SYMTUZA 800mg / 150mg / 200mg / 10mg film-coated tablets medication leaflet

Symtuza 800 mg/150 mg/200 mg/10 mg film-coated tablets

Each film-coated tablet contains 800 mg of darunavir (as ethanolate), 150 mg of cobicistat, 200 mg ofemtricitabine, and 10 mg of tenofovir alafenamide (as fumarate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Yellow to yellowish-brown capsule shaped tablet of 22 mm x 11 mm, debossed with “8121” on oneside and “JG” on the other side.

Symtuza is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection inadults and adolescents (aged 12 years and older with body weight at least 40 kg).

Genotypic testing should guide the use of Symtuza (see sections 4.2, pct. 4.4, and 5.1).

Therapy should be initiated by a physician experienced in the management of HIV-1 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.

Antiretroviral Therapy (ART)-naïve patients

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

ART-experienced patients

One film-coated tablet of Symtuza 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 5.1).

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

If a dose of Symtuza is missed within 12 hours of the time it is usually taken, patients should beinstructed to take the prescribed dose of Symtuza with food as soon as possible. If a missed dose isnoticed later than 12 hours of the time it is usually taken, it should not be taken and the patient shouldresume the usual dosing schedule.

In case a patient vomits within 1 hour of taking the medicinal product, another dose of Symtuza shouldbe taken with food as soon as possible. If a patient vomits more than 1 hour after taking the medicinalproduct, the patient does not need to take another dose of Symtuza until the next regularly scheduledtime.

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

No dose adjustment of Symtuza is required in patients with mild (Child-Pugh Class A) or moderate(Child-Pugh Class B) hepatic impairment, however, Symtuza should be used with caution in thesepatients, as the darunavir and cobicistat components of Symtuza are metabolised by the hepaticsystem.

Symtuza has not been studied in patients with severe hepatic impairment (Child-Pugh Class C),therefore, Symtuza must not be used in patients with severe hepatic impairment (see sections pct. 4.3, pct. 4.4and 5.2).

No dose adjustment of Symtuza is required in patients with estimated glomerular filtration rate (eGFR)according to the Cockcroft-Gault formula (eGFRCG) ≥ 30 mL/min.

Symtuza should not be initiated in patients with eGFRCG < 30 mL/min, as there are no data availableregarding the use of Symtuza in this population (see sections 5.1 and 5.2).

Symtuza should be discontinued in patients with eGFRCG that declines below 30 mL/min duringtreatment (see sections 5.1 and 5.2).

The safety and efficacy of Symtuza in children aged 3-11 years, or weighing < 40 kg, have not yetbeen established. No data are available.

Symtuza should not be used in paediatric patients below 3 years of age because of safety concerns (seesections 4.4 and 5.3).

Treatment with darunavir/cobicistat (two of the components of Symtuza) during pregnancy results inlow darunavir exposure (see sections 4.4 and 5.2). Therefore, therapy with Symtuza should not beinitiated during pregnancy, and women who become pregnant during therapy with Symtuza should beswitched to an alternative regimen (see sections 4.4 and 4.6).

Symtuza should be taken orally, once daily with food (see section 5.2). The tablet should not becrushed.

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, dronedarone, ivabradine, quinidine, ranolazine

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

- rifampicin

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

- dapoxetine

- domperidone

- naloxegol

- pimozide, quetiapine, sertindole, lurasidone (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

ART-experienced patients

Symtuza should not be used in treatment-experienced patients with one or more DRV-RAMs (seesection 5.1) or with HIV-1 RNA ≥ 100 000 copies/mL or CD4+ cell count < 100 cells x 106/L.

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 Symtuza should not be initiated duringpregnancy, and women who become pregnant during therapy with Symtuza should be switched to analternative regimen (see sections 4.2 and 4.6).

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk forsevere and potentially fatal hepatic adverse reactions.

The safety and efficacy of Symtuza in patients co-infected with HIV-1 and hepatitis C virus (HCV)have not been established. Tenofovir alafenamide is active against hepatitis B virus (HBV).

In case of concomitant antiviral therapy for hepatitis C, please refer also to the relevant Summary of

Product Characteristics for these medicinal products.

Discontinuation of Symtuza therapy in patients co-infected with HIV and HBV may be associatedwith severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue

Symtuza should be closely monitored with both clinical and laboratory follow-up for at least severalmonths after stopping treatment. If appropriate, initiation of hepatitis B therapy may be warranted. Inpatients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended sincepost-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Symtuza should not be administered concomitantly with medicinal products containing tenofovirdisoproxil (e.g. fumarate, phosphate, or succinate), lamivudine, or adefovir dipivoxil used for thetreatment of HBV infection.

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variabledegree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIVnegative infants exposed in utero and/or postnatally to nucleoside analogues. The main adversereactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders(hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurologicaldisorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurologicaldisorders are transient or permanent is currently unknown. Any child exposed in utero to nucleosideand nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-upand should be fully investigated for possible mitochondrial dysfunction in case of relevant signs orsymptoms. These findings do not affect current national recommendations to use antiretroviral therapyin pregnant women to prevent vertical transmission of HIV.

As limited information is available on the use of Symtuza in patients aged 65 and over, caution shouldbe exercised, reflecting the greater frequency of decreased hepatic function and of concomitant diseaseor other therapy (see sections 4.2 and 5.2).

Hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. Duringthe darunavir/ritonavir clinical development program (N = 3 063), hepatitis was reported in 0.5% ofpatients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients withpre-existing liver dysfunction, including chronic hepatitis B or C, have an increased risk for liverfunction 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 Symtuza 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 Symtuza 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 Symtuza, interruption or discontinuation of treatmentshould be considered promptly (see section 5.3).

Post-marketing cases of renal impairment, including acute renal failure and proximal renaltubulopathy have been reported with tenofovir alafenamide-containing products. A potential risk ofnephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofoviralafenamide cannot be excluded (see section 5.3). It is recommended that renal function is assessed inall patients prior to, or when, initiating therapy with Symtuza and that it is also monitored duringtherapy in all patients as clinically appropriate. In patients who develop clinically significant decreasesin renal function or evidence of proximal renal tubulopathy, discontinuation of Symtuza should beconsidered.

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 Symtuza is administered to patients, inwhom 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.

The safety and efficacy of Symtuza or its components have not been established in patients withsevere underlying liver disorders. Symtuza is, therefore, contraindicated in patients with severe hepaticimpairment. Due to an increase in the unbound darunavir plasma concentrations, Symtuza should beused with caution in patients with mild or moderate hepatic impairment (see sections 4.2, pct. 4.3 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 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.

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. Symtuza 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.

Sulphonamide allergy

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

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 treated with CART, IRIS has been reported. In HIV infected patients withsevere immune deficiency at the time of initiation of CART, an inflammatory reaction toasymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, oraggravation of symptoms. Typically, such reactions have been observed within the first weeks ormonths of initiation of CART. Relevant examples include cytomegalovirus retinitis, generalisedand/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerlyknown as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatmentinstituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has beenobserved in clinical trials with darunavir co-administered with low dose ritonavir.

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

Patients receiving Symtuza or any other antiretroviral therapy may continue to develop opportunisticinfections and other complications of HIV infection, and therefore should remain under close clinicalobservation by physicians experienced in the treatment of patients with HIV associated diseases.

Symtuza is indicated for use as a complete regimen for the treatment of HIV-1 infection and shouldnot be administered with other antiretroviral products (see section 4.5). Symtuza should not beadministered concomitantly with medicinal products requiring pharmacokinetic enhancement withritonavir or cobicistat. Symtuza should not be administered concomitantly with medicinal productscontaining tenofovir disoproxil (as fumarate, phosphate or succinate), lamivudine, or adefovirdipivoxil used for the treatment of HBV infection.

Symtuza should not be used in paediatric patients below 3 years of age (see sections 4.2 and 5.3).

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

No interaction trials have been performed using Symtuza. Interactions that have been identified instudies with individual components of Symtuza, i.e. with darunavir (in combination with low doseritonavir), cobicistat, emtricitabine or tenofovir alafenamide, determine the interactions that may occurwith Symtuza.

Darunavir and 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 Symtuza 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).

Symtuza 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 Symtuza and 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.

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 Symtuza 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 like clotrimazole). These interactions are described in theinteraction table below.

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

UGT1A1. If switching from ritonavir as a pharmacoenhancer to this regimen with cobicistat, cautionis required during the first two weeks of treatment with Symtuza, particularly if doses of anyconcomitantly administered medicinal products have been titrated or adjusted during use of ritonavir.

In vitro and clinical pharmacokinetic interaction studies have shown that the potential for

CYP-mediated interactions involving emtricitabine with other medicinal products is low.

Emtricitabine did not inhibit the glucuronidation reaction of a non-specific UGT substrate in vitro.

Co-administration of emtricitabine with medicinal products that are eliminated by active tubularsecretion may increase concentrations of emtricitabine, and/or the co-administered medicinal product.

Medicinal products that decrease renal function may increase concentrations of emtricitabine.

Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein(BCRP). Medicinal products that strongly affect P-gp activity and BCRP may lead to changes intenofovir alafenamide absorption. Medicinal products that induce P-gp activity (e.g., rifampicin,rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofoviralafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead toloss of therapeutic effect of tenofovir alafenamide and development of resistance. Co-administrationof tenofovir alafenamide with other medicinal products that inhibit P-gp (e.g., cobicistat, ritonavir,ciclosporin) are expected to increase the absorption and plasma concentration of tenofoviralafenamide. It is not known whether the co-administration of tenofovir alafenamide and xanthineoxidase inhibitors (e.g. febuxostat) would increase systemic exposure to tenofovir.

Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or

CYP2D6 in vitro. It is not an inhibitor of CYP3A4 in vivo. Tenofovir alafenamide is a substrate of

OATP1B1 and OATP1B3 in vitro. The distribution of tenofovir alafenamide in the body may beaffected by the activity of OATP1B1 and OATP1B3.

Expected interactions between Symtuza with potential concomitant medicinal products are listed in

Table 1 below and are based on the studies conducted with the components of Symtuza, as individualagents or combined, or are potential interactions that may occur.

Interaction trials with the components of Symtuza have only been performed in adults.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as apharmacokinetic enhancer; therefore, there may be different recommendations for the use of darunavirwith concomitant medicines. Refer to the prescribing information for darunavir for furtherinformation.

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

Table 1: Interactions between the individual components of Symtuza and other medicinalproducts

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

Medicinal product examples by Interaction Recommendations concerningtherapeutic area co-administration

ALPHA ADRENORECEPTOR ANTAGONISTS

Alfusozin Based on theoretical The concomitant use of Symtuzaconsiderations with alfusozin is contraindicated

DRV/COBI is expected to (see section 4.3).increase alfusozin concentrations(CYP3A4 inhibition)

ANAESTHETIC

Alfentanil Based on theoretical The concomitant use withconsiderations DRV/COBI is Symtuza may require to lower theexpected to increase alfentanil dose of alfentanil and requiresplasma concentrations. monitoring for risks of prolongedor delayed respiratory depression.

ANTACIDS

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

Calcium carbonate considerations. adjustment.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide Based on theoretical Caution is warranted and

Flecainide considerations DRV/COBI is concentration monitoring, if

Mexiletine expected to increase these available, is recommended for

Propafenone antiarrhythmic plasma these antiarrhythmics when

Lidocaine (systemic) concentrations. co-administered with Symtuza.

(CYP3A inhibition)

Co-administration of

Amiodarone amiodarone, dronedarone,

Dronedarone ivabradine, quinidine, or

Ivabradine ranolazine and Symtuza is

Quinidine contraindicated (see section 4.3).

Ranolazine

Digoxin Based on theoretical It is recommended that the lowestconsiderations DRV/COBI is possible dose of digoxin shouldexpected to increase digoxin initially be given to patients onplasma concentrations. Symtuza. 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 Symtuza.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

DRV/COBI. dose.(CYP3A inhibition)

ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR

Apixaban Based on theoretical Co-administration of Symtuza

Rivaroxaban considerations co-administration of with a direct oral anticoagulant

Symtuza with these anticoagulants (DOAC) that is metabolised bymay increase concentrations of the CYP3A4 and transported by P-gpanticoagulant. is not recommended as this may(CYP3A and/or P-glycoprotein lead to an increased bleedinginhibition) risk.

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 etexilateand edoxaban, is co-administereddarunavir/cobicistat 800/150 mg with Symtuza.

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

Concomitant administration of

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

DRV/COBI with ticagrelor mayincrease concentrations ofticagrelor.(CYP3A and/or P-glycoproteininhibition).

Co-administration of Symtuza

Clopidogrel Based on theoretical with clopidogrel is notconsiderations co-administration of recommended. Use of other

Symtuza with clopidogrel is antiplatelets not affected by CYPexpected to decrease clopidogrel inhibition or induction (e.g.

active metabolite plasma prasugrel) is recommended (seeconcentration, which may reduce section 4.3).

the antiplatelet activity ofclopidogrel.

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

Symtuza.

ANTICONVULSANTS

Carbamazepine Based on theoretical Co-administration of Symtuza

Phenobarbital considerations these and these anticonvulsants is

Phenytoin anticonvulsants are expected to contraindicated (see section 4.3).

decrease darunavir and/orcobicistat and/or tenofoviralafenamide plasmaconcentrations.(CYP3A and/or P-gp induction).

Oxcarbazepine Co-administration of Symtuzawith oxcarbazepine is notrecommended. Alternativeanticonvulsants should beconsidered.

Clonazepam Based on theoretical considerations Clinical monitoring is

Symtuza is expected to increase recommended whenconcentrations of clonazepam co-administering Symtuza with(inhibition of CYP3A) clonazepam.

ANTI-DEPRESSANTS

Herbal supplements Based on theoretical considerations Co-administration of

St. John’s Wort St. John’s Wort is expected to St. John’s Wort and Symtuza isdecrease darunavir and/or contraindicated (see section 4.3).cobicistat and/or tenofoviralafenamide plasmaconcentrations.(CYP3A and/or P-gp induction)

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

Sertraline DRV/COBI is expected to increase used with Symtuza clinicalthese anti-depressant plasma monitoring is recommended and aconcentrations. dose adjustment of the(CYP2D6 and/or CYP3A anti-depressant may be needed.inhibition)

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

Based on theoretical considerations

Amitriptyline DRV/COBI is expected to increase

Desipramine these anti-depressant plasma

Imipramine concentrations.

Nortriptyline (CYP2D6 and/or CYP3A

Trazodone inhibition)

ANTI-DIABETICS

Metformin Based on theoretical considerations Careful clinical monitoring and

DRV/COBI is expected to increase dose adjustment of metformin ismetformin plasma concentrations. recommended in patients who are(MATE1 inhibition) taking Symtuza.

ANTIEMETICS

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

ANTIFUNGALS

Clotrimazole Based on theoretical considerations Caution is warranted and clinical

Fluconazole DRV/COBI is expected to increase monitoring is recommended.

Itraconazole these antifungal plasma When co-administration isconcentrations, and darunavir, required, the daily dose of

Isavuconazole cobicistat and/or tenofovir itraconazole should not exceed

Posaconazole alafenamide plasma concentrations 200 mg.

may be increased by theantifungals.(CYP3A and/or P-gp inhibition)

Voriconazole Concentrations of voriconazole Voriconazole should not bemay increase or decrease when combined with Symtuza unless anco-administered with DRV/COBI. assessment of the benefit/riskratio justifies the use ofvoriconazole.

ANTIGOUT MEDICINES

Colchicine Based on theoretical considerations A reduction in colchicine dose or

DRV/COBI is expected to increase an interruption of colchicinecolchicine plasma concentrations. treatment is recommended in(CYP3A and/or P-glycoprotein patients with normal renal orinhibition) hepatic function if treatment with

Symtuza is required.

The combination of colchicineand Symtuza is contraindicated inpatients with renal or hepaticimpairment (see section 4.3).

ANTIMALARIALS

Artemether/Lumefantrine Based on theoretical considerations Symtuza and

DRV/COBI is expected to increase artemether/lumefantrine can belumefantrine plasma used without dose adjustments;concentrations. however, due to the increase in(CYP3A inhibition) lumefantrine exposure, thecombination should be used withcaution.

ANTIMYCOBACTERIALS

Rifampicin Based on theoretical considerations The combination of rifampicinrifampicin is expected to decrease and Symtuza is contraindicateddarunavir and/or cobicistat and/or (see section 4.3).tenofovir alafenamide plasmaconcentrations.(CYP3A and/or P-gp induction)

Rifabutin Based on theoretical considerations Co-administration of Symtuza

Rifapentine these antimycobacterials are with rifabutin and rifapentine isexpected to decrease darunavir not recommended. If theand/or cobicistat and/or tenofovir combination is needed, thealafenamide plasma recommended dose of rifabutin isconcentrations. 150 mg 3 times per week on set(CYP3A and/or P-gp induction) days (for example

Monday-Wednesday-Friday).

Increased monitoring for rifabutinassociated adverse reactionsincluding neutropenia and uveitisis warranted due to an expectedincrease in exposure to rifabutin.

Further dose reduction ofrifabutin has not been studied. Itshould be kept in mind that thetwice weekly dose of 150 mg maynot provide an optimal exposureto rifabutin thus leading to a riskof rifamycin 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 considerations Concentrations of these medicinal

Nilotinib DRV/COBI is expected to increase products may be increased when

Vinblastine these anti-neoplastic plasma co-administered with Symtuza

Vincristine concentrations. resulting in the potential for(CYP3A inhibition) increased adverse events usuallyassociated with these medicinalproducts.

Caution should be exercised whencombining one of theseanti-neoplastic agents with

Symtuza.

Everolimus Concomitant use of everolimus or

Irinotecan irinotecan and Symtuza is notrecommended.

ANTIPSYCHOTICS/NEUROLEPTICS

Perphenazine Based on theoretical considerations Clinical monitoring is

Risperidone DRV/COBI is expected to increase recommended when

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

Lurasidone The combination of lurasidone,

Pimozide pimozide, quetiapine or sertindole

Quetiapine and Symtuza is contraindicated

Sertindole (see section 4.3).

β-BLOCKERS

Carvedilol Based on theoretical considerations Clinical monitoring is

Metoprolol DRV/COBI is expected to increase recommended when

Timolol these beta-blocker plasma co-administering Symtuza withconcentrations. beta-blockers and a lower dose of(CYP2D6 inhibition) the beta-blocker should beconsidered.

CALCIUM CHANNEL BLOCKERS

Amlodipine Based on theoretical considerations Clinical monitoring is

Diltiazem DRV/COBI is expected to increase recommended when these

Felodipine these calcium channel blocker medicinal products are

Nicardipine plasma concentrations. co-administered with Symtuza.

Nifedipine (CYP3A inhibition)

Verapamil

CORTICOSTEROIDS

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

Co-administration with CYP3A-metabolised corticosteroids is notrecommended unless the potentialbenefit to the patient outweighsthe risk, in which case patientsshould be monitored for systemiccorticosteroid effects.

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

Dexamethasone (systemic) Based on theoretical considerations Systemic dexamethasone should(systemic) dexamethasone is be used with caution whenexpected to decrease darunavir combined with Symtuza.and/or cobicistat plasmaconcentrations.(CYP3A induction)

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan Based on theoretical considerations Co-administration of Symtuzabosentan is expected to decrease and bosentan is notdarunavir and/or cobicistat plasma recommended.concentrations.(CYP3A induction)

Symtuza is expected to increasebosentan plasma concentrations.(CYP3A inhibition)

ERGOT DERIVATIVESe.g. Based on theoretical considerations Co-administration of Symtuza

Dihydroergotamine DRV/COBI may increase ergot and ergot derivatives is

Ergometrine derivative exposure. contraindicated (see section 4.3).

Ergotamine

Methylergonovine

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A inhibitors

Elbasvir/grazoprevir Based on theoretical considerations Concomitant use of Symtuza with

Symtuza may increase the elbasvir/grazoprevir isexposure to grazoprevir. contraindicated (see section 4.3).(OATP1B and CYP3A inhibition)

Glecaprevir/pibrentasvir Based on theoretical considerations It is not recommended to

DRV/COBI may increase the co-administer Symtuza withexposure to glecaprevir and glecaprevir/pibrentasvir.pibrentasvir.(P-gp, BCRP and/or OATP1B1/3inhibition)

Daclatasvir Based on theoretical Symtuza and sofosbuvir,

Ledipasvir considerations, no clinically sofosbuvir/ledipasvir, or

Sofosbuvir relevant interaction is expected. daclatasvir can be usedconcomitantly without doseadjustment

Herbal products

St. John’s Wort (Hypericum Based on theoretical consideration, The concomitant use of Symtuzaperforatum) St. John’s Wort may substantially with these medicinal products isdecrease DRV/COBI (CYP3A4 contraindicated (see section 4.3).induction) and TAF exposures.(P-gp induction)

HMG CO-A REDUCTASE INHIBITORS

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

Fluvastatin atorvastatin AUC ↑ 290% reductase inhibitor and Symtuza

Pitavastatin atorvastatin Cmax ↑ 319% may increase plasma

Pravastatin atorvastatin Cmin ND concentrations of the lipid

Rosuvastatin lowering agent, which may lead

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

rosuvastatin C When administration ofmax ↑ 277%rosuvastatin C HMG CoA reductase inhibitorsmin NDand Symtuza is desired, it is

Based on theoretical considerations recommended to start with the

DRV/COBI is expected to increase lowest dose and titrate up to thethe plasma concentrations of desired clinical effect whilefluvastatin, pitavastatin, monitoring for safety.

pravastatin, lovastatin and

Lovastatin simvastatin. Concomitant use of Symtuza with

Simvastatin (CYP3A inhibition and/or lovastatin and simvastatin istransport) contraindicated (see section 4.3).

OTHER LIPID MODIFYING AGENTS

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

H2-RECEPTOR ANTAGONISTS

Cimetidine Based on theoretical Symtuza can be co-administered

Famotidine considerations, no mechanistic with H2-receptor antagonists

Nizatidine interaction is expected. without dose adjustments.

Ranitidine

IMMUNOSUPPRESSANTS

Ciclosporin Based on theoretical considerations Concentration monitoring of the

Sirolimus DRV/COBI is expected to increase immunosuppressive agent must

Tacrolimus these immunosuppressant plasma be done when co-administrationconcentrations. with Symtuza occurs.(CYP3A inhibition)

Co-administration of ciclosporin isexpected to increase plasmaconcentrations of tenofoviralafenamide.(P-gp inhibition) Concomitant use of everolimus

Everolimus and Symtuza is notrecommended.

INHALED BETA AGONISTS

Salmeterol Based on theoretical considerations Concomitant use of salmeterol

DRV/COBI is expected to increase and Symtuza is notsalmeterol plasma concentrations. recommended. The combination(CYP3A inhibition) may result in increased risk ofcardiovascular adverse eventswith salmeterol, including QTprolongation, palpitations andsinus tachycardia.

NARCOTIC ANALGESICS/TREATMENT OF OPIOID DEPENDENCE

Buprenorphine/naloxone Based on theoretical considerations Dose adjustment for

DRV/COBI may increase buprenorphine may not bebuprenorphine and/or necessary when co-administerednorbuprenorphine plasma with Symtuza, but a carefulconcentrations. clinical monitoring for signs ofopiate toxicity is recommended.

Methadone Based on theoretical considerations No adjustment of methadone dose

DRV/COBI may increase is expected when initiatingmethadone plasma concentrations. co-administration with Symtuza.

Clinical monitoring is

With ritonavir-boosted darunavir, a recommended, as maintenancesmall decrease in methadone therapy may need to be adjustedplasma concentrations was in some patients.observed. Consult the Summary of

Product Characteristics fordarunavir for further details.

Fentanyl Based on theoretical considerations Clinical monitoring is

Oxycodone DRV/COBI may increase plasma recommended when

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

OESTROGEN-BASED CONTRACEPTIVES

Drospirenone Ethinylestradiol drospirenone AUC ↑ 58% Alternative or additional(3 mg/0.02 mg once daily) drospirenone Cmax ↑ 15% contraceptive measures aredrospirenone Cmin ND recommended when oestrogenbased contraceptives are

Ethinylestradiol ethinylestradiol AUC  30% co-administered with Symtuza.

ethinylestradiol Cmax  14% Patients using oestrogens ashormone replacement therapyethinylestradiol Cmin NDshould be clinically monitored forsigns of oestrogen deficiency.

Norethindrone When Symtuza is co-administered

Based on theoretical considerationswith a drospirenone-containing

DRV/COBI may alterproduct, clinical monitoring isnorethindrone plasmarecommended due to the potentialconcentrations.

for hyperkalaemia.

OPIOID ANTAGONIST

Naloxegol Not studied. Co-administration of Symtuzaand naloxegol is contraindicated.

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

For the treatment of erectile Based on theoretical considerations Concomitant use of PDE-5dysfunction DRV/COBI is expected to increase inhibitors for the treatment of

Sildenafil these PDE-5 inhibitor plasma erectile dysfunction with Symtuza

Tadalafil concentrations. should be done with caution. If

Vardenafil (CYP3A inhibition) concomitant use of Symtuza withsildenafil, vardenafil or tadalafilis indicated, 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.

The combination of avanafil and

Avanafil Symtuza is contraindicated (seesection 4.3).

For the treatment of pulmonary Based on theoretical considerations A safe and effective dose ofarterial hypertension DRV/COBI is expected to increase sildenafil for the treatment of

Sildenafil these PDE-5 inhibitor plasma pulmonary arterial hypertension

Tadalafil concentrations. co-administered with Symtuza(CYP3A inhibition) has not been established. There isan increased potential forsildenafil-associated adverseevents (including visualdisturbances, hypotension,prolonged erection and syncope).

Therefore, co-administration of

Symtuza and sildenafil when usedfor the treatment of pulmonaryarterial hypertension iscontraindicated (see section 4.3).

Co-administration of tadalafil forthe treatment of pulmonaryarterial hypertension with

Symtuza is not recommended.

PROTON PUMP INHIBITORS

Dexlansoprazole Based on theoretical Symtuza can be co-administered

Esomeprazole considerations, no mechanistic with proton pump inhibitors

Lansoprazole interaction is expected. without dose adjustments.

Pantoprazole

Rabeprazole

SEDATIVES/HYPNOTICS

Buspirone Based on theoretical considerations Clinical monitoring is

Clorazepate DRV/COBI is expected to increase recommended when

Diazepam these sedative/hypnotic plasma co-administering Symtuza with

Estazolam concentrations. these sedatives/hypnotics and a

Flurazepam (CYP3A inhibition) lower dose of the

Midazolam (parenteral) sedative/hypnotic should be

Zolpidem considered.

Caution should be used withco-administration of Symtuza andparenteral midazolam.

If Symtuza is co-administeredwith parenteral midazolam, itshould be done in an intensivecare unit or similar setting, whichensures close clinical monitoringand appropriate medicalmanagement in case ofrespiratory depression and/orprolonged sedation. Doseadjustment for midazolam shouldbe considered, especially if morethan a single dose of midazolamis administered.

Co-administration of oral

Midazolam (oral) midazolam or triazolam and

Triazolam Symtuza is contraindicated (seesection 4.3).

TREATMENT FOR PREMATURE EJACULATION

Dapoxetine Not studied. Co-administration of Symtuzawith dapoxetine iscontraindicated.

UROLOGICAL MEDICINAL PRODUCTS

Fesoterodine Not studied. Use with caution. Monitor for

Solifenacin fesoterodine or solifenacinadverse reactions, dose reductionof fesoterodine or solifenacin maybe necessary.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of Symtuza inpregnant women. A moderate amount of data on pregnant women (between 300-1 000 pregnancyoutcomes) indicate no malformative or feto/neonatal toxicity of darunavir, cobicistat or tenofoviralafenamide. A large amount of data on pregnant women (more than 1 000 exposed outcomes)indicate no malformative nor foetal/neonatal toxicity associated with emtricitabine.

Animal studies do not indicate direct or indirect harmful effects of darunavir or emtricitabine withrespect to reproductive toxicity (see section 5.3). Animal studies do not indicate direct harmful effectsof cobicistat or tenofovir alafenamide with respect to reproductive toxicity (see section 5.3).

Treatment with darunavir/cobicistat (two of the components of Symtuza) during pregnancy results inlow darunavir exposure (see section 5.2), which may be associated with an increased risk of treatmentfailure and an increased risk of HIV transmission to the child. Therefore, therapy with Symtuza shouldnot be initiated during pregnancy, and women who become pregnant during therapy with Symtuzashould be switched to an alternative regimen (see sections 4.2 and 4.4).

Emtricitabine is excreted in human milk. It is unknown whether darunavir, cobicistat, or tenofoviralafenamide are excreted in human milk. Studies in animals have demonstrated that darunavir,cobicistat and tenofovir are excreted in milk. Studies in rats have demonstrated that darunavir isexcreted 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 Symtuza.

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, cobicistat, emtricitabine, or tenofovir alafenamide onfertility are available. There was no effect on mating or fertility in animals (see section 5.3). Based onanimal studies, no effect on reproduction or fertility is expected with Symtuza.

Symtuza has minor influence on the ability to drive and use machines. Patients should be informedthat dizziness may occur when treated with Symtuza (see section 4.8).

The overall safety profile of Symtuza is based on data from a randomised, double-blinded,comparative Phase 2 trial, GS-US-299-0102 (N = 103 on darunavir/cobicistat/emtricitabine/tenofoviralafenamide [D/C/F/TAF]), data from 2 Phase 3 trials TMC114FD2HTX3001 (AMBER, N = 362 on

D/C/F/TAF) and TMC114IFD3013 (EMERALD, N = 763 on D/C/F/TAF), and on all availableclinical trial and post-marketing data of its components. As Symtuza contains darunavir, cobicistat,emtricitabine, and tenofovir alafenamide, the adverse reactions associated with each of the individualcompounds may be expected.

The most frequent (> 5%) adverse reactions reported in treatment-naïve patients in the Phase 2 (GS-

US-299-0102) and Phase 3 Study (AMBER, TMC114FD2HTX3001, Week 96 analysis) werediarrhoea (22.6%), headache (13.1%), rash (12.7%), nausea (9.7%), fatigue (8.0%), and abdominalpain (5.8%).

The most frequent (> 5%) adverse reactions reported in suppressed treatment-experienced patients(EMERALD Study TMC114IFD3013, Week 96 analysis) were diarrhoea (10.5%), headache (10.4%),arthralgia (7.7%), abdominal pain (7.5%), fatigue (5.9%), and rash (5.1%).

Adverse reactions are listed by system organ class (SOC) and frequency category in Table 2.

Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10),uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000) and not known (frequency cannot beestimated from the available data)

Table 2

MedDRA system organ class Adverse reaction

Frequency category

Blood and lymphatic system disorderscommon anaemia

Immune system disorderscommon (drug) hypersensitivityuncommon immune reconstitution inflammatory syndrome

Metabolism and nutrition disorderscommon diabetes mellitus, anorexia,hypercholesterolaemia, low density lipoproteinincreased, hypertriglyceridaemia,hyperlipidaemia, dyslipidaemiauncommon hyperglycaemia

Psychiatric disorderscommon abnormal dreams

Nervous system disordersvery common headachecommon dizziness

Gastrointestinal disordersvery common diarrhoeacommon vomiting, nausea, abdominal pain, abdominaldistension, dyspepsia, flatulenceuncommon pancreatitis acute, pancreatic enzymes increased

Hepatobiliary disorderscommon hepatic enzyme increaseduncommon acute hepatitisa, cytolytic hepatitisa

Skin and subcutaneous tissue disordersvery common rash (including macular, maculopapular,papular, erythematous, pruritic rash, generalisedrash, and allergic dermatitis)common pruritus, urticariauncommon angioedemarare drug reaction with eosinophilia and systemicsymptomsa, Stevens-Johnson syndromeanot known toxic epidermal necrolysisa, acute generalisedexanthematous pustulosisa

Musculoskeletal and connective tissue disorderscommon arthralgia, myalgiauncommon osteonecrosis

Renal and urinary disordersrare crystal nephropathya§

Reproductive system and breast disordersuncommon gynaecomastiaa

General disorders and administration site conditionscommon asthenia, fatigue

Investigationscommon increased blood creatininea Additional adverse reactions only seen with darunavir/ritonavir in other trials or post-marketing experience§ 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'.

Rash is a common adverse reaction in patients treated with darunavir. Rash was mostly mild tomoderate, often occurring within the first four weeks of treatment and resolving with continued dosing(see section 4.4). In the Phase 2/3 trials in treatment-naïve patients, 12.7% (59/465) of patientsreceiving Symtuza experienced rash (most of which were grade 1), 1.5% (7/465) of patientsdiscontinued treatment due to rash, of whom one for rash and hypersensitivity. In the Phase 3 trial insuppressed treatment-experienced patients (EMERALD Study TMC114IFD3013), 5.1% (39/763) ofpatients receiving Symtuza experienced rash (most of which were grade 1), none discontinuedtreatment due to rash.

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

In the Phase 3 trial of Symtuza in treatment-naïve patients, increases from baseline were observed inthe fasting lipid parameters total cholesterol, direct low density lipoprotein (LDL) and high densitylipoprotein (HDL) cholesterol, and triglycerides at Week 48 and 96 (see Table 3). The medianincreases from baseline were greater in the D/C/F/TAF group compared with the DRV/ cobicistat(COBI)+F/ tenofovir disoproxil fumarate (TDF) group at Week 48.

Table 3

Median increase from baseline at

Lipid parameter Baseline median Week 48 Week 48 Week 96*

D/C/F/TAF D/C + F/TDF D/C/F/TAF

Total cholesterol 4.22 0.74 0.27 0.88(mmol/L)

LDL cholesterol 2.49 0.45 0.13 0.56(mmol/L)

HDL cholesterol 1.08 0.12 0.04 0.13(mmol/L)

Triglycerides 1.09 0.28 0.16 0.33(mmol/L)p < 0.001 for all 4 lipid parameters when comparing D/C/F/TAF versus D/C + F/TDF at Week 48

* No comparator data available beyond Week 48

Musculoskeletal abnormalities

Increased creatine phosphokinase (CPK), myalgia, myositis and rarely, rhabdomyolysis have beenreported with the use of HIV protease 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 CART. The frequency of this is unknown (seesection 4.4).

Immune reconstitution inflammatory syndrome

In HIV infected patients with severe immune deficiency at the time of CART, an inflammatoryreaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (suchas Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time toonset is more variable, and these events can occur many months after initiation of treatment (seesection 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 increases serum creatinine due to inhibition of tubular secretion of creatinine withoutaffecting renal glomerular function as assessed, for instance, by using Cystatin C (Cyst C) as filtrationmarker.

In the Phase 3 trial of Symtuza in treatment-naïve patients, increases in serum creatinine and decreasesin eGFRCG occurred at the first on-treatment assessment (Week 2) and remained stable through96 weeks. At Week 48 changes from baseline were smaller with D/C/F/TAF than D/C+F/TDF. Themedian change in eGFRCG was -5.5 mL/min with D/C/F/TAF and -12.0 mL/min with D/C+F/TDF(p < 0.001). Using Cyst C as filtration marker, the median changes in estimated glomerular filtrationrate calculated using the CKD-EPI (eGFRCKD-EPI CystC) formula were respectively 4.0 mL/min/1.73 m2and 1.6 mL/min/1.73 m2 (p <0.001). At Week 96, the median change in eGFRCG was -5.2 mL/minwith D/C/F/TAF. Using Cyst C as filtration marker, the median change in estimated glomerularfiltration rate calculated using the CKD-EPI (eGFRCKD-EPI Cyst C) formula (N = 22) was+4.4 mL/min/1.73 m2 with D/C/F/TAF.

The safety of Symtuza in paediatric patients has not been investigated. However,the safety ofcomponents of Symtuza was evaluated through the clinical trial TMC114-C230 (N = 12) for darunavirwith ritonavir and GS-US-292-0106 (N = 50) for a fixed dose combination containing elvitegravir,cobicistat, emtricitabine and tenofovir alafenamide. The data from these studies showed that theoverall safety profile of components of Symtuza in paediatric patients aged 12 to < 18 years andweighing at least 40 kg was similar to that observed in the adult population (see section 5.1).

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

Limited information is available on the use of Symtuza components in patients co-infected withhepatitis B and/or C virus.

Among 1 968 treatment-experienced patients receiving darunavir 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. The safety of emtricitabine and tenofovir alafenamide in combinationwith elvitegravir and cobicistat as a fixed-dose combination tablet was evaluated in approximately 70

HIV/HBV co-infected patients currently receiving treatment for HIV in an open-label clinical trial(GS-US-292-1249). Based on this limited experience, the safety profile of emtricitabine/tenofoviralafenamide in patients with HIV/HBV co-infection appears to be similar to that in patients with

HIV-1 monoinfection (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 Symtuza is limited.

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8).

There is no specific antidote for overdose with Symtuza. Treatment of overdose with Symtuza consistsof general supportive measures, including monitoring of vital signs as well as observation of theclinical status of the patient.

Since darunavir and cobicistat are highly bound to plasma proteins, it is unlikely that they will besignificantly removed by haemodialysis or peritoneal dialysis. Emtricitabine can be removed byhaemodialysis, which removes approximately 30% of the emtricitabine dose over a 3 hour dialysisperiod starting within 1.5 hours of emtricitabine dosing. Tenofovir is efficiently removed byhaemodialysis with an extraction coefficient of approximately 54%. It is not known whetheremtricitabine or tenofovir can be removed by peritoneal dialysis.

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infection,combinations, ATC code: J05AR22

Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease(K of 4.5 x 10-12

D M). 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 cytochrome P450 of the CYP3A subfamily. Inhibition of

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.

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and nucleoside analogue of2’-deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabinetriphosphate. Emtricitabine triphosphate inhibits HIV replication through incorporation into viral DNAby the HIV reverse transcriptase (RT), which results in DNA chain-termination.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and phosphonoamidateprodrug of tenofovir (2’-deoxyadenosine monophosphate analogue). Tenofovir alafenamide ispermeable into cells and due to increased plasma stability and intracellular activation throughhydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir disoproxil inconcentrating tenofovir in peripheral blood mononuclear cells (PBMC) (including lymphocytes andother HIV target cells) and macrophages. Intracellular tenofovir is subsequently phosphorylated to thepharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIVreplication through incorporation into viral DNA by the HIV RT, which results in DNAchain-termination.

Darunavir, emtricitabine and tenofovir alafenamide demonstrated additive to synergistic antiviraleffects in two-drug combination studies in cell culture.

Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratorystrains of HIV-2 in acutely infected T-cell lines, human PBMCs and human monocytes/macrophageswith median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstratesantiviral activity in vitro against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group Oprimary isolates with EC50 values ranging from < 0.1 to 4.3 nM. These EC50 values are well below the50% 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, emtricitabine, or tenofovir.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed inlymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs. The EC50 values for emtricitabinewere in the range of 0.0013 to 0.64 μM. Emtricitabine displayed antiviral activity in cell cultureagainst HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 μM) andshowed strain specific activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 μM).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV-1subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cellsand CD4+-T lymphocytes. The EC50 values for tenofovir alafenamide were in the range of 2.0 to14.7 nM. Tenofovir alafenamide displayed antiviral activity in cell culture against all HIV-1 groups(M, N, and O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM)and showed strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).

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.

In vivo, darunavir resistance-associated mutations (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P,

L76V, I84V and L89V) in HIV-1 protease were derived from clinical trial data of ART-experiencedpatients, all of whom were protease inhibitor experienced.

Reduced susceptibility to emtricitabine is associated with M184V/I mutations in HIV-1 RT.

HIV-1 isolates with reduced susceptibility to tenofovir alafenamide express a K65R mutation in

HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed. HIV-1 isolateswith the K65R mutation have low-level reduced susceptibility to abacavir, emtricitabine, tenofovir,and lamivudine.

Emerging resistance in HIV-1 infected, treatment-naïve and virologically suppressed patients

Over 96 weeks of treatment in the Phase 3 studies TMC114FD2HTX3001 (AMBER) in treatment-naïve patients and TMC114IFD3013 (EMERALD) in virologically suppressed treatment-experiencedpatients, resistance testing was performed on samples from patients experiencing protocol-definedvirologic failure (PDVF) and who had HIV-1 RNA ≥400 copies/mL at failure or at later time points.

Emerging resistance in the Symtuza groups is shown in Table 4. No DRV, primary PI, or TDF/TAFresistance-associated mutations were observed.

Table 4: Emerging resistance in AMBER and EMERALD trial (Week 96)

Subjects Subjects with ≥1 emergent RAM, n (%)with PDVF

Subjects evaluated Protease Reverse transcriptasewith for

Treatment Subjects, PDVF, resistance, Primary TDF/

Study group n n (%) n (%) PI/DRV TAF FTC

TMC114FD2HTX3001 Symtuza 362 15 (4.1) 9 (2.5) 0 0(M184I/V)a

TMC114IFD3013 Symtuza 763 24 (3.1) 4 (0.5) 0 0 0

Total Phase 3 Symtuza 1 125 39 (3.5) 13 (1.2) 0 0 1 (0.1)a At Week 36 M184M/I/V observed, conferring resistance to FTC. This subject harbored a K103N mutation at screening,indicating transmitted NNRTI resistance.

DRV = darunavir; FTC = emtricitabine; PDVF = protocol-defined virologic failure; PI = protease inhibitor; RAM = resistance-associated mutation; TDF = tenofovir disoproxil fumarate; TAF = tenofovir alafenamide

Cross-resistance in HIV-1 infected, treatment-naïve and virologically suppressed patients

The emtricitabine-resistant virus with the M184M/I/V mutation was cross-resistant to lamivudine, butretained sensitivity to abacavir, stavudine, tenofovir, and zidovudine.

HIV-1 Treatment-naïve patients

In double-blind Phase 3 Trial TMC114FD2HTX3001 (AMBER), treatment-naïve patients wererandomised to receive either Symtuza (N = 362) or a combination of fixed-dose combination ofdarunavir and cobicistat and fixed-dose combination of emtricitabine and tenofovir disoproxilfumarate (F/TDF) (N = 363) once daily. Virologic response was defined as < 50 copies/mL using thesnapshot approach (see Table 5).

The 725 patients in total had a median age of 34 years (range 18-71), 88.3% were male, 83.2% White,11.1% Black, 1.5% Asian. The mean baseline plasma HIV-1 RNA and the median baseline CD4+ cellcount were 4.48 log copies/mL (SD = 0.61) and 453 x 106 cells/L (range 38 - 1 456 x 10610 cells/L),respectively.

Table 5: Virologic outcomes in AMBER at Week 48 and 96 (FDA Snapshot)

Week 48 Week 96*

Symtuza DRV/COBI +F/TDF Symtuza

N = 362 N = 363 N = 362

Virologic response, %

HIV-1 RNA < 50 copies/mL 91.4% 88.4% 85.1%

Treatment differencea 2.7 (95% CI: -1.6; 7.1) -

Virologic failureb 4.4% 3.3% 5.5%

HIV-1 RNA ≥ 50 copies/mL 2.5% 2.5% 1.7%

Virologic failure leading to discontinuation 0.3% 0 1.4%d

Discontinued study drug due to other reasons 1.7% 0.8% 2.5%and last available HIV-1 RNA ≥ 50 copies/mL

No virologic datac 4.1% 8.3% 9.4%

Reasons

Discontinued trial due to adverse event or 2.2% 4.4% 2.2%death

Discontinued study drug due to other reasons 1.1% 2.5% 5.8%and last available HIV-1 RNA < 50 copies/mL

Missing data during window but on trial 0.8% 1.4% 1.4%

Virologic response (HIV-1-RNA< 50 copies/mL; Snapshot analysis) bysubgroup, n/N (%)

Age< 50 years 299/326 (91.7%) 293/331 (88.5%) 276/326 (84.7%)≥ 50 years 32/36 (88.9%) 28/32 (87.5%) 32/36 (88.9%)

Sex

Male 292/318 (91.8%) 289/322 (89.8%) 270/318 (84.9%)

Female 39/44 (88.6%) 32/41 (78.0%) 38/44 (86.4%)

Black 34/40 (85.0%) 34/40 (85.0%) 28/40 (70.0%)

Non-black 281/305 (92.1%) 275/309 (89.0%) 266/305 (87.2%)

Baseline viral load≤ 100 000 copies/mL 278/303 (91.7%) 265/293 (90.4%) 260/303 (85.8%)> 100 000 copies/mL 53/59 (89.8%) 56/70 (80.0%) 48/59 (81.4%)

Baseline CD4+ cell count< 200 cells/mm3 16/22 (72.7%) 25/29 (86.2%) 16/22 (72.7%)≥ 200 cells/mm3 315/340 (92.6%) 296/334 (88.6%) 292/340 (85.9%)

CD4+ cell count mean change from baseline 188.7 173.8 228.8a Based on stratum adjusted MH test where stratification factors are HIV-1 RNA level (≤ 100 000 or > 100 000 copies/mL)and CD4+ cell count (< 200 or ≥ 200 cells/µL).

b Included subjects who had HIV-1 RNA ≥ 50 copies/mL in the Week 48/96 window; subjects who discontinued early due tolack or loss of efficacy per investigator’s assessment; subjects who discontinued for reasons other than an adverse event (AE),death or lack or loss of efficacy and at the time of discontinuation had a HIV-1 RNA ≥ 50 copies/mL.

c Week 48 window: Day 295 - Day 378; Week 96 window: Day 631 - Day 714d Five subjects were discontinued from the study due to efficacy related reasons per investigator’s assessment (physiciandecision), of which 3 had last on treatment HIV-1 RNA <50 copies/mL.

* No comparator data available beyond Week 48

In the Phase 3 study TMC114FD2HTX3001in treatment-naïve patients, Symtuza was associated withno or smaller reductions in bone mineral density (BMD) compared DRV/COBI+F/TDF as measuredby DXA analysis of hip (LS means percent change: 0.17% vs -2.69%, p < 0.001) and lumbar spine(LS means percent change: -0.68% vs -2.38%, p =0.004) after 48 weeks of treatment. After 96 weeksof treatment with Symtuza, the (95% CI) percent changes from baseline in BMD at the hip and spineregion were respectively: -0.26 (-0.96; 0.45) % and -0.93 (-1.82; -0.05) %.

In studies in treatment-naïve patients, Symtuza was associated with a lower impact on the estimatedglomerular filtration rate by Cockcroft-Gault method compared to control group(DRV/COBI+F/TDF).

HIV-1 Treatment-experienced patients

Phase 3 trial TMC114IFD3013 (EMERALD) evaluated the efficacy of Symtuza in virologically-suppressed (HIV-1 RNA less than 50 copies/mL) HIV-1 infected patients. Patients were virologicallysuppressed for at least 2 months and no more than once had a viral load elevation above 50 HIV-1

RNA copies/mL during the year prior to enrollment. Patients were allowed in the study if they hadprevious failure on any non-darunavir ARV regimen. Patients had no history of virologic failure ondarunavir-based regimens, and if historical genotypes were available, absence of darunavir RAMs.

Patients were on a stable ARV regimen (for at least 6 months), consisting of a boosted proteaseinhibitor [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), orlopinavir with ritonavir] combined with emtricitabine and TDF. They either switched to Symtuza(N = 763) or continued their treatment regimen (N = 378) (randomised 2:1).

Patients had a median age of 46 years (range 19-78), 82% were male, 75.5% White, 20.9% Black, and2.3% Asian. The median baseline CD4+ cell count was 628 x 106 cells/mm3 (range111-1 921 x 106 cells/mm3). Week 48 and 96 virologic outcomes in the EMERALD trial are providedin Table 6.

Table 6: Week 48 and 96 virologic outcomes in EMERALD trial

Week 48 Week 96*

Symtuza bPI+F/TDF Symtuza

N = 763 N = 378 N = 763

Cumulative protocol-defined virologic rebounda, %

Protocol defined rebound rate 2.5% 2.1% 3.1%(95% CI)b (1.5; 3.9) (0.9; 4.1) (2.0; 4.6)

Difference in proportions 0.4 (95% CI: -1.5; 2.2) -

FDA snapshot outcome

HIV-1 RNA < 50 copies/mL 94.9% 93.7% 90.7%

Virologic failurec 0.8% 0.5% 1.2%

Treatment differenced 0.3 (95% CI: -0.7; 1.2) -

HIV-1 RNA ≥ 50 copies/mL 0.5% 0.5% 0.7%f

Virologic failure - leading to discontinuation 0 0 0

Virologic failure - discontinued due to other reason 0.3% 0 0.5%and last available HIV-1 RNA ≥ 50 copies/mL

No virologic datae 4.3% 5.8% 8.1%

Reasons

Discontinued trial due to adverse event or death 1.4% 1.1% 2.4%

Discontinued trial for other reasons 2.5% 4.2% 5.0%

Missing data during window but on trial 0.4% 0.5% 0.8%

Cumulative protocol-defined virologic rebound by subgroup, %

Age< 50 years 13/507 (2.6%) 7/252 (2.8%) 18/507 (3.6%)≥ 50 years 6/256 (2.3%) 1/126 (0.8%) 6/256 (2.3%)

Sex

Male 14/623 (2.2%) 7/313 (2.2%) 20/623 (3.2%)

Female 5/140 (3.6%) 1/65 (1.5%) 4/140 (2.9%)

Black 6/155 (3.9%) 1/82 (1.2%) 7/155 (4.5%)

Non-black 13/597 (2.2%) 7/293 (2.4%) 17/597 (2.8%)

Previous ARV failure0 16/647 (2.5%) 8/325 (2.5%) 19/647 (2.9%)≥ 1 3/116 (2.6%) 0/53 (0%) 5/116 (4.3%)a 2 consecutive HIV-1 RNA ≥ 50 copies/mL, or in case of discontinuation or at Week 48/96 for any reason, (single) HIV-1

RNA ≥ 50 copies/mL as of baseline (included)b Two-sided Exact Clopper-Pearson 95% CIc Included subjects who had ≥ 50 copies/mL in the Week 48/96 window; subjects who discontinued early due to lack or loss ofefficacy per investigator’s assessment; subjects who discontinued for reasons other than an adverse event (AE), death or lackor loss of efficacy and at the time of discontinuation had a viral value ≥ 50 copies/mL.

d Based on MH test adjusting for bPI at screening (ATV with rtv or COBI, DRV with rtv or COBI, LPV with rtv)e Week 48 window: Day 295 - Day 378; Week 96 window: Day 631 - Day 714f The following viral load values were observed for these subjects at Week 96: 54 copies/mL, 78 copies/mL, 111 copies/mL,152 copies/mL, and 210 copies/mL.

* No comparator data available beyond Week 48.

The use of Symtuza in ART-naïve adolescent patients from the age of 12 years to < 18 years, andweighing at least 40 kg is supported by two trials in HIV-1 infected paediatric patients(TMC114-C230 and GS-US-292-0106). For more details, refer to the prescribing information ofdarunavir and emtricitabine/ tenofovir alafenamide.

An open-label, Phase 2 trial (TMC114-C230) was conducted for evaluating the pharmacokinetics,safety, tolerability, and efficacy of darunavir with low dose ritonavir in 12 ART-naïve HIV-1 infectedpaediatric patients aged 12 to less than 18 years and weighing at least 40 kg. These patients receiveddarunavir/ritonavir 800/100 mg once daily in combination with other antiretroviral agents. Virologicresponse was defined as a decrease in plasma HIV-1 RNA viral load of at least 1.0 log10 versusbaseline (see Table 7).

Table 7: Virologic outcome in ART- naïve adolescents at Week 48 (TLOVR algorithm)

TMC114-C230

Outcomes at Week 48 Darunavir/ritonavir(N = 12)

HIV-1 RNA < 50 copies/mLa 83.3% (10)

CD4+ percent median change from baseline 14

CD4+ cell count mean change from baselineb 221≥ 1.0 log10 decrease from baseline in plasma 100%viral loada Imputations according to the TLOVR algorithm.b Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0.

In the study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of emtricitabine andtenofovir alafenamide were evaluated in an open-label study in which 50 HIV-1 infected,treatment-naïve adolescents received emtricitabine and tenofovir alafenamide (10 mg) given withelvitegravir and cobicistat as a fixed-dose combination tablet. Patients had a median age of 15 years(range: 12-17), and 56% were female, 12% were Asian, and 88% were Black. At baseline, medianplasma HIV-1 RNA was 4.7 log10 copies/mL, median CD4+ cell count was 456 cells/mm3 (range:

95-1 110), and median CD4+ % was 23% (range: 7-45%). Overall, 22% had baseline plasma HIV-1

RNA > 100 000 copies/mL. At 48 weeks, 92% (46/50) achieved HIV-1 RNA < 50 copies/mL, similarto response rates in studies of treatment-naïve HIV-1 infected adults. The mean increase from baselinein CD4+ cell count at Week 48 was 224 cells/mm3. No emergent resistance to E/C/F/TAF(elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) was detected through Week 48.

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

Symtuza in one or more subsets of the paediatric population in the treatment of HIV-1 infection (seesection 4.2 for information on paediatric use).

The bioavailability of all components of Symtuza was comparable to that when darunavir 800 mg,cobicistat 150 mg, and emtricitabine/tenofovir alafenamide 200/10 mg were co-administered asseparate formulations; bioequivalence was established following single-dose administration under fedconditions in healthy subjects (N = 96).

The absolute bioavailability of a single 600 mg dose of darunavir alone was approximately 37% andincreased to approximately 82% in the presence of 100 mg twice daily ritonavir. The absolutebioavailability of the emtricitabine 200 mg capsule was 93%.

All components were rapidly absorbed following oral administration of Symtuza in healthy subjects.

Maximum plasma concentrations of darunavir, cobicistat, emtricitabine and tenofovir alafenamidewere achieved at 4.00, 4.00, 2.00, and 1.50 hours after dosing, respectively. The bioavailability of thecomponents of Symtuza was not affected when administered orally as a split tablet compared toadministration as a tablet swallowed whole.

The exposure to darunavir and cobicistat administered as the Symtuza was 30-45% lower and 16-29%lower, respectively, in fasted compared to fed condition. For emtricitabine, the Cmax was 1.26-foldhigher in a fasted condition, while the area under the curve (AUC) was comparable in fed and fastedcondition. For tenofovir alafenamide, the Cmax was 1.82-fold higher in fasted condition, while the

AUC was 20% lower to comparable in a fasted compared to fed condition. Symtuza tablets should betaken with food. The type of food does not affect exposure to Symtuza.

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 bloodconcentration ratio was approximately 2.

In vitro binding of emtricitabine to human plasma proteins was < 4% and independent ofconcentration over the range of 0.02-200 mcg/mL. At peak plasma concentration, the mean plasma toblood concentration ratio was approximately 1.0 and the mean semen to plasma concentration ratiowas approximately 4.0.

In vitro binding of tenofovir to human plasma proteins is < 0.7% and is independent of concentrationover the range of 0.01-25 mcg/mL. Ex vivo binding of tenofovir alafenamide to human plasmaproteins in samples collected during clinical trials was approximately 80%.

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.

In vitro studies indicate that emtricitabine is not an inhibitor of human CYP enzymes. Followingadministration of [14C]-emtricitabine, complete recovery of the emtricitabine dose was achieved inurine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the dose wasrecovered in the urine as three putative metabolites. The biotransformation of emtricitabine includesoxidation of the thiol moiety to form the 3’-sulfoxide diastereomers (approximately 9% of dose) andconjugation with glucuronic acid to form 2’-O-glucuronide (approximately 4% of dose). No othermetabolites were identifiable.

Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for> 80% of an oral dose. In vitro studies have shown that tenofovir alafenamide is metabolised totenofovir (major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV targetcells) and macrophages; and by carboxylesterase-1 in hepatocytes. In vivo, tenofovir alafenamide ishydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the activemetabolite tenofovir diphosphate.

In vitro, tenofovir alafenamide is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or

CYP2D6. Tenofovir alafenamide is minimally metabolised by CYP3A4. Upon co-administration withthe moderate CYP3A inducer probe efavirenz, tenofovir alafenamide exposure was not significantlyaffected. Following administration of tenofovir alafenamide, plasma [14C]-radioactivity showed atime-dependent profile with tenofovir alafenamide as the most abundant species in the initial fewhours and uric acid in the remaining period.

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 intravenous clearance of darunavir alone (150 mg) and in the presence of low dose (100 mg)ritonavir was 32.8 l/h and 5.9 l/h, respectively. The median terminal plasma half-life of darunavirfollowing administration of Symtuza is 5.5 hours.

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

Symtuza is 3.6 hours.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved inurine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabinedose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged307 mL/min. Following oral administration of Symtuza, the median terminal elimination half-life ofemtricitabine is 17.2 hours.

Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir. The median terminalelimination half-life of tenofovir alafenamide was 0.3 hours when administered as Symtuza.

Tenofovir is eliminated from the body by the kidneys by both glomerular filtration and active tubularsecretion. Tenofovir has a median plasma half-life of approximately 32 hours. Renal excretion ofintact tenofovir alafenamide is a minor pathway with less than 1% of the dose eliminated in urine. Thepharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150-180 hours within

PBMCs.

The pharmacokinetics of Symtuza have not been investigated in paediatric patients. However, thereare pharmacokinetic data for the different components of Symtuza, indicating that doses of 800 mgdarunavir, 150 mg cobicistat, 200 mg emtricitabine and 10 mg tenofovir alafenamide result in similarexposures in adults and adolescents aged 12 years and older, weighing at least 40 kg.

Limited PK information is available in the elderly (age ≥ 65 years of age) for Symtuza as well as itsindividual components.

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 years) (see section 4.4).

No clinically relevant pharmacokinetic differences due to age have been identified for cobicistat,emtricitabine or tenofovir alafenamide in the age range ≤ 65 years.

Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV-1infected females compared to males. This difference is not clinically relevant.

No clinically relevant pharmacokinetic differences due to gender have been identified for cobicistat,emtricitabine or tenofovir alafenamide.

Symtuza has not been investigated in patients with renal impairment. There are pharmacokinetic datafor the (individual) components of Symtuza.

Results from a mass balance study with [14C]-darunavir with ritonavir showed that approximately7.7% 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 (eGFRCG 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 (eGFRCG below 30 mL/min). No meaningful differences in cobicistatpharmacokinetics were observed between subjects with severe renal impairment and healthy subjects,consistent with low renal clearance of cobicistat.

Mean systemic emtricitabine exposure was higher in patients with severe renal impairment(eGFRCG < 30 mL/min) (33.7 mcg*h/mL) than in subjects with normal renal function(11.8 mcg*h/mL).

No clinically relevant differences in tenofovir alafenamide, or tenofovir pharmacokinetics wereobserved between healthy subjects and patients with severe renal impairment (eGFRCG > 15 but< 30 mL/min) in studies of tenofovir alafenamide. There are no pharmacokinetic data on tenofoviralafenamide in patients with eGFRCG < 15 mL/min.

Symtuza has not been investigated in patients with hepatic impairment. There are pharmacokineticdata for the (individual) components of Symtuza.

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. The effect of severehepatic impairment on the pharmacokinetics of darunavir has not been studied (see sections 4.2, pct. 4.3and 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. The effect of severe hepaticimpairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.

The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment;however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liverimpairment should be limited.

Clinically relevant changes in tenofovir pharmacokinetics in patients with hepatic impairment werenot observed in patients with mild to moderate hepatic impairment. The effect of severe hepaticimpairment (Child-Pugh Class C) on the pharmacokinetics of tenofovir alafenamide has not beenstudied.

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,cobicistat, emtricitabine, or tenofoviralafenamide (refer to sections 4.4 and 4.8).

Treatment with darunavir/cobicistat 800/150 mg once daily during pregnancy results in low darunavirexposure (see Table 8). In women receiving darunavir/cobicistat during the second trimester ofpregnancy, mean intra-individual values for total darunavir Cmax, AUC24h and Cmin were 49%, 56% and92% lower, respectively, as compared with postpartum; during the third trimester of pregnancy, totaldarunavir Cmax, AUC24h and Cmin values were 37%, 50% and 89% lower, respectively, as comparedwith postpartum. The unbound fraction was also substantially reduced, including around 90%reductions of Cmin levels. The main cause of these low exposures is a marked reduction in cobicistatexposure as a consequence of pregnancy-associated enzyme induction (see below).

Table 8

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.

No pharmacokinetic data are available for emtricitabine and tenofovir alafenamide during pregnancy.

Non-clinical data on darunavir reveal no special hazard for humans based on conventional studies ofsafety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Darunavir has noeffect on fertility or early embryonic development and DRV shows no teratogenic potential, atexposure levels below those at the recommended clinical dose in humans.

In juvenile rats receiving darunavir up to days 23-26 (equivalent to less than 2 years of age inhumans), increased mortality was observed with convulsions in some animals. These findings wereattributed to the immaturity of the liver enzymes and of the blood brain barrier. Due to uncertaintiesregarding the rate of development of the human blood brain barrier and liver enzymes Symtuza shouldnot be used in paediatric patients below 3 years of age.

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 foetuses 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.

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studiesof safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity toreproduction and development.

Emtricitabine had demonstrated low carcinogenic potential in mice and rats.

Non-clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidney as the primarytarget organs of toxicity. Bone toxicity was observed as reduced bone mineral density in rats and dogsat tenofovir exposures at least four times greater than those expected after administration of Symtuza.

A minimal infiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide andtenofovir exposures of approximately 15 and 40 times greater, respectively, than those expected afteradministration of Symtuza.

Tenofovir alafenamide was not mutagenic or clastogenic in conventional genotoxicity assays.

Because there is a lower tenofovir exposure in rats and mice after the administration of tenofoviralafenamide compared to tenofovir disoproxil, carcinogenicity studies and a rat peri-postnatal studywere conducted only with tenofovir disoproxil. No special hazard for humans was revealed inconventional studies of carcinogenic potential and toxicity to reproduction and development.

Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy orfoetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in aperi-postnatal toxicity study at maternally toxic doses.

Croscarmellose sodium

Magnesium stearate

Cellulose, microcrystalline

Silica, colloidal anhydrous

Macrogol 4 000

Poly (vinyl alcohol)- partially hydrolysed

Talc

Titanium dioxide (E171)

Iron oxide yellow (E172)

Not applicable.

3 years

After first opening: 6 weeks

Store in the original package with desiccant inside the bottle in order to protect the tablets frommoisture. Keep the bottle tightly closed. Tablets may be stored outside of the original container for upto 7 days and should be discarded after that time if not taken. Tablets stored outside of the originalcontainer should not be placed back into the container.

White, high density polyethylene (HDPE) bottle with a silica gel desiccant (contained in a separatesachet or canister) fitted with polypropylene (PP) child resistant closure with induction seal.

Each bottle contains 30 tablets.

Pack size of one bottle or three bottles per carton.

Not all pack sizes may be marketed.

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/1/17/1225/001 - 30 film-coated tablets

EU/1/17/1225/002 - 90 film-coated tablets (3 x 30)

Date of first authorisation: 21 September 2017

Date of latest renewal: 24 May 2022

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

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