FDA Approves Changes to Tivicay Label

November 21, 2017

Tivicay(dolutegravir) label was updated for consistency with the new Juluca approval. The following changes were made to the Tivicay label.

• To expand the indication to include the use of TIVICAY (dolutegravir) in combination with rilpivirine as a complete regimen to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral.
• To update the WARNINGS AND PRECAUTIONS section to include subsections 5.2 Hepatotoxicity and 5.3 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

5.2         Hepatotoxicity
Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of Tivicay [see Adverse Reactions (6.1)]. 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immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure have been reported in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with Triumeq (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended.

5.3         Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
The concomitant use of TIVICAY and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4), Drug Interactions (7.3)]:

• Loss of therapeutic effect of TIVICAY and possible development of resistance.
• Possible clinically significant adverse reactions from greater exposures of concomitant drugs.

For concomitant drugs for which the interaction can be mitigated, please see Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TIVICAY; review concomitant medications during therapy with TIVICAY; and monitor for the adverse reactions associated with the concomitant drugs.

To update ADVERSE REACTIONS to include data from the SWORD trials.

• Virologically Suppressed Subjects: The ARs observed for TIVICAY plus rilpivirine in the Week 48 analysis of pooled data from two identical, international, multicenter, open-label trials (SWORD-1 and SWORD-2) of 513 HIV–1-infected, virologically suppressed subjects switching from their current antiretroviral regimen to dolutegravir plus rilpivirine, were consistent with the AR profiles and severities for the individual components when administered with other antiretroviral agents. There were no ARs (Grades 2 to 4) with an incidence of at least 2% in either treatment arm. The rates of adverse events leading to discontinuation were 4% in subjects receiving TIVICAY plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen.
• Virologically Suppressed Adults: Laboratory abnormalities observed in SWORD-1 and SWORD-2 were generally similar compared with observations seen in the other Phase 3 trials.

To update ADVERSE REACTIONS, 6.2 Postmarketing Experience with acute liver failure, hepatotoxicity, and anxiety.

To update the DRUG INTERACTIONS with new subsection 7.4 Drugs without Clinically Significant Interactions with Dolutegravir.

• Based on drug interaction trial results, the following drugs can be coadministered with dolutegravir without a dose adjustment: atazanavir/ritonavir, darunavir/ritonavir, daclatasvir, elbasvir/grazoprevir, methadone, midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, rilpivirine, sofosbuvir/velpatasvir, and tenofovir

To update CLINICAL PHARMACOLOGY, Tables 9 and 10 with information on hepatitis C direct-acting antivirals.

To update CLINICAL STUDIES section to include data from the SWORD trials.

• Virologically Suppressed Subjects: SWORD-1 and SWORD-2 are identical 148-week, Phase 3, randomized, multicenter, parallel-group, non-inferiority trials. A total of 1,024 adult HIV–1-infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 NRTIs plus either an INSTI, an NNRTI, or a PI) for at least 6 months (HIV-1 RNA less than 50 copies per mL), with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine received treatment in the trials. Subjects were randomized 1:1 to continue their current antiretroviral regimen or be switched to TIVICAY 50 mg plus rilpivirine 25 mg administered once daily. The primary efficacy endpoint for the SWORD trial was the proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL at Week 48. The proportion of subjects with HIV-1 RNA less than 50 copies per mL at Week 48 was 95% for both treatment groups; treatment difference and 95% CI was -0.2% (-3.0%, 2.5%). The proportion of subjects with HIV-1 RNA greater than or equal to 50 copies per mL (virologic failure) at Week 48 was 0.6% and 1.2% for the dolutegravir plus rilpivirine treatment group and the current antiretroviral regimen treatment groups, respectively; treatment difference and 95% CI was -0.6% (-1.7%, 0.6%). Refer to the Prescribing Information for JULUCA (dolutegravir and rilpivirine) tablet for complete virologic outcome information.

The updated label will soon be available at drugs@fda or DailyMed

Steve Morin

Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

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