VOCABRIA Film-coated tablet Ref.[10736] Active ingredients: Cabotegravir

5.1 Hypersensitivity Reactions

Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with VOCABRIA [see Adverse Reaction (6.1)]. Remain vigilant and discontinue VOCABRIA if a hypersensitivity reaction is suspected.

Discontinue VOCABRIA immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated [see Dosage and Administration (2.1), Contraindications (4), Adverse Reactions (6.1)].

5.2 Hepatotoxicity

Hepatotoxicity has been reported in patients receiving cabotegravir with or without known pre-existing hepatic disease or identifiable risk factors [see Adverse Reactions (6.1)].

Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations.

Monitoring of liver chemistries is recommended and treatment with VOCABRIA should be discontinued if hepatotoxicity is suspected.

5.3 Depressive Disorders

Depressive disorders (including depressed mood, depression, mood altered, mood swings) have been reported with VOCABRIA [see Adverse Reactions (6.1)]. Promptly evaluate patients with depressive symptoms to assess whether the symptoms are related to VOCABRIA and to determine whether the risks of continued therapy outweigh the benefits.

5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of VOCABRIA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of VOCABRIA, and possible development of viral resistance [see Contraindications (4), Drug Interactions (7.3)].

See Table 1 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 VOCABRIA; review concomitant medications during therapy with VOCABRIA.

5.5 Risks Associated with Rilpivirine Treatment

VOCABRIA is indicated for use in combination with EDURANT (rilpivirine) [see Dosage and Administration (2.1)]. Review the prescribing information for EDURANT for information on rilpivirine prior to initiation of VOCABRIA in combination with rilpivirine.

The following adverse reactions are described below and in other sections of the labeling:

• Hypersensitivity reactions [see Warnings and Precautions (5.1)]
• Hepatotoxicity [see Warnings and Precautions (5.2)
• Depressive disorders [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect rates observed in practice. See full prescribing information for CABENUVA (cabotegravir; rilpivirine) extended-release injectable suspensions for additional safety information. Since VOCABRIA is taken in combination with rilpivirine tablets, the prescribing information for EDURANT (rilpivirine) should be consulted for relevant information on rilpivirine.

The safety assessment of VOCABRIA for oral lead-in therapy prior to therapy with CABENUVA is based on the analysis of pooled 48-week data from 1,182 virologically suppressed subjects with HIV-1 infection in 2 international, multicenter, open-label pivotal trials, FLAIR and ATLAS.

Adverse reactions were reported following exposure to VOCABRIA tablets and EDURANT tablets administered in combination as oral lead-in therapy (median time exposure: 5.3 weeks). Adverse reactions included those attributable to the oral formulation of cabotegravir and rilpivirine administered as a combination regimen. Refer to the prescribing information for EDURANT for other adverse reactions associated with oral rilpivirine.

The most common adverse reactions during the oral lead-in period were headache, nausea, abnormal dreams, anxiety, and insomnia all of which occurred in at least 3 subjects, with an incidence less than or equal to 1%.

During the oral lead-in period, 6 (1%) subjects discontinued due to adverse events, including asthenia, myalgia, depression suicidal, and headache.

Because VOCABRIA in combination with EDURANT (rilpivirine) is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1), Drug Interactions (7.4), Clinical Pharmacology (12.3)]. Refer to the prescribing information for EDURANT for relevant information on rilpivirine.

Prior to initiating oral therapy, the prescribing information for CABENUVA (cabotegravir; rilpivirine) extended-release injectable suspensions should be consulted to ensure therapy with CABENUVA will be appropriate.

7.2 Potential for Other Drugs to Affect VOCABRIA

Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease cabotegravir plasma concentrations and may result in loss of virologic response; therefore, coadministration of VOCABRIA with these drugs is contraindicated [see Contraindications (4)].

Coadministration of oral cabotegravir with polyvalent cation-containing products may lead to decreased absorption of cabotegravir [see Drug Interactions (7.3)].

7.3 Established and Other Potentially Significant Drug Interactions

Information regarding potential drug interactions with cabotegravir are provided in Table 1. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for loss of virologic response [see Contraindications (4), Warnings and Precautions (5.4), Clinical Pharmacology (12.3)]. Table 1 includes potentially significant interactions but is not all inclusive.

VOCABRIA in combination with EDURANT (rilpivirine) is intended as a complete antiretroviral regimen for treatment of HIV-1 in patients who are virologically suppressed. Refer to the prescribing information for EDURANT for established or potentially significant interactions that should be considered during concomitant administration of VOCABRIA and EDURANT.

Table 1. Drug Interactions with VOCABRIA:

↓ = Decrease.
^a Rifabutin can be coadministered with cabotegravir; however, it is contraindicated with CABENUVA (cabotegravir; rilpivirine) extended-release injectable suspensions.
^b See Clinical Pharmacology (12.3) for magnitude of interaction.

7.4 Drugs without Clinically Significant Interactions with Cabotegravir

Based on drug interaction study results, the following drugs can be coadministered with cabotegravir without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, rifabutin, and rilpivirine [see Clinical Pharmacology (12.3)]. Prior to initiating oral therapy, note that use of CABENUVA (cabotegravir; rilpivirine) extended-release injectable suspensions with rifabutin is contraindicated.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VOCABRIA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

There are insufficient human data on the use of VOCABRIA during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. While there are insufficient human data to assess the risk of neural tube defects (NTDs) with exposure to VOCABRIA during pregnancy, NTDs were associated with dolutegravir, another integrase inhibitor. Discuss the benefit-risk of using VOCABRIA with individuals of childbearing potential or during pregnancy.

The rate of miscarriage is not reported in the APR. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks' gestation.

In animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at greater than 28 times the exposure at the recommended human dose (RHD). No evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (greater than 28 times or similar to the exposure at the RHD, respectively) given during organogenesis (see Data).

Data

Human Data: Data from an observational study in Botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of NTDs when administered at the time of conception and in early pregnancy. Data from clinical trials are insufficient to address this risk with cabotegravir.

Animal Data: Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. There were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (greater than 28 times the exposure in humans at the RHD). No drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD), and no drug-related fetal malformations were observed at any dose.

Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD).

In a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. A delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (greater than 28 times the exposure in humans at the RHD); there were no alterations to growth and development of surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. There was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 times the exposure at the RHD) was not associated with delayed parturition or neonatal mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue.

Risk Summary

The Centers for Disease Control and Prevention recommends that HIV‑1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

It is not known if cabotegravir is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, cabotegravir was present in milk (see Data).

Because of the potential for (1) HIV‑1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving VOCABRIA.

Data

Animal Data

Animal lactation studies with cabotegravir have not been conducted. However, cabotegravir was detected in the plasma of nursing pups on Lactation Day 10 in the rat pre- and postnatal development study.

The safety and efficacy of VOCABRIA have not been established in pediatric patients.

Clinical trials of VOCABRIA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of VOCABRIA in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

No dosage adjustment of VOCABRIA is necessary for patients with mild to moderate (creatinine clearance equal to 30 mL/min to less than 90 mL/min) or severe renal impairment (creatinine clearance less than 30 mL/min) [see Clinical Pharmacology (12.3)]. The effect of end-stage renal disease (creatinine clearance less than15 mL/min) on the pharmacokinetics of cabotegravir is unknown. As cabotegravir is greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir.

Since VOCABRIA is taken in combination with oral rilpivirine, the prescribing information for EDURANT (rilpivirine) should be consulted for additional recommendations in patients with severe impairment or end-stage renal disease.

No dosage adjustment of VOCABRIA is necessary for patients with mild or moderate hepatic impairment (Child-Pugh A or B). The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir is unknown [see Clinical Pharmacology (12.3)].