Symtuza Adverse Reactions

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 6. 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). (See Table 6.)

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Description of selected adverse reactions: Rash: Rash is a common adverse reaction in patients treated with darunavir. Rash was mostly mild to moderate, often occurring within the first four weeks of treatment and resolving with continued dosing (see Precautions). In the Phase 2/3 trials in treatment-naïve patients, 12.7% (59/465) of patients receiving Symtuza experienced rash (most of which were grade 1), 1.5% (7/465) of patients discontinued treatment due to rash, of whom one for rash and hypersensitivity. In the Phase 3 trial in suppressed treatment-experienced patients (EMERALD Study TMC114IFD3013), 5.1% (39/763) of patients receiving Symtuza experienced rash (most of which were grade 1), none discontinued treatment due to rash.
Metabolic parameters: Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see Precautions).
In the Phase 3 trial of Symtuza in treatment-naïve patients, increases from baseline were observed in the fasting lipid parameters total cholesterol, direct low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, and triglycerides at Week 48 and 96 (see Table 7). The median increases 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.

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Musculoskeletal abnormalities: Increased creatine phosphokinase (CPK), myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of HIV protease inhibitors, particularly in combination with NRTIs.
Osteonecrosis: Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see Precautions).
Immune reconstitution inflammatory syndrome: In HIV infected patients with severe immune deficiency at the time of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable, and these events can occur many months after initiation of treatment (see Precautions).
Bleeding in haemophiliac patients: There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see Precautions).
Decrease estimated creatinine clearance: Cobicistat increases serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function as assessed, for instance, by using Cystatin C (Cyst C) as filtration marker.
In the Phase 3 trial of Symtuza in treatment-naïve patients, increases in serum creatinine and decreases in eGFR_CG occurred at the first on-treatment assessment (Week 2) and remained stable through 96 weeks. At Week 48 changes from baseline were smaller with D/C/F/TAF than D/C+F/TDF. The median change in eGFR_CG 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 filtration rate calculated using the CKD-EPI (eGFR_{CKD-EPI Cyst C}) formula were respectively 4.0 mL/min/1.73 m² and 1.6 mL/min/1.73 m² (p < 0.001). At Week 96, the median change in eGFR_CG was -5.2 mL/min with D/C/F/TAF. Using Cyst C as filtration marker, the median change in estimated glomerular filtration rate calculated using the CKD-EPI (eGFR_{CKD-EPI Cyst C}) formula (N = 22) was +4.4 mL/min/1.73 m² with D/C/F/TAF.
Paediatric population: The safety of Symtuza in paediatric patients has not been investigated. However, the safety of components of Symtuza was evaluated through the clinical trial TMC114-C230 (N = 12) for darunavir with 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 the overall safety profile of components of Symtuza in paediatric patients aged 12 to < 18 years and weighing at least 40 kg was similar to that observed in the adult population (see Pharmacology: Pharmacodynamics under Actions).
Other special populations: 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 with hepatitis B and/or C virus.
Among 1,968 treatment-experienced patients receiving darunavir co-administered with ritonavir 600/100 mg twice daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis. The safety of emtricitabine and tenofovir alafenamide in combination with 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/tenofovir alafenamide in patients with HIV/HBV co-infection appears to be similar to that in patients with HIV-1 monoinfection (see Precautions).
Post-marketing experience: In addition to adverse reactions from clinical studies, the following adverse reactions were identified during postapproval use of products containing tenofovir alafenamide (TAF). Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.
Renal and urinary disorders: Acute renal failure, proximal renal tubulopathy, Fanconi syndrome.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.