Regulatory Decision Summary for Tivicay

Tivicay (dolutegravir) is currently authorized in Canada, in combination with other antiretroviral agents, for the treatment of H1V-1 infection in adults and Integrase-Strand Transfer Inhibitor (INSTI)-naïve pediatric patients at least 6 years of age and weighing at least 15 kg. The proposed extension of the pediatric indication to patients aged at least 4 weeks and less than 6 years and weighing at least 3 kg and less than 15 kg was based on the pharmacokinetic, safety and efficacy data from studies IMPAACT P1093 and ODYSSEY. In these trials, dolutegravir was administered either as film-coated tablets (currently approved formulation) or dispersible tablets (5 mg; new formulation).

IMPAACT P1093 (ING112578) is the ongoing Phase I/II multicentre, non-comparative, open-label study to evaluate the pharmacokinetics, safety, tolerability and efficacy of dolutegravir in combination regimens in HIV-1-infected treatment-naïve or treatment experienced INSTI-naïve infants, children and adolescents aged ≥ 4 weeks to < 18 years (n = 159). ODYSSEY is an ongoing, multicentre, open-label, randomized, non-inferiority study to evaluate the safety, efficacy, and pharmacokinetics of dolutegravir compared with standard of care in HIV-1-infected pediatric patients younger than 18 years of age (n = 99).

The efficacy of dolutegravir in IMPAACT P1093 and ODYSSEY was established mainly on extrapolation of dolutegravir exposure in pediatric patients to a known effective exposure in adults. This extrapolation was possible due to similarities in the disease course of HIV-1 infection and the antiviral effect of antiretroviral drugs between adult and pediatric patients. In the pooled analysis of IMPAACT P1093 and ODYSSEY, the pharmacokinetic parameters of dolutegravir in pediatric patients weighing at least 3 kg who received dispersible or film-coated tablets were comparable to those of HIV-1-infected adults receiving the recommended adult dose of 50 mg once daily. The higher Cmax (< 2-fold) compared to levels in adults is not considered to be clinically relevant, based on the lack of new or worse safety signals observed in pediatrics, and no apparent exposure-response relationship for adverse events in pediatric patients.

Virologic outcomes data were available from IMPAACT P1093 and demonstrated virologic suppression (defined as HIV-1 RNA < 50 copies/mL) in 62.1% (36/58) of patients at Week 24 and 66.7% (16/24) at Week 48. The efficacy evaluation in ODYSSEY is still ongoing and was not provided in this submission.

Overall, dolutegravir was well tolerated in IMPAACT P1093 and ODYSSEY with no additional safety concerns as compared to adults. In IMPAACT P1093, through Week 24, Grade 1 to 2 adverse drug reactions reported by more than one subject were decreased neutrophil count (n = 4), decreased blood bicarbonate (n = 3), decreased haemoglobin (n = 2), and immune reconstitution inflammatory syndrome (IRIS) (n = 2). There were no Grade 3 or 4 drug-related adverse events. No adverse drug reactions led to discontinuation. In ODYSSEY, no new adverse drug reactions or laboratory abnormalities were identified compared to those observed in IMPAACT P1093 and there was no adverse drug reactions leading to discontinuation.

Based on review of above data, it is considered that the benefit-harm-uncertainty of Tivicay in pediatric patients aged at least 4 weeks and less than 6 years and weighing at least 3 kg and less than 15 kg is favorable. The Tivicay Product Monograph has been updated with respect to dosing recommendations regarding the new formulation of 5 mg dispersible tablets.