On August 12, 2013, FDA approved Tivicay (dolutegravir), a new antiretroviral agent to treat HIV-1 infection.
Tivicay is an integrase strand transfer inhibitor (INSTI) that interferes with one of the enzymes necessary for HIV to multiply. It is a new molecular entity, which comes in pill form, to be taken daily in combination with other antiretroviral drugs.
Tivicay is approved for use in a broad population of HIV-infected patients. It can be used to treat HIV-infected adults who have never taken HIV therapy (treatment-naïve) and HIV-infected adults who have previously taken HIV therapy (treatment-experienced), including those who have been treated with other integrase strand transfer inhibitors. Tivicay is also approved for children ages 12 years and older weighing at least 40 kilograms (kg) who are treatment-naïve or treatment-experienced but have never taken other integrase strand transfer inhibitors (INSTI-naïve).
Tivicay’s safety and efficacy in adults was evaluated in 2,539 participants enrolled in four clinical trials. Depending on the trial, participants were randomly assigned to receive Tivicay or Isentress (raltegravir), each in combination with other antiretroviral drugs, or Atripla, a fixed-dose combination of efavirenz, emtricitabine and tenofovir. Results showed Tivicay-containing regimens were effective in reducing viral loads.
A fifth trial established the pharmacokinetics, safety and activity of Tivicay as part of treatment regimens for HIV-infected children ages 12 years and older weighing at least 40 kg who have not previously taken integrase strand transfer inhibitors.
Common side effects observed during clinical studies include difficulty sleeping (insomnia) and headache. Serious side effects include hypersensitivity reactions and abnormal liver function in participants co-infected with hepatitis B and/or C. The Tivicay label gives advice on how to monitor patients for the serious side effects.
INDICATION AND USAGE
Dolutegravir is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults and pediatric patients aged 12 years and older and weighing at least 40 kg.
The following should be considered prior to initiating therapy with dolutegravir:
- Poor virologic response was observed in subjects treated with dolutegravir 50 mg twice daily with an INSTI-resistance substitution at the 148 substitution plus 2 or more additional INSTI-resistance substitutions including L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R.
DOSAGE AND ADMINISTRATION
Dolutegravir is available as 50 mg tablets. Dolutegravir is taken orally without regard to meals. The dose recommendation is as follows:
- For treatment-naïve adults as well as treatment-experienced adults who are INSTI-naïve: 50 mg tablet taken once daily
- For treatment-experienced adults who are INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance: 50 mg tablet taken twice daily
- For children ages 12 years and older and weighing at least 40 kg who are treatment-naïve or treatment-experienced INSTI-naïve: 50 mg tablet taken once daily.
Dolutegravir plasma concentrations are reduced when coadminsitered with potent UGT1A/CYP3A inducers including efavirenz, tipranavir/ritonavir, fosamprenavir/ritonavir, or rifampin.
- For treatment-naïve or treatment-experienced INSTI-naïve patients taking efavirenz, tipranavir/ritonavir, fosamprenavir/ritonavir, or rifampin, the recommended dose is 50 mg taken twice daily.
- For INSTI experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance, alternative combinations that do not include metabolic inducers should be considered, where possible.
Treatment-naïve: The indication for treatment-naïve adults is supported by efficacy and safety analyses from 2 randomized, double blind, active controlled Phase 3 trials. In SPRING-2 trial, 822 treatment-naïve subjects were randomized. The comparator was raltegravir and the background nucleoside (tide) reverse transcriptase inhibitor [N(t)RTI] regimen was either abacavir/lamivudine or tenofovir/emtricitabine. In SINGLE trial, 833 subjects were randomized, the comparator was efavirenz (administered as fixed dose combination Atripla), and the background NRTI regimen was abacavir/lamivudine. In SPRING-2, the proportion of subjects with HIV-1 RNA less than 50 copies/ml at Week 48 for dolutegravir and raltegravir was 88% and 86%, respectively. The difference in virologic response was 2.6% (95% CI: -1.9%, 7.2%). In SINGLE, the proportion of subjects with HIV-1 RNA less than 50 copies/ml at Week 48 for dolutegravir and Atripla was 88% and 81%, respectively. The difference in virologic response was 7.4% (95% CI: 2.5%, 12.3%).
Treatment-experienced, INSTI-naïve: The safety and efficacy in treatment-experienced INSTI-naïve adults is supported by data from a randomized, double blind, active controlled Phase 3 trial, SAILING. A total of 719 subjects were randomized to receive dolutegravir or raltegravir, each with an optimized background regimen. At baseline, 51% of subjects had evidence of resistance to three or more antiretroviral drug classes. The proportion of subjects with HIV-1 RNA less than 50 copies/ml at Week 24 for dolutegravir and raltegravir was 79% and 70%, respectively. The difference in virologic response was 9.7% (95% CI: 3.4%, 15.9%).
Treatment-experienced, INSTI-experienced: The indication in the treatment-experienced, INSTI-experienced population is supported by data from VIKING-3, a multicenter open-label, single-arm trial. The trial enrolled 183 treatment-experienced adults with virological failure and current or historical evidence of resistance to raltegravir and/or elvitegravir. Subjects showed multiple-class antiretroviral treatment resistance at baseline: 79% had at least 2 NRTI, 75% at least 1 NNRTI, and 71% at least 2 protease inhibitor major substitutions. Subjects received dolutegravir 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8.
The mean reduction in HIV-1 RNA was 1.4 log10 copies/ml at Day 8. At week 24, 63% of subjects achieved HIV-1 RNA less than 50 copies/ml. Virologic outcomes at Week 24 were affected by certain INSTI-associated resistance substitutions present at baseline. The response was 18% in the presence of Q148H/R substitution plus 2 or more additional INSTI-resistance substitutions including L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R. The response was 80% in the presence of N155H substitution (without Q148), and 56% in the presence of Y143C/H/R substitution (without Q148).
The pharmacokinetics, safety, tolerability and efficacy were evaluated in 23 treatment-experienced, INSTI-naïve subjects ages12 to less than 18 years in an open-label trial, IMPAACT P1093. The initial dose-finding stage included intensive pharmacokinetic evaluation in 10 subjects. Dose selection was based on achieving similar dolutegravir plasma exposure and trough concentration as seen in adults. At 24 weeks, 70% of subjects had achieved HIV-1 RNA less than 50 copies/ml. The safety and efficacy of dolutegravir in children of ages less than 12 years, weighing less than 40 kg, and/or INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance have not been established.
Common adverse drug reactions of at least moderate severity and observed in at least 2% of dolutegravir subjects in the adult trials include insomnia and headache. The adverse reaction profile in pediatric subjects was similar to that of adults.
WARNINGS AND PRECAUTIONS
In addition to warnings for fat redistribution and immune reconstitution syndrome, the label carries the following warnings:
- Hypersensitivity Reactions: These events were characterized by rash, constitutional findings and sometimes organ dysfunction including liver injury. Discontinue TIVICAY and other suspect agents immediately if signs or symptoms of hypersensitivity develop. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. TIVICAY should not be used in patients who have experienced a previous hypersensitivity reaction to TIVICAY.
- Effects on Serum Liver Biochemistries in Patients with Hepatitis B or C Co-infection: Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY. In some cases the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TIVICAY are recommended.
Coadministration of dolutegravir with dofetilide is contraindicated due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events.
USE IN SPECIFIC POPULATIONS
Pregnancy: Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and dolutegravir was shown to cross the placenta in animal studies, this drug should be used during pregnancy only if clearly needed.
Hepatic Impairment No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY is not recommended for use in patients with severe hepatic impairment.
Renal Impairment: No dosage adjustment is necessary for treatment-naïve or treatment-experienced INSTI-naïve patients with mild, moderate, or severe renal impairment. No dose adjustment is necessary for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents. Dolutegravir has not been studied in patients requiring dialysis.
GlaxoSmithKline, the manufacturer of TIVICAY, is required to conduct additional studies in children and to submit 48 week safety and resistance analyses from the treatment-experienced adult Phase 3 trials.
The complete TIVICAY label will be available soon at Drugs@FDA, or at DailyMed.
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Food and Drug Administration
Division of Antiviral Products
Food and Drug Administration
Office of Health and Constituent Affairs
Food and Drug Administration