIV PIs. In some cases dosage 
of other medicines might need to be changed. Therefore always tell your doctor if you take other 
anti-HIV medicines and follow your doctor’s instruction carefully on which medicines can be 
combined.

The effects of PREZISTA might be reduced if you take any of the following products. Tell your 
doctor if you take:
- Phenobarbital, phenytoin (to prevent seizures)
- Dexamethasone (corticosteroid)
- Efavirenz (HIV infection)
- Boceprevir (hepatitis C infection)
- Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis)
- Saquinavir (HIV infection).

The effects of other medicines might be influenced if you take PREZISTA. Tell your doctor if you 
take:
- Amlodipine, diltiazem, disopyramide, carvedilol, felodipine, flecainide, lidocaine, metoprolol,

mexiletine, nifedipine, nicardipine, propafenone, timolol, verapamil (for heart disease) as the 
therapeutic effect or side effects of these medicines may be increased.

- Apixaban, edoxaban, rivaroxaban, warfarin (to reduce clotting of the blood) as their therapeutic 
effect or side effects may be altered; your doctor may have to check your blood.

- Oestrogen-based hormonal contraceptives and hormonal replacement therapy. PREZISTA 
might reduce its effectiveness. When used for birth control, alternative methods of 
non-hormonal contraception are recommended.

- Ethinylestradiol/drospirenone. PREZISTA might increase the risk for elevated potassium levels 
by drospirenone.



184

- Atorvastatin, pravastatin, rosuvastatin (to lower cholesterol levels). The risk of muscle damage
might be increased. Your doctor will evaluate which cholesterol lowering regimen is best for 
your specific situation.

- Clarithromycin (antibiotic)
- Ciclosporin, everolimus, tacrolimus, sirolimus (for dampening down your immune system) as 

the therapeutic effect or side effects of these medicines might be increased. Your doctor might 
want to do some additional tests.

- Corticosteroids including betamethasone, budesonide, fluticasone, mometasone, prednisone, 
triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel 
diseases, inflammatory conditions of the eyes, joints and muscles and other inflammatory 
conditions. If alternatives cannot be used, its use should only take place after medical evaluation 
and under close monitoring by your doctor for corticosteroid side effects.

- Buprenorphine/naloxone (medicines to treat opioid dependence)
- Salmeterol (medicine to treat asthma)
- Artemether/lumefantrine (a combination medicine to treat malaria)
- Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer)
- Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder 

called pulmonary arterial hypertension)
- Glecaprevir/pibrentasvir, simeprevir (to treat hepatitis C infection)
- Fentanyl, oxycodone, tramadol (to treat pain)
- Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or PREZISTA’s 
therapeutic effect or side effects may be influenced when combined.
Tell your doctor if you take:
- Alfentanil (injectable strong and short-acting painkiller that is used for surgical procedures)
- Digoxin (to treat certain heart disorders)
- Clarithromycin (antibiotic)
- Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal 

infections). Voriconazole should only be taken after medical evaluation.
- Rifabutin (against bacterial infections)
- Sildenafil, vardenafil, tadalafil (for erectile dysfunction or high blood pressure in the pulmonary 

circulation)
- Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat 

depression and anxiety)
- Maraviroc (to treat HIV infection)
- Methadone (to treat opiate dependance)
- Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain)
- Colchicine (to treat gout or familial Mediterranean fever)
- Bosentan (to treat high blood pressure in the pulmonary circulation)
- Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, 

zolpidem (sedative agents)
- Perphenazine, risperidone, thioridazine (to treat psychiatric conditions).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are 
taking.

PREZISTA with food and drink
See section 3 ‘How to take PREZISTA.’

Pregnancy and breast-feeding
Tell your doctor immediately if you are pregnant, planning to become pregnant or if you are 
breast-feeding. Pregnant or breast-feeding mothers should not take PREZISTA with ritonavir unless 
specifically directed by the doctor. Pregnant or breast-feeding mothers should not take PREZISTA 
with cobicistat.



185

It is recommended that HIV infected women must not breast-feed their infants because of both the 
possibility of your baby becoming infected with HIV through your breast milk and because of the 
unknown effects of the medicine on your baby.

Driving and using machines
Do not operate machines or drive if you feel dizzy after taking PREZISTA.

PREZISTA tablets contain sunset yellow FCF (E110) which may cause allergic reactions.

3. How to take PREZISTA

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has 
told you. Check with your doctor, pharmacist or nurse if you are not sure.
Even if you feel better, do not stop taking PREZISTA and ritonavir without talking to your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be 
stopped without instruction of the doctor.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine 
this)
You will require a different dose of PREZISTA which cannot be administered with these 
600 milligram tablets. Other strengths of PREZISTA are available.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this)
The dose is either:
- 600 milligram PREZISTA together with 100 milligram ritonavir twice daily.

OR
- 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet 

containing 800 milligram of PREZISTA) together with 100 milligram ritonavir once daily. 
PREZISTA 400 milligram and 800 milligram tablets are only to be used to construct the once 
daily 800 milligram regimen.

Please discuss with your doctor which dose is right for you.

Instructions for adults
- Take PREZISTA always together with ritonavir. PREZISTA cannot work properly without 

ritonavir.
- In the morning, take one 600 milligram PREZISTA tablet together with 100 milligram ritonavir.
- In the evening, take one 600 milligram PREZISTA tablet together with 100 milligram ritonavir.
- Take PREZISTA with food. PREZISTA cannot work properly without food. The type of food is 

not important.
- Swallow the tablets with a drink such as water or milk.
- PREZISTA 75 milligram and 150 milligram tablets and 100 milligram per milliliter oral 

suspension have been developed for use in children, but can also be used in adults in some
cases.

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have not taken 
antiretroviral medicines before (your child’s doctor will determine this)
The doctor will work out the right once daily dose based on the weight of the child (see table below). 
This dose must not exceed the recommended adult dose, which is 800 milligram PREZISTA together 
with 100 milligram ritonavir once a day.
The doctor will inform you on how much PREZISTA tablets and how much ritonavir (capsules, 
tablets or solution) the child must take.

Weight One PREZISTA dose is One ritonavira dose is
between 15 and 30 kilograms 600 milligram 100 milligram



186

between 30 and 40 kilograms 675 milligram 100 milligram
more than 40 kilograms 800 milligram 100 milligram
a

ritonavir oral solution: 80 milligram per milliliter

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have taken 
antiretroviral medicines before (your child’s doctor will determine this)
The doctor will work out the right dose based on the weight of the child (see table below). The doctor 
will determine if once daily dosing or twice daily dosing is appropriate for the child. This dose must 
not exceed the recommended adult dose, which is 600 milligram PREZISTA together with 
100 milligram of ritonavir two times per day or 800 milligram PREZISTA together with 
100 milligram ritonavir once a day. The doctor will inform you on how many PREZISTA tablets and 
how much ritonavir (capsules, tablets or solution) the child must take. Tablets of lower strengths are 
available to construct the appropriate dosing regimen. PREZISTA oral suspension is also available. 
Your doctor will determine whether PREZISTA tablets or oral suspension is right for the child.

Twice daily dosing
Weight One dose is

between 15 and 30 kilograms 375 milligram PREZISTA + 50 milligram ritonavir twice a day
between 30 and 40 kilograms 450 milligram PREZISTA + 60 milligram ritonavir twice a day
more than 40 kilograms* 600 milligram PREZISTA + 100 milligram ritonavir twice a day
* For children aged 12 or more and weighing at least 40 kilograms, your child’s doctor will determine if PREZISTA 

800 milligram once daily dosing may be used. This cannot be administered with these 600 milligram tablets. Other 
strengths of PREZISTA are available.

Once daily dosing
Weight One PREZISTA dose is One ritonavira dose is

between 15 and 30 kilograms 600 milligram 100 milligram
between 30 and 40 kilograms 675 milligram 100 milligram
more than 40 kilograms 800 milligram 100 milligram
a

ritonavir oral solution: 80 milligram per milliliter

Instructions for children
- The child must take PREZISTA always together with ritonavir. PREZISTA cannot work 

properly without ritonavir.
- The child must take the appropriate doses of PREZISTA and ritonavir two times per day or once 

a day. If prescribed PREZISTA twice daily the child must take one dose in the morning, and 
one dose in the evening. Your child’s doctor will determine the appropriate dosing regimen for 
your child.

- The child must take PREZISTA with food. PREZISTA cannot work properly without food. The 
type of food is not important.

- The child must swallow the tablets with a drink such as water or milk.
- PREZISTA 75 milligram and 150 milligram tablets and 100 milligram per milliliter oral 

suspension have been developed for use in children weighing less than 40 kilograms, but can 
also be used in some cases.

Removing the child resistant cap
The plastic bottle comes with a child resistant cap and must be opened as 
follows:
- Push the plastic screw cap down while turning it counter clockwise.
- Remove the unscrewed cap.

If you take more PREZISTA than you should
Contact your doctor, pharmacist or nurse immediately.



187

If you forget to take PREZISTA
If you notice within 6 hours, you must take your missed dose immediately. Always take with 
ritonavir and food. If you notice after 6 hours, then skip the intake and take the next doses as usual. 
Do not take a double dose to make up for a forgotten dose.

Do not stop taking PREZISTA without talking to your doctor first
Anti-HIV medicine may make you feel better. Even when you feel better, do not stop taking 
PREZISTA. Talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor if you develop any of the following side effects.

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests 
before you start PREZISTA. If you have chronic hepatitis B or C infection, your doctor should check 
your blood tests more often because you have an increased chance of developing liver problems. Talk 
to your doctor about the signs and symptoms of liver problems. These may include yellowing of your 
skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), 
nausea, vomiting, loss of appetite, or pain, aching, or pain and discomfort on your right side below 
your ribs.

Skin rash (more often when used in combination with raltegravir), itching. The rash is usually mild to 
moderate. A skin rash might also be a symptom of a rare severe situation. It is therefore important to 
talk to your doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms 
or whether PREZISTA must be stopped.

Other severe side effects were diabetes (common) and inflammation of the pancreas (uncommon).

Very common side effects (may affect more than 1 in 10 people)
- diarrhoea.

Common side effects (may affect up to 1 in 10 people)
- vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence
- headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of 

strength, difficulty falling asleep.

Uncommon side effects (may affect up to 1 in 100 people)
- chest pain, changes in electrocardiogram, rapid heart beating
- decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory, 

problems with your balance
- difficulty breathing, cough, nosebleed, throat irritation
- inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the 

abdomen, constipation, belching
- kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of 

urine, sometimes at night
- urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, 

excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails
- muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis



188

- slowing down of the thyroid gland function. This can be seen in a blood test.
- high blood pressure, flushing
- red or dry eyes
- fever, swelling of lower limbs due to fluids, malaise, irritability, pain
- symptoms of infection, herpes simplex
- erectile dysfunction, enlargement of breasts
- sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive

Rare side effects (may affect up to 1 in 1,000 people)
- a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of 

the face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver, 
kidney or lung]

- heart attack, slow heart beating, palpitations
- visual disturbance
- chills, feeling abnormal
- a feeling of confusion or disorientation, altered mood, restlessness
- fainting, epileptic fits, changes or loss of taste
- mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue
- running nose
- skin lesions, dry skin
- stiffness of muscles or joints, joint pain with or without inflammation
- changes in some values of your blood cells or chemistry. These can be seen in the results of 

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some 
white blood cells.

Some side effects are typical for anti-HIV medicines in the same family as PREZISTA. These are:
- muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been 

serious.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store PREZISTA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the bottle after 
EXP. The expiry date refers to the last day of that month.

PREZISTA does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away any medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What PREZISTA contains
- The active substance is darunavir. Each tablet contains 600 milligram of darunavir (as 

ethanolate).
- The other ingredients are microcrystalline cellulose, colloidal anhydrous silica, crospovidone, 

magnesium stearate. The film-coating contains poly(vinyl alcohol) - partially hydrolysed, 
macrogol 3350, titanium dioxide (E171), talc, sunset yellow FCF (E110).

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


189

- This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially ‘sodium-free’.

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 milligram, 150 milligram, 400 milligram and 800 milligram 
film-coated tablets and 100 milligram per milliliter oral suspension.

Marketing Authorisation Holder
Janssen-Cilag International NV, Turnhoutseweg 30, 2340 Beerse, Belgium

Manufacturer
Janssen-Cilag SpA, Via C. Janssen, Borgo San Michele, 04100 Latina, Italy

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: +32 14 64 94 11
janssen@jacbe.jnj.com

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00
jjsafety@its.jnj.com

Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: +32 14 64 94 11
janssen@jacbe.jnj.com

Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858
janssenhu@its.jnj.com

Danmark
Janssen-Cilag A/S
Tlf: +45 4594 8282
jacdk@its.jnj.com

Malta
AM MANGION LTD
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955 955
jancil@its.jnj.com

Nederland
Janssen-Cilag B.V.
Tel: +31 76 711 1111
janssen@jacnl.jnj.com

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00
jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00
contacto@its.jnj.com

Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.: +48 22 237 60 00



190

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800

Ireland
Janssen Sciences Ireland UC
Tel: +353 1 800 709 122

Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com

Ísland
Janssen-Cilag AB
c/o Vistor hf.
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Tel: 800.688.777 / +39 02 2510 1
janssenita@its.jnj.com

Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300
jacfi@its.jnj.com

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Tfn: +46 8 626 50 00
jacse@its.jnj.com

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Janssen-Cilag Ltd.
Tel: +44 1 494 567 444

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

http://www.ema.europa.eu/
mailto:janssenita@its.jnj.com


191

Package leaflet: Information for the user

PREZISTA 800 mg film-coated tablets
darunavir

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What PREZISTA is and what it is used for
2. What you need to know before you take PREZISTA
3. How to take PREZISTA
4. Possible side effects
5. How to store PREZISTA
6. Contents of the pack and other information

1. What PREZISTA is and what it is used for

What is PREZISTA?
PREZISTA contains the active substance darunavir. PREZISTA is an antiretroviral medicine used in 
the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of medicines 
called protease inhibitors. PREZISTA works by reducing the amount of HIV in your body. This will 
improve your immune system and reduces the risk of developing illnesses linked to HIV infection.

What it is used for?
The PREZISTA 800 milligram tablet is used to treat adults and children (3 years of age and above, at 
least 40 kilograms body weight) who are infected by HIV and
- who have not used antiretroviral medicines before.
- in certain patients who have used antiretroviral medicines before (your doctor will determine 

this).

PREZISTA must be taken in combination with a low dose of cobicistat or ritonavir and other anti-HIV 
medicines. Your doctor will discuss with you which combination of medicines is best for you.

2. What you need to know before you take PREZISTA

Do not take PREZISTA
- if you are allergic to darunavir or any of the other ingredients of this medicine (listed in section 

6) or to cobicistat or ritonavir.
- if you have severe liver problems. Ask your doctor if you are unsure about the severity of your 

liver disease. Some additional tests might be necessary.

Do not combine PREZISTA with any of the following medicines
If you are taking any of these, ask your doctor about switching to another medicine.

Medicine Purpose of the medicine
Avanafil to treat erectile dysfunction 
Astemizole or terfenadine to treat allergy symptoms
Triazolam and oral (taken by mouth) midazolam to help you sleep and/or relieve anxiety



192

Cisapride to treat some stomach conditions
Colchicine (if you have kidney and/or liver 
problems)

to treat gout or familial Mediterranean fever

Lurasidone, pimozide, quetiapine or sertindole to treat psychiatric conditions
Ergot alkaloids like ergotamine, 
dihydroergotamine, ergometrine and 
methylergonovine

to treat migraine headaches

Amiodarone, bepridil, dronedarone, ivabradine
quinidine, ranolazine 

to treat certain heart disorders e.g. abnormal 
heart beat

Lovastatin, simvastatin and lomitapide to lower cholesterol levels
Rifampicin to treat some infections such as tuberculosis
The combination product lopinavir/ritonavir this anti-HIV medicine belongs to the same class 

as PREZISTA
Elbasvir/grazoprevir to treat hepatitis C infection
Alfuzosin to treat enlarged prostate
Sildenafil to treat high blood pressure in the pulmonary 

circulation
Dabigatran, ticagrelor to help stop the clumping of platelets in the 

treatment of patients with a history of a heart 
attack

Naloxegol to treat opioid induced constipation
Dapoxetine to treat premature ejaculation
Domperidone to treat nausea and vomiting

Do not combine PREZISTA with products that contain St John’s wort (Hypericum perforatum).

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking PREZISTA.

PREZISTA is not a cure for HIV infection. You can still pass on HIV when taking this medicine, 
although the risk is lowered by effective antiretroviral therapy. Discuss with your physician the 
precautions needed to avoid infecting other people.

People taking PREZISTA may still develop infections or other illnesses associated with HIV infection. 
You must keep in regular contact with your doctor.

People taking PREZISTA may develop a skin rash. Infrequently a rash may become severe or 
potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking PREZISTA and raltegravir (for HIV infection), rashes (generally mild or moderate) 
may occur more frequently than in patients taking either medicine separately.

Tell your doctor about your situation BEFORE and DURING your treatment
Make sure that you check the following points and tell your doctor if any of these apply to you.
- Tell your doctor if you have had problems with your liver before, including hepatitis B or C

infection. Your doctor may evaluate how severe your liver disease is before deciding if you can 
take PREZISTA.

- Tell your doctor if you have diabetes. PREZISTA might increase sugar levels in the blood.
- Tell your doctor immediately if you notice any symptoms of infection (for example enlarged 

lymph nodes and fever). In some patients with advanced HIV infection and a history of 
opportunistic infection, signs and symptoms of inflammation from previous infections may 
occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an 
improvement in the body’s immune response, enabling the body to fight infections that may 
have been present with no obvious symptoms.

- In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 



193

for the treatment of your HIV infection. Autoimmune disorders may occur many months after 
the start of treatment. If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 
the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment.

- Tell your doctor if you have haemophilia. PREZISTA might increase the risk of bleeding.
- Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).
- Tell your doctor if you notice any musculoskeletal problems. Some patients taking 

combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of 
bone tissue caused by loss of blood supply to the bone). The length of combination 
antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, 
higher body mass index, among others, may be some of the many risk factors for developing 
this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, 
knee and shoulder) and difficulty in movement. If you notice any of these symptoms please 
inform your doctor.

Elderly
PREZISTA has only been used in limited numbers of patients 65 years or older. If you belong to this 
age group, please discuss with your doctor if you can use PREZISTA.

Children and adolescents
The PREZISTA 800 milligram tablet is not for use in children younger than 3 years of age or 
weighing less than 40 kilograms.

Other medicines and PREZISTA
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

There are some medicines that you must not combine with PREZISTA. These are mentioned above 
under the heading ‘Do not combine PREZISTA with any of the following medicines:’

In most cases, PREZISTA can be combined with anti-HIV medicines belonging to another class [e.g. 
NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase 
inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. PREZISTA with cobicistat or ritonavir has 
not been tested with all PIs (protease inhibitors) and must not be used with other HIV PIs. In some 
cases dosage of other medicines might need to be changed. Therefore always tell your doctor if you 
take other anti-HIV medicines and follow your doctor’s instruction carefully on which medicines can 
be combined.

The effects of PREZISTA might be reduced if you take any of the following products. Tell your 
doctor if you take:
- Phenobarbital, phenytoin (to prevent seizures)
- Dexamethasone (corticosteroid)
- Efavirenz (HIV infection)
- Boceprevir (hepatitis C infection)
- Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis)
- Saquinavir (HIV infection).

The effects of other medicines might be influenced if you take PREZISTA. Tell your doctor if you 
take:
- Amlodipine, diltiazem, disopyramide, carvedilol, felodipine, flecainide, lidocaine, metoprolol,

mexiletine, nifedipine, nicardipine, propafenone, timolol, verapamil (for heart disease) as the 
therapeutic effect or side effects of these medicines may be increased.

- Apixaban, edoxaban, rivaroxaban, warfarin (to reduce clotting of the blood) as their therapeutic 
effect or side effects may be altered; your doctor may have to check your blood.

- Oestrogen-based hormonal contraceptives and hormonal replacement therapy. PREZISTA 
might reduce its effectiveness. When used for birth control, alternative methods of 
non-hormonal contraception are recommended.



194

- Ethinylestradiol/drospirenone. PREZISTA might increase the risk for elevated potassium levels 
by drospirenone.

- Atorvastatin, pravastatin, rosuvastatin (to lower cholesterol levels). The risk of muscle damage
might be increased. Your doctor will evaluate which cholesterol lowering regimen is best for 
your specific situation.

- Clarithromycin (antibiotic)
- Ciclosporin, everolimus, tacrolimus, sirolimus (for dampening down your immune system) as 

the therapeutic effect or side effects of these medicines might be increased. Your doctor might 
want to do some additional tests.

- Corticosteroids including betamethasone, budesonide, fluticasone, mometasone, prednisone, 
triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel 
diseases, inflammatory conditions of the eyes, joints and muscles and other inflammatory 
conditions. If alternatives cannot be used, its use should only take place after medical evaluation 
and under close monitoring by your doctor for corticosteroid side effects.

- Buprenorphine/naloxone (medicines to treat opioid dependence)
- Salmeterol (medicine to treat asthma)
- Artemether/lumefantrine (a combination medicine to treat malaria)
- Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer)
- Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder 

called pulmonary arterial hypertension)
- Glecaprevir/pibrentasvir, simeprevir (to treat hepatitis C infection)
- Fentanyl, oxycodone, tramadol (to treat pain)
- Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or PREZISTA’s 
therapeutic effect or side effects may be influenced when combined.
Tell your doctor if you take:
- Alfentanil (injectable strong and short-acting painkiller that is used for surgical procedures)
- Digoxin (to treat certain heart disorders)
- Clarithromycin (antibiotic)
- Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal 

infections). Voriconazole should only be taken after medical evaluation.
- Rifabutin (against bacterial infections)
- Sildenafil, vardenafil, tadalafil (for erectile dysfunction or high blood pressure in the pulmonary 

circulation)
- Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat 

depression and anxiety)
- Maraviroc (to treat HIV infection)
- Methadone (to treat opiate dependance)
- Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain)
- Colchicine (to treat gout or familial Mediterranean fever)
- Bosentan (to treat high blood pressure in the pulmonary circulation)
- Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, 

zolpidem (sedative agents)
- Perphenazine, risperidone, thioridazine (to treat psychiatric conditions)
- Metformin (to treat type 2 diabetes).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are 
taking.

PREZISTA with food and drink
See section 3 ‘How to take PREZISTA.’

Pregnancy and breast-feeding
Tell your doctor immediately if you are pregnant, planning to become pregnant or if you are 
breast-feeding. Pregnant or breast-feeding mothers should not take PREZISTA with ritonavir unless 



195

specifically directed by the doctor. Pregnant or breast-feeding mothers should not take PREZISTA 
with cobicistat.

It is recommended that HIV infected women must not breast-feed their infants because of both the 
possibility of your baby becoming infected with HIV through your breast milk and because of the 
unknown effects of the medicine on your baby.

Driving and using machines
Do not operate machines or drive if you feel dizzy after taking PREZISTA.

3. How to take PREZISTA

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has 
told you. Check with your doctor, pharmacist or nurse if you are not sure.
Even if you feel better, do not stop taking PREZISTA and cobicistat or ritonavir without talking to 
your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be 
stopped without instruction of the doctor.

PREZISTA 800 milligram tablets are intended for once daily use only.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine 
this)
The usual dose of PREZISTA is 800 milligram (2 tablets containing 400 milligram of PREZISTA or 
1 tablet containing 800 milligram of PREZISTA) once daily.
You must take PREZISTA every day and always in combination with 150 milligram of cobicistat or 
100 milligram of ritonavir and with food. PREZISTA cannot work properly without cobicistat or 
ritonavir and food. You must eat a meal or a snack within 30 minutes prior to taking your PREZISTA 
and cobicistat or ritonavir. The type of food is not important. Even if you feel better, do not stop taking 
PREZISTA and cobicistat or ritonavir without talking to your doctor.

Instructions for adults
- Take one 800 milligram tablet at the same time, once a day, every day.
- Take PREZISTA always together with 150 milligram of cobicistat or 100 milligram of ritonavir.
- Take PREZISTA with food.
- Swallow the tablet with a drink such as water or milk.
- Take your other HIV medicines used in combination with PREZISTA and cobicistat or ritonavir 

as recommended by your doctor.
- PREZISTA 100 milligram per milliliter oral suspension has been developed for use in children, 

but can also be used in adults in some cases.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this)
The dose is either:
- 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet 

containing 800 milligram of PREZISTA) together with 150 milligram cobicistat or
100 milligram ritonavir once daily.
OR

- 600 milligram PREZISTA together with 100 milligram ritonavir twice daily.

Please discuss with your doctor which dose is right for you.



196

Dose for children 3 years of age and above, weighing more than 40 kilograms who have not 
taken antiretroviral medicines before (your child’s doctor will determine this)
- The usual dose of PREZISTA is 800 milligram (2 tablets containing 400 milligram of 

PREZISTA or 1 tablet containing 800 milligram of PREZISTA) together with 100 milligram 
ritonavir once daily.

Dose for children 3 years of age and above, weighing more than 40 kilograms who have taken 
antiretroviral medicines before (your child’s doctor will determine this)
The dose is either:
- 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet 

containing 800 milligram of PREZISTA) together with 100 milligram ritonavir once daily.
OR

- 600 milligram PREZISTA together with 100 milligram ritonavir twice daily.

Please discuss with your doctor which dose is right for you.

Instructions for children 3 years of age and above, weighing more than 40 kilograms
- Take 800 milligram PREZISTA (2 tablets containing 400 milligram of PREZISTA or 1 tablet 

containing 800 milligram of PREZISTA) at the same time, once a day, every day.
- Take PREZISTA always together with 100 milligram of ritonavir.
- Take PREZISTA with food.
- Swallow the tablets with a drink such as water or milk.
- Take your other HIV medicines used in combination with PREZISTA and ritonavir as 

recommended by your doctor

Removing the child resistant cap
The plastic bottle comes with a child resistant cap and must be opened as 
follows:
- Push the plastic screw cap down while turning it counter clockwise.
- Remove the unscrewed cap.

If you take more PREZISTA than you should
Contact your doctor, pharmacist or nurse immediately.

If you forget to take PREZISTA
If you notice within 12 hours, you must take the tablets immediately. Always take with cobicistat or 
ritonavir and food. If you notice after 12 hours, then skip the intake and take the next doses as usual. 
Do not take a double dose to make up for a forgotten dose.

Do not stop taking PREZISTA without talking to your doctor first
Anti-HIV medicines may make you feel better. Even when you feel better, do not stop taking 
PREZISTA. Talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.



197

Tell your doctor if you develop any of the following side effects.

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests 
before you start PREZISTA. If you have chronic hepatitis B or C infection, your doctor should check 
your blood tests more often because you have an increased chance of developing liver problems. Talk 
to your doctor about the signs and symptoms of liver problems. These may include yellowing of your 
skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), 
nausea, vomiting, loss of appetite, or pain, aching, or pain and discomfort on your right side below 
your ribs.

Skin rash (more often when used in combination with raltegravir), itching. The rash is usually mild to 
moderate. A skin rash might also be a symptom of a rare severe situation. It is therefore important to 
talk to your doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms 
or whether PREZISTA must be stopped.

Other severe side effects were diabetes (common) and inflammation of the pancreas (uncommon).

Very common side effects (may affect more than 1 in 10 people)
- diarrhoea.

Common side effects (may affect up to 1 in 10 people)
- vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence
- headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of 

strength, difficulty falling asleep.

Uncommon side effects (may affect up to 1 in 100 people)
- chest pain, changes in electrocardiogram, rapid heart beating
- decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory, 

problems with your balance
- difficulty breathing, cough, nosebleed, throat irritation
- inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the 

abdomen, constipation, belching
- kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of 

urine, sometimes at night
- urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, 

excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails
- muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis
- slowing down of the thyroid gland function. This can be seen in a blood test.
- high blood pressure, flushing
- red or dry eyes
- fever, swelling of lower limbs due to fluids, malaise, irritability, pain
- symptoms of infection, herpes simplex
- erectile dysfunction, enlargement of breasts
- sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive

Rare side effects (may affect up to 1 in 1,000 people)
- a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of 

the face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver, 
kidney or lung]

- heart attack, slow heart beating, palpitations
- visual disturbance
- chills, feeling abnormal
- a feeling of confusion or disorientation, altered mood, restlessness
- fainting, epileptic fits, changes or loss of taste
- mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue
- running nose
- skin lesions, dry skin



198

- stiffness of muscles or joints, joint pain with or without inflammation
- changes in some values of your blood cells or chemistry. These can be seen in the results of 

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some 
white blood cells.

Some side effects are typical for anti-HIV medicines in the same family as PREZISTA. These are:
- muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been 

serious.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store PREZISTA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the bottle after 
EXP. The expiry date refers to the last day of that month.

PREZISTA does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away any medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What PREZISTA contains
- The active substance is darunavir. Each tablet contains 800 milligram of darunavir (as 

ethanolate).
- The other ingredients are microcrystalline cellulose, colloidal anhydrous silica, crospovidone, 

magnesium stearate, hypromellose. The film-coating contains poly(vinyl alcohol) - partially 
hydrolysed, macrogol 3350, titanium dioxide (E171), talc, iron oxide red (E172).

- This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially ‘sodium-free’.

What PREZISTA looks like and contents of the pack
Film-coated, dark red, oval shaped tablet, mentioning T on one side, 800 on the other side. 30 tablets 
in a plastic bottle. The PREZISTA 800 milligram tablets are available in packs containing one bottle 
or three bottles per carton.
Not all pack sizes may be marketed.

PREZISTA is also available as 75 milligram, 150 milligram, 400 milligram and 600 milligram 
film-coated tablets and 100 milligram per milliliter oral suspension.

Marketing Authorisation Holder
Janssen-Cilag International NV, Turnhoutseweg 30, 2340 Beerse, Belgium

Manufacturer
Janssen-Cilag SpA, Via C. Janssen, Borgo San Michele, 04100 Latina, Italy

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


199

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Janssen-Cilag NV
Tel/Tél: +32 14 64 94 11
janssen@jacbe.jnj.com

Lietuva
UAB "JOHNSON & JOHNSON"
Tel: +370 5 278 68 88
lt@its.jnj.com

България
„Джонсън & Джонсън България” ЕООД
Тел.: +359 2 489 94 00
jjsafety@its.jnj.com

Luxembourg/Luxemburg
Janssen-Cilag NV
Tél/Tel: +32 14 64 94 11
janssen@jacbe.jnj.com

Česká republika
Janssen-Cilag s.r.o.
Tel: +420 227 012 227

Magyarország
Janssen-Cilag Kft.
Tel.: +36 1 884 2858
janssenhu@its.jnj.com

Danmark
Janssen-Cilag A/S
Tlf: +45 4594 8282
jacdk@its.jnj.com

Malta
AM MANGION LTD
Tel: +356 2397 6000

Deutschland
Janssen-Cilag GmbH
Tel: +49 2137 955 955
jancil@its.jnj.com

Nederland
Janssen-Cilag B.V.
Tel: +31 76 711 1111
janssen@jacnl.jnj.com

Eesti
UAB "JOHNSON & JOHNSON" Eesti filiaal
Tel: +372 617 7410
ee@its.jnj.com

Norge
Janssen-Cilag AS
Tlf: +47 24 12 65 00
jacno@its.jnj.com

Ελλάδα
Janssen-Cilag Φαρμακευτική Α.Ε.Β.Ε.
Tηλ: +30 210 80 90 000

Österreich
Janssen-Cilag Pharma GmbH
Tel: +43 1 610 300

España
Janssen-Cilag, S.A.
Tel: +34 91 722 81 00
contacto@its.jnj.com

Polska
Janssen-Cilag Polska Sp. z o.o.
Tel.: +48 22 237 60 00

France
Janssen-Cilag
Tél: 0 800 25 50 75 / +33 1 55 00 40 03
medisource@its.jnj.com

Portugal
Janssen-Cilag Farmacêutica, Lda.
Tel: +351 214 368 600

Hrvatska
Johnson & Johnson S.E. d.o.o.
Tel: +385 1 6610 700
jjsafety@JNJCR.JNJ.com

România
Johnson & Johnson România SRL
Tel: +40 21 207 1800

Ireland
Janssen Sciences Ireland UC
Tel: +353 1 800 709 122

Slovenija
Johnson & Johnson d.o.o.
Tel: +386 1 401 18 00
Janssen_safety_slo@its.jnj.com



200

Ísland
Janssen-Cilag AB
c/o Vistor hf.
Sími: +354 535 7000
janssen@vistor.is

Slovenská republika
Johnson & Johnson, s.r.o.
Tel: +421 232 408 400

Italia
Janssen-Cilag SpA
Tel: 800.688.777 / +39 02 2510 1
janssenita@its.jnj.com

Suomi/Finland
Janssen-Cilag Oy
Puh/Tel: +358 207 531 300
jacfi@its.jnj.com

Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
Τηλ: +357 22 207 700

Sverige
Janssen-Cilag AB
Tfn: +46 8 626 50 00
jacse@its.jnj.com

Latvija
UAB "JOHNSON & JOHNSON" filiāle Latvijā
Tel: +371 678 93561
lv@its.jnj.com

United Kingdom
Janssen-Cilag Ltd.
Tel: +44 1 494 567 444

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

http://www.ema.europa.eu/
mailto:janssenita@its.jnj.com

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET