PREZISTA 100mg / ml oral suspension medication leaflet

PREZISTA 100 mg/ml oral suspension

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.

Oral suspension

White to off-white opaque suspension

PREZISTA, co-administered with low dose ritonavir is indicated in combination with otherantiretroviral 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 (seesection 4.2).

PREZISTA, co-administered with cobicistat is indicated in combination with other antiretroviralmedicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adultsand adolescents (aged 12 years and older, weighing at least 40 kg) (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 patternsof mutations associated with different agents. Genotypic or phenotypic testing (when available) andtreatment history should guide the use of PREZISTA (see sections 4.2, pct. 4.4 and 5.1).

Therapy should be initiated by a healthcare 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 healthcare provider.

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

PREZISTA must always be given orally with cobicistat or low dose ritonavir as a pharmacokineticenhancer 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 initiationof therapy with PREZISTA. Cobicistat is not indicated for use in twice daily regimens or for use in thepaediatric population less than 12 years of age and weighing less than 40 kg.

ART-naïve adult patients

The recommended dose regimen is 800 mg once daily with cobicistat 150 mg once daily or ritonavir100 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 takenwith food.

A dose regimen of 800 mg once daily with cobicistat 150 mg once daily or ritonavir 100 mg oncedaily taken with food may be used in patients with prior exposure to antiretroviral medicinal productsbut 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 mgtwice 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 taken with ritonavir or cobicistat taken with food in paediatricpatients is provided in the table below. The dose of cobicistat to be used with PREZISTA in childrenless than 12 years of age has not been established.

Recommended dose for treatment-naïve paediatric patients (3 to 17 years) with PREZISTAand ritonavira or cobicistatb

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)c PREZISTA/100 mg (1.2 ml) ritonavir once daily≥ 40 kg 800 mg (8 ml) PREZISTA/100 mg (1.2 ml) ritonavir once daily or800 mg (8 ml) PREZISTA/150 mg (tablet) cobicistatb once dailya ritonavir oral solution: 80 mg/mlb adolescents 12 years and olderc 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 or cobicistat taken with food may beused in patients with prior exposure to antiretroviral medicinal products but without darunavirresistance 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 taken with ritonavir or cobicistat in paediatric patients isprovided in the table below. The recommended dose of PREZISTA with low dose ritonavir should notexceed the recommended adult dose (600/100 mg twice daily or 800/100 mg once daily). The dose of

PREZISTA with cobicistat in adolescent patients 12 years of age and older weighing at least 40 kg is800/150 mg once daily taken with food. The dose of cobicistat to be used with PREZISTA in childrenless than 12 years of age has not been established.

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

PREZISTA and ritonavira or cobicistatb

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 380 mg (3.8 ml) PREZISTA/50 mg(1.2 ml) ritonavir once daily (0.6 ml) ritonavir twice daily≥ 30 kg to < 40 kg 675 mg (6.8 ml)c PREZISTA/100 mg 460 mg (4.6 ml) PREZISTA/60 mg(1.2 ml) ritonavir once daily (0.8 ml) ritonavir twice daily≥ 40 kg 800 mg (8 ml) PREZISTA/100 mg 600 mg (6 ml) PREZISTA/100 mg(1.2 ml) ritonavir once daily or (1.2 ml) ritonavir twice daily800 mg (8 ml) PREZISTA/150 mg(tablet) cobicistatb once dailya ritonavir oral solution: 80 mg/mlb adolescents 12 years and olderc rounded up for suspension dosing convenience

For ART-experienced paediatric patients HIV genotypic testing is recommended. However, when HIVgenotypic testing is not feasible, the PREZISTA (taken with ritonavir or cobicistat) once daily dosingregimen is recommended in HIV protease inhibitor-naïve paediatric patients and the PREZISTA takenwith ritonavir twice daily dosing regimen is recommended in HIV protease inhibitor-experiencedpatients.

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

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

- If using the twice daily regimen: in case a dose of PREZISTA and/or ritonavir is missed within6 hours of the time it is usually taken, patients should be instructed to take the prescribed doseof PREZISTA and ritonavir with food as soon as possible. If this is noticed later than 6 hoursafter the time it is usually taken, the missed dose should not be taken and the patient shouldresume the usual dosing schedule.

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

If a patient vomits within 4 hours of taking the medicine, another dose of PREZISTA with cobicistator ritonavir should be taken with food as soon as possible. If a patient vomits more than 4 hours aftertaking the medicine, the patient does not need to take another dose of PREZISTA with cobicistat orritonavir until the next regularly scheduled time.

Limited information is available in this population, and therefore, PREZISTA should be used withcaution in this age group (see sections 4.4 and 5.2).

Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients withmild (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 inpatients with severe hepatic impairment. Severe hepatic impairment could result in an increase ofdarunavir exposure and a worsening of its safety profile. Therefore, PREZISTA must not be used inpatients with severe hepatic impairment (Child-Pugh Class C) (see sections pct. 4.3, pct. 4.4 and 5.2).

No dose adjustment is required for darunavir/ritonavir in patients with renal impairment (see sections4.4 and 5.2). Cobicistat has not been studied in patients receiving dialysis, and, therefore, norecommendation 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 serumcreatinine and modest declines in creatinine clearance. Hence, the use of creatinine clearance as anestimate of renal elimination capacity may be misleading. Cobicistat as a pharmacokinetic enhancer ofdarunavir should, therefore, not be initiated in patients with creatine clearance less than 70 ml/min ifany 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.

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 asufficient number of patients (see section 5.1).

PREZISTA taken with cobicistat should not be used in children aged 3 to 11 years of age weighing< 40 kg as the dose of cobicistat to be used in these children has not been established (see sections 4.4and 5.3).

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 thepotential risk (see sections 4.4, pct. 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 duringpregnancy, and women who become pregnant during therapy with PREZISTA/cobicistat should beswitched to an alternative regimen, (see sections 4.4 and 4.6). PREZISTA/ritonavir may be consideredas an alternative.

Patients should be instructed to take PREZISTA with cobicistat or low dose ritonavir within30 minutes after completion of a meal. The type of food does not affect the exposure to darunavir (seesections 4.4, 4.5 and 5.2).

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

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 inplasma concentrations of darunavir, ritonavir and cobicistat and the potential for loss of therapeuticeffect (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).

- Strong CYP3A inducers such as rifampicin and herbal preparations containing St John’s Wort(Hypericum perforatum). Co-administration is expected to reduce plasma concentrations ofdarunavir, ritonavir and cobicistat, which could lead to loss of therapeutic effect and possibledevelopment 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 darunavirboosted with ritonavir. Concomitant use with strong CYP3A inducers is contraindicated, sincethese 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 sections4.4 and 4.5).

Darunavir boosted with either ritonavir or cobicistat inhibits the elimination of active substances thatare highly dependent on CYP3A for clearance, which results in increased exposure to theco-administered medicinal product. Therefore, concomitant treatment with such medicinal productsfor which elevated plasma concentrations are associated with serious and/or life-threatening events iscontraindicated (applies to darunavir boosted with either ritonavir or cobicistat). These activesubstances 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, lomitapide (see section 4.5)

- ticagrelor (see section 4.5).

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

PREZISTA must always be given orally with cobicistat or low dose ritonavir as a pharmacokineticenhancer 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 beconsulted prior to initiation of therapy with PREZISTA.

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

Darunavir binds predominantly to 1-acid glycoprotein. This protein binding isconcentration-dependent indicative for saturation of binding. Therefore, protein displacement ofmedicinal 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-experiencedpatients 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 (seesection 4.2). Combinations with optimised background regimen (OBRs) other than ≥ 2 NRTIs havenot been studied in this population. Limited data are available in patients with HIV-1 clades other than

B (see section 5.1).

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

PREZISTA/ritonavir should be used during pregnancy only if the potential benefit justifies thepotential risk. Caution should be used in pregnant women with concomitant medications which mayfurther 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 hasbeen shown to result in low darunavir exposure, with a reduction of around 90% in Cmin levels (seesection 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantialreduction in darunavir exposure may result in virological failure and an increased risk of mother tochild transmission of HIV infection. Therefore, therapy with PREZISTA/cobicistat should not beinitiated 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.

As limited information is available on the use of PREZISTA in patients aged 65 and over, cautionshould be exercised in the administration of PREZISTA in elderly patients, reflecting the greaterfrequency of decreased hepatic function and of concomitant disease or other therapy (see sections 4.2and 5.2).

Severe skin reactions

During the darunavir/ritonavir clinical development program (N=3,063), severe skin reactions, whichmay be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% ofpatients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson

Syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermalnecrolysis and acute generalised exanthematous pustulosis have been reported. PREZISTA should bediscontinued 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 orjoint 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 withoutraltegravir or raltegravir without PREZISTA (see section 4.8).

Darunavir contains a sulphonamide moiety. PREZISTA should be used with caution in patients with aknown sulphonamide allergy.

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 in0.5% of patients receiving combination antiretroviral therapy with PREZISTA/ritonavir. Patients withpre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk forliver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case ofconcomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information forthese medicinal products.

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA used incombination 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 firstseveral 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 ofliver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, livertenderness, hepatomegaly) in patients using PREZISTA used in combination with cobicistat or lowdose ritonavir, interruption or discontinuation of treatment should be considered promptly.

Patients with coexisting conditions

The safety and efficacy of PREZISTA have not been established in patients with severe underlyingliver 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 withcaution in patients with mild or moderate hepatic impairment (see sections 4.2, pct. 4.3 and 5.2).

No special precautions or dose adjustments for darunavir/ritonavir are required in patients with renalimpairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that theywill be significantly removed by haemodialysis or peritoneal dialysis. Therefore, no specialprecautions or dose adjustments are required in these patients (see sections 4.2 and 5.2). Cobicistat hasnot been studied in patients receiving dialysis, therefore, no recommendation can be made for the useof darunavir/cobicistat in these patients (see section 4.2).

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

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

There have been reports of increased bleeding, including spontaneous skin haematomas andhaemarthrosis in patients with haemophilia type A and B treated with PIs. In some patients additionalfactor VIII was given. In more than half of the reported cases, treatment with PIs was continued orreintroduced if treatment had been discontinued. A causal relationship has been suggested, althoughthe mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be madeaware of the possibility of increased bleeding.

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

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly in patients with advanced HIV disease and/or long-term exposure to combinationantiretroviral therapy (CART). Patients should be advised to seek medical advice if they experiencejoint 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 combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens 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. Relevantexamples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections andpneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Anyinflammatory 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 PREZISTAco-administered with low dose ritonavir.

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

Several of the interaction studies have been performed with darunavir at lower than recommendeddoses. The effects on co-administered medicinal products may thus be underestimated and clinicalmonitoring of safety may be indicated. For full information on interactions with other medicinalproducts see section 4.5.

Pharmacokinetic enhancer and concomitant medications

Darunavir has different interaction profiles depending on whether the compound is boosted withritonavir or cobicistat:

- Darunavir boosted with cobicistat is more sensitive for CYP3A induction: concomitant use ofdarunavir/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 section4.5). Concomitant use of darunavir/ritonavir and darunavir/cobicistat with strong CYP3Ainducers such as 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 (seesection 4.5). If switching the pharmacoenhancer from ritonavir to cobicistat, caution is requiredduring the first two weeks of treatment with darunavir/cobicistat, particularly if doses of anyconcomitantly administered medicinal products have been titrated or adjusted during use ofritonavir as a pharmacoenhancer. A dose reduction of the co-administered drug may be neededin these cases.

Efavirenz in combination with boosted PREZISTA may result in sub-optimal darunavir Cmin. Ifefavirenz is to be used in combination with PREZISTA, the PREZISTA/ritonavir 600/100 mg twicedaily 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 andstrong 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 causeallergic reactions (possibly delayed).

PREZISTA oral suspension contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially‘sodium-free’.

The interaction profile of darunavir may differ depending on whether ritonavir or cobicistat is used aspharmacoenhancer. The recommendations given for concomitant use of darunavir and other medicinalproducts 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 switchingthe 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 activitywould be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasmaconcentrations of these compounds and consequently that of darunavir, leading to loss of therapeuticeffect and possible development of resistance (see sections 4.3 and 4.4). CYP3A inducers that arecontraindicated include rifampicin, St John’s Wort and lopinavir.

Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A maydecrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrationsof darunavir and ritonavir. Co-administration with strong CYP3A4 inhibitors is not recommended andcaution 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 inducersmay therefore result in subtherapeutic plasma exposure to darunavir. Darunavir boosted withcobicistat is more sensitive to CYP3A induction than ritonavir-boosted darunavir: co-administration ofdarunavir/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, fluticasone, and bosentan) is not recommended (see interaction table below).

For co-administration with strong CYP3A4 inhibitors, the same recommendations apply independentof 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 ofdarunavir/ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 ortransported by P-gp may result in increased systemic exposure to such medicinal products, whichcould increase or prolong their therapeutic effect and adverse reactions.

Co-administration of boosted darunavir with drugs that have active metabolite(s) formed by CYP3Amay result in reduced plasma concentrations of these active metabolite(s), potentially leading to lossof their therapeutic effect (see the Interaction table below).

Darunavir co-administered with low dose ritonavir must not be combined with medicinal products thatare highly dependent on CYP3A for clearance and for which increased systemic exposure is associatedwith 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 inthe systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally incombination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used incombination 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 andinhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to thepresence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal productswhich are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may resultin increased plasma concentrations of these medicinal products, which could increase or prolong theirtherapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir with medicinalproducts 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 orshorten their therapeutic effect.

Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir andritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone,repaglinide) may result in decreased systemic exposure to such medicinal products, which coulddecrease or shorten their therapeutic effect.

Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administrationwith 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 similar to the recommendations fordarunavir boosted with cobicistat with regard to substrates of CYP3A4, CYP2D6, P-glycoprotein,

OATP1B1 and OATP1B3 (see contraindications and recommendations presented in the sectionabove). Cobicistat 150 mg given with darunavir 800 mg once daily enhances darunavirpharmacokinetic 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 studies have only been performed in adults.

Several of the interaction studies (indicated by # in the table below) have been performed at lower thanrecommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). Theeffects on co-administered medicinal products may thus be underestimated and clinical monitoring ofsafety may be indicated.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used aspharmacokinetic enhancer. Darunavir may therefore have different recommendations for concomitantmedications depending on whether the compound is boosted with ritonavir or cobicistat. The samerecommendations apply, unless specifically indicated. For further information on cobicistat, consultthe cobicistat Summary of Product Characteristics.

Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal productsare listed in the table below. The direction of the arrow for each pharmacokinetic parameter is basedon 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 ritonaviror cobicistat, the term “boosted PREZISTA” is used.

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

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

Medicinal product Interaction Recommendations concerningexamples by therapeutic Geometric mean change (%) co-administrationarea

HIV ANTIRETROVIRALS

Integrase strand transfer inhibitors

Dolutegravir dolutegravir AUC ↓ 22% Boosted PREZISTA anddolutegravir C24h ↓ 38% dolutegravir can be used withoutdolutegravir Cmax ↓ 11% dose adjustment.

darunavir ↔*

* Using cross-study comparisons to historicalpharmacokinetic data

Raltegravir Some clinical studies suggest raltegravir At present the effect of raltegravirmay cause a modest decrease in on darunavir plasmadarunavir plasma concentrations. concentrations does not appear tobe clinically relevant. Boosted

PREZISTA and raltegravir can beused without dose adjustments.

Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)

Didanosine didanosine AUC ↓ 9% Boosted PREZISTA and400 mg once daily didanosine Cmin ND didanosine can be used withoutdidanosine Cmax ↓ 16% dose adjustments.

darunavir AUC ↔ Didanosine is to be administereddarunavir C ↔ on an empty stomach, thus itmindarunavir C should be administered 1 hourmax ↔before or 2 hours after boosted

PREZISTA given with food.

Tenofovir disoproxil tenofovir AUC ↑ 22% Monitoring of renal function may245 mg once daily‡ tenofovir Cmin ↑ 37% be indicated when boostedtenofovir Cmax ↑ 24% PREZISTA is given in#darunavir AUC ↑ 21% combination with tenofovir#darunavir C ↑ 24% disoproxil, particularly in patientsmin# with underlying systemic or renaldarunavir Cmax ↑ 16%disease, or in patients taking(↑ tenofovir from effect on MDR-1nephrotoxic agents.transport in the renal tubules)

PREZISTA co-administered withcobicistat lowers the creatinineclearance. Refer to section 4.4 ifcreatinine clearance is used fordose adjustment of tenofovirdisoproxil.

Emtricitabine/tenofovir Tenofovir alafenamide ↔ The recommended dose ofalafenamide Tenofovir ↑ emtricitabine/tenofoviralafenamide is 200/10 mg oncedaily when used with boosted

PREZISTA.

Abacavir Not studied. Based on the different Boosted PREZISTA can be used

Emtricitabine elimination pathways of the other NRTIs with these NRTIs without dose

Lamivudine zidovudine, emtricitabine, stavudine, adjustment.

Stavudine lamivudine, that are primarily renally

Zidovudine excreted, and abacavir for which PREZISTA co-administered withmetabolism is not mediated by CYP450, cobicistat lowers the creatinineno interactions are expected for these clearance. Refer to section 4.4 ifmedicinal compounds and boosted creatinine clearance is used for

PREZISTA. dose adjustment of emtricitabine orlamivudine.

Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)

Efavirenz efavirenz AUC ↑ 21% Clinical monitoring for central600 mg once daily efavirenz Cmin ↑ 17% nervous system toxicity associatedefavirenz Cmax ↑ 15% with increased exposure to#darunavir AUC ↓ 13% efavirenz may be indicated when#darunavir Cmin ↓ 31% PREZISTA co-administered with# low dose ritonavir is given indarunavir Cmax ↓ 15%combination with efavirenz.(↑ efavirenz from CYP3A inhibition)(↓ darunavir from CYP3A induction)

Efavirenz in combination with

PREZISTA/ritonavir 800/100 mgonce daily may result insub-optimal darunavir Cmin. Ifefavirenz is to be used incombination with

PREZISTA/ritonavir, the

PREZISTA/ritonavir 600/100 mgtwice daily regimen should be used(see section 4.4).

Co-administration with

PREZISTA co-administered withcobicistat is not recommended (seesection 4.4).

Etravirine etravirine AUC ↓ 37% PREZISTA co-administered with100 mg twice daily etravirine Cmin ↓ 49% low dose ritonavir and etravirineetravirine Cmax ↓ 32% 200 mg twice daily can be useddarunavir AUC ↑ 15% without dose adjustments.

darunavir Cmin ↔darunavir C Co-administration withmax ↔

PREZISTA co-administered withcobicistat is not recommended (seesection 4.4).

Nevirapine nevirapine AUC ↑ 27% PREZISTA co-administered with200 mg twice daily nevirapine Cmin ↑ 47% low dose ritonavir and nevirapinenevirapine Cmax ↑ 18% can be used without dose#darunavir: concentrations were adjustments.

consistent with historical data(↑ nevirapine from CYP3A inhibition) Co-administration with

PREZISTA co-administered withcobicistat is not recommended (seesection 4.4).

Rilpivirine rilpivirine AUC ↑ 130% Boosted PREZISTA and rilpivirine150 mg once daily rilpivirine Cmin ↑ 178% can be used without doserilpivirine Cmax ↑ 79% adjustments.

darunavir AUC ↔darunavir Cmin ↓ 11%darunavir Cmax ↔

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

Atazanavir atazanavir AUC ↔ PREZISTA co-administered with300 mg once daily atazanavir Cmin ↑ 52% low dose ritonavir and atazanaviratazanavir Cmax ↓ 11% can be used without dose#darunavir AUC ↔ adjustments.#darunavir Cmin ↔# PREZISTA co-administered withdarunavir Cmax ↔cobicistat should not be used incombination with another

Atazanavir: comparison ofantiretroviral agent that requiresatazanavir/ritonavir 300/100 mg oncepharmacoenhancement by meansdaily vs. atazanavir 300 mg once daily inof co-administration with ancombination with darunavir/ritonavirinhibitor of CYP3A4 (see section400/100 mg twice daily.4.5).

Darunavir: comparison ofdarunavir/ritonavir 400/100 mg twicedaily vs. darunavir/ritonavir 400/100 mgtwice daily in combination withatazanavir 300 mg once daily.

Indinavir indinavir AUC ↑ 23% When used in combination with800 mg twice daily indinavir Cmin ↑ 125% PREZISTA co-administered withindinavir Cmax ↔ low dose ritonavir, dose#darunavir AUC ↑ 24% adjustment of indinavir from#darunavir Cmin ↑ 44% 800 mg twice daily to 600 mg# twice daily may be warranted indarunavir Cmax ↑ 11%case of intolerance.

Indinavir: comparison of

PREZISTA co-administered withindinavir/ritonavir 800/100 mg twicecobicistat should not be used indaily vs. indinavir/darunavir/ritonavircombination with another800/400/100 mg twice daily.antiretroviral agent that requires

Darunavir: comparison ofpharmacoenhancement by meansdarunavir/ritonavir 400/100 mg twiceof co-administration with andaily vs. darunavir/ritonavir 400/100 mginhibitor of CYP3A4 (see sectionin combination with indinavir 800 mg4.5).

twice daily.

Saquinavir #darunavir AUC ↓ 26% It is not recommended to combine1,000 mg twice daily #darunavir Cmin ↓ 42% PREZISTA co-administered with#darunavir C ↓ 17% low dose ritonavir with saquinavir.maxsaquinavir AUC ↓ 6%saquinavir C ↓ 18% PREZISTA co-administered withmincobicistat should not be used insaquinavir Cmax ↓ 6%combination with anotherantiretroviral agent that requires

Saquinavir: comparison ofpharmacoenhancement by meanssaquinavir/ritonavir 1,000/100 mg twiceof co-administration with andaily vs. saquinavir/darunavir/ritonavirinhibitor of CYP3A4 (see section1,000/400/100 mg twice daily4.5).

Darunavir: comparison ofdarunavir/ritonavir 400/100 mg twicedaily vs. darunavir/ritonavir 400/100 mgin combination with saquinavir 1,000 mgtwice daily.

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

Lopinavir/ritonavir lopinavir AUC ↑ 9% Due to a decrease in the exposure400/100 mg twice daily lopinavir Cmin ↑ 23% (AUC) of darunavir by 40%,lopinavir Cmax ↓ 2% appropriate doses of thedarunavir AUC ↓ 38%‡ combination have not beendarunavir C ↓ 51%‡ established. Hence, concomitantminuse of boosted PREZISTA and thedarunavir Cmax ↓ 21%‡

Lopinavir/ritonavir combination productlopinavir AUC ↔533/133.3 mg twice daily lopinavir/ritonavir islopinavir Cmin ↑ 13% contraindicated (see section 4.3).lopinavir Cmax ↑ 11%darunavir AUC ↓ 41%darunavir Cmin ↓ 55%darunavir Cmax ↓ 21%‡ based upon non dose normalised values

CCR5 ANTAGONIST

Maraviroc maraviroc AUC ↑ 305% The maraviroc dose should be150 mg twice daily maraviroc Cmin ND 150 mg twice daily whenmaraviroc Cmax ↑ 129% co-administered with boosteddarunavir, ritonavir concentrations were PREZISTA.

consistent with historical dataα1-ADRENORECEPTOR ANTAGONIST

Alfuzosin Based on theoretical considerations Co-administration of boosted

PREZISTA is expected to increase PREZISTA and alfuzosin isalfuzosin plasma concentrations. contraindicated (see section 4.3).(CYP3A inhibition)

ANAESTHETIC

Alfentanil Not studied. The metabolism of alfentanil The concomitant use with boostedis mediated via CYP3A, and may as such PREZISTA may require to lowerbe inhibited by boosted PREZISTA. the dose of alfentanil and requiresmonitoring for risks of prolongedor delayed respiratory depression.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide Not studied. Boosted PREZISTA is Caution is warranted and

Flecainide expected to increase these antiarrhythmic therapeutic concentration

Lidocaine (systemic) plasma concentrations. monitoring, if available, is

Mexiletine (CYP3A and/or CYP2D6 inhibition) recommended for these

Propafenone antiarrhythmics whenco-administered with boosted

PREZISTA.

Amiodarone Co-administration of boosted

Bepridil PREZISTA and amiodarone,

Dronedarone bepridil, dronedarone, ivabradine,

Ivabradine quinidine, or ranolazine is

Quinidine contraindicated (see section 4.3).

Ranolazine

Digoxin digoxin AUC ↑ 61% Given that digoxin has a narrow0.4 mg single dose digoxin Cmin ND therapeutic index, it isdigoxin Cmax ↑ 29% recommended that the lowest(↑ digoxin from probable inhibition of possible dose of digoxin should

P-gp) initially be prescribed in casedigoxin is given to patients onboosted PREZISTA therapy. Thedigoxin dose should be carefullytitrated to obtain the desiredclinical effect while assessing theoverall clinical state of the subject.

ANTIBIOTIC

Clarithromycin clarithromycin AUC ↑ 57% Caution should be exercised when500 mg twice daily clarithromycin Cmin ↑ 174% clarithromycin is combined withclarithromycin Cmax ↑ 26% boosted PREZISTA.#darunavir AUC ↓ 13%#darunavir C ↑ 1% For patients with renal impairmentmin# the Summary of Productdarunavir Cmax ↓ 17%

Characteristics for clarithromycin14-OH-clarithromycin concentrationsshould be consulted for thewere not detectable when combined withrecommended dose.

PREZISTA/ritonavir.(↑ clarithromycin from CYP3A inhibitionand possible P-gp inhibition)

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR

Apixaban Not studied. Co-administration of The use of boosted PREZISTA

Rivaroxaban boosted PREZISTA with these with a direct oral anticoagulantanticoagulants may increase (DOAC) that is metabolised byconcentrations of the anticoagulant. CYP3A4 and transported by P-gp(CYP3A and/or P-gp inhibition) is not recommended as this maylead to an increased bleeding risk.

Dabigatran etexilate dabigatran etexilate (150 mg): Darunavir/ritonavir:

Edoxaban darunavir/ritonavir 800/100 mg single Clinical monitoring and/or dosedose: reduction of the DOAC should bedabigatran AUC ↑ 72% considered when a DOACdabigatran Cmax ↑ 64% transported by P-gp but notmetabolised by CYP3A4,darunavir/ritonavir 800/100 mg once including dabigatran etexilate anddaily: edoxaban, is co-administered withdabigatran AUC ↑ 18% PREZISTA/rtv.

dabigatran Cmax ↑ 22%

Darunavir/cobicistat:

darunavir/cobicistat 800/150 mg single Clinical monitoring and dosedose: reduction is required when adabigatran AUC ↑ 164% DOAC transported by P-gp but notdabigatran C ↑ 164% metabolised by CYP3A4,maxincluding dabigatran etexilate anddarunavir/cobicistat 800/150 mg once edoxaban, is co-administered withdaily: PREZISTA/cobi.

dabigatran AUC ↑ 88%dabigatran Cmax ↑ 99%

Ticagrelor Concomitant administration of

Based on theoretical considerations,boosted PREZISTA with ticagrelorco-administration of boosted PREZISTAis contraindicated (see section 4.3).with ticagrelor may increaseconcentrations of ticagrelor (CYP3Aand/or P-glycoprotein inhibition).

Clopidogrel Co-administration of clopidogrel

Not studied. Co-administration ofwith boosted PREZISTA is notclopidogrel with boosted PREZISTA isrecommended. Use of otherexpected to decrease clopidogrel activeantiplatelets not affected by CYPmetabolite plasma concentration, whichinhibition or induction (e.g.may reduce the antiplatelet activity ofprasugrel) is recommended.clopidogrel.

Warfarin Not studied. Warfarin concentrations may It is recommended that thebe affected when co-administered with international normalised ratioboosted PREZISTA. (INR) be monitored when warfarinis combined with boosted

PREZISTA.

ANTICONVULSANTS

Phenobarbital Not studied. Phenobarbital and phenytoin PREZISTA co-administered with

Phenytoin are expected to decrease plasma low dose ritonavir should not beconcentrations of darunavir and its used in combination with thesepharmacoenhancer. medicines.(induction of CYP450 enzymes)

The use of these medicines with

PREZISTA/cobicistat iscontraindicated (see section 4.3).

Carbamazepine carbamazepine AUC ↑ 45% No dose adjustment for200 mg twice daily carbamazepine Cmin ↑ 54% PREZISTA/ritonavir iscarbamazepine Cmax ↑ 43% recommended. If there is a need todarunavir AUC ↔ combine PREZISTA/ritonavir anddarunavir C ↓ 15% carbamazepine, patients should bemindarunavir C ↔ monitored for potentialmaxcarbamazepine-related adverseevents. Carbamazepineconcentrations should bemonitored and its dose should betitrated for adequate response.

Based upon the findings, thecarbamazepine dose may need tobe reduced by 25% to 50% in thepresence of PREZISTA/ritonavir.

The use of carbamazepine with

PREZISTA co-administered withcobicistat is contraindicated (seesection 4.3).

Clonazepam Not studied. Co-administration of Clinical monitoring isboosted PREZISTA with clonazepam recommended whenmay increase concentrations of co-administering boostedclonazepam. (CYP3A inhibition) PREZISTA with clonazepam.

ANTIDEPRESSANTS

Paroxetine paroxetine AUC ↓ 39% If antidepressants are20 mg once daily paroxetine Cmin ↓ 37% co-administered with boostedparoxetine Cmax ↓ 36% PREZISTA, the recommended#darunavir AUC ↔ approach is a dose titration of the#darunavir C ↔ antidepressant based on a clinicalmin# assessment of antidepressantdarunavir Cmax ↔

Sertraline response. In addition, patients on asertraline AUC ↓ 49%50 mg once daily stable dose of these antidepressantssertraline Cmin ↓ 49% who start treatment with boostedsertraline Cmax ↓ 44% PREZISTA should be monitored#darunavir AUC ↔ for antidepressant response.#darunavir Cmin ↓ 6%#darunavir Cmax ↔

In contrast to these data with

PREZISTA/ritonavir,

PREZISTA/cobicistat may increase theseantidepressant plasma concentrations(CYP2D6 and/or CYP3A inhibition).

Amitriptyline Clinical monitoring is

Desipramine Concomitant use of boosted PREZISTA recommended when

Imipramine and these antidepressants may increase co-administering boosted

Nortriptyline concentrations of the antidepressant. PREZISTA with these

Trazodone (CYP2D6 and/or CYP3A inhibition) antidepressants and a doseadjustment of the antidepressantmay be needed.

ANTI-DIABETICS

Metformin Not studied. Based on theoretical Careful patient monitoring andconsiderations PREZISTA dose adjustment of metformin isco-administered with cobicistat is recommended in patients who areexpected to increase metformin plasma taking PREZISTA co-administeredconcentrations. with cobicistat.(MATE1 inhibition) (not applicable for PREZISTAco-administered with ritonavir)

ANTIEMETICS

Domperidone Not studied. Co-administration of domperidonewith boosted PREZISTA iscontraindicated.

ANTIFUNGALS

Voriconazole Not studied. Ritonavir may decrease Voriconazole should not beplasma concentrations of voriconazole. combined with boosted(induction of CYP450 enzymes) PREZISTA unless an assessmentof the benefit/risk ratio justifies the

Concentrations of voriconazole may use of voriconazole.increase or decrease whenco-administered with PREZISTAco-administered with cobicistat.(inhibition of CYP450 enzymes)

Fluconazole Not studied. Boosted PREZISTA may Caution is warranted and clinical

Isavuconazole increase antifungal plasma concentrations monitoring is recommended. When

Itraconazole and posaconazole, isavuconazole, co-administration is required the

Posaconazole itraconazole or fluconazole may increase daily dose of itraconazole shoulddarunavir concentrations. not exceed 200 mg.(CYP3A and/or P-gp inhibition)

Clotrimazole Not Studied. Concomitant systemic useof clotrimazole and boosted PREZISTAmay increase plasma concentrations ofdarunavir and/or clotrimazole.darunavir AUC24h ↑ 33% (based onpopulation pharmacokinetic model)

ANTIGOUT MEDICINES

Colchicine Not studied. Concomitant use of A reduction in colchicine dosagecolchicine and boosted PREZISTA may or an interruption of colchicineincrease the exposure to colchicine. treatment is recommended in(CYP3A and/ or P-gp inhibition) patients with normal renal orhepatic function if treatment withboosted PREZISTA is required.

For patients with renal or hepaticimpairment colchicine withboosted PREZISTA iscontraindicated (see sections 4.3and 4.4).

ANTIMALARIALS

Artemether/Lumefantrine artemether AUC ↓ 16% The combination of boosted80/480 mg, 6 doses at 0, artemether Cmin ↔ PREZISTA and8, 24, 36, 48, and artemether Cmax ↓ 18% artemether/lumefantrine can be60 hours dihydroartemisinin AUC ↓ 18% used without dose adjustments;dihydroartemisinin C ↔ however, due to the increase inmindihydroartemisinin Cmax ↓ 18% lumefantrine exposure, thelumefantrine AUC ↑ 175% combination should be used withcaution.

lumefantrine Cmin ↑ 126%lumefantrine Cmax ↑ 65%darunavir AUC ↔darunavir Cmin ↓ 13%darunavir Cmax ↔

ANTIMYCOBACTERIALS

Rifampicin Not studied. Rifapentine and rifampicin The combination of rifapentine and

Rifapentine are strong CYP3A inducers and have boosted PREZISTA is notbeen shown to cause profound decreases recommended.in concentrations of other proteaseinhibitors, which can result in virological The combination of rifampicin andfailure and resistance development boosted PREZISTA is(CYP450 enzyme induction). During contraindicated (see section 4.3).attempts to overcome the decreasedexposure by increasing the dose of otherprotease inhibitors with low doseritonavir, a high frequency of liverreactions was seen with rifampicin.

Rifabutin rifabutin AUC** ↑ 55% A dosage reduction of rifabutin by150 mg once every other rifabutin C **min ↑ ND 75% of the usual dose ofday rifabutin C ** ↔ 300 mg/day (i.e. rifabutin 150 mgmaxdarunavir AUC ↑ 53% once every other day) anddarunavir C ↑ 68% increased monitoring for rifabutinminrelated adverse events is warranteddarunavir Cmax ↑ 39%

** in patients receiving thesum of active moieties of rifabutin (parent combination with PREZISTAdrug + 25-O-desacetyl metabolite)co-administered with ritonavir. Incase of safety issues, a further

The interaction trial showed aincrease of the dosing interval forcomparable daily systemic exposure forrifabutin and/or monitoring ofrifabutin between treatment at 300 mgrifabutin levels should beonce daily alone and 150 mg once everyconsidered.

other day in combination with

Consideration should be given to

PREZISTA/ritonavir (600/100 mg twiceofficial guidance on thedaily) with an about 10-fold increase inappropriate treatment ofthe daily exposure to the activetuberculosis in HIV infectedmetabolite 25-O-desacetylrifabutin.patients.

Furthermore, AUC of the sum of active

Based upon the safety profile ofmoieties of rifabutin (parent drug

PREZISTA/ritonavir, the increase+ 25-O-desacetyl metabolite) wasin darunavir exposure in theincreased 1.6-fold, while Cmax remained presence of rifabutin does notcomparable. warrant a dose adjustment for

Data on comparison with a 150 mg once PREZISTA/ritonavir.daily reference dose is lacking. Based on pharmacokineticmodeling, this dosage reduction of(Rifabutin is an inducer and substrate of 75% is also applicable if patients

CYP3A.) An increase of systemic receive rifabutin at doses otherexposure to darunavir was observed when than 300 mg/day.

PREZISTA co-administered with 100 mgritonavir was co-administered with Co-administration of PREZISTArifabutin (150 mg once every other day). co-administered with cobicistatand rifabutin is not recommended.

ANTINEOPLASTICS

Dasatinib Not studied. Boosted PREZISTA is Concentrations of these medicinal

Nilotinib expected to increase these antineoplastic products may be increased when

Vinblastine plasma concentrations. co-administered with boosted

Vincristine (CYP3A inhibition) PREZISTA resulting in thepotential for increased adverseevents usually associated withthese agents.

Caution should be exercised whencombining one of theseantineoplastic agents with boosted

PREZISTA.

Everolimus Concomitant use of everolimus or

Irinotecan irinotecan and boosted PREZISTAis not recommended.

ANTIPSYCHOTICS/NEUROLEPTICS

Quetiapine Not studied. Boosted PREZISTA is Concomitant administration ofexpected to increase these antipsychotic boosted PREZISTA and quetiapineplasma concentrations. is contraindicated as it may(CYP3A inhibition) increase quetiapine-relatedtoxicity. Increased concentrationsof quetiapine may lead to coma(see section 4.3).

Perphenazine Not studied. Boosted PREZISTA is A dose decrease may be needed for

Risperidone expected to increase these antipsychotic these drugs when co-administered

Thioridazine plasma concentrations. with boosted PREZISTA.

(CYP3A, CYP2D6 and/or P-gp

Lurasidone inhibition) Concomitant administration of

Pimozide boosted PREZISTA and

Sertindole lurasidone, pimozide or sertindoleis contraindicated (see section 4.3).β-BLOCKERS

Carvedilol Not studied. Boosted PREZISTA is Clinical monitoring is

Metoprolol expected to increase these β-blocker recommended when

Timolol plasma concentrations. co-administering boosted(CYP2D6 inhibition) PREZISTA with β-blockers. Alower dose of the β-blocker shouldbe considered.

CALCIUM CHANNEL BLOCKERS

Amlodipine Not studied. Boosted PREZISTA can be Clinical monitoring of therapeutic

Diltiazem expected to increase the plasma and adverse effects is

Felodipine concentrations of calcium channel recommended when these

Nicardipine blockers. medicines are concomitantly

Nifedipine (CYP3A and/or CYP2D6 inhibition) administered with boosted

Verapamil PREZISTA.

CORTICOSTEROIDS

Corticosteroids primarily Fluticasone: in a clinical study where Concomitant use of boostedmetabolised by CYP3A ritonavir 100 mg capsules twice daily PREZISTA and corticosteroids (all(including were co-administered with 50 g routes of administration) that arebetamethasone, intranasal fluticasone propionate (4 times metabolised by CYP3A maybudesonide, fluticasone, daily) for 7 days in healthy subjects, increase the risk of development ofmometasone, prednisone, fluticasone propionate plasma systemic corticosteroid effects,triamcinolone) concentrations increased significantly, including Cushing’s syndrome andwhereas the intrinsic cortisol levels adrenal suppression.decreased by approximately 86% (90%

CI 82-89%). Greater effects may be Co-administration with CYP3A-expected when fluticasone is inhaled. metabolised corticosteroids is not

Systemic corticosteroid effects including recommended unless the potential

Cushing’s syndrome and adrenal benefit to the patient outweighs thesuppression have been reported in risk, in which case patients shouldpatients receiving ritonavir and inhaled or be monitored for systemicintranasally administered fluticasone. The corticosteroid effects.effects of high fluticasone systemicexposure on ritonavir plasma levels are Alternative corticosteroids whichunknown. are less dependent on CYP3Ametabolism e.g. beclomethasone

Other corticosteroids: interaction not should be considered, particularlystudied. Plasma concentrations of these for long term use.medicinal products may be increasedwhen co-administered with boosted

PREZISTA, resulting in reduced serumcortisol concentrations.

Dexamethasone Not studied. Dexamethasone may Systemic dexamethasone should(systemic) decrease plasma concentrations of be used with caution whendarunavir. combined with boosted(CYP3A induction) PREZISTA.

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan Not studied. Concomitant use of bosentan When administered concomitantlyand boosted PREZISTA may increase with PREZISTA and low doseplasma concentrations of bosentan. ritonavir, the patient’s tolerabilityof bosentan should be monitored.

Bosentan is expected to decrease plasmaconcentrations of darunavir and/or its Co-administration of PREZISTApharmacoenhancer. co-administered with cobicistat(CYP3A induction) and bosentan is not recommended.

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A protease inhibitors

Elbasvir/grazoprevir Boosted PREZISTA may increase the Concomitant use of boostedexposure to grazoprevir. PREZISTA and(CYP3A and OATP1B inhibition) elbasvir/grazoprevir iscontraindicated (see section 4.3).

Glecaprevir/pibrentasvir Based on theoretical considerations It is not recommended toboosted PREZISTA may increase the co-administer boosted PREZISTAexposure to glecaprevir and pibrentasvir. with glecaprevir/pibrentasvir.(P-gp, BCRP and/or OATP1B1/3inhibition)

HERBAL PRODUCTS

St John's Wort Not studied. St John’s Wort is expected Boosted PREZISTA must not be(Hypericum perforatum) to decrease the plasma concentrations of used concomitantly with productsdarunavir or its pharmacoenhancers. containing St John’s Wort(CYP450 induction) (Hypericum perforatum) (seesection 4.3). If a patient is alreadytaking St John’s Wort, stop

St John’s Wort and if possiblecheck viral levels. Darunavirexposure (and also ritonavirexposure) may increase onstopping St John’s Wort. Theinducing effect may persist for atleast 2 weeks after cessation oftreatment with St John’s Wort.

HMG CO-A REDUCTASE INHIBITORS

Lovastatin Not studied. Lovastatin and simvastatin Increased plasma concentrations of

Simvastatin are expected to have markedly increased lovastatin or simvastatin mayplasma concentrations when cause myopathy, includingco-administered with boosted rhabdomyolysis. Concomitant use

PREZISTA. of boosted PREZISTA with(CYP3A inhibition) lovastatin and simvastatin istherefore contraindicated (seesection 4.3).

Atorvastatin atorvastatin AUC ↑ 3-4 fold When administration of10 mg once daily atorvastatin Cmin ↑ ≈5.5-10 fold atorvastatin and boostedatorvastatin Cmax ↑ ≈2 fold PREZISTA is desired, it is# darunavir/ritonavir recommended to start with anatorvastatin dose of 10 mg onceatorvastatin AUC ↑ 290% Ω daily. A gradual dose increase ofatorvastatin may be tailored to theatorvastatin C ↑ 319% Ωmaxclinical response.atorvastatin C Ωmin ND

Ω with darunavir/cobicistat 800/150 mg

Pravastatin pravastatin AUC ↑ 81%¶ When administration of pravastatin40 mg single dose pravastatin Cmin ND and boosted PREZISTA ispravastatin C ↑ 63% required, it is recommended tomax¶ an up to five-fold increase was seen in a start with the lowest possible doselimited subset of subjects of pravastatin and titrate up to thedesired clinical effect whilemonitoring for safety.

Rosuvastatin rosuvastatin AUC ↑ 48%║ When administration of10 mg once daily rosuvastatin Cmax ↑ 144%║ rosuvastatin and boosted║ based on published data with PREZISTA is required, it isdarunavir/ritonavir recommended to start with thelowest possible dose ofrosuvastatin AUC ↑ 93%§ rosuvastatin and titrate up to therosuvastatin C ↑ 277%§ desired clinical effect whilemaxrosuvastatin C ND§ monitoring for safety.min§ with darunavir/cobicistat 800/150 mg

OTHER LIPID MODIFYING AGENTS

Lomitapide Based on theoretical considerations Co-administration isboosted PREZISTA is expected to contraindicated (see section 4.3).increase the exposure of lomitapide whenco-administered.(CYP3A inhibition)

H2-RECEPTOR ANTAGONISTS

Ranitidine #darunavir AUC ↔ Boosted PREZISTA can be150 mg twice daily #darunavir Cmin ↔ co-administered with H2-receptor#darunavir Cmax ↔ antagonists without doseadjustments.

IMMUNOSUPPRESSANTS

Ciclosporin Not studied. Exposure to these Therapeutic drug monitoring of the

Sirolimus immunosuppressants will be increased immunosuppressive agent must be

Tacrolimus when co-administered with boosted done when co-administration

PREZISTA. occurs.(CYP3A inhibition)

Everolimus Concomitant use of everolimusand boosted PREZISTA is notrecommended.

INHALED BETA AGONISTS

Salmeterol Not studied. Concomitant use of Concomitant use of salmeterol andsalmeterol and boosted darunavir may boosted PREZISTA is notincrease plasma concentrations of recommended. The combinationsalmeterol. may result in increased risk ofcardiovascular adverse event withsalmeterol, including QTprolongation, palpitations andsinus tachycardia.

NARCOTIC ANALGESICS/TREATMENT OF OPIOID DEPENDENCE

Methadone R(-) methadone AUC ↓ 16% No adjustment of methadoneindividual dose ranging R(-) methadone Cmin ↓ 15% dosage is required when initiatingfrom 55 mg to 150 mg R(-) methadone Cmax ↓ 24% co-administration with boostedonce daily PREZISTA. However, adjustment

PREZISTA/cobicistat may, in contrast, of the methadone dose may beincrease methadone plasma necessary when concomitantlyconcentrations (see cobicistat SmPC). administered for a longer period oftime. Therefore, clinicalmonitoring is recommended, asmaintenance therapy may need tobe adjusted in some patients.

Buprenorphine/naloxone buprenorphine AUC ↓ 11% The clinical relevance of the8/2 mg-16/4 mg once buprenorphine Cmin ↔ increase in norbuprenorphinedaily buprenorphine Cmax ↓ 8% pharmacokinetic parameters hasnorbuprenorphine AUC ↑ 46% not been established. Dosenorbuprenorphine C ↑ 71% adjustment for buprenorphine mayminnorbuprenorphine C not be necessary whenmax ↑ 36%naloxone AUC ↔ co-administered with boosted

PREZISTA but a careful clinicalnaloxone Cmin NDmonitoring for signs of opiatenaloxone Cmax ↔ toxicity is recommended.

Fentanyl Based on theoretical considerations Clinical monitoring is

Oxycodone boosted PREZISTA may increase plasma recommended when

Tramadol concentrations of these analgesics. co-administering boosted(CYP2D6 and/or CYP3A inhibition) PREZISTA with these analgesics.

OESTROGEN-BASED CONTRACEPTIVES

Drospirenone drospirenone AUC ↑ 58%€ When PREZISTA is

Ethinylestradiol drospirenone C €min ND co-administered with a(3 mg/0.02 mg once drospirenone Cmax ↑ 15%€ drospirenone-containing product,daily) ethinylestradiol AUC  30%€ clinical monitoring isrecommended due to the potentialethinylestradiol C €min NDfor hyperkalaemia.

ethinylestradiol Cmax  14%€€ with darunavir/cobicistat Alternative or additionalcontraceptive measures are

Ethinylestradiol ethinylestradiol AUC ↓ 44%βrecommended whenβ

Norethindrone ethinylestradiol Cmin ↓ 62% oestrogen-based contraceptives areβ35 g/1 mg once daily ethinylestradiol Cmax ↓ 32% co-administered with boostednorethindrone AUC ↓ 14%β PREZISTA. Patients usingnorethindrone Cmin ↓ 30%β oestrogens as hormonenorethindrone C ↔β replacement therapy should bemaxβ with darunavir/ritonavir clinically monitored for signs ofoestrogen deficiency.

OPIOID ANTAGONIST

Naloxegol Not studied. Co-administration of boosted

PREZISTA and naloxegol iscontraindicated.

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

For the treatment of In an interaction study #, a comparable The combination of avanafil anderectile dysfunction systemic exposure to sildenafil was boosted PREZISTA is

Avanafil observed for a single intake of 100 mg contraindicated (see section 4.3).

Sildenafil sildenafil alone and a single intake of Concomitant use of other PDE-5

Tadalafil 25 mg sildenafil co-administered with inhibitors for the treatment of

Vardenafil PREZISTA and low dose ritonavir. erectile dysfunction with boosted

PREZISTA should be done withcaution. If concomitant use ofboosted PREZISTA withsildenafil, vardenafil or tadalafil isindicated, sildenafil at a singledose not exceeding 25 mg in48 hours, vardenafil at a singledose not exceeding 2.5 mg in72 hours or tadalafil at a singledose not exceeding 10 mg in72 hours is recommended.

For the treatment of Not studied. Concomitant use of A safe and effective dose ofpulmonary arterial sildenafil or tadalafil for the treatment of sildenafil for the treatment ofhypertension pulmonary arterial hypertension and pulmonary arterial hypertension

Sildenafil boosted PREZISTA may increase plasma co-administered with boosted

Tadalafil concentrations of sildenafil or tadalafil. PREZISTA has not been(CYP3A inhibition) established. There is an increasedpotential for sildenafil-associatedadverse events (including visualdisturbances, hypotension,prolonged erection and syncope).

Therefore, co-administration ofboosted PREZISTA and sildenafilwhen used for the treatment ofpulmonary arterial hypertension iscontraindicated (see section 4.3).

Co-administration of tadalafil forthe treatment of pulmonary arterialhypertension with boosted

PREZISTA is not recommended.

PROTON PUMP INHIBITORS

Omeprazole #darunavir AUC ↔ Boosted PREZISTA can be20 mg once daily #darunavir Cmin ↔ co-administered with proton pump#darunavir C ↔ inhibitors without dosemaxadjustments.

SEDATIVES/HYPNOTICS

Buspirone Not studied. Sedative/hypnotics are Clinical monitoring is

Clorazepate extensively metabolised by CYP3A. recommended when

Diazepam Co-administration with boosted co-administering boosted

Estazolam PREZISTA may cause a large increase in PREZISTA with these

Flurazepam the concentration of these medicines. sedatives/hypnotics and a lower

Midazolam (parenteral) dose of the sedatives/hypnotics

Zolpidem should be considered.

If parenteral midazolam is If parenteral midazolam isco-administered with boosted PREZISTA co-administered with boostedit may cause a large increase in the PREZISTA, it should be done inconcentration of this benzodiazepine. an intensive care unit (ICU) or

Data from concomitant use of parenteral similar setting, which ensuresmidazolam with other protease inhibitors close clinical monitoring andsuggest a possible 3-4 fold increase in appropriate medical managementmidazolam plasma levels. in case of respiratory depressionand/or prolonged sedation. Doseadjustment for midazolam shouldbe considered, especially if morethan a single dose of midazolam isadministered.

Midazolam (oral) Boosted PREZISTA with

Triazolam triazolam or oral midazolam iscontraindicated (see section 4.3).

TREATMENT FOR PREMATURE EJACULATION

Dapoxetine Not studied. Co-administration of boosted

PREZISTA with dapoxetine iscontraindicated.

UROLOGICAL DRUGS

Fesoterodine Not studied. Use with caution. Monitor for

Solifenacin fesoterodine or solifenacin adversereactions, dose reduction offesoterodine or solifenacin may benecessary.

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

† The efficacy and safety of the use of PREZISTA with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavirand tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual therapy withprotease inhibitors is generally not recommended.

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

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection inpregnant 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 pregnantwomen. 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 thepotential 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 increasedrisk of HIV transmission to the child. Therapy with PREZISTA/cobicistat should not be initiatedduring pregnancy, and women who become pregnant during therapy with PREZISTA/cobicistatshould be switched to an alternative regimen (see sections 4.2 and 4.4).

It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated thatdarunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity of the offspring.

Because of the potential for adverse reactions in breast-fed infants, women should be instructed not tobreast-feed if they are receiving PREZISTA.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed.

No human data on the effect of darunavir on fertility are available. There was no effect on mating orfertility with darunavir treatment in rats (see section 5.3).

PREZISTA in combination with cobicistat or ritonavir has no or negligible influence on the ability todrive and use machines. However, dizziness has been reported in some patients during treatment withregimens containing PREZISTA co-administered with cobicistat or low dose ritonavir and should beborne in mind when considering a patient’s ability to drive or operate machinery (see section 4.8).

During the clinical development program (N=2,613 treatment-experienced subjects who initiatedtherapy with PREZISTA/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least oneadverse reaction. The total mean treatment duration for subjects was 95.3 weeks. The most frequentadverse 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, myocardialinfarction, 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 intreatment-naïve subjects was similar to that seen with PREZISTA/ritonavir 600/100 mg twice daily intreatment-experienced subjects except for nausea which was observed more frequently intreatment-naïve subjects. This was driven by mild intensity nausea. No new safety findings wereidentified in the 192 week analysis of the treatment-naïve subjects in which the mean treatmentduration 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-naïveand treatment-experienced subjects), 66.5% of subjects experienced at least one adverse reaction. Themean 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.

Adverse reactions are listed by system organ class (SOC) and frequency category. Within eachfrequency category, adverse reactions are presented in order of decreasing seriousness. Frequencycategories 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 estimatedfrom the available data).

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

MedDRA system organ class Adverse reaction

Frequency category

Infections and infestationsuncommon herpes simplex

Blood and lymphatic system disordersuncommon thrombocytopenia, neutropenia, anaemia,leukopeniarare increased eosinophil count

Immune system disordersuncommon immune reconstitution inflammatory syndrome,(drug) hypersensitivity

Endocrine disordersuncommon hypothyroidism, increased blood thyroidstimulating hormone

Metabolism and nutrition disorderscommon diabetes mellitus, hypertriglyceridaemia,hypercholesterolaemia, hyperlipidaemiauncommon gout, anorexia, decreased appetite, decreasedweight, increased weight, hyperglycaemia,insulin resistance, decreased high densitylipoprotein, increased appetite, polydipsia,increased blood lactate dehydrogenase

Psychiatric disorderscommon insomniauncommon depression, disorientation, anxiety, sleepdisorder, abnormal dreams, nightmare,decreased libidorare confusional state, altered mood, restlessness

Nervous system disorderscommon headache, peripheral neuropathy, dizzinessuncommon lethargy, paraesthesia, hypoaesthesia, dysgeusia,disturbance in attention, memory impairment,somnolencerare syncope, convulsion, ageusia, sleep phaserhythm disturbance

Eye disordersuncommon conjunctival hyperaemia, dry eyerare visual disturbance

Ear and labyrinth disordersuncommon vertigo

Cardiac disordersuncommon myocardial infarction, angina pectoris,prolonged electrocardiogram QT, tachycardiarare acute myocardial infarction, sinus bradycardia,palpitations

Vascular disordersuncommon hypertension, flushing

Respiratory, thoracic and mediastinal disordersuncommon dyspnoea, cough, epistaxis, throat irritationrare rhinorrhoea

Gastrointestinal disordersvery common diarrhoeacommon vomiting, nausea, abdominal pain, increasedblood amylase, dyspepsia, abdominal distension,flatulenceuncommon pancreatitis, gastritis, gastrooesophageal refluxdisease, aphthous stomatitis, retching, drymouth, abdominal discomfort, constipation,increased lipase, eructation, oral dysaesthesiarare stomatitis, haematemesis, cheilitis, dry lip,coated tongue

Hepatobiliary disorderscommon increased alanine aminotransferaseuncommon hepatitis, cytolytic hepatitis, hepatic steatosis,hepatomegaly, increased transaminase, increasedaspartate aminotransferase, increased bloodbilirubin, increased blood alkaline phosphatase,increased gamma-glutamyltransferase

Skin and subcutaneous tissue disorderscommon rash (including macular, maculopapular,papular, erythematous and pruritic rash), pruritusuncommon angioedema, generalised rash, allergicdermatitis, urticaria, eczema, erythema,hyperhidrosis, night sweats, alopecia, acne, dryskin, nail pigmentationrare DRESS, Stevens-Johnson syndrome, erythemamultiforme, dermatitis, seborrhoeic dermatitis,skin lesion, xerodermanot known toxic epidermal necrolysis, acute generalisedexanthematous pustulosis

Musculoskeletal and connective tissue disordersuncommon myalgia, osteonecrosis, muscle spasms,muscular weakness, arthralgia, pain inextremity, osteoporosis, increased blood creatinephosphokinaserare musculoskeletal stiffness, arthritis, joint stiffness

Renal and urinary disordersuncommon acute renal failure, renal failure, nephrolithiasis,increased blood creatinine, proteinuria,bilirubinuria, dysuria, nocturia, pollakiuriarare decreased creatinine renal clearancerare crystal nephropathy§

Reproductive system and breast disordersuncommon erectile dysfunction, gynaecomastia

General disorders and administration site conditionscommon asthenia, fatigueuncommon pyrexia, chest pain, peripheral oedema, malaise,feeling hot, irritability, painrare chills, abnormal feeling, xerosis§ adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics(Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determinedusing the 'Rule of 3'.

Adverse reactions observed with darunavir/cobicistat in adult patients

MedDRA system organ class Adverse reaction

Frequency category

Immune system disorderscommon (drug) hypersensitivityuncommon immune reconstitution inflammatory syndrome

Metabolism and nutrition disorderscommon anorexia, diabetes mellitus,hypercholesterolaemia, hypertriglyceridaemia,hyperlipidaemia

Psychiatric disorderscommon abnormal dreams

Nervous system disordersvery common headache

Gastrointestinal disordersvery common diarrhoea, nauseacommon vomiting, abdominal pain, abdominal distension,dyspepsia, flatulence, pancreatic enzymesincreaseduncommon pancreatitis acute

Hepatobiliary disorderscommon hepatic enzyme increaseduncommon hepatitis*, cytolytic hepatitis*

Skin and subcutaneous tissue disordersvery common rash (including macular, maculopapular,papular, erythematous, pruritic rash, generalisedrash, and allergic dermatitis)common angioedema, pruritus, urticariarare drug reaction with eosinophilia and systemicsymptoms*, Stevens-Johnson syndrome*not known toxic epidermal necrolysis*, acute generalisedexanthematous pustulosis*

Musculoskeletal and connective tissue disorderscommon myalgiauncommon osteonecrosis*

Renal and urinary disordersrare crystal nephropathy*§

Reproductive system and breast disordersuncommon gynaecomastia*

General disorders and administration site conditionscommon fatigueuncommon asthenia

Investigationscommon increased blood creatinine

* these adverse drug reactions have not been reported in clinical trial experience with darunavir/cobicistat but have beennoted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.§ adverse reaction identified in the post-marketing setting. Per the guideline on Summary of Product Characteristics(Revision 2, September 2009), the frequency of this adverse reaction in the post-marketing setting was determinedusing the 'Rule of 3'.

In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks oftreatment and resolving with continued dosing. In cases of severe skin reaction see the warning insection 4.4. In a single arm trial investigating darunavir 800 mg once daily in combination withcobicistat 150 mg once daily and other antiretrovirals 2.2% of patients discontinued treatment due torash.

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 withoutraltegravir or raltegravir without PREZISTA/ritonavir. Rash considered by the investigator to bedrug-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 2.3per 100 PYR, respectively. The rashes observed in clinical studies were mild to moderate in severityand did not result in discontinuation of therapy (see section 4.4).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (seesection 4.4).

Musculoskeletal abnormalities

Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use ofprotease inhibitors, particularly in combination with NRTIs.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, 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 combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and these events can occurmany months after initiation of treatment (see section 4.4).

Bleeding in haemophiliac patients

There have been reports of increased spontaneous bleeding in haemophiliac patients receivingantiretroviral protease inhibitors (see section 4.4).

The safety assessment of PREZISTA with ritonavir in paediatric patients is based on the 48-weekanalysis 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 atleast 20 kg who received PREZISTA tablets with low dose ritonavir twice daily in combinationwith other antiretroviral agents.

- 21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing10 kg to < 20 kg (16 participants from 15 kg to < 20 kg) who received PREZISTA oralsuspension 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 least40 kg who received PREZISTA tablets with low dose ritonavir once daily in combination withother antiretroviral agents (see section 5.1).

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

The safety assessment of PREZISTA with cobicistat in paediatric patients was evaluated inadolescents aged 12 to less than 18 years, weighing at least 40 kg through the clinical trial

GS-US-216-0128 (treatment-experienced, virologically suppressed, N=7). Safety analyses of thisstudy in adolescent subjects did not identify new safety concerns compared to the known safety profileof darunavir and cobicistat in adult subjects.

Patients co-infected with hepatitis B and/or hepatitis C virus

Among 1,968 treatment-experienced patients receiving PREZISTA co-administered with ritonavir600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients weremore likely to have baseline and treatment emergent hepatic transaminase elevations than thosewithout chronic viral hepatitis (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Human experience of acute overdose with PREZISTA co-administered with cobicistat or low doseritonavir is limited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mgof the tablet formulation of darunavir in combination with ritonavir have been administered to healthyvolunteers without untoward symptomatic effects.

There is no specific antidote for overdose with PREZISTA. Treatment of overdose with PREZISTAconsists of general supportive measures including monitoring of vital signs and observation of theclinical status of the patient. Since darunavir is highly protein bound, dialysis is unlikely to bebeneficial in significant removal of the active substance.

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

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 virusinfected cells, thereby preventing the formation of mature infectious virus particles.

Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratorystrains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells andhuman monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to5.0 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.

In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). Theselected 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 decreasedsusceptibility to darunavir of the emerging viruses in the selection experiment could not be explainedby 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 PREZISTAco-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 thesemutations developed during treatment.

Increasing baseline darunavir fold change in EC50 (FC) was associated with decreasing virologicresponse. 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 > 40are resistant (see Clinical results).

Viruses isolated from patients on PREZISTA/ritonavir 600/100 mg twice daily experiencing virologicfailure by rebound that were susceptible to tipranavir at baseline remained susceptible to tipranavirafter treatment in the vast majority of cases.

The lowest rates of developing resistant HIV virus are observed in ART-naïve patients who are treatedfor 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 PIsin virologic failures at endpoint in the ARTEMIS, ODIN and TITAN trials.

ARTEMIS ODIN TITAN

Week 192 Week 48 Week 48

PREZISTA/ PREZISTA/ PREZISTA/ PREZISTA/ritonavir ritonavir ritonavir ritonavir800/100 mg 800/100 mg 600/100 mg 600/100 mgonce daily once daily twice daily twice daily

N=343 N=294 N=296 N=298

Total number of 55 (16.0%) 65 (22.1%) 54 (18.2%) 31 (10.4%)virologic failuresa, n(%)

Rebounders 39 (11.4%) 11 (3.7%) 11 (3.7%) 16 (5.4%)

Never suppressed 16 (4.7%) 54 (18.4%) 43 (14.5%) 15 (5.0%)subjects

Number of subjects with virologic failure and paired baseline/endpoint genotypes, developing mutationsb atendpoint, n/N

Primary (major) PI 0/43 1/60 0/42 6/28mutations

PI RAMs 4/43 7/60 4/42 10/28

Number of subjects with virologic failure and paired baseline/endpoint phenotypes, showing loss ofsusceptibility to PIs at endpoint compared to baseline, n/N

PIdarunavir 0/39 1/58 0/41 3/26amprenavir 0/39 1/58 0/40 0/22atazanavir 0/39 2/56 0/40 0/22indinavir 0/39 2/57 0/40 1/24lopinavir 0/39 1/58 0/40 0/23saquinavir 0/39 0/56 0/40 0/22tipranavir 0/39 0/58 0/41 1/25a 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 treatedfor 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 combinationwith other ART. The table below shows the development of HIV-1 protease mutations and resistanceto PIs in virologic failures at endpoint in the GS-US-216-130 trial.

GS-US-216-130

Week 48

Treatment-naïve Treatment-experienceddarunavir/cobicistat 800/150 mg darunavir/cobicistat 800/150 mgonce daily once daily

N=295 N=18

Number of subjects with virologic failurea and genotype data that develop mutationsb at endpoint, n/N

Primary (major) PI 0/8 1/7mutations

PI RAMs 2/8 1/7

Number of subjects with virologic failurea and phenotype data that show resistance to PIs at endpointc, n/N

HIV PIdarunavir 0/8 0/7amprenavir 0/8 0/7atazanavir 0/8 0/7indinavir 0/8 0/7lopinavir 0/8 0/7saquinavir 0/8 0/7tipranavir 0/8 0/7a 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 visitb IAS-USA listsc In GS-US216-130 baseline phenotype was not available

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 tomost 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 wasobserved.

The pharmacokinetic enhancing effect of cobicistat on darunavir was evaluated in a Phase I study inhealthy subjects that were administered darunavir 800 mg with either cobicistat at 150 mg or ritonavirat 100 mg once daily. The steady-state pharmacokinetic parameters of darunavir were comparablewhen 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 oncedaily in combination with cobicistat 150 mg once daily with an investigator selected backgroundregimen 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 the48 week analyses from the GS-US-216-130 trial:

GS-US-216-130

Treatment-naïve Treatment-experienced All subjectsdarunavir/cobicistat darunavir/cobicistat darunavir/cobicistat

Outcomes at Week 48 800/150 mg once 800/150 mg once daily 800/150 mg once dailydaily+ OBR + OBR + OBR

N=295 N=18 N=313

HIV-1 RNA < 50 copies/mla 245 (83.1%) 8 (44.4%) 253 (80.8%)mean HIV-1 RNA log change -3.01 -2.39 -2.97from baseline(log10 copies/ml)

CD4+ cell count mean +174 +102 +170change from baselineba Imputations according to the TLOVR algorithmb 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 of192 week data from the randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviraltreatment-naïve HIV-1 infected patients comparing PREZISTA/ritonavir 800/100 mg once daily withlopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both armsused a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily andemtricitabine 200 mg once daily.

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

ARTEMIS

Week 48a Week 96b

Outcomes PREZISTA/ Lopinavir/ Treatment PREZISTA/ Lopinavir/ Treatmentritonavir ritonavir difference ritonavir ritonavir difference800/100 mg 800/200 mg (95% CI of 800/100 mg 800/200 m (95% CI ofonce daily per day difference) once daily g per day difference)

N=343 N=346 N=343 N=346

HIV-1 RNA< 50 copies/mlc

All patients 83.7% 78.3% 5.3% 79.0% 70.8% 8.2%(287) (271) (-0.5; 11.2)d (271) (245) (1.7; 14.7)d

With baseline 85.8% 84.5% 1.3% 80.5% 75.2% 5.3%

HIV-RNA (194/226) (191/226) (-5.2; 7.9)d (182/226) (170/226) (-2.3; 13.0)d< 100,000

With baseline 79.5% 66.7% 12.8% 76.1% 62.5% 13.6%

HIV-RNA (93/117) (80/120) (1.6; 24.1)d (89/117) (75/120) (1.9; 25.3)d≥ 100,000

With baseline 79.4% 70.3% 9.2% 78.7% 64.9% 13.9%

CD4+ cell (112/141) (104/148) (-0.8; 19.2)d (111/141) (96/148) (3.5; 24.2)dcount < 200

With baseline 86.6% 84.3% 2.3% 79.2% 75.3% 4.0%

CD4+ cell (175/202) (167/198) (-4.6; 9.2)d (160/202) (149/198) (-4.3; 12.2)dcount ≥ 200median 137 141 171 188

CD4+ cell countchange frombaseline(x 106/L)ea Data based on analyses at week 48b Data based on analyses at week 96c Imputations according to the TLOVR algorithmd Based on normal approximation to the difference in % responsee 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 percentageof 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 the48 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-administeredwith 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 Lopinavir/ritonavir Treatment difference600/100 mg twice daily + 400/100 mg twice daily + (95% CI of difference)

OBR OBR

N=298 N=297

HIV-1 RNA 70.8% (211) 60.3% (179) 10.5% (2.9; 18.1)b< 50 copies/mlamedian CD4+ cell 88 81count changefrom baseline(x 106/L)ca Imputations according to the TLOVR algorithmb Based on a normal approximation of the difference in % responsec NC=F

At 48 weeks non-inferiority in virologic response to the PREZISTA/ritonavir treatment, defined as thepercentage of patients with plasma HIV-1 RNA level < 400 and < 50 copies/ml, was demonstrated (atthe pre-defined 12% non-inferiority margin) for both ITT and OP populations. These results wereconfirmed in the analysis of data at 96 weeks of treatment in the TITAN trial, with 60.4% of patients inthe PREZISTA/ritonavir arm having HIV-1 RNA < 50 copies/ml at week 96 compared to 55.2% in thelopinavir/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 oncedaily versus PREZISTA/ritonavir 600/100 mg twice daily in ART-experienced HIV-1 infectedpatients 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 armsused an optimised background regimen (OBR) of ≥ 2 NRTIs.

ODIN

Outcomes PREZISTA/ritonavir PREZISTA/ritonavir Treatment difference800/100 mg once daily + 600/100 mg twice daily + (95% CI of difference)

OBR OBR

N=294 N=296

HIV-1 RNA 72.1% (212) 70.9% (210) 1.2% (-6.1; 8.5)b< 50 copies/mla

With Baseline HIV-1

RNA (copies/ml)< 100,000 77.6% (198/255) 73.2% (194/265) 4.4% (-3.0; 11.9)≥ 100,000 35.9% (14/39) 51.6% (16/31) -15.7% (-39.2; 7.7)

With Baseline CD4+cell count (x 106/L)≥ 100 75.1% (184/245) 72.5% (187/258) 2.6% (-5.1; 10.3)< 100 57.1% (28/49) 60.5% (23/38) -3.4% (-24.5; 17.8)

With HIV-1 clade

Type B 70.4% (126/179) 64.3% (128/199) 6.1% (-3.4; 15.6)

Type AE 90.5% (38/42) 91.2% (31/34) -0.7% (-14.0; 12.6)

Type C 72.7% (32/44) 78.8% (26/33) -6.1% (-2.6; 13.7)

Otherc 55.2% (16/29) 83.3% (25/30) -28.2% (-51.0; -5.3)mean CD4+ cell count 108 112 -5d (-25; 16)change from baseline(x 106/L)ea Imputations according to the TLOVR algorithmb Based on a normal approximation of the difference in % responsec Clades A1, D, F1, G, K, CRF02_AG, CRF12_BF, and CRF06_CPXd Difference in meanse 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 benon-inferior (at the pre-defined 12% non-inferiority margin) compared to PREZISTA/ritonavir600/100 mg twice daily for both ITT and OP populations.

PREZISTA/ritonavir 800/100 mg once daily in ART-experienced patients should not be used inpatients 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 isavailable in patients with HIV-1 clades other than B.

POWER 1 and POWER 2 are randomised, controlled trials comparing PREZISTA co-administeredwith 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/ Control Treatment PREZISTA/ Control Treatmentritonavir n=124 difference ritonavir n=124 difference600/100 mg 600/100 mgtwice daily twice dailyn=131 n=131

HIV RNA 45.0% 11.3% 33.7% 38.9% 8.9% 30.1%< 50 copies/mla (59) (14) (23.4%; (51) (11) (20.1; 40.0)c44.1%)c

CD4+ cell count 103 17 86 133 15 118mean change from (57; 114)c (83.9;baseline 153.4)c(x 106/L)ba Imputations according to the TLOVR algorithmb Last Observation Carried Forward imputationc 95% confidence intervals.

Analyses of data through 96 weeks of treatment in the POWER trials demonstrated sustainedantiretroviral 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 apredictive factor of virologic outcome.

Proportion (%) of patients with response (HIV-1 RNA < 50 copies/ml at week 24) to PREZISTAco-administered with ritonavir (600/100 mg twice daily) by baseline genotypea, and baselinedarunavir FC and by use of enfuvirtide (ENF): As treated analysis of the POWER and DUET trials.

Number of baseline mutationsa Baseline DRV FCb

Response (HIV-1

RNA < 50 copies/ml All0-2 3 ≥ 4 All ranges ≤ 10 10-40 > 40at week 24) ranges%, n/N45% 54% 39% 12% 45% 55% 29% 8%

All patients455/1,014 359/660 67/172 20/171 455/1,014 364/659 59/203 9/118

Patients with39% 50% 29% 7% 39% 51% 17% 5%no/non-naïve use ofc 290/741 238/477 35/120 10/135 290/741 244/477 25/147 5/94

ENF

Patients with naïve 60% 66% 62% 28% 60% 66% 61% 17%use of ENFd 165/273 121/183 32/52 10/36 165/273 120/182 34/56 4/24a 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 EC50c “Patients with no/non-naïve use of ENF” are patients who did not use ENF or who used ENF but not for the first timed “Patients with naïve use of ENF” are patients who used ENF for the first time

Efficacy of PREZISTA with ritonavir in 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, andefficacy of PREZISTA with low dose ritonavir in 80 ART-experienced HIV-1 infected paediatricpatients aged 6 to 17 years and weighing at least 20 kg. These patients received PREZISTA/ritonavirtwice daily in combination with other antiretroviral agents (see section 4.2 for dosagerecommendations 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 oralsolution (e.g. taste aversion) were allowed to switch to the capsule formulation. Of the 44 patientstaking ritonavir oral solution, 27 switched to the 100 mg capsule formulation and exceeded theweight-based ritonavir dose without changes in observed safety.

DELPHI

PREZISTA/ritonavir

Outcomes at week 48

N=80

HIV-1 RNA < 50 copies/mla 47.5% (38)

CD4+ cell count mean change from baselineb 147a 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 experiencedvirological failure, of which 17 (21.3%) patients were rebounders and 7 (8.8%) patients werenon-responders.

ART-experienced paediatric patients from the age of 3 to < 6 years

The pharmacokinetics, safety, tolerability and efficacy of PREZISTA/ritonavir twice daily incombination with other antiretroviral agents in 21 ART-experienced HIV-1 infected paediatric patientsaged 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 kgreceived darunavir/ritonavir 375/50 mg twice daily. At week 48, the virologic response, defined as thepercentage of patients with confirmed plasma viral load < 50 HIV-1 RNA copies/ml, was evaluated in16 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 dosagerecommendations per body weight).

ARIEL

Outcomes at week 48 PREZISTA/ritonavir10 kg to < 15 kg 15 kg to < 20 kg

N=5 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 16 241baselineba Imputations according to the TLOVR algorithm.b NC=F

Limited efficacy data are available in paediatric patients below 15 kg and no recommendation on aposology 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, andefficacy of PREZISTA with low dose ritonavir in 12 ART-naïve HIV-1 infected paediatric patientsaged 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. Virologicresponse was defined as a decrease in plasma HIV-1 RNA viral load of at least 1.0 log10 versusbaseline.

DIONE

PREZISTA/ritonavir

Outcomes at week 48

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.

Efficacy of PREZISTA with cobicistat in paediatric patients

In the open-label, Phase II/III trial GS-US-216-0128, the efficacy, safety, and pharmacokinetics ofdarunavir 800 mg and cobicistat 150 mg (administered as separate tablets) and at least 2 NRTIs wereevaluated in 7 HIV-1 infected, treatment-experienced, virologically suppressed adolescents weighingat least 40 kg. Patients were on a stable antiretroviral regimen (for at least 3 months), consisting ofdarunavir administered with ritonavir, combined with 2 NRTIs. They were switched from ritonavir tocobicistat 150 mg once daily and continued darunavir (N=7) and 2 NRTIs.

Virologic outcome in ART-experienced, virologically suppressed adolescents at week 48

GS-US-216-0128

Outcomes at Week 48 Darunavir/cobicistat + at least 2 NRTIs(N=7)

HIV-1 RNA < 50 copies/mL per FDA Snapshot 85.7% (6)

Approach

CD4+ percent median change from baselinea -6.1%

CD4+ cell count median change from baselinea -342 cells/mm³a No imputation (observed data).

Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with abackground regimen was evaluated in a clinical trial of 36 pregnant women (18 in each arm) duringthe second and third trimesters, and postpartum. Virologic response was preserved throughout thestudy period in both arms. No mother to child transmission occurred in the infants born to the31 subjects who stayed on the antiretroviral treatment through delivery. There were no new clinicallyrelevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1infected adults (see sections 4.2, pct. 4.4 and 5.2).

The pharmacokinetic properties of darunavir, co-administered with cobicistat or ritonavir, have beenevaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higherin HIV-1 infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1infected patients compared to healthy subjects may be explained by the higher concentrations ofα1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding toplasma AAG and, therefore, higher plasma concentrations.

Darunavir is primarily metabolised by CYP3A. Cobicistat and ritonavir inhibit CYP3A, therebyincreasing the plasma concentrations of darunavir considerably.

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

Characteristics.

Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration ofdarunavir 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 overallpharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemicexposure of darunavir when a single dose of 600 mg darunavir was given orally in combination withritonavir at 100 mg twice daily (see section 4.4).

When administered without food, the relative bioavailability of darunavir in the presence of cobicistator low dose ritonavir is lower as compared to intake with food. Therefore, PREZISTA tablets shouldbe taken with cobicistat or ritonavir and with food. The type of food does not affect exposure todarunavir.

Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma α1-acidglycoprotein.

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-dailyritonavir.

In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarilyundergoes oxidative metabolism. Darunavir is extensively metabolised by the hepatic CYP system andalmost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that amajority of the radioactivity in plasma after a single 400/100 mg darunavir with ritonavir dose was dueto the parent active substance. At least 3 oxidative metabolites of darunavir have been identified inhumans; all showed activity that was at least 10-fold less than the activity of darunavir against wildtype HIV.

After a 400/100 mg 14C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of theadministered dose of 14C-darunavir could be retrieved in faeces and urine, respectively. Unchangeddarunavir 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 whencombined with ritonavir.

The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was32.8 l/h and 5.9 l/h, respectively.

The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in74 treatment-experienced paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showedthat the administered weight-based doses of PREZISTA/ritonavir resulted in darunavir exposurecomparable 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 in14 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 thatachieved 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-naïvepaediatric 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 thatachieved in adults receiving PREZISTA/ritonavir 800/100 mg once daily. Therefore the same oncedaily dosage may be used in treatment-experienced adolescents aged 12 to < 18 years and weighing atleast 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 in10 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 thatachieved 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 agesof 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and allowedthe identification of weight-based PREZISTA/ritonavir once daily dosing regimens for paediatricpatients weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patientswithout 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 800 mg co-administered with cobicistat 150 mg in paediatricpatients have been studied in 7 adolescents aged 12 to less than 18 years, weighing at least 40 kg in

Study GS-US-216-0128. The geometric mean adolescent exposure (AUCtau) was similar for darunavirand increased 19% for cobicistat compared to exposures achieved in adults who received darunavir800 mg co-administered with cobicistat 150 mg in Study GS-US-216-0130. The difference observedfor cobicistat was not considered clinically relevant.

Adults in Study Adolescents in Study GLSM Ratio

GS-US-216-0130, week 24 GS-US-216-0128, day 10 (90% CI)(Reference)a (Test)b (Test/Reference)

Mean (%CV) Mean (%CV)

GLSM GLSM

N 60c 7

DRV PK

Parameter

AUCtau (h.ng/mL)d 81,646 (32.2) 80,877 (29.5) 1.00 (0.79-1.26)77,534 77,217

Cmax (ng/mL) 7,663 (25.1) 7,506 (21.7) 0.99 (0.83-1.17)7,422 7,319

C dtau (ng/mL) 1,311 (74.0) 1,087 (91.6) 0.71 (0.34-1.48)947 676

COBI PK

Parameter

AUCtau (h.ng/mL)d 7,596 (48.1) 8,741 (34.9) 1.19 (0.95-1.48)7,022 8,330

Cmax (ng/mL) 991 (33.4) 1,116 (20.0) 1.16 (1.00-1.35)945 1,095

Ctau (ng/mL)d 32.8 (289.4) 28.3 (157.2) 1.28 (0.51-3.22)17.2e 22.0ea Week 24 intensive PK data from subjects who received DRV 800 mg + COBI 150 mg.b Day 10 intensive PK data from subjects who received DRV 800 mg + COBI 150 mg.c N=59 for AUCtau and Ctau.d Concentration at predose (0 hours) was used as surrogate for concentration at 24 hours for the purposes of estimating

AUCtau and Ctau in Study GS-US-216-0128.e N=57 and N=5 for GLSM of Ctau in Study GS-US-216-0130 and Study GS-US-216-0128, respectively.

Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokineticsare 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 ageof 65 year.

Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIVinfected females compared to males. This difference is not clinically relevant.

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, populationpharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantlyaffected in HIV infected patients with moderate renal impairment (CrCl between 30-60 ml/min, n=20)(see sections 4.2 and 4.4).

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 totalplasma 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) and100% (Child-Pugh Class B) higher, respectively. The clinical relevance of this increase is unknowntherefore, PREZISTA should be used with caution. The effect of severe hepatic impairment on thepharmacokinetics of darunavir has not been studied (see sections 4.2, pct. 4.3 and 4.4).

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

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at600/100 mg twice daily as part of an antiretroviral regimen, during the second trimester ofpregnancy, the third trimester of pregnancy and postpartum

Pharmacokinetics of Second trimester of Third trimester of Postpartumtotal darunavir pregnancy pregnancy (6-12 weeks)(mean ± SD) (n=12)a (n=12) (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 ± 2,216a n=11 for AUC12h

Pharmacokinetic results of total darunavir after administration of darunavir/ritonavir at800/100 mg once daily as part of an antiretroviral regimen, during the second trimester ofpregnancy, the third trimester of pregnancy and postpartum

Pharmacokinetics of Second trimester of Third Trimester of Postpartumtotal darunavir pregnancy pregnancy (6-12 weeks)(mean ± SD) (n=17) (n=15) (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 ofpregnancy, mean intra-individual values for total darunavir Cmax, AUC12h and Cmin were 28%, 26% and26% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, totaldarunavir Cmax, AUC12h and Cmin values were 18%, 16% lower and 2% higher, respectively, ascompared with postpartum.

In women receiving darunavir/ritonavir 800/100 mg once daily during the second trimester ofpregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 33%, 31% and30% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, totaldarunavir Cmax, AUC24h and Cmin values were 29%, 32% and 50% lower, respectively, as comparedwith postpartum.

Treatment with darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavirexposure. In women receiving darunavir/cobicistat during the second trimester of pregnancy, meanintra-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 withpostpartum. 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 aconsequence of pregnancy-associated enzyme induction (see below).

Pharmacokinetic results of total darunavir after administration of darunavir/cobicistat800/150 mg once daily as part of an antiretroviral regimen, during the second trimester ofpregnancy, the third trimester of pregnancy, and postpartum

Pharmacokinetics of Second trimester Third trimester Postpartumtotal darunavir of pregnancy of pregnancy (6-12 weeks)(mean ± SD) (n=7) (n=6) (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 ofdarunavir. 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 ofpregnancy, cobicistat Cmax, AUC24h, and Cmin, were 27%, 49%, and 83% lower, respectively, ascompared with postpartum.

Animal toxicology studies have been conducted at exposures up to clinical exposure levels withdarunavir 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 treatmentwith darunavir. In rodents the target organs identified were the haematopoietic system, the bloodcoagulation system, liver and thyroid. A variable but limited decrease in red blood cell-relatedparameters was observed, together with increases in activated partial thromboplastin time.

Changes were observed in liver (hepatocyte hypertrophy, vacuolation, increased liver enzymes) andthyroid (follicular hypertrophy). In the rat, the combination of darunavir with ritonavir lead to a smallincrease in effect on RBC parameters, liver and thyroid and increased incidence of islet fibrosis in thepancreas (in male rats only) compared to treatment with darunavir alone. In the dog, no major toxicityfindings or target organs were identified up to exposures equivalent to clinical exposure at therecommended dose.

In a study conducted in rats, the number of corpora lutea and implantations were decreased in thepresence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavirtreatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at theclinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir inrats and rabbits when treated alone nor in mice when treated in combination with ritonavir. Theexposure levels were lower than those with the recommended clinical dose in humans. In a pre- andpostnatal development assessment in rats, darunavir with and without ritonavir, caused a transientreduction in body weight gain of the offspring pre-weaning and there was a slight delay in the openingof eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pupsthat 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 maternaltoxicity. No post weaning functions were affected with darunavir alone or in combination withritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed withconvulsions in some animals. Exposure in plasma, liver and brain was considerably higher than inadult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, theexposure was comparable to that in adult rats. The increased exposure was likely at least partly due toimmaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalitieswere noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile werecomparable to those observed in adult rats.

Due to uncertainties regarding the rate of development of the human blood brain barrier and liverenzymes, PREZISTA with low dose ritonavir should not be used in paediatric patients below 3 yearsof age.

Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats upto 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 ofhepatocellular adenomas and carcinomas were observed in males and females of both species. Thyroidfollicular cell adenomas were noted in male rats. Administration of darunavir did not cause astatistically significant increase in the incidence of any other benign or malignant neoplasm in mice orrats. The observed hepatocellular and thyroid tumours in rodents are considered to be of limitedrelevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzymeinduction and increased thyroid hormone elimination, which predispose rats, but not humans, tothyroid neoplasms. At the highest tested doses, the systemic exposures (based on AUC) to darunavirwere between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humansat the recommended therapeutic doses.

After 2 years administration of darunavir at exposures at or below the human exposure, kidneychanges 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 includingbacterial reverse mutation (Ames), chromosomal aberration in human lymphocytes and in vivomicronucleus test in mice.

Hydroxypropyl cellulose

Microcrystalline cellulose

Carmellose sodium

Citric acid monohydrate

Sucralose

Strawberry cream flavour

Masking flavour

Sodium methyl parahydroxybenzoate (E219)

Hydrochloric acid (for pH adjustment)

Purified water

Not applicable.

2 years

Do not store above 30°C.

Do not refrigerate or freeze. Avoid exposure to excessive heat.

Store in the original 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 filledwith a low density polyethylene (LDPE) insert that accommodates the dosing pipette.

PREZISTA oral suspension is available in packs of one bottle.

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

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/06/380/006

Date of first authorisation: 12 February 2007

Date of latest renewal: 19 September 2013

Detailed information on this medicinal product is available on the website of the European Medicines

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