cabotegravir/rilpivirine (Rx)

Brand and Other Names:Cabenuva
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

Cabotegravir and rilpivirine are copackaged as 2 separate IM injections

Each dosing kit also contains 2 syringes, 2 syringe labels, 2 vial adapters, and 2 needles for IM injection (23-gauge, 1.5-inch)

Vial stoppers are not made with natural rubber latex

injection, IM suspension 400mg/600mg kit

  • Cabotegravir: 400mg/2mL
  • Rilpivirine: 600mg/2mL

injection, IM suspension 600mg/900mg kit

  • Cabotegravir: 600mg/3mL
  • Rilpivirine: 900mg/3mL

HIV Infection

Indicated as a complete regimen for treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace a current stable antiretroviral therapy (ART) regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine

Oral lead-in dosing

  • Administer oral lead-in dosing prior to administration of Cabenuva to help identify patients who may be at risk of a hypersensitivity reaction
  • Before starting once monthly IM injections of cabotegravir and rilpivirine, use daily oral regimen of cabotegravir (Vocabria) 30 mg plus rilpivirine (Edurant) 25 mg for at least 1 month to ensure medications are well tolerated

IM dosing

  • Administer each drug as 2 separate IM injections
  • One-time initiating injection
    • Administer at month 2 (on last day of oral lead-in dosing)
    • Cabotegravir 600 mg (3 mL) IM once PLUS
    • Rilpivirine 900 mg (3 mL) IM once
  • Once-monthly continuation injections
    • Administer at month 3 and once monthly thereafter
    • Cabotegravir 400 mg (2 mL) IM once PLUS
    • Rilpivirine 600 mg (2 mL) IM once

Dosage Modifications

Renal impairment

  • Mild-to-moderate (CrCl 30 to <90 mL/min): No dosage adjustment required
  • Severe (CrCl <15 mL/min) or ESRD: Increased monitoring recommended
  • ESRD not on dialysis: Pharmacokinetic effects of each drug are unknown
  • Dialysis: Cabotegravir and rilpivirine are >99% protein bound; dialysis is not expected to alter systemic exposure

Hepatic impairment

  • Mild or moderate (Child-Pugh A or B): No dosage adjustment required
  • Severe (Child-Pugh C): Pharmacokinetic effects are unknown

Dosing Considerations

Patient selection

  • Must be administered by a healthcare professional
  • Before initiating, carefully select patients who agree to required monthly IM injection dosing schedule
  • Educate patients regarding importance of adherence to scheduled dosing visits to maintain viral suppression and reduce risk of viral rebound and potential development of resistance with missed doses

Safety and efficacy not established

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Interactions

Interaction Checker

and cabotegravir/rilpivirine

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Injection site reactions, all grades (83%)

            Injection site reactions, ≥Grade 2 (37%)

            1-10%

            All grades

            • Pyrexia (8%)
            • Fatigue (5%)
            • Headache (4%)
            • Musculoskeletal pain (3%)
            • Nausea (3%)
            • Sleep disorders (2%)
            • Dizziness (2%)
            • Rash (2%)

            Grade ≥2

            • Pyrexia (2%)
            • Fatigue (1%)
            • Musculoskeletal pain (1%)

            Grade 3 or 4 laboratory parameters

            • Creatine phosphokinase ≥10 x ULN (8%)
            • Lipase ≥3 x ULN (5%)
            • ALT/AST ≥5 x ULN (2%)

            <2%

            • Gastrointestinal disorders: Abdominal pain (including upper abdominal pain), gastritis, dyspepsia, vomiting, diarrhea, and flatulence
            • Hepatobiliary disorders: Hepatotoxicity
            • Investigations: Weight increase
            • Psychiatric disorders: Anxiety (including anxiety and irritability), depression, abnormal dreams
            • Skin and hypersensitivity reactions: Hypersensitivity reactions

            <1%

            Grade ≥2

            • Total bilirubin ≥2.6 x ULN
            • Headache
            • Nausea
            • Sleep disorders
            • Dizziness
            • Rash

            Postmarketing Reports

            Renal and genitourinary disorders: Nephrotic syndrome

            Skin and subcutaneous tissue disorders: Severe skin and hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS)

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            Warnings

            Contraindications

            Documented hypersensitivity

            UGT1A1 or CYP3A inducers

            • Coadministration with UGT1A1 inducers and/or CYP3A inducers may significantly decrease cabotegravir and/or rilpivirine plasma concentrations owing to possible loss of virologic response
            • Examples of UGT1A1 inducers include carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine
            • Examples of CYP3A inducers include systemic glucocorticoids (eg, >1 dose of dexamethasone) and St John’s wort

            Cautions

            Serious postinjection reactions were reported within minutes after injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure; symptoms began to resolve within a few minutes after injection; these events may have been associated with inadvertent (partial) IV administration; observe patient for 10 minutes after injection

            Hepatotoxicity reported in patients with or without known preexisting hepatic disease or known risk factors; monitoring of liver chemistries recommended; discontinue treatment if hepatotoxicity suspected

            Depressive disorders (including depressed mood, depression, mood altered, mood swings) reported; promptly evaluate if symptoms emerge; determine whether risks of continued therapy outweigh benefits

            Hypersensitivity

            • Serious or severe hypersensitivity reactions reported 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)
            • Postmarketing experience with rilpivirine-containing regimens has included drug reaction with eosinophilia and systemic symptoms (DRESS)
            • Monitor clinical status, including liver transaminases, and initiate appropriate therapy as warranted

            Drug interaction overview

            • Other antiretroviral medications for HIV-1 infection
              • Cabotegravir plus rilpivirine is a complete ART regimen
              • Coadministration with other ARTs is not recommended
              • Residual concentrations of IM 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 ARTs initiated after discontinuation of cabotegravir and rilpivirine
            • UGT1A1 or UGT1A9 inducers
              • Contraindicated
              • Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9
              • Strong UGT1A1 or 1A9 inducers are expected to decrease cabotegravir plasma concentrations and may result in loss of virologic response
            • CYP3A inducers
              • Contraindicated
              • Rilpivirine is primarily metabolized by CYP3A
              • Strong CYP3A inducers are contraindicated with rilpivirine owing to concern for decreased rilpivirine plasma concentrations and potential loss of virologic response
            • QT-prolonging drugs or strong CYP3A inhibitors
              • Caution if coadministered with drugs that prolong QT interval or drugs that may raise rilpivirine systemic exposure
              • QT prolongation may occur with rilpivirine peak plasma concentrations 4.4-fold and 11.6-fold higher than those observed with rilpivirine 600 IM qMonth
            • Macrolide or ketolide antibiotics
              • Macrolides are expected to increase rilpivirine concentrations and are associated with torsade de pointes
              • When possible, consider azithromycin, which increases rilpivirine concentrations less than other macrolides
            • Polyvalent cation-containing products
              • Modify dosage schedule
              • Coadministration with antacids containing polyvalent cations (eg, aluminum, magnesium hydroxide, calcium carbonate) may decrease cabotegravir absorption
              • Administer antacids at least 2 hr before or 4 hr after taking cabotegravir
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            Pregnancy & Lactation

            Pregnancy

            Encourage patients to register for the Antiretroviral Pregnancy Registry (APR) by calling 1-800-258-4263

            Data are insufficient regarding use during pregnancy to adequately assess 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 cabotegravir during pregnancy, NTDs were associated with dolutegravir, another integrase inhibitor

            Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing; therefore, consider potential for fetal exposure during pregnancy

            Rilpivirine human data

            • Prospective reports to APR to PO rilpivirine-containing regimens during the first trimester of pregnancy (>390 reports) and during second/third trimester of pregnancy (>170 reports), the prevalence of birth defects was 1.3% and 1.1% following first and second/third trimester exposures, respectively, compared with the background birth defect rate of 2.7% in the US reference population

            Lactation

            Unknown if present in human breast milk, affects human milk production, or effects on breastfed infants

            CDC recommends that women in the United States should not breastfeed their infants because of risk of the following H4

            Postnatal HIV transmission (in HIV-negative infants)

            Developing viral resistance (in HIV-positive infants)

            Adverse reactions in nursing infants

            Animal data

            • Animal lactation studies have not been conducted; however, cabotegravir and rilpivirine were detected in plasma of nursing pups on lactation days 10 and 7 respectively in rat prenatal and postnatal development study

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Cabotegravir: HIV-1 integrase strand transfer inhibitor (INSTI); cabotegravir, an analog of dolutegravir, prevents viral DNA integration into the host genome and inhibits HIV replication

            Rilpivirine: Non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1; inhibits HIV-1 replication by noncompetitive inhibition of HIV-1 reverse transcriptase

            Absorption

            Peak plasma time

            • Cabotegravir: 7 days
            • Rilpivirine: 3-4 days

            Peak plasma concentration

            • Cabotegravir, monthly IM: 4.2 mcg/mL
            • Rilpivirine, monthly IM: 116 ng/mL

            AUC

            • Cabotegravir, monthly IM: 2,415 mcg⋅h/mL
            • Rilpivirine, monthly IM: 65,603 ng⋅h/mL

            Distribution

            Protein bound: >99%

            Metabolism

            Cabotegravir: Metabolized by UGT1A1 (major) and UGT1A9 (minor)

            Rilpivirine: Metabolized primarily by CYP3A

            Elimination

            Half-life

            • Cabotegravir: 5.6-11.5 weeks
            • Rilpivirine: 13-28 weeks

            Excretion

            • Cabotegravir: Urine 27%; feces 59%
            • Rilpivirine: Urine 6%; feces 85%
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            Administration

            IM Preparation

            Remove from refrigerator and wait at least 15 minutes to allow vials to come to room temperature; not to exceed 25ºC (77ºF)

            Vials may remain in the carton at room temperature for up to 6 hr; discard if not used within 6 hr

            Inspect visually for particulate matter and discoloration before administration; cabotegravir vial has a brown tint to the glass which may limit visual inspection

            Shake each vial vigorously until suspensions look uniform before injecting; small air bubbles are expected and acceptable

            Do not mix with any other product or diluent

            Once cabotegravir and rilpivirine suspensions have been drawn into their separate syringes, administer as soon as possible; suspension may remain in syringes for up to 2 hr; discard if 2 hr exceeded

            IM Administration

            Suspension are for gluteal intramuscular injections

            No further dilution or reconstitution needed

            Ventrogluteal site recommended; administer each injection at separate gluteal injection sites (on opposite sides or 2 cm apart) during the same visit

            Do not administer by any other route or anatomical site

            Consider patient’s BMI to ensure needle length is sufficient to reach the gluteus muscle; longer needle lengths (not included in the dosing kit) may be required for patients with higher BMI (eg, >30 kg/m2) to ensure that injections are administered IM as opposed to SC

            Administration order of cabotegravir and rilpivirine injections is not important

            Monitor patient for 10 minutes after injection to observe for injection related adverse effects

            Missed injections

            • Adherence to monthly injection dosing schedule is strongly recommended to avoid viral resistance
            • Reassess patients to ensure resumption of therapy remains appropriate
            • Planned missed IM injections
              • Plans to miss scheduled injection visit by >7 days: Take daily PO therapy to replace up to 2 consecutive monthly injection visits
              • Take first dose of PO therapy ~1 month after the last injection and continue until the day injection dosing restarted
            • Unplanned missed IM injections
              • If monthly injections are missed or delayed by >7 days and PO therapy has not been taken in the interim, clinically reassess patient to determine if resumption of injection dosing remains appropriate
              • If injection dosing will be continued, see below for resuming IM injection dosing
            • Resume IM injection dosing
              • Time since last injection ≤2 months: Resume cabotegravir 400 mg and rilpivirine 600 mg IM
              • Time since last injection >2 months: Reinitiate with cabotegravir 600 mg and rilpivirine 900 mg IM once, then continue to follow with cabotegravir 400 mg and rilpivirine 600 mg IM qMonth

            Storage

            Refrigerate at 2-8ºC (36-46ºF) in original carton until ready to use

            Do not freeze

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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