Dovato Adverse Reactions

DOVATO contains dolutegravir and lamivudine, therefore the adverse drug reactions (ADRs) associated with these individual components may be expected (Tables 4 and 5). For many of the adverse events listed it is unclear whether they are related to the active substance, the wide range of other medicinal products used in the management of HIV infection, or whether they are a result of the underlying disease process.
ADRs identified in an analysis of pooled data from Phase 2b and Phase 3 clinical trials of the individual components are listed in Table 4 as follows by MedDRA system organ class and by frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <1/1,000) and very rare (<1/10,000), including isolated reports.
Clinical Trial Data: Clinical safety data with DOVATO are limited. The ADRs observed for the combination of dolutegravir and lamivudine in an analysis of pooled data from Phase 3 clinical trials (GEMINI-1 and GEMINI-2) conducted in antiretroviral naïve subjects, and from the Phase 3 clinical trial (TANGO) conducted in antiretroviral therapy experienced, virologically suppressed adult subjects who received DOVATO, were generally consistent with the ADR profiles and severities for the individual components when administered with other antiretroviral agents. A single treatment emergent adverse reaction [Nervous system disorders: somnolence; frequency common] was observed with the combination which was not listed in the prescriber information for dolutegravir or lamivudine. There was no difference between the combination and the individual components in severity for any observed adverse reactions. Treatment-emergent ADRs observed in at least 2% of subjects in either treatment arm of the pooled analysis of the GEMINI-1 and GEMINI-2 trials were nausea, headache, diarrhoea, insomnia and dizziness. Insomnia, observed in the DOVATO arm, was the only treatment-emergent ADR observed in at least 2% of subjects in either treatment arm of the TANGO trial. (See Table 4.)

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Changes in laboratory chemistries: Increases in serum creatinine occurred within the first 4 weeks of treatment with dolutegravir plus lamivudine and remained stable through 48 weeks. A mean change from baseline of 10.3 µmol/L (range: -36.3 µmol/L to 55.7 µmol/L) was observed after 48 weeks of treatment. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate (see PHARMACOLOGY: Pharmacodynamics: Pharmacodynamic Effects: Effects on Renal Function under Actions).
Small increases in total bilirubin (without clinical jaundice) were observed with dolutegravir plus lamivudine. These changes are not considered clinically relevant as they likely reflect competition between dolutegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1) (see PHARMACOLOGY: Pharmacokinetics: Metabolism under Actions).
Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with dolutegravir therapy.
Paediatric population: There are no clinical study data with DOVATO in the paediatric population.
Based on limited available data with the dolutegravir single entity used in combination with other antiretroviral agents to treat adolescents (12 to less than 18 years of age), there were no additional types of adverse reactions beyond those observed in the adult population.
Lamivudine has been investigated separately, and as a part of a dual nucleoside backbone, in combination antiretroviral therapy to treat ART-naive and ART-experienced HIV-infected paediatric patients (data available on the use of lamivudine in children less than three months are limited). No additional types of undesirable effects have been observed beyond those characterised for the adult population.
Post-marketing data: In addition to the adverse reactions included from clinical trial data, the adverse reactions listed in Table 5 as follows have been identified during post-approval use of dolutegravir and/or lamivudine in use with other antiretroviral agents. These events have been chosen for inclusion due to a potential causal connection to dolutegravir and/or lamivudine. (See Table 5.)

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