Adult Dosing

• Must be administered by gluteal intramuscular injection
• Prior to initiating treatment, oral lead-in dosing may be considered to assess the tolerability of cabotegravir and rilpivirine with the recommended dosage used for approximately 1 month in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kg.
• If oral lead-in is used, the recommended oral lead-in daily dose is one 30-mg tablet of cabotegravir and one 25-mg tablet of rilpivirine taken with a meal for approximately 1 month (at least 28 days), followed by intramuscular initiation injections of cabotegravir/rilpivirine

• Initiate Gluteal Intramuscular Injections of single 600 mg (3 mL) of cabotegravir and single 900 mg (3 mL) of rilpivirine) on the last day of current antiretroviral therapy or oral lead-in. Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart during the same visit)
• Continuation injections should be initiated a month after the initiation injections. Continue with injections of single 400 mg (2 mL) of cabotegravir and single 600 mg (2 mL) of rilpivirine every month thereafter. Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart during the same visit.
• Breastfeeding: Breastfeeding not recommended in patients with HIV

• A complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine

Contraindicated in:

• with previous hypersensitivity to cabotegravir or rilpivirine
• Coadministration is contraindicated due to potential for loss of virologic response and development of resistance
• Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• Antimycobacterials: Rifampin, rifapentine
• Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment)
• Herbal product: St John’s wort (Hypericum perforatum)

• Pregnancy:Not recommended for use during pregnancy
• Breast feeding: Breastfeeding not recommended in patients with HIV.

Renal Dose Adjustment

• Renal impairment: No dosage adjustment is necessary for patients with mild to moderate (creatinine clearance equal to 60 mL/min to less than 90 mL/min) or moderate renal impairment (creatinine clearance equal to 30 mL/min to less than 60 mL/min). In patients with severe renal impairment (creatinine clearance 15 to less than 30 mL/min) or end-stage renal disease (creatinine clearance less than15 mL/min) increased monitoring for adverse effects is recommended. In patients with end-stage renal disease not on dialysis, effects on the pharmacokinetics of cabotegravir or rilpivirine are unknown. As cabotegravir and rilpivirine are greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir or rilpivirine.

Hepatic Dose Adjustment

• Hepatic impairment: No dosage adjustment 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.

• Hypersensitivity reactions have been reported in association with other integrase inhibitors. Discontinue 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).
• Post-Injection Reactions. Serious post-injection reactions were reported within minutes after the injection of rilpivirine. These events included symptoms such as dyspnea, bronchospasm, agitation, abdominal cramping, rash/urticaria, dizziness, flushing, sweating, oral numbness, changes in blood pressure, and pain (e.g., back and chest). These events were reported in <1% of subjects and began to resolve within minutes after the injection, with some patients receiving supportive care.
• Hepatotoxicity. 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.
• Depressive disorders (including depressed mood, depression, mood altered, mood swings)

Interactions

• Because cabotegravir/rilpivirine is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.
• Strong inducers of UGT1A1 or cytochrome P450 (CYP)3A4, including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine may significantly decrease levels and effectiveness; concurrent use contraindicated.
• Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). These residual concentrations are not expected to affect the exposures of antiretroviral drugs that are initiated after discontinuation of cabotegravir/rilpivirine.
• cabotegravir/rilpivirine should be used with caution in combination with drugs with a known risk of Torsade de Pointes.
• No dose adjustment of methadone is required when starting coadministration of methadone with cabotegravir/rilpivirine. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

Pregnancy Category:B After oral use of rilpivirine, exposures were generally lower during pregnancy compared with the postpartum period.

Breastfeeding: The Centers for Disease Control and Prevention recommend that HIV-infected mothers do not breastfeed their infants to avoid risking postnatal transmission of HIV infection. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving cabotegravir.

• GI: Hepatotoxicity, nausea
• NEURO: Abnormal dreams, headache, insomnia
• PSYC: Anxiety, depressive disorders
• MISC: hypersensitivity reactions

cabotegravir

• Mechanism of Action: inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.
• Absorption: Increased with high-fat meals.
• Distribution: Distributed to extravascular tissues.
• Protein Binding: >99%.
• Metabolism/Excretion: Primarily metabolized by the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme system, with some involvement of UGT1A9. Primarily excreted in feces as unchanged drug (47%), with 27% excreted in urine as metabolites.
• Half-life: 41 hr.

rilpivirine

• Mechanism of Action:Rilpivirine is a diarylpyrimidine NNRTI of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, ß, and γ.
• Absorption: Well absorbed following oral administration.
• Distribution: Unknown.
• Protein Binding: 99.7%.
• Metabolism/Excretion: Primarily metabolized by the liver via the CYP3A isoenzyme; 25% excreted in feces unchanged, <1% excreted unchanged in urine.
• Half-life: 50 hr.

US Trade Name(s)

• Cabenuva

US Availability

Cabenuva

• Extended-release injectable suspension: 400-mg/600-mg Kit:
• single-dose vial of 400 mg/2 mL (200 mg/mL) cabotegravir
• single-dose vial of 600 mg/2 mL (300 mg/mL) rilpivirine

• Extended-release injectable suspension: 600-mg/900-mg Kit
• single-dose vial of 600 mg/3 mL (200 mg/mL) cabotegravir
• single-dose vial of 900 mg/3 mL (300 mg/mL) rilpivirine

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