cabotegravir/rilpivirine

Cabotegravir

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

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

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
cabotegravir IM	unknown	7 days	unknown
rilpivirine IM	unknown	3–4 days	unknown

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity to cabotegravir or rilpivirine;
Concurrent use of carbamazepine, dexamethasone (more than a single dose), oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, or St. John's wort;
OB: Pregnancy;
Lactation: Breastfeeding not recommended in patients with HIV.

Use Cautiously in:

History of depression or suicide attempt;
Hepatic impairment;
Severe renal impairment (CCr 15–30 mL/min) or end-stage renal disease (CCr <15 mL/min);
Pedi: Children 12 yr (safety and effectiveness not established);
Geri: Use with caution in older adults, considering concurrent disease states, drug therapy, and age-related in hepatic and renal function.

Adv. Reactions/Side Effects ⬆ ⬇

CV: QT interval prolongation

Derm: DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), rash

GI: ↑lipase, HEPATOTOXICITY, nausea

Local: injection site reactions

Metab: ↑weight

MS: ↑creatine kinase, pain

Neuro: depression, dizziness, fatigue, headache, insomnia, mood disturbances, negative thoughts, somnolence, SUICIDAL THOUGHTS/BEHAVIORS

Misc: fever, HYPERSENSITIVITY REACTIONS (INCLUDING ANGIOEDEMA)

Interactions ⬆ ⬇

Drug-drug:

Strong UGT1A1 inducers or CYP3A inducers, including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, or rifapentine may significantly ↓ cabotegravir and rilpivirine levels and effectiveness; concurrent use contraindicated.
Use of more than a single dose of dexamethasone may significantly ↓ rilpivirine levels and effectiveness; concurrent use contraindicated.
Macrolide antibiotics, including azithromycin, clarithromycin, and erythromycin may ↑ rilpivirine levels and risk of toxicity, including QT interval prolongation; use alternative antibiotic therapy.
QT interval prolonging drugs may ↑ risk of QT interval prolongation and torsades de pointes.
May ↓ levels and effects of methadone.

Drug-Natural Products:

St. John's wort may significantly ↓ rilpivirine levels and effectiveness; concurrent use contraindicated.

Route/Dosage ⬆ ⬇

Lead-in therapy with oral cabotegravir and oral rilpivirine must be used for at least 28 days to assess tolerability to both cabotegravir and rilpivirine prior to initiating cabotegravir/rilpivirine extended-release injection therapy.

Monthly Dosing

IM (Adults and Children ≥12 yr and ≥35 kg): Initiation injections: Cabotegravir 600 mg as single injection and rilpivirine 900 mg as single injection, both administered on the final day of lead-in therapy with oral cabotegravir and oral rilpivirine. Continuation injections: Cabotegravir 400-mg injection and rilpvirine 600-mg injection once monthly (administer both injections during same visit). Start continuation injections 1 mo following initiation injections. Monthly injections may be given within 7 days of originally scheduled date of injection. Switching to every 2-mo injection dosing: Administer cabotegravir 600-mg injection and rilpivirine 900-mg injection 1 mo after the last monthly continuation injection and then every 2 mo thereafter. Planned missed injections: If patient plans to miss a scheduled injection visit by >7 days, give oral cabotegravir 30 mg once daily and oral rilpivirine 25 mg once daily initiated at the same time as missed injection of cabotegravir/rilpivirine and then continued until day the cabotegravir/rilpivirine extended-release injection is restarted (oral replacement therapy can be continued for up to 2 mo). If time since last injection ≤2 mo, resume injection with cabotegravir 400-mg injection and rilpivirine 600-mg injection once monthly. If time since last injection >2 mo, resume injection with initiation injection of cabotegravir 600-mg single injection and rilpivirine 900-mg single injection followed in 1 mo by continuation injections of cabotegravir 400-mg injection and rilpivirine 600-mg injection once monthly (start continuation injections 1 mo following initiation injections). Unplanned missed injections: If monthly injections are missed or delayed by >7 days and oral cabotegravir and oral rilpivirine therapy have not been taken in the interim, reassess patient to determine if resumption of injection dosing remains appropriate.

Every 2-Month Dosing

IM (Adults and Children ≥12 yr and ≥35 kg): Initiation injections: Cabotegravir 600-mg injection and rilpivirine 900-mg injection once monthly for 2 consecutive mo, with the first set of injections being administered on the final day of lead-in therapy with oral cabotegravir and oral rilpivirine. Second initiation injection may be given within 7 days of originally scheduled date of injection. Continuation injections: Cabotegravir 600-mg injection and rilpvirine 900-mg injection every 2 mo (administer both injections during same visit). Start continuation injections 2 mo following second initiation injection. Every 2-mo injections may be given within 7 days of originally scheduled date of injection. Switching to monthly injection dosing: Administer cabotegravir 400-mg injection and rilpivirine 600-mg injection 2 mo after the last monthly continuation injection and then once monthly thereafter. Planned missed injections: If patient plans to miss a scheduled injection visit by >7 days, give oral cabotegravir 30 mg once daily and oral rilpivirine 25 mg once daily initiated at the same time as missed injection of cabotegravir/rilpivirine and then continued until day the cabotegravir/rilpivirine extended-release injection is restarted (oral replacement therapy can be continued for up to 2 mo). If time since second initiation injection ≤2 mo, resume initiation injection with cabotegravir 600-mg injection and rilpivirine 900-mg injection, followed by continuation injections every 2 mo (starting 2 mo following second initiation injection). If time since second initiation injection >2 mo, restart the two initiation injections (see above) given once monthly for 2 consecutive months, followed by the continuation injections (see above) given every 2 mo. If patient misses a continuation injection by ≤3 mo, resume injection with cabotegravir 600-mg injection and rilpivirine 900-mg injection every 2 mo. If time since last injection >3 mo, restart the two initiation injections (see above) given once monthly for 2 consecutive mo followed by the continuation injections (see above) given every 2 mo. Unplanned missed injections: If monthly injections are missed or delayed by >7 days and oral cabotegravir and oral rilpivirine therapy have not been taken in the interim, reassess patient to determine if resumption of injection dosing remains appropriate.

Availability ⬆ ⬇

Extended-release suspension for injection: 400-mg/600-mg kit (200 mg/mL vial of cabotegravir and 300 mg/mL vial of rilpivirine); 600-mg/900-mg kit (200 mg/mL vial of cabotegravir and 300 mg/mL vial of rilpivirine)

Assessment ⬆ ⬇

Assess patient for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.
Monitor for anxiety, depression (especially in patients with a history of psychiatric illness), suicidal ideation, and paranoia during therapy.
Monitor for signs and symptoms of hypersensitivity reactions (severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing) during therapy. Discontinue cabotegravir immediately if reactions occur.
Observe patient for 10 min following injections for post-injection reactions (dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, changes in blood pressure).

Lab Test Considerations:

Monitor liver function tests periodically during therapy. Discontinue therapy if hepatotoxicity is suspected.

Implementation ⬆ ⬇

Lead-in therapy with oral cabotegravir and oral rilpivirine must be used for at least 28 days to assess tolerability to both cabotegravir and rilpivirine prior to initiating cabotegravir/rilpivirine extended-release injection therapy. Start injections of cabotegravir/rilpivirine on last day of PO lead-in therapy.
Injection must be administered by health care provider.
IM: Administer cabotegravir and rilpivirine at separate gluteal (preferably ventrogluteal) injection sites (on opposite sides or 2 cm apart) during the same visit. Use needles long enough for IM injection. Allow suspensions to come to room temperature for 15 min before administration. Stable at room temperature for up to 6 hr. Shake suspensions vigorously to mix. Do not administer solutions that contain particulate matter. Administer within 2 hr of drawing into syringe; if >2 hr, discard injection. Do not refrigerate syringes. Start continuation injections a month after the initiation injections. Injections may be given 7 days before or after the date to receive the injection.

Patient/Family Teaching ⬆ ⬇

Instruct patient in the importance of adhering to monthly schedule of injections. Planned Missed Injections: If a 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 approximately 1 mo after the last injection dose and continued until the day injection dosing is restarted. Unplanned Missed Injections: If monthly injections are missed or delayed by >7 days and PO therapy has not been taken in the interim, health care professional will reassess patient to determine if resumption of injection dosing remains appropriate. Instruct patient to read Patient Information before starting cabotegravir/rilpivirine therapy and with each injection in case of changes.
Advise patient to notify health care professional if signs and symptoms of allergic reaction (fever, generally ill feeling, tiredness, muscle or joint aches, trouble breathing, blisters or sores in mouth, blisters, redness or swelling of eyes, swelling of mouth, face, lips, or tongue), post-injection reactions (trouble breathing, stomach cramps, sweating, numbness of mouth, feeling anxious, feeling warm, feeling lightheaded or faint, blood pressure changes), liver problems (yellow skin or white part of eyes, dark or "tea-colored" urine, light-colored stools, nausea or vomiting, loss of appetite, pain, aching, or tenderness on the right side of stomach area, itching), or depression (feeling sad or hopeless, feeling anxious or restless, have thoughts of hurting yourself [suicide] or have tried to hurt yourself) occur.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during therapy and to avoid breastfeeding. Cabotegravir is detected in systemic circulation for 12 mo after discontinuing cabotegravir/rilpivirine. Inform patient of pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cabotegravir during pregnancy. Register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇