Summary of the safety profile: Dolutegravir: The safety profile is based on pooled data from Phase IIb and Phase III clinical studies in 1222 previously untreated patients, 357 previously treated patients unexposed to integrase inhibitors and 264 patients with prior treatment failure that included an integrase inhibitor (including integrase class resistance). The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see Precautions). The most commonly seen treatment emergent adverse reactions were nausea (13%), diarrhoea (18%) and headache (13%).
The safety profile was similar across the different treatment populations mentioned previously.
Emtricitabine and Tenofovir Alafenamide: Assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies in which 2,832 HIV-1 infected patients received medicinal products containing emtricitabine and tenofovir alafenamide. In clinical studies of 866 treatment-naïve adult patients receiving emtricitabine and tenofovir alafenamide with elvitegravir and cobicistat as the fixed-dose combination tablet elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide (as fumarate) 10 mg (E/C/F/TAF), the most frequently reported adverse reactions were diarrhoea (7%), nausea (10%), and headache (6%).
Tabulated summary of adverse reactions for combination of Dolutegravir, Emtricitabine and Tenofovir Alafenamide: The adverse reactions in Table 9 are listed by system organ class and frequency. Frequencies 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), very rare (<1/10,000). (See Table 9.)
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Description of selected adverse reactions: Changes in laboratory biochemistries: Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained stable through 48 weeks. A mean change from baseline of 9.96 μmol/L was observed after 48 weeks of treatment. Creatinine increases were comparable by various background regimens. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate.
Co-infection with Hepatitis B or C: In Phase III studies patients with hepatitis B and/or C co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C co-infection at the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see Precautions).
Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) 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).
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).
Changes in lipid laboratory tests: Increases from baseline were observed in both the Tenofovir alafenamide and tenofovir disoproxil fumarate containing treatment groups for the fasting lipid parameters total cholesterol, direct low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, and triglycerides at Week 48. The median increase from baseline for those parameters was greater in the E/C/F/TAF group compared with the elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg (E/C/F/TDF) group at Week 48 (p < 0.001 for the difference between treatment groups for fasting total cholesterol, direct LDL- and HDL-cholesterol, and triglycerides). The median (Q1, Q3) change from baseline in total cholesterol to HDL-cholesterol ratio at Week 48 was 0.1 (-0.3, 0.5) in the E/C/F/TAF group and 0.0 (-0.5, 0.4) in the E/C/F/TDF group (p < 0.001 for the difference between treatment groups).
Metabolic parameters: Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see Precautions).
Paediatric population: Based on limited available data for the use of dolutegravir in adolescents (12 to less than 18 year of age and weighing at least 40 kg), there were no additional types of adverse reactions beyond those observed in the adult population.
The safety of emtricitabine and tenofovir alafenamide was evaluated through 48 weeks in an open-label clinical study (GS-US-292-0106) in which HIV-1 infected, treatment-naïve paediatric patients aged 12 to < 18 years received emtricitabine and tenofovir alafenamide as a fixed-dose combination tablet. The safety profile of emtricitabine, tenofovir alafenamide in 50 adolescent patients was similar to that in adults (see Pharmacology: Pharmacodynamics under Actions).
Other special populations: Patients with renal impairment: The safety of emtricitabine and tenofovir alafenamide was evaluated through 48 weeks in an open-label clinical study (GS-US-292-0112) in which 248 HIV-1 infected patients who were either treatment-naïve (n = 6) or virologically suppressed (n = 242) with mild to moderate renal impairment (estimated glomerular filtration rate by Cockcroft-Gault method [eGFRCG]: 30-69 mL/min) received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet. The safety profile in patients with mild to moderate renal impairment was similar to that in patients with normal renal function (see Pharmacology: Pharmacodynamics under Actions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization 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 via the national reporting system.