PREZISTA 600mg tablets medication leaflet

PREZISTA 75 mg film-coated tablets

PREZISTA 150 mg film-coated tablets

PREZISTA 600 mg film-coated tablets

PREZISTA 75 mg film-coated tablets

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

PREZISTA 150 mg film-coated tablets

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

PREZISTA 600 mg film-coated tablets

Each film-coated tablet contains 600 mg of darunavir (as ethanolate).

Each tablet contains a maximum of 2.750 mg sunset yellow FCF (E110).

For the full list of excipients, see section 6.1.

PREZISTA 75 mg film-coated tablets

Film-coated tablet.

White caplet shaped tablet of 9.2 mm, debossed with “75” on one side and “TMC” on the other side.

PREZISTA 150 mg film-coated tablets

Film-coated tablet.

White oval shaped tablet of 13.7 mm, debossed with “150” on one side and “TMC” on the other side.

PREZISTA 600 mg film-coated tablets

Film-coated tablet.

Orange oval shaped tablet of 21.1 mm, debossed with “600MG” on one side and “TMC” on the otherside.

PREZISTA, co-administered with low dose ritonavir is indicated in combination with otherantiretroviral medicinal products for the treatment of patients with human immunodeficiency virus(HIV-1) infection (see section 4.2).

PREZISTA 75 mg, 150 mg, and 600 mg tablets may be used to provide suitable dose regimens (seesection 4.2):

- For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adultpatients, including those that have been highly pre-treated.

- For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least15 kg body weight.

In deciding to initiate treatment with PREZISTA co-administered with low dose ritonavir, carefulconsideration should be given to the treatment history of the individual patient and the patterns ofmutations 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.

PREZISTA must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and incombination with other antiretroviral medicinal products. The Summary of Product Characteristics ofritonavir must, therefore, be consulted prior to initiation of therapy with PREZISTA.

PREZISTA is also available as an oral suspension for use in patients who are unable to swallow

PREZISTA tablets (please refer to the Summary of Product Characteristics for PREZISTA oralsuspension).

ART-experienced adult patients

The recommended dose regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily takenwith food. PREZISTA 75 mg, 150 mg, and 600 mg tablets can be used to construct the twice daily600 mg regimen.

The use of 75 mg and 150 mg tablets to achieve the recommended dose is appropriate when there is apossibility of hypersensitivity to specific colouring agents, or difficulty in swallowing the 600 mgtablets.

ART-naïve adult patients

For dosage recommendations in ART-naïve patients see the Summary of Product Characteristics for

PREZISTA 400 mg and 800 mg tablets.

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 15 kg)

The weight-based dose of PREZISTA and ritonavir in paediatric patients is provided in the tablebelow.

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

Body weight (kg) Dose (once daily with food)≥ 15 kg to < 30 kg 600 mg PREZISTA/100 mg ritonavir once daily≥ 30 kg to < 40 kg 675 mg PREZISTA/100 mg ritonavir once daily≥ 40 kg 800 mg PREZISTA/100 mg ritonavir once dailya ritonavir oral solution: 80 mg/ml

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 15 kg)

PREZISTA twice daily taken with ritonavir taken with food is usually recommended.

A once daily dose regimen of PREZISTA taken with ritonavir taken with food may be used in patientswith prior exposure to antiretroviral medicinal products but without darunavir resistance associatedmutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cellcount ≥ 100 cells x 106/L.

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

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

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

PREZISTA tablets and ritonavira

Body weight (kg) Dose (once daily with food) Dose (twice daily with food)≥ 15 kg-< 30 kg 600 mg PREZISTA/100 mg ritonavir 375 mg PREZISTA/50 mg ritonavironce daily twice daily≥ 30 kg-< 40 kg 675 mg PREZISTA/100 mg ritonavir 450 mg PREZISTA/60 mg ritonavironce daily twice daily≥ 40 kg 800 mg PREZISTA/100 mg ritonavir 600 mg PREZISTA/100 mg ritonavironce daily twice dailya ritonavir oral solution: 80 mg/ml

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

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

In case a dose of PREZISTA and/or ritonavir is missed within 6 hours of the time it is usually taken,patients should be instructed to take the prescribed dose of PREZISTA and ritonavir with food as soonas possible. If this is noticed later than 6 hours after the time it is usually taken, the missed dose shouldnot be taken and the patient should resume the usual dosing schedule.

This guidance is based on the 15 hour half-life of darunavir in the presence of ritonavir and therecommended dosing interval of approximately 12 hours.

If a patient vomits within 4 hours of taking the medicine, another dose of PREZISTA with ritonavirshould be taken with food as soon as possible. If a patient vomits more than 4 hours after taking themedicine, the patient does not need to take another dose of PREZISTA with ritonavir until the nextregularly 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 in patients with renal impairment (see sections 4.4 and 5.2).

PREZISTA/ritonavir should not be used in children with a body weight of less than 15 kg as the dosefor this population has not been established in a sufficient number of patients (see section 5.1).

PREZISTA/ritonavir should not be used in children below 3 years of age because of safety concerns(see sections 4.4 and 5.3).

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

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).

Patients should be instructed to take PREZISTA with low dose ritonavir within 30 minutes aftercompletion of a meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5and 5.2).

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

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

Combination of strong CYP3A inducers such as rifampicin with PREZISTA with concomitant lowdose ritonavir (see section 4.5).

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

Co-administration with herbal preparations containing St John’s Wort (Hypericum perforatum) (seesection 4.5).

Co-administration of PREZISTA with low dose ritonavir, with active substances that are highlydependent on CYP3A for clearance and for which elevated plasma concentrations are associated withserious and/or life-threatening events. These active substances include e.g.:

- alfuzosin

- amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine

- astemizole, terfenadine

- colchicine when used in patients with renal and/or hepatic impairment (see section 4.5)

- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)

- elbasvir/grazoprevir

- cisapride

- dapoxetine

- domperidone

- naloxegol

- lurasidone, pimozide, quetiapine, sertindole (see section 4.5)

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

- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil

- simvastatin, lovastatin and lomitapide (see section 4.5)

- 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 low dose ritonavir as a pharmacokinetic enhancer and incombination with other antiretroviral medicinal products (see section 5.2). The Summary of Product

Characteristics of ritonavir as appropriate, must therefore be consulted prior to initiation of therapywith 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 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).

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/ritonavir and patients should be monitored during treatment. Increased AST/ALTmonitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patientswho have pre-treatment elevations of transaminases, especially during the first several months of

PREZISTA/ritonavir treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation ofliver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, livertenderness, hepatomegaly) in patients using PREZISTA/ritonavir, interruption or discontinuation oftreatment 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).

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.

Efavirenz in combination with boosted PREZISTA once daily may result in sub-optimal darunavir

Cmin. If efavirenz is to be used in combination with PREZISTA, the PREZISTA/ritonavir 600/100 mgtwice daily regimen should be used (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 600 mg tablets contain sunset yellow FCF (E110) which may cause an allergic reaction.

PREZISTA 75 mg, 150 mg, and 600 mg tablets contain less than 1 mmol sodium (23 mg) per tablet,that is to say essentially ‘sodium-free’.

Interaction studies have only been performed in adults.

Medicinal products that may be affected by darunavir boosted with ritonavir

Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration 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 darunavir/ritonavir 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).

PREZISTA co-administered with low dose ritonavir must not be combined with medicinal productsthat are highly dependent on CYP3A for clearance and for which increased systemic exposure isassociated with serious and/or life-threatening events (narrow therapeutic index) (see section 4.3).

The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase 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, PREZISTA must only be used incombination with low dose ritonavir as a pharmacokinetic enhancer (see sections 4.4 and 5.2).

A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes

CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity 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 affect darunavir/ritonavir exposure

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 darunavir and ritonavir (e.g. rifampicin, St John’s Wort, lopinavir).

Co-administration of darunavir and ritonavir and other medicinal products that inhibit CYP3A maydecrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations ofdarunavir and ritonavir (e.g. indinavir, azole antifungals like clotrimazole). These interactions aredescribed in the interaction table below.

Interactions between PREZISTA/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”).

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 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% PREZISTA co-administered withdolutegravir C24h ↓ 38% low dose ritonavir and dolutegravirdolutegravir Cmax ↓ 11% can be used without dosedarunavir ↔* adjustment.

* 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. PREZISTAco-administered with low doseritonavir and raltegravir can beused without dose adjustments.

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

Didanosine didanosine AUC ↓ 9% PREZISTA co-administered with400 mg once daily didanosine Cmin ND low dose ritonavir and didanosinedidanosine Cmax ↓ 16% can be used without dosedarunavir AUC ↔ adjustments.

darunavir C ↔ Didanosine is to be administeredmindarunavir C ↔ on an empty stomach, thus itmaxshould be administered 1 hourbefore or 2 hours after

PREZISTA/ritonavir given withfood.

Tenofovir disoproxil tenofovir AUC ↑ 22% Monitoring of renal function may245 mg once daily‡ tenofovir Cmin ↑ 37% be indicated when PREZISTAtenofovir Cmax ↑ 24% co-administered with low dose#darunavir AUC ↑ 21% ritonavir is given in combination#darunavir C ↑ 24% with tenofovir disoproxil,min# particularly in patients withdarunavir Cmax ↑ 16%underlying systemic or renal(↑ tenofovir from effect on MDR-1disease, or in patients takingtransport in the renal tubules)nephrotoxic agents.

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

Abacavir Not studied. Based on the different PREZISTA co-administered with

Emtricitabine elimination pathways of the other NRTIs low dose ritonavir can be used

Lamivudine zidovudine, emtricitabine, stavudine, with these NRTIs without dose

Stavudine lamivudine, that are primarily renally adjustment.

Zidovudine excreted, and abacavir for whichmetabolism is not mediated by CYP450,no interactions are expected for thesemedicinal compounds and PREZISTAco-administered with low dose ritonavir.

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 C ↓ 31% PREZISTA co-administered withmin# 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).

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 Cmax ↔

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)

Rilpivirine rilpivirine AUC ↑ 130% PREZISTA co-administered with150 mg once daily rilpivirine Cmin ↑ 178% low dose ritonavir and rilpivirinerilpivirine Cmax ↑ 79% can be used without dosedarunavir AUC ↔ adjustments.

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 ↔#darunavir Cmax ↔

Atazanavir: comparison ofatazanavir/ritonavir 300/100 mg oncedaily vs. atazanavir 300 mg once daily incombination with darunavir/ritonavir400/100 mg twice daily.

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 C 800 mg twice daily to 600 mgmin ↑ 44%# twice daily may be warranted indarunavir Cmax ↑ 11%case of intolerance.

Indinavir: comparison ofindinavir/ritonavir 800/100 mg twicedaily vs. indinavir/darunavir/ritonavir800/400/100 mg twice daily.

Darunavir: comparison ofdarunavir/ritonavir 400/100 mg twicedaily vs. darunavir/ritonavir 400/100 mgin combination with indinavir 800 mgtwice 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 Cmin ↓ 18%saquinavir Cmax ↓ 6%

Saquinavir: comparison ofsaquinavir/ritonavir 1,000/100 mg twicedaily vs. saquinavir/darunavir/ritonavir1,000/400/100 mg twice daily

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, concomitantmin‡ use of PREZISTA co-administereddarunavir Cmax ↓ 21%with low dose ritonavir and thelopinavir AUC ↔

Lopinavir/ritonavir combination product533/133.3 mg twice daily lopinavir Cmin ↑ 13% lopinavir/ritonavir islopinavir Cmax ↑ 11% contraindicated (see section 4.3).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 PREZISTAdarunavir, ritonavir concentrations were with low dose ritonavir.

consistent with historical dataα1-ADRENORECEPTOR ANTAGONIST

Alfuzosin Based on theoretical considerations Co-administration of PREZISTA

PREZISTA is expected to increase with low dose ritonavir andalfuzosin plasma concentrations. alfuzosin is contraindicated (see(CYP3A inhibition) section 4.3).

ANAESTHETIC

Alfentanil Not studied. The metabolism of alfentanil The concomitant use withis mediated via CYP3A, and may as such PREZISTA and low dose ritonavirbe inhibited by PREZISTA may require to lower the dose ofco-administered with low dose ritonavir. alfentanil and requires monitoringfor risks of prolonged or delayedrespiratory depression.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide Not studied. PREZISTA is expected to Caution is warranted and

Flecainide increase these antiarrhythmic plasma therapeutic concentration

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

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

Propafenone antiarrhythmics whenco-administered with PREZISTAwith low dose ritonavir.

Amiodarone PREZISTA co-administered with

Bepridil low dose ritonavir and

Dronedarone amiodarone, bepridil, dronedarone,

Ivabradine ivabradine, quinidine, or

Quinidine ranolazine is contraindicated (see

Ranolazine section 4.3).

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 ondarunavir/ritonavir 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% PREZISTA co-administered with#darunavir AUC ↓ 13% low dose ritonavir.#darunavir Cmin ↑ 1%# For patients with renal impairmentdarunavir Cmax ↓ 17%the Summary of Product14-OH-clarithromycin concentrations

Characteristics for clarithromycinwere not detectable when combined withshould be consulted for the

PREZISTA/ritonavir.

recommended dose.(↑ 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%

Ticagrelor Based on theoretical considerations, Concomitant administration ofco-administration of boosted PREZISTA boosted PREZISTA with ticagrelorwith ticagrelor may increase is contraindicated (see section 4.3).

concentrations of ticagrelor (CYP3Aand/or P-glycoprotein inhibition).

Clopidogrel Not studied. Co-administration of Co-administration of clopidogrelclopidogrel with boosted PREZISTA is with boosted PREZISTA is notexpected to decrease clopidogrel active recommended. Use of othermetabolite plasma concentration, which antiplatelets not affected by CYPmay reduce the antiplatelet activity of inhibition or induction (e.g.

clopidogrel. prasugrel) is recommended.

Warfarin Not studied. Warfarin concentrations may It is recommended that thebe affected when co-administered with international normalised ratiodarunavir with low dose ritonavir. (INR) be monitored when warfarinis combined with PREZISTAco-administered with low doseritonavir.

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)

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 Cmin ↓ 15% carbamazepine, patients should bedarunavir 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.

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 PREZISTAparoxetine Cmax ↓ 36% with low dose ritonavir, the#darunavir AUC ↔ recommended approach is a dose#darunavir C ↔ titration of the antidepressantmin# based on a clinical assessment ofdarunavir Cmax ↔

Sertraline antidepressant response. Insertraline AUC ↓ 49%50 mg once daily addition, patients on a stable dosesertraline Cmin ↓ 49% of these antidepressants who startsertraline Cmax ↓ 44% treatment with PREZISTA with#darunavir AUC ↔ low dose ritonavir should be#darunavir Cmin ↓ 6% monitored for antidepressant#darunavir Cmax ↔ response.

Concomitant use of PREZISTA Clinical monitoring isco-administered with low dose ritonavir recommended whenand these antidepressants may increase co-administering PREZISTA withconcentrations of the antidepressant. low dose ritonavir with these(CYP2D6 and/or CYP3A inhibition) antidepressants and a doseadjustment of the antidepressant

Amitriptyline may be needed.

Desipramine

Imipramine

Nortriptyline

Trazodone

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 PREZISTA(induction of CYP450 enzymes) co-administered with low doseritonavir unless an assessment ofthe benefit/risk ratio justifies theuse of voriconazole.

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

Isavuconazole antifungal plasma concentrations and monitoring is recommended. When

Itraconazole 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 use ofclotrimazole and darunavirco-administered with low dose ritonavirmay 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 darunavir co-administered or an interruption of colchicinewith low dose ritonavir may increase the treatment is recommended inexposure to colchicine. patients with normal renal or(CYP3A and/ or P-gp inhibition) hepatic function if treatment with

PREZISTA co-administered withlow dose ritonavir is required. Forpatients with renal or hepaticimpairment colchicine with

PREZISTA co-administered withlow dose ritonavir iscontraindicated (see sections 4.3and 4.4).

ANTIMALARIALS

Artemether/Lumefantrine artemether AUC ↓ 16% The combination of PREZISTA80/480 mg, 6 doses at 0, artemether Cmin ↔ and artemether/lumefantrine can8, 24, 36, 48, and artemether Cmax ↓ 18% be used without dose adjustments;60 hours dihydroartemisinin AUC ↓ 18% however, due to the increase indihydroartemisinin C lumefantrine exposure, themin ↔dihydroartemisinin C ↓ 18% combination should be used withmaxlumefantrine AUC ↑ 175% caution.

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 PREZISTA with concomitant lowbeen shown to cause profound decreases dose ritonavir is not recommended.in concentrations of other proteaseinhibitors, which can result in virological The combination of rifampicin andfailure and resistance development PREZISTA with concomitant low(CYP450 enzyme induction). During dose ritonavir is contraindicatedattempts to overcome the decreased (see section 4.3).exposure 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 withrifabutin (150 mg once every other day).

ANTINEOPLASTICS

Dasatinib Not studied. PREZISTA is expected to Concentrations of these medicinal

Nilotinib increase these antineoplastic plasma products may be increased when

Vinblastine concentrations. co-administered with PREZISTA

Vincristine (CYP3A inhibition) with low dose ritonavir resulting inthe potential for increased adverseevents usually associated withthese agents.

Caution should be exercised whencombining one of theseantineoplastic agents with

PREZISTA with low doseritonavir.

Everolimus Concomitant use of everolimus or

Irinotecan irinotecan and PREZISTAco-administered with low doseritonavir is not recommended.

ANTIPSYCHOTICS/NEUROLEPTICS

Quetiapine Not studied. PREZISTA is expected to Concomitant administration ofincrease these antipsychotic plasma PREZISTA with low doseconcentrations. ritonavir and quetiapine is(CYP3A inhibition) contraindicated as it may increasequetiapine-related toxicity.

Increased concentrations ofquetiapine may lead to coma (seesection 4.3).

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

Risperidone increase these antipsychotic plasma these drugs when co-administered

Thioridazine concentrations. with PREZISTA co-administered(CYP3A, CYP2D6 and/or P-gp with low dose ritonavir.inhibition)

Lurasidone Concomitant administration of

Pimozide PREZISTA with low dose

Sertindole ritonavir and lurasidone, pimozideor sertindole is contraindicated(see section 4.3).

β-BLOCKERS

Carvedilol Not studied. PREZISTA is expected to Clinical monitoring is

Metoprolol increase these β-blocker plasma recommended when

Timolol concentrations. co-administering PREZISTA with(CYP2D6 inhibition) β-blockers. A lower dose of theβ-blocker should be considered.

CALCIUM CHANNEL BLOCKERS

Amlodipine Not studied. PREZISTA co-administered Clinical monitoring of therapeutic

Diltiazem with low dose ritonavir can be expected and adverse effects is

Felodipine to increase the plasma concentrations of recommended when these

Nicardipine calcium channel blockers. medicines are concomitantly

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

Verapamil low dose ritonavir.

CORTICOSTEROIDS

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

CI 82-89%). Greater effects may beexpected when fluticasone is inhaled. Co-administration with CYP3A-

Systemic corticosteroid effects including metabolised corticosteroids is not

Cushing’s syndrome and adrenal recommended unless the potentialsuppression have been reported in benefit to the patient outweighs thepatients receiving ritonavir and inhaled or risk, in which case patients shouldintranasally administered fluticasone. The be monitored for systemiceffects of high fluticasone systemic corticosteroid effects.exposure on ritonavir plasma levels areunknown. Alternative corticosteroids whichare less dependent on CYP3A

Other corticosteroids: interaction not metabolism e.g. beclomethasonestudied. Plasma concentrations of these should be considered, particularlymedicinal products may be increased for long term use.when co-administered with PREZISTAwith low dose ritonavir, resulting inreduced serum cortisol concentrations.

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

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan Not studied. Concomitant use of bosentan When administered concomitantlyand PREZISTA co-administered with with PREZISTA and low doselow dose ritonavir may increase plasma ritonavir, the patient’s tolerabilityconcentrations of bosentan. of bosentan should be monitored.

Bosentan is expected to decrease plasmaconcentrations of darunavir and/or itspharmacoenhancer.(CYP3A induction)

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A protease inhibitors

Elbasvir/grazoprevir PREZISTA with low dose ritonavir may Concomitant use of PREZISTAincrease the exposure to grazoprevir. with low dose ritonavir 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 PREZISTA co-administered with(Hypericum perforatum) to decrease the plasma concentrations of low dose ritonavir must not bedarunavir and ritonavir. used concomitantly with products(CYP450 induction) containing St John’s Wort(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 rhabdomyolysis. Concomitant use

PREZISTAco-administered with low of PREZISTA co-administereddose ritonavir. with low dose ritonavir 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 PREZISTAatorvastatin Cmax ↑ ≈2 fold co-administered with low dose#darunavir/ritonavir ritonavir is desired, it isrecommended to start with anatorvastatin dose of 10 mg oncedaily. A gradual dose increase ofatorvastatin may be tailored to theclinical response.

Pravastatin pravastatin AUC ↑ 81%¶ When administration of pravastatin40 mg single dose pravastatin Cmin ND and PREZISTA co-administeredpravastatin C ↑ 63% with low dose ritonavir is required,max¶ an up to five-fold increase was seen in a it is recommended to start with thelimited subset of subjects lowest possible dose of pravastatinand titrate up to the desired clinicaleffect while monitoring for safety.

Rosuvastatin rosuvastatin AUC ↑ 48%║ When administration of10 mg once daily rosuvastatin Cmax ↑ 144%║ rosuvastatin and PREZISTA║ based on published data with co-administered with low dosedarunavir/ritonavir ritonavir is required, it isrecommended to start with thelowest possible dose ofrosuvastatin and titrate up to thedesired clinical effect whilemonitoring for safety.

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 ↔ PREZISTA co-administered with150 mg twice daily #darunavir Cmin ↔ low dose ritonavir can be#darunavir Cmax ↔ co-administered with H2-receptorantagonists 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 PREZISTA done when co-administrationco-administered with low dose ritonavir. occurs.(CYP3A inhibition)

Everolimus Concomitant use of everolimusand PREZISTA co-administeredwith low dose ritonavir is notrecommended.

INHALED BETA AGONISTS

Salmeterol Not studied. Concomitant use of Concomitant use of salmeterol andsalmeterol and darunavir co-administered PREZISTA co-administered withwith low dose ritonavir may increase low dose ritonavir is notplasma concentrations of salmeterol. recommended. The combinationmay 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 withonce daily PREZISTA/ritonavir. However,increased methadone dose may benecessary when concomitantlyadministered for a longer period oftime due to induction ofmetabolism by ritonavir.

Therefore, clinical monitoring isrecommended, as maintenancetherapy may need to be adjusted insome 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 ↑ 36% not be necessary whenmaxnaloxone AUC ↔ co-administered with

PREZISTA/ritonavir but a carefulnaloxone Cmin NDclinical monitoring for signs ofnaloxone Cmax ↔ opiate 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 Not studied with darunavir/ritonavir. When PREZISTA is co-

Ethinylestradiol administered with a drospirenone-(3 mg/0.02 mg once containing product, clinicaldaily) monitoring is recommended due tothe potential for hyperkalaemia.

Ethinylestradiol ethinylestradiol AUC ↓ 44%β Alternative or additional

Norethindrone ethinylestradiol Cmin ↓ 62%β contraceptive measures are35 g/1 mg once daily ethinylestradiol C β recommended whenmax ↓ 32%norethindrone AUC ↓ 14%β oestrogen-based contraceptives areβ co-administered with PREZISTAnorethindrone Cmin ↓ 30%β and low dose ritonavir.norethindrone Cmax ↔β with darunavir/ritonavir Patients using oestrogens ashormone replacement therapyshould be clinically monitored forsigns of oestrogen 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 PREZISTA with low dose

Avanafil observed for a single intake of 100 mg ritonavir is contraindicated (see

Sildenafil sildenafil alone and a single intake of section 4.3). Concomitant use of

Tadalafil 25 mg sildenafil co-administered with other PDE-5 inhibitors for the

Vardenafil PREZISTA and low dose ritonavir. treatment of erectile dysfunctionwith PREZISTA co-administeredwith low dose ritonavir should bedone with caution. If concomitantuse of PREZISTA co-administeredwith low dose ritonavir 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 darunavir co-administered with low dose co-administered with PREZISTA

Tadalafil ritonavir may increase plasma and low dose ritonavir has notconcentrations of sildenafil or tadalafil. been established. There is an(CYP3A inhibition) increased potential forsildenafil-associated adverseevents (including visualdisturbances, hypotension,prolonged erection and syncope).

Therefore, co-administration of

PREZISTA with low doseritonavir and sildenafil when usedfor the treatment of pulmonaryarterial hypertension iscontraindicated (see section 4.3).

Co-administration of tadalafil forthe treatment of pulmonary arterialhypertension with PREZISTA andlow dose ritonavir is notrecommended.

PROTON PUMP INHIBITORS

Omeprazole #darunavir AUC ↔ PREZISTA co-administered with20 mg once daily #darunavir Cmin ↔ low dose ritonavir can be#darunavir C ↔ co-administered with proton pumpmaxinhibitors without doseadjustments.

SEDATIVES/HYPNOTICS

Buspirone Not studied. Sedative/hypnotics are Clinical monitoring is

Clorazepate extensively metabolised by CYP3A. recommended when

Diazepam Co-administration with co-administering PREZISTA with

Estazolam PREZISTA/ritonavir may cause a large these sedatives/hypnotics and a

Flurazepam increase in the concentration of these lower dose of the

Midazolam (parenteral) medicines. sedatives/hypnotics should be

Zolpidem considered.

If parenteral midazolam is If parenteral midazolam isco-administered with PREZISTA co-administered with PREZISTAco-administered with low dose ritonavir it with low dose ritonavir, it shouldmay cause a large increase in the be done in an intensive care unitconcentration of this benzodiazepine. (ICU) or similar setting, which

Data from concomitant use of parenteral ensures close clinical monitoringmidazolam with other protease inhibitors and appropriate medicalsuggest a possible 3-4 fold increase in management in case of respiratorymidazolam plasma levels. depression and/or prolongedsedation. Dose adjustment formidazolam should be considered,especially if more than a singledose of midazolam isadministered.

Midazolam (oral) PREZISTA with low dose

Triazolam ritonavir with triazolam or oralmidazolam is contraindicated (seesection 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.

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 ritonavir has no or negligible influence on the ability to drive and usemachines. However, dizziness has been reported in some patients during treatment with regimenscontaining PREZISTA co-administered with low dose ritonavir and should be borne in mind whenconsidering 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.

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

Uncommon herpes simplex

Uncommon thrombocytopenia, neutropenia, anaemia,leukopenia

Rare increased eosinophil count

Uncommon immune reconstitution inflammatory syndrome,(drug) hypersensitivity

Uncommon hypothyroidism, increased blood thyroidstimulating hormone

Common diabetes mellitus, hypertriglyceridaemia,hypercholesterolaemia, hyperlipidaemia

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

Common insomniauncommon depression, disorientation, anxiety, sleepdisorder, abnormal dreams, nightmare,decreased libido

Rare confusional state, altered mood, restlessness

Common headache, peripheral neuropathy, dizziness

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

Rare syncope, convulsion, ageusia, sleep phaserhythm disturbance

Uncommon conjunctival hyperaemia, dry eye

Rare visual disturbance

Ear and labyrinth disorders

Uncommon vertigo

Uncommon myocardial infarction, angina pectoris,prolonged electrocardiogram QT, tachycardia

Rare acute myocardial infarction, sinus bradycardia,palpitations

Uncommon hypertension, flushing

Uncommon dyspnoea, cough, epistaxis, throat irritation

Rare rhinorrhoea

Gastrointestinal disordersvery common diarrhoea

Common vomiting, nausea, abdominal pain, increasedblood amylase, dyspepsia, abdominal distension,flatulence

Uncommon pancreatitis, gastritis, gastrooesophageal refluxdisease, aphthous stomatitis, retching, drymouth, abdominal discomfort, constipation,increased lipase, eructation, oral dysaesthesia

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

Common increased alanine aminotransferase

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

Common rash (including macular, maculopapular,papular, erythematous and pruritic rash), pruritus

Uncommon angioedema, generalised rash, allergicdermatitis, urticaria, eczema, erythema,hyperhidrosis, night sweats, alopecia, acne, dryskin, nail pigmentation

Rare DRESS, Stevens-Johnson syndrome, erythemamultiforme, dermatitis, seborrhoeic dermatitis,skin lesion, xerodermanot known toxic epidermal necrolysis, acute generalisedexanthematous pustulosis

Uncommon myalgia, osteonecrosis, muscle spasms,muscular weakness, arthralgia, pain inextremity, osteoporosis, increased blood creatinephosphokinase

Rare musculoskeletal stiffness, arthritis, joint stiffness

Uncommon acute renal failure, renal failure, nephrolithiasis,increased blood creatinine, proteinuria,bilirubinuria, dysuria, nocturia, pollakiuria

Rare decreased creatinine renal clearance

Rare crystal nephropathy§

Uncommon erectile dysfunction, gynaecomastia

Common asthenia, fatigue

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

Rare 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'.

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.

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 in paediatric patients is based on the 48-week analysis of safety data from three

Phase II trials. The following patient populations were evaluated (see section 5.1):

- 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing 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.

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 low dose ritonavir islimited. Single doses up to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of thetablet 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

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.

Adult patients

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

Efficacy of PREZISTA 600 mg twice daily co-administered with 100 mg ritonavir twice daily in

ART-experienced patients

The evidence of efficacy of PREZISTA co-administered with ritonavir (600/100 mg twice daily) in

ART-experienced patients is based on the 96 weeks analysis of the Phase III trial TITAN in

ART-experienced lopinavir naïve patients, on the 48 week analysis of the Phase III trial ODIN in

ART-experienced patients with no DRV-RAMs, and on the analyses of 96 weeks data from the

Phase IIb trials POWER 1 and 2 in ART-experienced patients with high level of PI resistance.

TITAN is a randomised, controlled, open-label Phase III trial comparing PREZISTA co-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 (x 153.4)c106/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 All All0-2 3 ≥ 4 ≤ 10 10-40 > 40at week 24) ranges 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

For clinical trial results in ART-naïve paediatric patients aged 12 to 17 years, refer to the Summary of

Product Characteristics for PREZISTA 400 mg and 800 mg tablets or PREZISTA 100 mg/ml oralsuspension.

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 baselineb 16 241a 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.

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 ritonavir, have been evaluated inhealthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1infected patients than in healthy subjects. The increased exposure to darunavir in HIV-1 infectedpatients compared to healthy subjects may be explained by the higher concentrations of α1-acidglycoprotein (AAG) in HIV-1 infected patients, resulting in higher darunavir binding to plasma AAGand, therefore, higher plasma concentrations.

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

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 low doseritonavir is 30% lower as compared to intake with food. Therefore, PREZISTA tablets should be takenwith ritonavir and with food. The type of food does not affect exposure to darunavir.

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

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.

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.

PREZISTA 75 mg film-coated tablets

Microcrystalline cellulose

Colloidal anhydrous silica

Crospovidone

Magnesium stearate

Tablet film-coat

Poly(vinyl alcohol) - partially hydrolysed

Macrogol 3350

Titanium dioxide (E171)

Talc

PREZISTA 150 mg film-coated tablets

Microcrystalline cellulose

Colloidal anhydrous silica

Crospovidone

Magnesium stearate

Tablet film-coat

Poly(vinyl alcohol) - partially hydrolysed

Macrogol 3350

Titanium dioxide (E171)

Talc

PREZISTA 600 mg film-coated tablets

Microcrystalline cellulose

Colloidal anhydrous silica

Crospovidone

Magnesium stearate

Tablet film-coat

Poly(vinyl alcohol) - partially hydrolysed

Macrogol 3350

Titanium dioxide (E171)

Talc

Sunset yellow FCF (E110)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PREZISTA 75 mg film-coated tablets

Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 480 tablets, fittedwith polypropylene (PP) child resistant closure.

Pack size of one bottle.

PREZISTA 150 mg film-coated tablets

Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 240 tablets, fittedwith polypropylene (PP) child resistant closure.

Pack size of one bottle.

PREZISTA 600 mg film-coated tablets

Opaque, white, high density polyethylene (HDPE) plastic, 160 ml bottle containing 60 tablets, fittedwith polypropylene (PP) child resistant closure.

Pack size of one bottle.

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

PREZISTA 75 mg film-coated tablets

EU/1/06/380/005

PREZISTA 150 mg film-coated tablets

EU/1/06/380/004

PREZISTA 600 mg film-coated tablets

EU/1/06/380/002

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.