CABOTEGRAVIR Drug Interactions: What You Need to Know

INTERACTIONS

• Refer to the full prescribing information for important drug interactions with VOCABRIA. ( 4 , 5.5 , 7 )
• VOCABRIA in combination with EDURANT is a complete regimen for HIV-1 treatment. Coadministration with other antiretroviral medications for PrEP is not recommended. ( 7.1 )
• Drugs that induce uridine diphosphate glucuronosyltransferase (UGT)1A1 may decrease the plasma concentrations of cabotegravir. ( 4 , 7.2 , 7.3 )

7.1 Concomitant Use with Other Antiretroviral Medicines VOCABRIA in combination with EDURANT (rilpivirine) is a complete regimen for the treatment of HIV-1 infection. Refer to the prescribing information for EDURANT for relevant information on rilpivirine. Coadministration of VOCABRIA with other antiretroviral medications for PrEP is not recommended <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.3 )]</span> . Prior to initiating dosing with VOCABRIA, the prescribing information for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) or APRETUDE should be consulted to ensure use of CABENUVA or APRETUDE will be appropriate for either the treatment of HIV-1 infection or HIV-1 PrEP, respectively.

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 UGT1A9 are expected to decrease cabotegravir plasma concentrations and may result in loss of efficacy; therefore, coadministration of VOCABRIA with these drugs is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Coadministration of oral cabotegravir with polyvalent cation-containing products may lead to decreased absorption of cabotegravir <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span> .

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 efficacy <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.3 )]</span> .

Table

1 includes potentially significant interactions but is not all inclusive. Refer to the prescribing information for EDURANT (rilpivirine) for established or potentially significant interactions that should be considered during concomitant administration of VOCABRIA and EDURANT for HIV-1 treatment.

Table

1.

Drug

Interactions with VOCABRIA ↓ = Decrease; PrEP = Pre-exposure prophylaxis. a Rifabutin can be coadministered with cabotegravir; however, it is contraindicated with CABENUVA for HIV-1 treatment. Dosage modification is recommended with APRETUDE for HIV-1 PrEP.

Concomitant Drug

Class: Drug Name Effect on Concentration Clinical Comment Antacids containing polyvalent cations (e.g., aluminum or magnesium hydroxide, calcium carbonate) ↓Cabotegravir Administer antacid products at least 2 hours before or 4 hours after taking VOCABRIA. Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital Phenytoin ↓Cabotegravir Coadministration is contraindicated with VOCABRIA due to potential for loss of efficacy and development of resistance [see Contraindications ( 4 )] . Antimycobacterials a : Rifampin Rifapentine ↓Cabotegravir Antimycobacterial: Rifabutin ↓Cabotegravir Dose modification is not required for VOCABRIA. Dose modification is recommended for APRETUDE for HIV-1 PrEP. Coadministration is contraindicated with CABENUVA for HIV-1 treatment.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Prior to initiating oral therapy, note that use of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated for the treatment of HIV-1 infection. Dosage modification is recommended when APRETUDE is used with rifabutin for HIV-1 PrEP.

Treatment of HIV-1 Infection VOCABRIA is contraindicated in patients:

• with previous hypersensitivity reaction to cabotegravir [see Warnings and Precautions ( 5.2 )] .
• receiving the following coadministered drugs for which significant decreases in cabotegravir plasma concentrations may occur due to uridine diphosphate glucuronosyltransferase (UGT)1A1 enzyme induction, which may result in loss of virologic response [see Drug Interactions ( 7.2 , 7.3 ), Clinical Pharmacology ( 12.3 )] : o Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin o Antimycobacterials: Rifampin, rifapentine Prior to initiation of VOCABRIA, note that use of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated. Since VOCABRIA is taken in combination with EDURANT tablets, the prescribing information for EDURANT should be consulted for additional contraindications. HIV-1 Pre-Exposure Prophylaxis VOCABRIA is contraindicated in individuals:
• with unknown or positive HIV-1 status [see Warnings and Precautions ( 5.1 )] .
• with previous hypersensitivity reaction to cabotegravir [see Warnings and Precautions ( 5.2 )] .
• receiving the following coadministered drugs for which significant decreases in cabotegravir plasma concentrations may occur due to UGT1A1 enzyme induction, which may result in loss of efficacy [see Drug Interactions ( 7.2 , 7.3 ), Clinical Pharmacology ( 12.3 )] : o Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin o Antimycobacterials: Rifampin, rifapentine
• Previous hypersensitivity reaction to cabotegravir. ( 4 )
• Coadministration with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, and rifapentine. ( 4 )
• Positive HIV-1 status for HIV-1 PrEP. ( 4 )

AND PRECAUTIONS

• Comprehensive management to reduce the risk of HIV-1 acquisition. ( 5.1 )
• Potential risk of developing resistance to APRETUDE if an individual acquires HIV-1 either before or while taking APRETUDE or following discontinuation of APRETUDE. Reassess risk of HIV-1 acquisition and test before each injection to confirm HIV-1 negative status. ( 5.2 )
• Residual concentrations of cabotegravir may remain in the systemic circulation of individuals up to 12 months or longer. ( 5.3 )
• Serious or severe hypersensitivity reactions have been reported with cabotegravir and include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Discontinue APRETUDE immediately if signs or symptoms of hypersensitivity reactions develop. ( 5.4 )
• Hepatotoxicity has been reported in individuals receiving cabotegravir. Clinical and laboratory monitoring should be considered. Discontinue APRETUDE if hepatotoxicity is suspected. ( 5.5 )
• Depressive disorders have been reported with APRETUDE. Prompt evaluation is recommended for depressive symptoms. ( 5.6 )

5.1 Comprehensive Management to Reduce the Risk of HIV-1 Infection Use APRETUDE for HIV-1 PrEP to reduce the risk of HIV-1 infection as part of a comprehensive prevention strategy including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). APRETUDE is not always effective in preventing HIV-1 acquisition <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> . The time from initiation of APRETUDE for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including, but not limited to, condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network. Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use; knowledge of partner(s)’ HIV-1 status, including viral suppression status; regular testing for STIs that can facilitate HIV-1 transmission). Inform individuals about and support their efforts in reducing sexual risk behavior. Use APRETUDE to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV‑1 negative <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV‑1 infection who are taking only APRETUDE, because APRETUDE alone does not constitute a complete regimen for HIV-1 treatment <span class="opacity-50 text-xs">[see Microbiology ( 12.4 )]</span> ; therefore, care should be taken to minimize the risk of initiating or continuing APRETUDE before confirming the individual is HIV-1 negative.

• Prior to initiating APRETUDE for HIV-1 PrEP, ask seronegative individuals about recent (in past month) potential exposure events (e.g., condomless sex or condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, a recent STI), and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash).
• If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection. When using APRETUDE for HIV-1 PrEP, HIV-1 testing should be repeated prior to each injection and upon diagnosis of any other STIs [see Dosage and Administration ( 2.2 , 2.5 )] .
• If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following an exposure event, additional HIV testing to determine HIV status is needed. If an individual has confirmed HIV-1 infection, then the individual must be transitioned to a complete HIV-1 treatment regimen. Counsel individuals without HIV-1 to strictly adhere to the recommended dosing and testing schedule for APRETUDE in order to reduce the risk of HIV-1 acquisition and the potential development of resistance [see Dosage and Administration ( 2.3 , 2.5 ), Microbiology ( 12.4 )] . Some individuals, such as adolescents, may benefit from frequent visits and counseling to support adherence to the dosing and testing schedule [see Use in Specific Populations ( 8.4 ), Microbiology ( 12.4 ), Clinical Studies ( 14 )] .

5.2 Potential Risk of Resistance with APRETUDE There is a potential risk of developing resistance to APRETUDE if an individual acquires HIV-1 either before or while taking APRETUDE or following discontinuation of APRETUDE <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.3 )]</span> . To minimize this risk, it is essential to clinically reassess individuals for risk of HIV-1 acquisition and to test before each injection to confirm HIV-1 negative status. Individuals who are confirmed to have HIV-1 infection must transition to a complete HIV-1 treatment regimen. Alternative forms of PrEP should be considered following discontinuation of APRETUDE for those individuals at continuing risk of HIV-1 acquisition and initiated within 2 months of the final injection of APRETUDE.

5.3 Long-Acting Properties and Potential Associated Risks with APRETUDE Residual concentrations of cabotegravir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer). It is important to carefully select individuals who agree to the required every-2-month injection dosing schedule because non-adherence to every‑2-monthly injections or missed doses could lead to HIV-1 acquisition and development of resistance. Healthcare providers should take the prolonged-release characteristics of cabotegravir into consideration when APRETUDE is prescribed <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 , 5.2 ), Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.1 , 8.2 ), Overdosage ( 10 )]</span> .

5.4 Hypersensitivity Reactions Serious or severe hypersensitivity reactions have been reported with cabotegravir and include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Administration of cabotegravir oral lead-in dosing was used in clinical studies to help identify participants who may be at risk of a hypersensitivity reaction. Remain vigilant and discontinue APRETUDE if a hypersensitivity reaction is suspected <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ), Contraindications ( 4 ), Adverse Reactions ( 6 )]</span> . Discontinue APRETUDE 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. For information regarding the long-acting properties of APRETUDE <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> .

5.5 Hepatotoxicity Hepatotoxicity has been reported in a limited number of individuals receiving cabotegravir with or without known pre-existing hepatic disease or identifiable risk factors <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Clinical and laboratory monitoring should be considered and APRETUDE should be discontinued if hepatotoxicity is suspected and individuals managed as clinically indicated. For information regarding the long-acting properties of APRETUDE <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> .

5.6 Depressive Disorders Depressive disorders (including depression, depressed mood, major depression, persistent depressive disorder, suicidal ideation, suicide attempt) have been reported with APRETUDE <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Promptly evaluate individuals with depressive symptoms to assess whether the symptoms are related to APRETUDE and to determine whether the risks of continued therapy outweigh the benefits.

5.7 Risk of Reduced Drug Concentration of APRETUDE Due to Drug Interactions The concomitant use of APRETUDE and other drugs may result in reduced drug concentration of APRETUDE <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Drug Interactions ( 7.2 , 7.3 )]</span> .

See Table

8 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 use of, and after discontinuation of APRETUDE; review concomitant medications during use of APRETUDE [see Drug Interactions ( 7.3 , 7.4 )] .