Symtuza

HOS-098207 · has-adverse-reaction-information · PDF-Seite 19

Summary of the safety profile 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/tenofovir alafenamide [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 available clinical 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 individual compounds 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) were diarrhoea (22.6%), headache (13.1%), rash (12.7%), nausea (9.7%), fatigue (8.0%), and abdominal pain (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%). Tabulated list of adverse reactions 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 be estimated from the available data). 19 Table 2 MedDRA system organ class Adverse reaction Frequency category Blood and lymphatic system disorders common anaemia Immune system disorders common (drug) hypersensitivity uncommon immune reconstitution inflammatory syndrome Metabolism and nutrition disorders common diabetes mellitus, anorexia, hypercholesterolaemia, low density lipoprotein increased, hypertriglyceridaemia, hyperlipidaemia, dyslipidaemia uncommon hyperglycaemia Psychiatric disorders common

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HOS-098203 · has-contraindication-information · PDF-Seite 4

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 the potential 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 for serious 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

HOS-098202 · has-indication-information · PDF-Seite 2

Symtuza is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and paediatric patients aged 6 years and older with body weight at least 25 kg. Genotypic testing should guide the use of Symtuza (see sections 4.2, 4.4, and 5.1).

HOS-098205 · has-interaction-information · PDF-Seite 8

No interaction trials have been performed using Symtuza. Interactions that have been identified in studies with individual components of Symtuza, i.e. with darunavir (in combination with low dose ritonavir), cobicistat, emtricitabine or tenofovir alafenamide, determine the interactions that may occur with Symtuza. Darunavir and cobicistat Darunavir is an inhibitor of CYP3A, a weak inhibitor of CYP2D6 and an inhibitor of P-gp. Cobicistat is a mechanism based inhibitor of CYP3A, and a weak CYP2D6 inhibitor. Cobicistat inhibits the transporters p-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat is not expected to induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, UGT1A1, or P-gp (MDR1). Co-administration of Symtuza and medicinal products primarily metabolised by CYP3A or transported by P-gp, BCRP, MATE1, OATP1B1 and OATP1B3 may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions (see section 4.3 or table below). Symtuza must not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index). 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 leading to 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 activity would be expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations 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 the clearance of darunavir and cobicistat and may result in increased plasma concentrations of darunavir and cobicistat (e.g. azole antifungals like clotrimazole). These interactions are described in the interaction table below. Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. If switching from ritonavir as a pharmacoenhan

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HOS-098206 · has-pregnancy-information · PDF-Seite 18

Pregnancy There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of Symtuza in pregnant women. A moderate amount of data on pregnant women (between 300-1 000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of darunavir, cobicistat or tenofovir alafenamide. 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 with respect to reproductive toxicity (see section 5.3). Animal studies do not indicate direct harmful effects of cobicistat or tenofovir alafenamide with respect to reproductive toxicity (see section 5.3). 18 Treatment with darunavir/cobicistat (two of the components of Symtuza) during pregnancy results in low darunavir exposure (see section 5.2), which may be associated with an increased risk of treatment failure and an increased risk of HIV transmission to the child. Therefore, therapy with Symtuza should not be initiated during pregnancy, and women who become pregnant during therapy with this FDC should be switched to an alternative regimen (see sections 4.2 and 4.4). Breast-feeding Emtricitabine is excreted in human milk. Based on published data, tenofovir alafenamide is excreted in human milk at low levels. The relative infant dose (RID) is estimated to be below 0.1% of the maternal weight-adjusted dose. It is unknown whether darunavir or cobicistat are excreted in human milk. Studies in animals have demonstrated that darunavir and cobicistat are excreted in milk. Studies in rats have demonstrated that darunavir is excreted in milk and at high levels (1 000 mg/kg/day) resulted in toxicity of the offspring. Because of the potential for adverse reactions in breast-fed infants, women should be instructed not to breast-feed if they are receiving Symtuza. In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed. Fertility No human data on the effect of darunavir, cobicistat, emtricitabine, or tenofovir alafenamide on fertility are available. There was no effect on mating or fertility in animals (see section 5.3). Based on animal studies, no effect on reproduction or fertility is expected with Symtuza.

HOS-098204 · has-warning-information · PDF-Seite 4

ART-experienced patients Symtuza should not be used in treatment-experienced patients with one or more DRV-RAMs (see section 5.1) or with HIV-1 RNA ≥ 100 000 copies/mL or CD4+ cell count < 100 cells x 106/L. 4 Pregnancy Treatment with darunavir/cobicistat 800/150 mg during the second and third trimester has been shown to result in low darunavir exposure, with a reduction of around 90% in Cmin levels (see section 5.2). Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in darunavir exposure may result in virological failure and an increased risk of mother to child transmission of HIV infection. Therefore, therapy with Symtuza should not be initiated during pregnancy, and women who become pregnant during therapy with Symtuza should be switched to an alternative regimen (see sections 4.2 and 4.6). Patients co-infected with HIV and hepatitis B or C virus Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe 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 associated with 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 several months after stopping treatment. If appropriate, initiation of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Symtuza should not be administered concomitantly with medicinal products containing tenofovir disoproxil (e.g. fumarate, phosphate, or succinate), lamivudine, or adefovir dipivoxil used for the treatment of HBV infection. Mitochondrial dysfunction Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negat

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