REZOLSTA 800mg / 150mg tablets medication leaflet

REZOLSTA 800 mg/150 mg film-coated tablets

Each film-coated tablet contains 800 mg of darunavir (as ethanolate) and 150 mg of cobicistat.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Pink oval shaped tablet of 23 mm x 11.5 mm, debossed with “800” on one side and “TG” on the otherside.

REZOLSTA is indicated, in combination with other antiretroviral medicinal products, for thetreatment of human immunodeficiency virus-1 (HIV-1) infection in adults and adolescents (aged12 years and older, weighing at least 40 kg).

Genotypic testing should guide the use of REZOLSTA (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.

The recommended dose regimen in adults and adolescents aged 12 years and older, weighing at least40 kg, is one tablet taken once daily with food.

ART-naïve patients

The recommended dose regimen is one film-coated tablet of REZOLSTA once daily taken with food.

ART-experienced patients

One film-coated tablet of REZOLSTA once daily taken with food may be used in patients with priorexposure to antiretroviral medicinal products, but without darunavir resistance associated mutations(DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/mL and CD4+ cell count≥ 100 cells x 106/L (see section 4.1).

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

In all other ART-experienced patients or if HIV-1 genotype testing is not available, the use of

REZOLSTA is not appropriate and another antiretroviral regimen should be used. Refer to the

Summary of Product Characteristics of other antiretroviral medicinal products for dosing information.

If REZOLSTA is missed within 12 hours of the time it is usually taken, patients should be instructedto take the prescribed dose of REZOLSTA with food as soon as possible. If this is noticed later than12 hours of the time it is usually taken, the missed dose should not be taken and the patient shouldresume the usual dosing schedule.

If a patient vomits within 4 hours of taking the medicine, another dose of REZOLSTA should be takenwith food as soon as possible. If a patient vomits more than 4 hours after taking the medicine, thepatient does not need to take another dose of REZOLSTA until the next regularly scheduled time.

Limited information is available in this population, and therefore, REZOLSTA should be used withcaution in patients above 65 years of age (see sections 4.4 and 5.2).

There are no pharmacokinetic data regarding the use of REZOLSTA in patients with hepaticimpairment.

Darunavir and cobicistat are metabolised by the hepatic system. Separate trials of darunavir/ritonavirand cobicistat suggest no dose adjustment is recommended in patients with mild (Child-Pugh Class A)or moderate (Child-Pugh Class B) hepatic impairment, however, REZOLSTA should be used withcaution in these patients.

There are no data regarding the use of darunavir or cobicistat in patients with severe hepaticimpairment. Severe hepatic impairment could result in an increase of darunavir and/or cobicistatexposure and a worsening of its safety profile. Therefore, REZOLSTA must not be used in patientswith severe hepatic impairment (Child-Pugh Class C) (see sections pct. 4.3, pct. 4.4 and 5.2).

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubularsecretion of creatinine. REZOLSTA should not be initiated in patients with creatinine clearance lessthan 70 mL/min, if any co-administered medicinal product (e.g. emtricitabine, lamivudine, tenofovirdisoproxil (as fumarate, phosphate or succinate), or adefovir dipivoxil) requires dose adjustment basedon creatinine clearance (see sections 4.4, pct. 4.8 and 5.2).

Based on the very limited renal elimination of cobicistat and darunavir, no special precautions or doseadjustments of REZOLSTA are required for patients with renal impairment. Darunavir, cobicistat, orthe combination of both have not been studied in patients receiving dialysis, and therefore norecommendation can be made for these patients (see section 5.2).

For more information consult the cobicistat Summary of Product Characteristics.

The safety and efficacy of REZOLSTA in paediatric patients aged 3 to 11 years, or weighing < 40 kg,have not been established (see sections 4.4 and 5.3). No data are available. REZOLSTA should not beused in paediatric patients below 3 years of age because of safety concerns (see sections 4.4 and 5.3).

Treatment with REZOLSTA during pregnancy results in low darunavir exposure (see sections 4.4 and5.2). Therefore, therapy with REZOLSTA should not be initiated during pregnancy, and women whobecome pregnant during therapy with REZOLSTA should be switched to an alternative regimen (seesections 4.4 and 4.6). Darunavir/ritonavir may be considered as an alternative.

Oral use

To ensure administration of the entire dose of both darunavir and cobicistat, the tablet should beswallowed whole. For patients unable to swallow the whole tablet, REZOLSTA may be split into twopieces using a tablet-cutter, and the entire dose should be consumed immediately after splitting.

Patients should be instructed to take REZOLSTA within 30 minutes after completion of a meal (seesections 4.4, 4.5 and 5.2).

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

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

Co-administration with strong CYP3A inducers such as the medicinal products listed below due to thepotential for loss of therapeutic effect (see section 4.5):

- carbamazepine, phenobarbital, phenytoin

- rifampicin

- lopinavir/ritonavir

- St John’s Wort (Hypericum perforatum).

Co-administration with medicinal products such as those products listed below due to the potential forserious and/or life-threatening adverse reactions (see section 4.5):

- alfuzosin

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

- astemizole, terfenadine

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

- rifampicin

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

- cisapride

- dapoxetine

- domperidone

- naloxegol

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

- elbasvir/grazoprevir

- 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.

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

Darunavir binds predominantly to α1-acid glycoprotein. This protein binding is concentrationdependent indicative for saturation of binding. Therefore, protein displacement of medicinal productshighly bound to α1-acid glycoprotein cannot be ruled out (see section 4.5).

ART-experienced patients

REZOLSTA should not be used in treatment-experienced patients with one or more DRV-RAMs or

HIV-1 RNA ≥ 100,000 copies/mL or CD4+ cell count < 100 cells x 106/L (see section 4.2).

Combinations with optimised background regimens (OBRs) other than ≥ 2 NRTIs have not beenstudied in this population. Limited data is available in patients with HIV-1 clades other than B (seesection 5.1).

Treatment with darunavir/cobicistat 800/150 mg during the second and third trimester has been shownto result in low darunavir exposure, with a reduction of around 90% in Cmin levels (see section 5.2).

Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction indarunavir exposure may result in virological failure and an increased risk of mother to childtransmission of HIV infection. Therefore, therapy with REZOLSTA should not be initiated duringpregnancy, and women who become pregnant during therapy with REZOLSTA should be switched toan alternative regimen (see sections 4.2 and 4.6). Darunavir given with low dose ritonavir may beconsidered as an alternative.

As limited information is available on the use of REZOLSTA in patients aged 65 and over, cautionshould be exercised, reflecting the greater frequency of decreased hepatic function and of concomitantdisease or other therapy (see sections 4.2 and 5.2).

Severe skin reactions

During the darunavir/ritonavir clinical development program (N = 3,063), severe skin reactions, 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-Johnsonsyndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermalnecrolysis and acute generalised exanthematous pustulosis have been reported. REZOLSTA 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 with 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 containingdarunavir/ritonavir + raltegravir compared to patients receiving darunavir/ritonavir without raltegraviror raltegravir without darunavir/ritonavir (see section 4.8).

Sulphonamide allergy

Darunavir contains a sulphonamide moiety. REZOLSTA should be used with caution in patients witha known sulphonamide allergy.

Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported withdarunavir/ritonavir. During the clinical development program (N = 3,063), hepatitis was reported in0.5% of patients receiving combination antiretroviral therapy with darunavir/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 REZOLSTA andpatients should be monitored during treatment. Increased AST/ALT monitoring should be consideredin patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatmentelevations of transaminases, especially during the first several months of REZOLSTA 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 REZOLSTA, interruption or discontinuation of treatmentshould be considered promptly.

Patients with coexisting conditions

The safety and efficacy of REZOLSTA, darunavir, or cobicistat have not been established in patientswith severe underlying liver disorders. REZOLSTA is, therefore, contraindicated in patients withsevere hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations,

REZOLSTA should be used with caution in patients with mild or moderate hepatic impairment (seesections 4.2, pct. 4.3 and 5.2).

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubularsecretion of creatinine. This effect on serum creatinine, leading to a decrease in the estimatedcreatinine clearance, should be taken into consideration when REZOLSTA is administered to patients,in whom the estimated creatinine clearance is used to guide aspects of their clinical management,including adjusting doses of co-administered medicinal products. For more information consult thecobicistat Summary of Product Characteristics.

REZOLSTA should not be initiated in patients with creatinine clearance less than 70 mL/min whenco-administered with one or more agent requiring dose adjustment based on creatinine clearance (e.g.emtricitabine, lamivudine, tenofovir disoproxil (as fumarate, phosphate or succinate) or adefovirdipivoxil) (see sections 4.2, pct. 4.8 and 5.2).

No special precautions or dose adjustments are required in patients with renal impairment. Asdarunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will besignificantly removed by haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2).

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

There have been reports of increased bleeding, including spontaneous skin haematomas andhaemarthrosis in patients with haemophilia type A and B treated with HIV PIs. In some patientsadditional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs wascontinued or reintroduced if treatment had been discontinued. A causal relationship has beensuggested, although the mechanism of action has not been elucidated. Haemophiliac patients should,therefore, be made aware 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 (IRIS)

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 trials with darunavirco-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).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine andstrong inhibitors of CYP3A and P-glycoprotein (see section 4.5).

REZOLSTA should not be used in combination with another antiretroviral that requirespharmacoenhancement since dosing recommendations for such combination have not beenestablished. REZOLSTA should not be used concurrently with products containing ritonavir orregimens containing ritonavir or cobicistat.

Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or

UGT1A1. If switching from ritonavir as a pharmacoenhancer to cobicistat, caution is required duringthe first two weeks of treatment with REZOLSTA, particularly if doses of any concomitantlyadministered medicinal products have been titrated or adjusted during use of ritonavir as apharmacoenhancer.

REZOLSTA is not recommended for use in paediatric patients (3 to 11 years of age). REZOLSTAshould not be used in paediatric patients below 3 years of age (see sections 4.2 and 5.3).

REZOLSTA contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

As REZOLSTA contains darunavir and cobicistat, interactions that have been identified withdarunavir (in combination with cobicistat or with low dose ritonavir) or with cobicistat determine theinteractions that may occur with REZOLSTA. Interaction trials with darunavir/cobicistat,darunavir/ritonavir and with cobicistat have only been performed in adults.

Medicinal products that may be affected by darunavir/cobicistat

Darunavir is an inhibitor of CYP3A, a weak inhibitor of CYP2D6 and an inhibitor of P-gp. Cobicistatis a mechanism based inhibitor of CYP3A, and a weak CYP2D6 inhibitor. Cobicistat inhibits thetransporters p-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Cobicistat is notexpected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat is not expected toinduce CYP1A2, CYP3A4, CYP2C9, CYP2C19, UGT1A1, or P-gp (MDR1).

Co-administration of darunavir/cobicistat and medicinal products primarily metabolised by CYP3A ortransported by P-gp, BCRP, MATE1, OATP1B1 and OATP1B3 may result in increased systemicexposure to such medicinal products, which could increase or prolong their therapeutic effect andadverse reactions (see section 4.3 or table below).

REZOLSTA must not be combined with medicinal products that are highly dependent on CYP3A forclearance and for which increased systemic exposure is associated with serious and/or life-threateningevents (narrow therapeutic index).

Co-administration of REZOLSTA with medicinal products that have active metabolite(s) formed by

CYP3A may result in reduced plasma concentrations of these active metabolite(s) potentially leadingto loss of their therapeutic effect. These interactions are described in the interaction table below.

Medicinal products that affect darunavir/cobicistat exposure

Darunavir and cobicistat are metabolised by CYP3A. Medicinal products that induce CYP3A activitywould be expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasmaconcentrations of darunavir and cobicistat (e.g. efavirenz, carbamazepine, phenytoin, phenobarbital,rifampicin, rifapentine, rifabutin, St John’s Wort) (see section 4.3 and interaction table below).

Co-administration of REZOLSTA and other medicinal products that inhibit CYP3A may decrease theclearance of darunavir and cobicistat and may result in increased plasma concentrations of darunavirand cobicistat (e.g. azole antifungals such as clotrimazole). These interactions are described in theinteraction table below.

REZOLSTA should not be used concurrently with products or regimens containing ritonavir orcobicistat. REZOLSTA should not be used in combination with the individual components of

REZOLSTA (darunavir or cobicistat). REZOLSTA should not be used in combination with anotherantiretroviral that requires pharmacoenhancement since dosing recommendations for suchcombination have not been established.

Expected interactions between REZOLSTA and antiretroviral and non-antiretroviral medicinalproducts are listed in the table below and are based on the identified interactions withdarunavir/ritonavir, darunavir/cobicistat and with cobicistat.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used aspharmacokinetic enhancer, therefore there may be different recommendations for the use of darunavirwith concomitant medicine. In the table below it is specified when recommendations for REZOLSTAdiffer from those for darunavir boosted with low dose ritonavir. Refer to the Summary of Product

Characteristics for PREZISTA for further information.

The below list of examples of drug drug interactions is not comprehensive and therefore the label ofeach drug that is co-administered with REZOLSTA 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 examples by Interaction Recommendations concerningtherapeutic area co-administration

HIV ANTIRETROVIRALS

Integrase strand transfer inhibitors

Dolutegravir Based on theoretical REZOLSTA and dolutegravir canconsiderations dolutegravir is not be used without doseexpected to affect the adjustments.pharmacokinetics of REZOLSTA.

Raltegravir Some clinical trials suggest At present the effect ofraltegravir may cause a modest raltegravir on darunavir plasmadecrease in darunavir plasma concentrations does not appear toconcentrations. be clinically relevant;

REZOLSTA and raltegravir canbe used without doseadjustments.

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

Didanosine No mechanistic interaction REZOLSTA and didanosine can400 mg once daily expected based on theoretical be used without doseconsideration. adjustments.

When didanosine isco-administered with

REZOLSTA, didanosine shouldbe administered on an emptystomach 1 hour before or 2 hoursafter REZOLSTA (which isadministered with food).

Tenofovir disoproxil * Based on theoretical REZOLSTA and tenofovirconsiderations REZOLSTA is disoproxil can be used without

*study was done with tenofovir expected to increase tenofovir dose adjustments.disoproxil fumarate plasma concentrations. Monitoring of renal function may(P-glycoprotein inhibition) be indicated when REZOLSTA isgiven in combination withtenofovir disoproxil, particularlyin patients with underlyingsystemic or renal disease, or inpatients taking nephrotoxicagents.

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

REZOLSTA.

Abacavir Based on the different elimination REZOLSTA can be used with

Emtricitabine pathways of the other NRTIs (i.e. these NRTIs without dose

Lamivudine emtricitabine, lamivudine, adjustment.

Stavudine stavudine and zidovudine) that are

Zidovudine primarily renally excreted, andabacavir for which metabolism isnot mediated by CYP, nointeractions are expected for thesemedicinal compounds and

REZOLSTA.

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

Efavirenz Based on theoretical Co-administration ofconsiderations efavirenz is REZOLSTA and efavirenz is notexpected to decrease darunavir recommended.and/or cobicistat plasmaconcentrations. This recommendation is different(CYP3A induction) from ritonavir-boosted darunavir.

Consult the Summary of Product

Characteristics for darunavir forfurther details.

Etravirine Based on theoretical Co-administration ofconsiderations etravirine is REZOLSTA and etravirine is notexpected to decrease darunavir recommended.and/or cobicistat plasmaconcentrations. This recommendation is different(CYP3A induction) from ritonavir-boosted darunavir.

Consult the Summary of Product

Characteristics for darunavir forfurther details.

Nevirapine Based on theoretical Co-administration ofconsiderations nevirapine is REZOLSTA and nevirapine isexpected to decrease darunavir not recommended.and/or cobicistat plasmaconcentrations, (CYP3A This recommendation is differentinduction). REZOLSTA is from ritonavir-boosted darunavir.expected to increase nevirapine Consult the Summary of Productplasma concentrations. Characteristics for darunavir for(CYP3A inhibition) further details.

Rilpivirine Based on theoretical Co-administration ofconsiderations REZOLSTA is REZOLSTA and rilpivirine canexpected to increase rilpivirine be used without doseplasma concentrations. adjustments, as the expected(CYP3A inhibition) increase in rilpivirineconcentrations is not consideredclinically relevant.

CCR5 ANTAGONIST

Maraviroc Based on theoretical The recommended dose of150 mg twice daily considerations REZOLSTA is maraviroc is 150 mg twice dailyexpected to increase maraviroc when co-administered withplasma concentrations. REZOLSTA. For further details,(CYP3A inhibition) consult the maraviroc Summaryof Product Characteristics.α1-ADRENORECEPTOR ANTAGONIST

Alfuzosin Based on theoretical Co-administration ofconsiderations REZOLSTA is REZOLSTA with alfuzosin isexpected to increase alfuzosin contraindicated (see section 4.3).plasma concentrations.(CYP3A inhibition)

ANAESTHETIC

Alfentanil Based on theoretical The concomitant use withconsiderations REZOLSTA is REZOLSTA may require toexpected to increase alfentanil lower the dose of alfentanil andplasma concentrations. requires monitoring for risks ofprolonged or delayed respiratorydepression.

ANTACIDS

Aluminium/magnesium No mechanistic interaction REZOLSTA and antacids can behydroxide expected based on theoretical used concomitantly without dose

Calcium carbonate consideration. adjustment.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide Based on theoretical Caution is warranted and

Flecainide considerations REZOLSTA is therapeutic concentration

Lidocaine (systemic) expected to increase these monitoring, if available, is

Mexiletine antiarrhythmic plasma recommended for these

Propafenone concentrations. antiarrhythmics when(CYP3A and/or CYP2D6 co-administered withinhibition) REZOLSTA.

Amiodarone Co-administration of amiodarone,

Bepridil bepridil, dronedarone, ivabradine,

Dronedarone quinidine, or ranolazine and

Ivabradine REZOLSTA is contraindicated

Quinidine (see section 4.3).

Ranolazine

Digoxin Based on theoretical It is recommended that the lowestconsiderations REZOLSTA is possible dose of digoxin shouldexpected to increase digoxin initially be given to patients onplasma concentrations. REZOLSTA. The digoxin dose(P-glycoprotein inhibition) should be carefully titrated toobtain the desired clinical effectwhile assessing the overallclinical state of the subject.

ANTIBIOTIC

Clarithromycin Based on theoretical Caution should be exercisedconsiderations clarithromycin is when clarithromycin is combinedexpected to increase darunavir with REZOLSTA.and/or cobicistat plasmaconcentrations. For patients with renal(CYP3A inhibition) impairment the Summary of

Concentrations of clarithromycin Product Characteristics formay be increased upon clarithromycin should beco-administration with consulted for the recommended

REZOLSTA. dose.(CYP3A inhibition)

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR

Apixaban Based on theoretical Co-administration of

Rivaroxaban considerations co-administration REZOLSTA with a direct oralof REZOLSTA with these anticoagulant (DOAC) that isanticoagulants may increase metabolised by CYP3A4 andconcentrations of the transported by P-gp is notanticoagulant. recommended as this may lead to(CYP3A and/or P-glycoprotein an increased bleeding risk.inhibition)

Dabigatran etexilate dabigatran etexilate (150 mg): Clinical monitoring and dose

Edoxaban darunavir/cobicistat 800/150 mg reduction is required when asingle dose: DOAC transported by P-gp butdabigatran AUC ↑ 164% not metabolised by CYP3A4,dabigatran Cmax ↑ 164% including dabigatran etexilate andedoxaban, is co-administereddarunavir/cobicistat 800/150 mg with REZOLSTA.

once daily:dabigatran AUC ↑ 88%dabigatran Cmax ↑ 99%

Concomitant administration of

Ticagrelor Based on theoretical REZOLSTA with ticagrelor isconsiderations co-administration contraindicated (see section 4.3).

of REZOLSTA with ticagrelormay increase concentrations ofticagrelor.(CYP3A and/or P-glycoproteininhibition). Co-administration of

Clopidogrel REZOLSTA with clopidogrel is

Based on theoretical not recommended. Use of otherconsiderations co-administration antiplatelets not affected by CYPof REZOLSTA with clopidogrel is inhibition or induction (e.g.

expected to decrease clopidogrel prasugrel) is recommended (seeactive metabolite plasma section 4.3).

concentration, which may reducethe antiplatelet activity ofclopidogrel.

Warfarin Based on theoretical It is recommended that theconsiderations REZOLSTA may international normalised ratioalter warfarin plasma (INR) be monitored whenconcentrations. warfarin is co-administered with

REZOLSTA.

ANTICONVULSANTS

Carbamazepine Based on theoretical Co-administration of

Phenobarbital considerations these REZOLSTA and these

Phenytoin anticonvulsants are expected to anticonvulsants is contraindicateddecrease darunavir and/or (see section 4.3).cobicistat plasma concentrations.(CYP3A induction)

Clonazepam Based on theoretical Clinical monitoring isconsiderations REZOLSTA is recommended whenexpected to increase co-administering REZOLSTAconcentrations of clonazepam. with clonazepam.(inhibition of CYP3A)

ANTI-DEPRESSANTS

Herbal supplements Based on theoretical Co-administration of

St John’s Wort considerations St John’s Wort is St John’s Wort and REZOLSTAexpected to decrease darunavir is contraindicated (seeand/or cobicistat plasma section 4.3).concentrations.(CYP3A induction)

Paroxetine Based on theoretical If these anti-depressants are to be

Sertraline considerations REZOLSTA is used with REZOLSTA clinicalexpected to increase these monitoring is recommended andanti-depressant plasma a dose adjustment of theconcentrations. anti-depressant may be needed.(CYP2D6 and/or CYP3Ainhibition)

Prior data with ritonavir-boosteddarunavir however showed adecrease in these anti-depressantplasma concentrations (unknownmechanism); the latter may bespecific to ritonavir.

Amitriptyline Based on theoretical

Desipramine considerations REZOLSTA is

Imipramine expected to increase these

Nortriptyline anti-depressant plasma

Trazodone concentrations.

(CYP2D6 and/or CYP3Ainhibition)

ANTI-DIABETICS

Metformin Based on theoretical Careful patient monitoring andconsiderations REZOLSTA is dose adjustment of metformin isexpected to increase metformin recommended in patients who areplasma concentrations. taking REZOLSTA.(MATE1 inhibition)

ANTIEMETICS

Domperidone Not studied. Co-administration ofdomperidone with REZOLSTA iscontraindicated.

ANTIFUNGALS

Clotrimazole Based on theoretical Caution is warranted and clinical

Fluconazole considerations REZOLSTA is monitoring is recommended.

Itraconazole expected to increase these

Isavuconazole antifungal plasma concentrations, When co-administration is

Posaconazole and darunavir and/or cobicistat required, the daily dose ofplasma concentrations may be itraconazole should not exceedincreased by the antifungals. 200 mg.(CYP3A inhibition and/or P-gpinhibition)

Voriconazole Concentrations of voriconazole Voriconazole should not bemay increase or decrease when combined with REZOLSTAco-administered with unless an assessment of the

REZOLSTA. benefit/risk ratio justifies the useof voriconazole.

ANTIGOUT MEDICINES

Colchicine Based on theoretical A reduction in colchicine dosageconsiderations REZOLSTA is or an interruption of colchicineexpected to increase colchicine treatment is recommended inplasma concentrations. patients with normal renal or(CYP3A and/or P-glycoprotein hepatic function if treatment withinhibition) REZOLSTA is required.

The combination of colchicineand REZOLSTA iscontraindicated in patients withrenal or hepatic impairment (seesection 4.3).

ANTIMALARIALS

Artemether/Lumefantrine Based on theoretical REZOLSTA andconsiderations REZOLSTA is artemether/lumefantrine can beexpected to increase lumefantrine used without dose adjustments;plasma concentrations. however, due to the increase in(CYP3A inhibition) lumefantrine exposure, thecombination should be used withcaution.

ANTIMYCOBACTERIALS

Rifampicin Based on theoretical The combination of rifampicinconsiderations rifampin is and REZOLSTA isexpected to decrease darunavir contraindicated (see section 4.3).and/or cobicistat plasmaconcentrations.(CYP3A induction)

Rifabutin Based on theoretical Co-administration of

Rifapentine considerations these REZOLSTA with rifabutin andantimycobacterials are expected to rifapentine is not recommended.decrease darunavir and/or If the combination is needed, thecobicistat plasma concentrations. recommended dose of rifabutin is(CYP3A induction) 150 mg 3 times per week on setdays (for example

Monday-Wednesday-Friday).

Increased monitoring forrifabutin associated adversereactions including neutropeniaand uveitis is warranted due to anexpected increase in exposure torifabutin. Further dosagereduction of rifabutin has notbeen studied. It should be kept inmind that the twice weeklydosage of 150 mg may notprovide an optimal exposure torifabutin thus leading to a risk ofrifamycin resistance and atreatment failure. Considerationshould be given to officialguidance on the appropriatetreatment of tuberculosis in HIVinfected patients.

This recommendation is differentfrom ritonavir-boosted darunavir.

Consult the Summary of Product

Characteristics for darunavir forfurther details.

ANTI-NEOPLASTICS

Dasatinib Based on theoretical Concentrations of these

Nilotinib considerations REZOLSTA is medicinal products may be

Vinblastine expected to increase these increased when co-administered

Vincristine anti-neoplastic plasma with REZOLSTA resulting in theconcentrations. potential for increased adverse(CYP3A inhibition) events usually associated withthese medicinal products.

Caution should be exercisedwhen combining one of theseanti-neoplastic agents with

REZOLSTA.

Concomitant use of everolimus or

Everolimus irinotecan and REZOLSTA is not

Irinotecan recommended.

ANTIPSYCHOTICS/NEUROLEPTICS

Perphenazine Based on theoretical Clinical monitoring is

Risperidone considerations REZOLSTA is recommended when

Thioridazine expected to increase these co-administering REZOLSTAneuroleptic plasma concentrations. perphenazine, risperidone or(CYP3A, CYP2D6 and/or P-gp thioridazine. For theseinhibition) neuroleptics, consider reducingthe dose of the neuroleptic uponco-administration with

REZOLSTA.

Lurasidone The combination of lurasidone,

Pimozide pimozide, quetiapine or

Sertindole sertindole and REZOLSTA is

Quetiapine contraindicated (see section 4.3).

β-BLOCKERS

Carvedilol Based on theoretical Clinical monitoring is

Metoprolol considerations REZOLSTA is recommended when

Timolol expected to increase these beta co-administering REZOLSTAblocker plasma concentrations. with beta-blockers and a lower(CYP3A inhibition) dose of the beta-blocker shouldbe considered.

CALCIUM CHANNEL BLOCKERS

Amlodipine Based on theoretical Clinical monitoring of

Diltiazem considerations REZOLSTA is therapeutic and adverse effects is

Felodipine expected to increase these calcium recommended when these

Nicardipine channel blocker plasma medicines are co-administered

Nifedipine concentrations. with REZOLSTA.

Verapamil (CYP3A and/or CYP2D6inhibition)

CORTICOSTEROIDS

Corticosteroids primarily Based on theoretical Concomitant use of REZOLSTAmetabolised by CYP3A considerations REZOLSTA is and corticosteroids (all routes of(including betamethasone, expected to increase these administration) that arebudesonide, fluticasone, corticosteroid plasma metabolised by CYP3A maymometasone, prednisone, concentrations. (CYP3A increase the risk of developmenttriamcinolone). inhibition) of systemic corticosteroid effects,including Cushing’s syndromeand adrenal suppression.

Co-administration with CYP3A-metabolised corticosteroids is notrecommended unless thepotential benefit to the patientoutweighs the risk, in which casepatients should be monitored forsystemic corticosteroid effects.

Alternative corticosteroids whichare less dependent on CYP3Ametabolism e.g. beclomethasoneshould be considered, particularlyfor long term use.

Dexamethasone (systemic) Based on theoretical Systemic dexamethasone shouldconsiderations (systemic) be used with caution whendexamethasone is expected to combined with REZOLSTA.decrease darunavir and/orcobicistat plasma concentrations.(CYP3A induction)

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan Based on theoretical Co-administration ofconsiderations bosentan is REZOLSTA and bosentan is notexpected to decrease darunavir recommended.and/or cobicistat plasmaconcentrations.(CYP3A induction)

REZOLSTA is expected toincrease bosentan plasmaconcentrations.(CYP3A inhibition)

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A inhibitors

Elbasvir/grazoprevir Based on theoretical Concomitant use of REZOLSTAconsiderations REZOLSTA may with elbasvir/grazoprevir isincrease the exposure to contraindicated (see section 4.3).grazoprevir.(OATP1B and CYP3A inhibition)

Glecaprevir/pibrentasvir Based on theoretical It is not recommended toconsiderations REZOLSTA may co-administer REZOLSTA withincrease the exposure to glecaprevir/pibrentasvir.glecaprevir and pibrentasvir.(P-gp, BCRP and/or OATP1B1/3inhibition)

HMG CO-A REDUCTASE INHIBITORS

Atorvastatin Atorvastatin (10 mg once daily): Concomitant use of a HMG CoA

Fluvastatin atorvastatin AUC ↑ 290% reductase inhibitor and

Pitavastatin atorvastatin Cmax ↑ 319% REZOLSTA may increase

Pravastatin atorvastatin Cmin ND plasma concentrations of the lipid

Rosuvastatin lowering agent, which may lead

Rosuvastatin (10 mg once daily): to adverse events such asrosuvastatin AUC ↑ 93% myopathy.

rosuvastatin Cmax ↑ 277%rosuvastatin C ND When administration ofmin

HMG CoA reductase inhibitors

Based on theoretical and REZOLSTA is desired, it isconsiderations REZOLSTA is recommended to start with theexpected to increase the plasma lowest dose and titrate up to theconcentrations of fluvastatin, desired clinical effect whilepitavastatin, pravastatin, lovastatin monitoring for safety.

and simvastatin.(CYP3A inhibition and/ortransport)

Lovastatin Concomitant use of REZOLSTA

Simvastatin with lovastatin and simvastatin iscontraindicated (see section 4.3).

OTHER LIPID MODIFYING AGENTS

Lomitapide Based on theoretical Co-administration isconsiderations, REZOLSTA is contraindicated (see section 4.3)expected to increase the exposureof lomitapide whenco-administered.(CYP3A inhibition)

H2-RECEPTOR ANTAGONISTS

Cimetidine Based on theoretical REZOLSTA can be

Famotidine considerations, no mechanistic co-administered with H2-receptor

Nizatidine interaction is expected. antagonists without dose

Ranitidine adjustments.

IMMUNOSUPPRESSANTS

Ciclosporin Based on theoretical Therapeutic drug monitoring of

Sirolimus considerations REZOLSTA is the immunosuppressive agent

Tacrolimus expected to increase these must be done whenimmunosuppressant plasma co-administration occurs.concentrations.(CYP3A inhibition)

Everolimus Concomitant use of everolimusand REZOLSTA is notrecommended.

INHALED BETA AGONISTS

Salmeterol Based on theoretical Concomitant use of salmeterolconsiderations REZOLSTA is and REZOLSTA is notexpected to increase salmeterol recommended. The combinationplasma concentrations. may result in increased risk of(CYP3A inhibition) cardiovascular adverse event withsalmeterol, including QTprolongation, palpitations andsinus tachycardia.

NARCOTIC ANALGESICS/TREATMENT OF OPIOID DEPENDENCE

Buprenorphine/naloxone Based on theoretical Dose adjustment forconsiderations REZOLSTA may buprenorphine may not beincrease buprenorphine and/or necessary when co-administerednorbuprenorphine plasma with REZOLSTA but a carefulconcentrations. clinical monitoring for signs ofopiate toxicity is recommended.

Methadone Based on theoretical No adjustment of methadoneconsiderations REZOLSTA may dosage is expected whenincrease methadone plasma initiating co-administration withconcentrations. REZOLSTA. Clinical monitoringis recommended, as maintenance

With ritonavir-boosted darunavir, therapy may need to be adjusteda small decrease in methadone in some patients.plasma concentrations wasobserved. Consult the Summary of

Product Characteristics fordarunavir for further details.

Fentanyl Based on theoretical Clinical monitoring is

Oxycodone considerations REZOLSTA may recommended when

Tramadol increase plasma concentrations of co-administering REZOLSTAthese analgesics. with these analgesics.(CYP2D6 and/or CYP3Ainhibition)

OESTROGEN-BASED CONTRACEPTIVES

Drospirenone (3 mg once daily) drospirenone AUC ↑ 58% Alternative or additionaldrospirenone Cmax ↑ 15% contraceptive measures aredrospirenone Cmin ND recommended when oestrogenbased contraceptives are co

Ethinylestradiol (0.02 mg once ethinylestradiol AUC ↓ 30% administered with REZOLSTA.daily) ethinylestradiol C Patients using oestrogens asmax ↓ 14%ethinylestradiol C ND hormone replacement therapyminshould be clinically monitored for

Norethindrone Based on theoretical signs of oestrogen deficiency.

considerations REZOLSTA may When REZOLSTA isalter norethindrone plasma co-administered with aconcentrations. drospirenone-containing product,(CYP3A inhibition, UGT/SULT clinical monitoring isinduction) recommended due to the potentialfor hyperkalaemia.

OPIOID ANTAGONIST

Naloxegol Not studied. Co-administration of

REZOLSTA and naloxegol iscontraindicated.

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

For the treatment of erectile Based on theoretical Concomitant use of PDE-5dysfunction considerations REZOLSTA is inhibitors for the treatment of

Sildenafil expected to increase these PDE-5 erectile dysfunction with

Tadalafil inhibitor plasma concentrations. REZOLSTA should be done with

Vardenafil (CYP3A inhibition) caution. If concomitant use of

REZOLSTA with sildenafil,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.

Avanafil The combination of avanafil and

REZOLSTA is contraindicated(see section 4.3).

For the treatment of pulmonary Based on theoretical A safe and effective dose ofarterial hypertension considerations REZOLSTA is sildenafil for the treatment of

Sildenafil expected to increase these PDE-5 pulmonary arterial hypertension

Tadalafil inhibitor plasma concentrations. co-administered with(CYP3A inhibition) REZOLSTA has not beenestablished. There is an increasedpotential for sildenafil-associatedadverse events (including visualdisturbances, hypotension,prolonged erection and syncope).

Therefore, co-administration of

REZOLSTA and sildenafil whenused for the treatment ofpulmonary arterial hypertensionis contraindicated (seesection 4.3).

Co-administration of tadalafil forthe treatment of pulmonaryarterial hypertension with

REZOLSTA is notrecommended.

PROTON PUMP INHIBITORS

Dexlansoprazole Based on theoretical REZOLSTA can be

Esomeprazole considerations, no mechanistic co-administered with proton

Lansoprazole interaction is expected. pump inhibitors without dose

Omeprazole adjustments.

Pantoprazole

Rabeprazole

SEDATIVES/HYPNOTICS

Buspirone Based on theoretical Clinical monitoring is

Clorazepate considerations REZOLSTA is recommended when

Diazepam expected to increase these co-administering REZOLSTA

Estazolam sedative/hypnotic plasma with these sedatives/hypnotics

Flurazepam concentrations. and a lower dose of the

Midazolam (parenteral) (CYP3A inhibition) sedatives/hypnotics should be

Zolpidem considered.

Caution should be used withco-administration of REZOLSTAand parenteral midazolam.

If REZOLSTA isco-administered with parenteralmidazolam, it should be done inan intensive care unit or similarsetting, which ensures closeclinical monitoring andappropriate medical managementin case of respiratory depressionand/or prolonged sedation. Doseadjustment for midazolam shouldbe considered, especially if morethan a single dose of midazolamis administered.

Co-administration of oralmidazolam or triazolam and

Midazolam (oral) REZOLSTA is contraindicated

Triazolam (see section 4.3).

TREATMENT FOR PREMATURE EJACULATION

Dapoxetine Not studied. Co-administration of

REZOLSTA with dapoxetine iscontraindicated.

UROLOGICAL DRUGS

Fesoterodine Not studied. Use with caution. Monitor for

Solifenacin fesoterodine or solifenacinadverse reactions, dose reductionof fesoterodine or solifenacinmay be necessary.

There are no adequate and well controlled trials with darunavir, or cobicistat, in pregnant women.

Studies in animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetaldevelopment, parturition or postnatal development (see section 5.3).

Treatment with darunavir/cobicistat 800/150 mg during pregnancy results in low darunavir exposure(see section 5.2), which may be associated with an increased risk of treatment failure and an increasedrisk of HIV transmission to the child. Therapy with REZOLSTA should not be initiated duringpregnancy, and women who become pregnant during therapy with REZOLSTA should be switched toan alternative regimen (see sections 4.2 and 4.4).

It is not known whether darunavir or cobicistat are excreted in human milk. Studies in rats havedemonstrated that darunavir is excreted in milk and at high levels (1,000 mg/kg/day) resulted intoxicity of the offspring. Studies in animals have demonstrated that cobicistat is excreted in milk.

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

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 or cobicistat on fertility are available. There was no effect onmating or fertility in animals (see section 5.3). Based on animal studies, no effect on mating or fertilityis expected with REZOLSTA.

REZOLSTA may have a minor influence on the ability to drive and use machines. Dizziness has beenreported in some patients during treatment with regimens containing darunavir administered withcobicistat and should be borne in mind when considering a patient’s ability to drive or operatemachinery.

The overall safety profile of REZOLSTA is based on available clinical trial data from darunavirboosted with either cobicistat or ritonavir, from cobicistat and from post-marketing data fromdarunavir/ritonavir.

As REZOLSTA contains darunavir and cobicistat, the adverse reactions associated with each of theindividual compounds may be expected.

The most frequent adverse reactions reported in the pooled data of the Phase III study GS-US-216-130and the REZOLSTA arm of Phase III study TMC114FD2HTX3001 were diarrhoea (23%), nausea(17%), rash (13%), and headache (10%). Serious adverse reactions were diabetes mellitus, (drug)hypersensitivity, immune reconstitution inflammatory syndrome, rash, Stevens-Johnson syndrome,and vomiting. All of these serious ADRs occurred in one (0.1%) subject except for rash in 4 (0.6%)subjects.

The most frequent adverse reactions reported during the darunavir/ritonavir clinical developmentprogram and as spontaneous reports are diarrhoea, nausea, rash, headache, and vomiting. The mostfrequent serious reactions are acute renal failure, myocardial infarction, immune reconstitutioninflammatory syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis, and pyrexia.

In the 96 week analysis, the safety profile of darunavir/ritonavir 800/100 mg once daily intreatment-naïve subjects was similar to that seen with darunavir/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.

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 with darunavir/cobicistat in adult patients

MedDRA system organ class Adverse reaction

Frequency category

Common (drug) hypersensitivity

Uncommon immune reconstitution inflammatory syndrome

Common anorexia, hypercholesterolaemia,hypertriglyceridaemia

Uncommon diabetes mellitus, dyslipidaemia,hyperglycaemia, hyperlipidaemia

Common abnormal dreams

Very common headache

Very common diarrhoea, nausea

Common vomiting, abdominal pain, abdominaldistension, dyspepsia, flatulence

Uncommon pancreatitis acute, pancreatic enzymesincreased

Common hepatic enzyme increased

Uncommon hepatitis*, cytolytic hepatitis*

Very common rash (including macular, maculopapular,papular, erythematous, pruritic rash,generalised rash, and allergic dermatitis)

Common pruritus

Uncommon Stevens-Johnson syndrome#, angioedema,urticaria

Rare drug reaction with eosinophilia and systemicsymptoms*

Not known toxic epidermal necrolysis*, acute generalisedexanthematous pustulosis*

Common myalgia

Uncommon osteonecrosis*

Rare crystal nephropathy*§

Uncommon gynaecomastia*

Common fatigue, asthenia

Common increased blood creatinine

* These adverse drug reactions have not been reported in clinical trial experience with darunavir/cobicistat but havebeen noted with darunavir/ritonavir treatment and could be expected with darunavir/cobicistat too.# When also taking into account the clinical trial data of DRV/COBI/emtricitabine/tenofovir alafenamide, Stevens-

Johnson syndrome occurred rarely (in 1 out of 2,551 subjects) consistent with the DRV/rtv clinical trial program(see Severe skin reactions in section 4.4).

§ 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 with darunavir/ritonavir and darunavir/cobicistat, rash was mostly mild to moderate,often occurring within the first four weeks of treatment and resolving with continued dosing (seesection 4.4). The pooled data of a single-arm trial investigating darunavir 800 mg once daily incombination with cobicistat 150 mg once daily and other antiretrovirals and one arm of a trial in which

REZOLSTA 800/150 mg once daily and other antiretrovirals were administered, showed that 1.9% ofpatients discontinued treatment due to rash.

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 of HIVprotease 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).

Decrease estimated creatinine clearance

Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of renal tubularsecretion of creatinine. An increase in serum creatinine due to the inhibitory effect of cobicistatgenerally does not exceed 0.4 mg/dL.

The effect of cobicistat on serum creatinine was investigated in a Phase I trial in subjects with normalrenal function (eGFR ≥ 80 mL/min, n = 12) and mild to moderate renal impairment(eGFR:50-79 mL/min, n = 18). Change of estimated glomerular filtration rate calculated by

Cockcroft-Gault method (eGFRCG) from baseline was observed within 7 days after start of treatmentwith cobicistat 150 mg among subjects with normal renal function (-9.9 ± 13.1 mL/min) and mild tomoderate renal impairment (-11.9 ± 7.0 mL/min). These decreases in eGFRCG were reversible aftercobicistat was discontinued and did not affect the actual glomerular filtration rate, as determined bythe clearance of probe drug iohexol.

In the Phase III single-arm trial (GS-US-216-130), a decrease in eGFRCG was noted at week 2, whichremained stable through week 48. The mean eGFRCG change from baseline was -9.6 mL/min atweek 2, and -9.6 mL/min at week 48. In the REZOLSTA arm of Phase III trial

TMC114FD2HTX3001, mean eGFRCG change from baseline was -11.1 mL/min at week 48 and meaneGFRcystatin C change from baseline was +2.9 mL/min/1.73 m² at week 48.

For more information consult the cobicistat Summary of Product Characteristics.

The safety of components of REZOLSTA was evaluated in adolescents aged 12 to less than 18 years,weighing at least 40 kg through the clinical trial GS-US-216-0128 (treatment-experienced,virologically suppressed, N = 7). Safety analyses of this study in adolescent subjects did not identifynew safety concerns compared to the known safety profile of darunavir and cobicistat in adultsubjects.

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

Limited information is available on the use of REZOLSTA in patients co-infected with hepatitis Band/or C virus. Among 1,968 treatment-experienced patients receiving darunavir co-administered withritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infectedpatients were more likely to have baseline and treatment emergent hepatic transaminase elevationsthan those without 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 REZOLSTA or darunavir in combination with cobicistat 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 REZOLSTA. Treatment of overdose with REZOLSTAconsists of general supportive measures including monitoring of vital signs and observation of theclinical status of the patient. Since darunavir and cobicistat are highly protein bound, dialysis isunlikely to be beneficial in significant removal of the active substances.

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infection,combinations ATC code: J05AR14

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.

Cobicistat is a mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibitionof CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates,such as darunavir, where bioavailability is limited and half-life is shortened due to CYP3A-dependentmetabolism.

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.

Cobicistat has no detectable antiviral activity against HIV-1 and does not antagonise the antiviraleffect of darunavir.

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 resistance profile of REZOLSTA is driven by darunavir. Cobicistat does not select any HIVresistance mutations, due to its lack of antiviral activity. The resistance profile of REZOLSTA issupported by two Phase III trials conducted with darunavir/ritonavir in treatment-naïve (ARTEMIS)and treatment-experienced (ODIN) patients and the analysis of 48 week data from trial

GS-US-216-130 in treatment-naïve and treatment-experienced patients.

Low rates of developing resistant HIV-1 virus were observed in ART-naïve patients who are treatedfor the first time with REZOLSTA or darunavir/ritonavir 800/100 mg once daily in combination withother ART, and in ART-experienced patients with no darunavir RAMs receiving REZOLSTA ordarunavir/ritonavir 800/100 mg once daily in combination with other ART. The table below shows thedevelopment of HIV-1 protease mutations and loss of susceptibility to HIV PIs in virologic failures atendpoint in the GS-US-216-130, ARTEMIS and ODIN trials.

GS-US-216-130a ARTEMISb ODINb

Treatment-naïv Treatment-experie Treatment-naïv Treatment-experie Treatment-experiee nced e nced nceddarunavir/cobic darunavir/cobicist darunavir/riton darunavir/ritonavi darunavir/ritonaviistat 800/150 mg at 800/150 mg avir r ronce daily once daily 800/100 mg 800/100 mg 600/100 mg

N = 295 N = 18 once daily once daily twice daily

N = 343 N = 294 N = 296

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

Primary 0/8 1/7 0/43 1/60 0/42(major)

PImutations

PI 2/8 1/7 4/43 7/60 4/42

RAMs

Number of subjects with virologic failure and phenotype data that show a loss of susceptibility to PIs at endpointcompared to baselined, n/N

HIV PIdarunav 0/8 0/7 0/39 1/58 0/41irampren 0/8 0/7 0/39 1/58 0/40aviratazana 0/8 0/7 0/39 2/56 0/40virindinavi 0/8 0/7 0/39 2/57 0/40rlopinavi 0/8 0/7 0/39 1/58 0/40rsaquina 0/8 0/7 0/39 0/56 0/40virtipranav 0/8 0/7 0/39 0/58 0/41ira Virologic failures selected for resistance testing were defined as: never suppressed: HIV-1 RNA < 1 log10 reduction from baselineand ≥ 50 copies/mL at week 8, confirmed at the following visit; rebound: HIV-1 RNA < 50 copies/mL followed by confirmed

HIV-1 RNA to ≥ 400 copies/mL or confirmed > 1 log10 HIV-1 RNA increase from the nadir; discontinuations with HIV-1 RNA≥ 400 copies/mL at last visitb Virologic failures based on TLOVR non-VF censored algorithm (HIV-1 RNA > 50 copies/mL)c IAS-USA listsd In GS-US-216-130 baseline phenotype was not available

In the virologic failures of the GS-US-216-130 trial no cross-resistance with other HIV PIs wasobserved. Refer to the table above for information on ARTEMIS and ODIN.

The antiretroviral effect of REZOLSTA is due to the darunavir component. The activity of cobicistatas a pharmacokinetic enhancer to darunavir has been demonstrated in pharmacokinetic trials. In thesepharmacokinetic trials, the exposure of darunavir 800 mg boosted with cobicistat 150 mg wasconsistent with that observed when boosted with ritonavir 100 mg. Darunavir as a component of

REZOLSTA is bioequivalent to darunavir 800 mg once daily in combination with cobicistat 150 mgonce daily co-administered as single medicinal products (see section 5.2).

The evidence of efficacy of REZOLSTA once daily is based on the analysis of 48 week data from trial

GS-US-216-130 in ART-naïve and ART-experienced patients, trial TMC114FD2HTX3001 in

ART-naïve patients, and two Phase III trials ARTEMIS and ODIN conducted with darunavir/ritonavir800/100 mg q.d. in ART-naïve and ART-experienced patients, respectively.

Description of clinical studies of REZOLSTA in adults

Efficacy of darunavir 800 mg once daily co-administered with 150 mg cobicistat once daily in

ART-naïve and ART-experienced patients

GS-US-216-130 is a single-arm, open-label, Phase III trial evaluating the pharmacokinetics, safety,tolerability, and efficacy of darunavir with cobicistat in 313 HIV-1 infected adult patients(295 treatment-naïve and 18 treatment-experienced). These patients received darunavir 800 mg oncedaily in combination with cobicistat 150 mg once daily with an investigator selected optimisedbackground regimen (OBR) consisting of 2 active NRTIs.

HIV-1 infected patients who were eligible for this trial had a screening genotype showing no darunavir

RAMs and plasma HIV-1 RNA ≥ 1,000 copies/mL. The table below shows the efficacy data of the48 week analyses from the GS-US-216-130 trial:

GS-US-216-130

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

Outcomes at week 48 800/150 mg once daily 800/150 mg once daily 800/150 mg once daily+ OBR + OBR + OBR

N = 295 N = 18 N = 313

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

CD4+ cell count mean +174 +102 +170change from baselineba Imputations according to the TLOVR algorithmb Last Observation Carried Forward imputation

Efficacy of darunavir/cobicistat fixed-dose combination 800/150 mg once daily in ART-naïve patients

TMC114FD2HTX3001 is a randomised, active-controlled, double blind, Phase III trial to evalate theefficacy and safety of darunavir/cobicistat/emtricitabine/tenofovir alafenamide versusdarunavir/cobicistat fixed-dose combination + emtricitabine/tenofovir disoproxil fumarate. In thedarunavir/cobicistat fixed-dose combination treament arm, 363 HIV-1 infected, adult, treatment-naïvepatients were treated.

HIV-1 infected patients who were eligible for this trial had a plasma HIV-1 RNA ≥ 1,000 copies/mL.

The table below shows the 48-week efficacy data of the darunavir/cobicistat arm of the

TMC114FD2HTX3001 trial:

TMC114FD2HTX3001 (darunavir/cobicistat arm)

Treatment-naïvedarunavir/cobicistat 800/150 mg once daily

Outcomes at week 48+ emtricitabine/tenofovir disoproxil fumarate

N = 363

HIV-1 RNA < 50 copies/mLa 321 (88.4%)

Virologic failurea 12 (3.3%)

No virologic data in 48-week 30 (8.3%)windowa

CD4+ cell count mean +173.8change from baselineba Imputations according to the Snapshot algorithm.b Non completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0

Description of clinical studies of darunavir/ritonavir in adults

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in

ART-naïve patients

The evidence of efficacy of darunavir/ritonavir 800/100 mg once daily is based on the analyses of192 week data from the randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviraltreatment-naïve HIV-1 infected patients comparing darunavir/ritonavir 800/100 mg once daily withlopinavir/ritonavir 800/200 mg per day (given as a twice-daily or as a once-daily regimen). Both armsused a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily andemtricitabine 200 mg once daily.

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

ARTEMIS

Week 48a Week 96b

Outcomes darunavir/ lopinavir/ Treatment darunavir/ lopinavir/ Treatmentritonavir ritonavir difference ritonavir ritonavir difference800/100 mg 800/200 mg (95% CI 800/100 mg 800/200 mg (95% CI ofonce daily per day of once daily per day difference)

N = 343 N = 346 difference) N = 343 N = 346

HIV-1 RNA 83.7% 78.3% 5.3% 79.0% 70.8% 8.2%< 50 copies/mLc (287) (271) (-0.5; (271) (245) (1.7; 14.7)d

All patients 11.2)d

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

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

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

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

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

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

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

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

CD4+ cell countchange frombaseline(x 106/L)ea Data based on analyses at week 48b Data based on analyses at week 96c Imputations according to the TLOVR algorithmd Based on normal approximation to the difference in % responsee Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0

Non-inferiority in virologic response to the darunavir/ritonavir treatment, defined as the percentage ofpatients with plasma HIV-1 RNA level < 50 copies/mL, was demonstrated (at the pre-defined 12%non-inferiority margin) for both Intent-To-Treat (ITT) and On Protocol (OP) populations in the48 week analysis. These results were confirmed in the analyses of data at 96 weeks of treatment in the

ARTEMIS trial. These results were sustained up to 192 weeks of treatment in the ARTEMIS trial.

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in

ART-experienced patients

ODIN is a Phase III, randomised, open-label trial comparing darunavir/ritonavir 800/100 mg oncedaily versus darunavir/ritonavir 600/100 mg twice daily in ART-experienced HIV-1 infected patientswith screening genotype resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V,

I50V, I54M, I54L, T74P, L76V, I84V, L89V) and a screening HIV-1 RNA > 1,000 copies/mL.

Efficacy analysis is based on 48 weeks of treatment (see table below). Both arms used an optimisedbackground regimen (OBR) of ≥ 2 NRTIs.

ODIN

Week 48

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

N = 294 N = 296

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

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+ cellcount (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 darunavir/ritonavir 800/100 mg once daily treatment was demonstrated to benon-inferior (at the pre-defined 12% non-inferiority margin) compared to darunavir/ritonavir600/100 mg twice daily for both ITT and OP populations.

REZOLSTA 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 (seesections 4.2 and 4.4). Limited data is available in patients with HIV-1 clades other than B.

The use of REZOLSTA in adolescent patients from the age of 12 years to less than 18 years, andweighing at least 40 kg is supported by adult trials and by trial GS-US-216-0128 in HIV-1 infectedadolescents evaluating components of REZOLSTA. For additional supportive information, refer to the

Summary of Product Characteristics of darunavir and cobicistat.

In the open-label, Phase II/III trial GS-US-216-0128, the efficacy, safety, and pharmacokinetics ofdarunavir 800 mg and cobicistat 150 mg (administered as separate tablets) and at least 2 NRTIs wereevaluated in 7 HIV-1 infected, treatment-experienced, virologically suppressed adolescents (seesection 5.2). Patients were on a stable antiretroviral regimen (for at least 3 months), consisting ofdarunavir adminstered with ritonavir, combined with 2 NRTIs. They were switched from ritonavir tocobicistat 150 mg once daily and continued darunavir (N = 7) and 2 NRTIs.

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

GS-US-216-0128

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

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

Approach

CD4+ percent median change from baselinea -6.1%

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

The European Medicines Agency has deferred the obligation to submit the results of studies with

REZOLSTA in one or more subsets of the paediatric population in the condition of treatment of HIV-1infection.

Darunavir exposure was shown to be comparable in a bioavailability trial between REZOLSTA anddarunavir/ritonavir 800/100 mg q.d. at steady-state and fed conditions in healthy subjects.

The bioequivalence between REZOLSTA and darunavir/cobicistat 800/150 mg co-administered assingle agents was established under fed and fasted conditions in healthy subjects.

The absolute oral bioavailability of a single 600 mg dose of darunavir alone is approximately 37%.

Darunavir was rapidly absorbed following oral administration of REZOLSTA in healthy volunteers.

Maximum plasma concentration of darunavir in the presence of cobicistat is generally achieved within3 to 4.5 hours. Following oral administration of REZOLSTA in healthy volunteers, maximum plasmaconcentrations of cobicistat were observed 2 to 5 hours post-dose.

When administered with food, the relative exposure of darunavir is 1.7-fold higher as compared tointake without food. Therefore, REZOLSTA tablets should be taken with food. The type of food doesnot affect exposure to REZOLSTA.

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.

Cobicistat is 97 to 98% bound to human plasma proteins and the mean plasma to blood-drugconcentration ratio was approximately 2.

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.

Cobicistat is metabolised via CYP3A (major)- and CYP2D6 (minor)-mediated oxidation and does notundergo glucuronidation. Following oral administration of 14C-cobicistat, 99% of circulatingradioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine andfaeces and do not contribute to the CYP3A inhibitory activity of cobicistat.

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.

Following oral administration of 14C-cobicistat, 86% and 8.2% of the dose were recovered in faecesand urine, respectively. The median terminal plasma half-life of cobicistat following administration of

REZOLSTA is approximately 3-4 hours.

Available pharmacokinetic data for the different components of REZOLSTA indicate there were noclinically relevant differences in exposure between adults and adolescents. In addition, thepharmacokinetics of darunavir 800 mg co-administered with cobicistat 150 mg in paediatric patientshave been studied in 7 adolescents aged 12 to less than 18 years, weighing at least 40 kg who receiveddarunavir 800 mg co-administered with cobicistat 150 mg in Study GS-US-216-0128. The geometricmean adolescent exposure (AUCtau) was similar for darunavir and increased 19% for cobicistatcompared to exposures achieved in adults who received darunavir 800 mg co-administered withcobicistat 150 mg in Study GS-US-216-0130. The difference observed for cobicistat was notconsidered clinically relevant.

Adults in Study Adolescents in Study GLSM Ratio

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

Mean (%CV) Mean (%CV)

GLSM GLSM

N 60c 7

DRV PK

Parameter

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

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

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

COBI PK

Parameter

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

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

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

AUCtau and Ctau in Study GS-US-216-0128.e N = 57 and N = 5 for GLSM of Ctau in Study GS-US-216-0130 and Study GS-US-216_0128, respectively.

Limited information is available in this population. Population pharmacokinetic analysis in HIVinfected patients showed that darunavir pharmacokinetics are not considerably different in the agerange (18 to 75 years) evaluated in HIV infected patients (n = 12, age  65 years) (see section 4.4).

However, only limited data were available in patients above the age of 65 years.

Pharmacokinetics of cobicistat have not been fully evaluated in older people (65 years of age andolder).

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

No clinically relevant pharmacokinetic differences due to gender have been identified for cobicistat.

REZOLSTA has not been investigated in patients with renal impairment.

Results from a mass balance study with 14C-darunavir with ritonavir showed that approximately 7.7%of the administered dose of darunavir is excreted in the urine unchanged.

Although darunavir has not been studied in patients with renal impairment, 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).

A trial of the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects withsevere renal impairment (estimated creatinine clearance below 30 mL/min). No meaningfuldifferences in cobicistat pharmacokinetics were observed between subjects with severe renalimpairment and healthy subjects, consistent with low renal clearance of cobicistat.

REZOLSTA has not been investigated in patients with hepatic impairment.

Darunavir is primarily metabolised and eliminated by the liver. In a multiple dose trial withdarunavir/ritonavir (600/100 mg) twice daily, it was demonstrated that the total plasma concentrationsof 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, unbounddarunavir concentrations were approximately 55% (Child-Pugh Class A) and 100% (Child-Pugh

Class B) higher, respectively. The clinical relevance of this increase is unknown, therefore,darunavir/ritonavir 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).

Cobicistat is primarily metabolised and eliminated by the liver. A trial of the pharmacokinetics ofcobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment(Child-Pugh Class B). No clinically relevant differences in cobicistat pharmacokinetics were observedbetween subjects with moderate impairment and healthy subjects. No dosage adjustment of

REZOLSTA is necessary for patients with mild to moderate hepatic impairment. The effect of severehepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.

There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis Band/or C virus infection on the pharmacokinetics of darunavir and cobicistat (refer to sections 4.4 and4.8).

Treatment with REZOLSTA during pregnancy results in low darunavir exposure. In women receiving

REZOLSTA during the second trimester of pregnancy, mean intra-individual values for totaldarunavir Cmax, AUC24h and Cmin were 49%, 56% and 92% lower, respectively, as compared withpostpartum; during the third trimester of pregnancy, total darunavir Cmax, AUC24h and Cmin values were37%, 50% and 89% lower, respectively, as compared with postpartum. The unbound fraction was alsosubstantially reduced, including around 90% reductions of Cmin levels. The main cause of these lowexposures is a marked reduction in cobicistat exposure as a consequence of pregnancy-associatedenzyme induction (see below).

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

Pharmacokinetics of Second trimester Third trimester Postpartumtotal darunavir of pregnancy of pregnancy (6-12 weeks)(mean ± SD) N = 7 N = 6 N = 6

Cmax, ng/mL 4,340 ± 1,616 4,910 ± 970 7,918 ± 2,199

AUC24h, ng.h/mL 47,293 ± 19,058 47,991 ± 9,879 99,613 ± 34,862

Cmin, ng/mL 168 ± 149 184 ± 99 1,538 ± 1,344

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

Animal toxicology studies have been conducted at exposures up to clinical exposure levels withdarunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs.

In repeated-dose toxicology studies in mice, rats and dogs, there were only limited effects of treatmentwith darunavir. In rodents the target organs identified were the haematopoietic system, the bloodcoagulation system, liver and thyroid. A variable but limited decrease in red blood cell-relatedparameters was observed, together with increases in activated partial thromboplastin time.

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

In a study conducted in rats, the number of corpora lutea and implantations were decreased in thepresence of maternal toxicity. Otherwise, there were no effects on mating or fertility with darunavirtreatment up to 1,000 mg/kg/day and exposure levels below (AUC-0.5 fold) of that in human at theclinically recommended dose. Up to same dose levels, there was no teratogenicity with darunavir inrats and rabbits when treated alone nor in mice when treated in combination with ritonavir. Theexposure levels were lower than those with the recommended clinical dose in humans. In a pre- andpostnatal development assessment in rats, darunavir with and without ritonavir, caused a transientreduction in body weight gain of the offspring pre-weaning and there was a slight delay in the openingof eyes and ears. Darunavir in combination with ritonavir caused a reduction in the number of pupsthat exhibited the startle response on day 15 of lactation and a reduced pup survival during lactation.

These effects may be secondary to pup exposure to the active substance via the milk and/or maternaltoxicity. No post weaning functions were affected with darunavir alone or in combination withritonavir. In juvenile rats receiving darunavir up to days 23-26, increased mortality was observed withconvulsions in some animals. Exposure in plasma, liver and brain was considerably higher than inadult rats after comparable doses in mg/kg between days 5 and 11 of age. After day 23 of life, theexposure was comparable to that in adult rats. The increased exposure was likely at least partly due toimmaturity of the drug-metabolising enzymes in juvenile animals. No treatment related mortalitieswere noted in juvenile rats dosed at 1,000 mg/kg darunavir (single dose) on day 26 of age or at500 mg/kg (repeated dose) from day 23 to 50 of age, and the exposures and toxicity profile werecomparable to those observed in adult rats.

Due to uncertainties regarding the rate of development of the human blood brain barrier and liverenzymes REZOLSTA should not be used in paediatric patients below 3 years of age.

Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats 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 darunavirwhen co-administered with ritonavir were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats),relative to those observed in humans at the recommended therapeutic doses.

After 2 years administration of darunavir at exposures at or below the human exposure, 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.

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dosetoxicity, genotoxicity, and toxicity to reproduction and development. No teratogenic effects wereobserved in rats and rabbit developmental toxicity studies. In rats, ossification changes in the spinalcolumn and sternebrae of fetuses occurred at a dose that produced significant maternal toxicity.

Ex vivo rabbit studies and in vivo dog studies suggest that cobicistat has a low potential for QTprolongation, and may slightly prolong the PR interval and decrease left ventricular function at meanconcentrations at least 10-fold higher than the human exposure at the recommended 150 mg dailydose.

A long term carcinogenicity study of cobicistat in rats revealed tumourigenic potential specific for thisspecies, that is regarded as of no relevance for humans. A long term carcinogenicity study in mice didnot show any carcinogenic potential.

Hypromellose

Colloidal silicon dioxide

Silicified microcrystalline cellulose

Crospovidone

Magnesium stearate

Tablet film-coat

Polyvinyl alcohol- partially hydrolysed

Macrogol 3350

Titanium dioxide

Talc

Iron oxide red

Iron oxide black

Not applicable

3 years6 weeks after opening the bottle.

This medicinal product does not require any special storage conditions.

White, high density polyethylene (HDPE) bottle containing 30 tablets, fitted with polypropylene (PP)child resistant closure with induction seal.

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

EU/1/14/967/001

Date of first authorisation: 19 November 2014

Date of latest renewal: 31 July 2019

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

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