HIV-1 infection, treatment: Note: An oral lead-in period of ~1 month (≥28 days) should be completed prior to initiation of cabotegravir and rilpivirine injections. Initiate injections on the final day of oral lead-in.
Monthly injection dosing:
Initiation injections: IM: Cabotegravir 600 mg and rilpivirine 900 mg once on the last day of oral lead-in; begin continuation injections in 1 month.
Continuation injections: IM: Beginning 1 month after initiation injections, cabotegravir 400 mg and rilpivirine 600 mg once monthly; may be given up to 7 days before or after the date of the scheduled monthly injections.
Every-2-month injection dosing:
Initiation injections: IM: Cabotegravir 600 mg and rilpivirine 900 mg once monthly for 2 doses; first initiation injections should be given on the last day of oral lead-in. Note: Second initiation injections may be administered up to 7 days before or after the date the individual is scheduled to receive the injections.
Continuation injections: IM: Beginning 2 months after the last initiation injections, cabotegravir 600 mg and rilpivirine 900 mg once every 2 months; may be given up to 7 days before or after the date of the scheduled every-2-month injections.
Switching injection schedules:
Switching from monthly to every-2-month injection dosing: IM: Administer cabotegravir 600 mg and rilpivirine 900 mg 1 month after the last monthly continuation injections, and then cabotegravir 600 mg and rilpivirine 900 mg every 2 months thereafter.
Switching from every-2-month to monthly injection dosing: IM: Administer cabotegravir 400 mg and rilpivirine 600 mg 2 months after the last every-2-month continuation injections, and then cabotegravir 400 mg and rilpivirine 600 mg monthly thereafter.
Missed doses:
Planned missed injections:
Monthly injection dosing: If a patient plans to miss a scheduled monthly injection visit by >7 days, administer oral therapy for up to 2 months to replace missed injection visits. The first dose of oral therapy should be administered ~1 month after the last injections and continued until the day the injection dosing is restarted.
Every-2-month injection dosing: If a patient plans to miss a scheduled monthly injection visit by >7 days, administer oral therapy to replace 1 missed injection visit. The first dose of oral therapy should be administered ~2 months after the last injections and continued until the day the injection dosing is restarted.
Unplanned missed injections:
If monthly injections are missed or delayed by >7 days and oral therapy has not been administered in the interim, clinically reassess patient to determine appropriateness of resumption of injection dosing. If injection dosing will be continued, administer as follows:
Monthly injection dosing:
≤2 months since last injection: Continue with cabotegravir 400 mg and rilpivirine 600 mg IM monthly injections.
>2 months since last injection: Reinitiate with cabotegravir 600 mg and rilpivirine 900 mg IM injections, then continue to follow the cabotegravir 400 mg and rilpivirine 600 mg IM monthly injection dosing schedule.
Every-2-month injection dosing:
Second injections missed:
≤2 months since first injection: Administer cabotegravir 600 mg and rilpivirine 900 mg IM injections as soon as possible, then continue to follow the every-2-month injection dosing schedule.
>2 months since first injection: Reinitiate with cabotegravir 600 mg and rilpivirine 900 mg IM once, followed by cabotegravir 600 mg and rilpivirine 900 mg IM 1 month later. Then, continue to follow the every-2-month injection dosing schedule.
Third or subsequent injections missed:
≤3 months since last injection: Administer cabotegravir 600 mg and rilpivirine 900 mg IM injections as soon as possible, then continue with every-2-month injection dosing schedule.
>3 months since last injection: Reinitiate with cabotegravir 600 mg and rilpivirine 900 mg IM once, followed by cabotegravir 600 mg and rilpivirine 900 mg IM 1 month later. Then, continue to follow the every-2-month injection dosing schedule.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl 15 to <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
Patients on dialysis: There are no dosage adjustments provided in the manufacturer's labeling; because of high protein binding, dialysis is not expected to alter cabotegravir exposure.
Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.
Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension Extended Release, Intramuscular [preservative free]:
Cabenuva: Cabotegravir 400 mg and rilpivirine 600 mg per 2 mL (4 mL); Cabotegravir 600 mg and rilpivirine 900 mg per 3 mL (6 mL) [contains polyethylene glycol]
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension Extended Release, Intramuscular:
Generic: Cabotegravir 400 mg and rilpivirine 600 mg per 2 mL (2 mL); Cabotegravir 600 mg and rilpivirine 900 mg per 3 mL (3 mL)
IM: Note: Injections must be administered by a health care professional.
For gluteal IM administration only; do not administer by any other route. A complete dose requires 2 injections: 1 cabotegravir injection and 1 rilpivirine injection. Administer each injection at a separate gluteal injection site (on opposite sides or 2 cm apart) during the same visit; the ventrogluteal site is recommended. A dorsogluteal approach is acceptable if preferred by health care professional. Consider the BMI of the patient to ensure needle length is sufficient to reach the gluteus muscle; longer needles (not supplied) may be required in patients with BMI >30 kg/m2 to ensure injections are administered IM. Prior to administration, remove from refrigeration and wait ≥15 minutes for injection to come to room temperature; vials may remain in carton at room temperature for ≤6 hours. Shake each vial vigorously to ensure uniform suspension prior to drawing into syringes. Once drawn into syringes, administer as soon as possible; suspensions may remain in syringes for ≤2 hours.
HIV-1 infection, treatment: Treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see individual agents.
>10%: Local: Discomfort at injection site (≤79%), induration at injection site (12%), injection site nodule (14%), injection site reaction (83%), pain at injection site (≤79%)
1% to 10%:
Dermatologic: Injection site pruritus (4%), skin rash (2%)
Endocrine & metabolic: Weight gain (<2%)
Gastrointestinal: Abdominal pain (<2%; including upper abdominal pain), diarrhea (<2%), dyspepsia (<2%), flatulence (<2%), gastritis (<2%), increased serum lipase (5%), nausea (3%), vomiting (<2%)
Hepatic: Hepatotoxicity (<2%), increased serum alanine aminotransferase (2%), increased serum aspartate aminotransferase (2%)
Hypersensitivity: Hypersensitivity reaction (<2%; including severe hypersensitivity reaction)
Local: Bruising at injection site (3%), erythema at injection site (4%), hematoma at injection site (2%), swelling at injection site (8%), warm sensation at injection site (2%)
Nervous system: Abnormal dreams (<2%), anxiety (<2%; including irritability), depression (<2%), dizziness (2%), fatigue (5%), headache (4%), sleep disorder (2%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (8%), musculoskeletal pain (3%)
Miscellaneous: Fever (8%)
<1%:
Cardiovascular: Altered blood pressure, flushing, syncope (including presyncope and vasovagal)
Dermatologic: Diaphoresis
Gastrointestinal: Abdominal cramps, oral paresthesia
Hepatic: Increased serum bilirubin
Local: Abscess at injection site, cellulitis at injection site
Nervous system: Agitation
Respiratory: Dyspnea
Frequency not defined: Nervous system: Sciatica
Postmarketing:
Dermatologic: Severe dermatological reaction
Genitourinary: Nephrotic syndrome
Immunologic: Drug reaction with eosinophilia and systemic symptoms
Nervous system: Abnormality in thinking (negative thoughts), depressed mood, dysphoria, emotional liability, major depressive disorder, mood changes, suicidal ideation, suicidal tendencies
Hypersensitivity to cabotegravir, rilpivirine, or any component of the formulation; concomitant use with uridine diphosphate-glucuronosyl transferase and/or cytochrome P450 3A enzyme inducers (antiseizure medications [eg, carbamazepine, oxcarbazepine, phenobarbital, phenytoin], antimycobacterials [eg, rifabutin, rifampin, rifapentine], systemic dexamethasone [more than a single dose], St John's wort).
Concerns related to adverse effects:
• Depressive disorders: Depressive disorders, including depression, depressed mood, dysphoria, major depression, mood changes, negative thoughts, suicide attempts, or suicidal ideation, have been reported. Promptly evaluate patients with depressive symptoms to assess if symptoms are related to cabotegravir and rilpivirine and determine if risks of continued treatment outweigh the benefits.
• Hepatotoxicity: Hepatoxicity has been reported in patients with or without known preexisting hepatic disease or other risk factors. Patients with underlying hepatic disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. Monitor liver chemistries and discontinue treatment if hepatotoxicity is suspected.
• Hypersensitivity reactions: Hypersensitivity reactions have been reported postmarketing with rilpivirine, including cases of drug reaction with eosinophilia and systemic symptoms. Some skin reactions were accompanied by constitutional symptoms (eg, fever); other skin reactions were associated with organ dysfunction (eg, hepatic serum biochemistry elevations). Serious or severe hypersensitivity reactions have been reported with other integrase inhibitors. Discontinue immediately if signs or symptoms of reactions (eg, severe rash, rash with fever, malaise, fatigue, muscle/joint aches, blisters, oral blisters/lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing) occur. Monitor liver transaminases and clinical status and institute appropriate therapy as indicated. Oral lead-in dosing should be administered prior to initiation of cabotegravir and rilpivirine to help identify patients who may be at risk for hypersensitivity.
• Injection-related reactions: Serious postinjection reactions were reported within minutes after injection of rilpivirine, including abdominal cramping, agitation, BP changes, bronchospasm, dizziness, dyspnea, flushing, oral numbness, pain (eg, back, chest), rash/urticaria, and sweating. These events were reported in <1% of subjects, began to resolve a few minutes after injection, and may have been associated with inadvertent (partial) IV administration. Observe patients for ~10 minutes after injection. If a patient experiences a postinjection reaction, monitor and treat as clinically indicated.
Disease-related concerns:
• Renal impairment: Use with caution in patients with CrCl <30 mL/minute.
Concurrent drug therapy issues:
• QTc prolongation: Doses of oral rilpivirine 3 and 12 times the recommended oral dose have been associated with QTc prolongation; plasma rilpivirine concentrations after injection are comparable to those seen with the usual recommended oral doses that do not prolong the QT interval. Use caution when coadministering with a drug with a known risk of torsades de pointes.
Dosage form specific issues:
• Discontinuation of therapy: Residual concentrations of cabotegravir and rilpivirine long-acting injections may remain in the systemic circulation of patients for ≥12 months; consider this if cabotegravir and rilpivirine are discontinued.
Other warnings/precautions:
• Resistance: Carefully select patients who agree to the required injection schedule; nonadherence to injection schedule or missed doses could lead to loss of virologic response and development of resistance. In addition, to minimize risk of developing resistance upon discontinuation, a fully suppressive antiretroviral regimen must be adopted no later than 1 month after the final monthly injection or 2 months after the final every-2-month injection of cabotegravir and rilpivirine.
Refer to individual components.
Antacids: May decrease the serum concentration of Rilpivirine. Management: Administer antacids at least 2 hours before or 4 hours after rilpivirine when used with most rilpivirine products. However, administer antacids at least 6 hours before or 4 hours after the rilpivirine/dolutegravir combination product. Risk D: Consider therapy modification
Antihepaciviral Combination Products: May increase the serum concentration of Rilpivirine. Risk X: Avoid combination
CarBAMazepine: May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Rilpivirine. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Rilpivirine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for reduced rilpivirine efficacy (eg, loss of virologic response or resistance). Risk X: Avoid combination
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Rilpivirine. Risk C: Monitor therapy
DexAMETHasone (Systemic): May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
Didanosine: Rilpivirine may decrease the absorption of Didanosine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Didanosine may decrease the absorption of Rilpivirine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Management: Administer didanosine on an empty stomach at least 2 hours before or 4 hours after rilpivirine, due to the requirement that rilpivirine be administered with food. Risk D: Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Ergonovine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Ergonovine. Specifically, this would be most likely with delavrdine, while other Non-Nucleoside Reverse Transcriptase Inhibitors may be more likely to decrease the concentration of Ergonovine. Risk X: Avoid combination
Fosphenytoin: May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Histamine H2 Receptor Antagonists: May decrease the serum concentration of Rilpivirine. Management: Administer histamine H2 receptor antagonists at least 12 hours before or 4 hours after rilpivirine. Risk D: Consider therapy modification
Inhibitors of the Proton Pump (PPIs and PCABs): May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Ketoconazole (Systemic): May increase the serum concentration of Rilpivirine. Rilpivirine may decrease the serum concentration of Ketoconazole (Systemic). Risk C: Monitor therapy
Levoketoconazole: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Levoketoconazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Levomethadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Levomethadone. Management: Levomethadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Risk C: Monitor therapy
Macrolide Antibiotics: May increase the serum concentration of Rilpivirine. Management: Consider the use of azithromycin or another non-macrolide alternative when appropriate to avoid this potential interaction. Risk D: Consider therapy modification
Methadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Risk C: Monitor therapy
Orlistat: May decrease the serum concentration of Antiretroviral Agents. Risk C: Monitor therapy
OXcarbazepine: May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
OXcarbazepine: May decrease the serum concentration of Cabotegravir. Risk X: Avoid combination
PHENobarbital: May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
Phenytoin: May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
Polyvalent Cation Containing Products: May decrease the serum concentration of Cabotegravir. Management: Administer polyvalent cation containing products at least 2 hours before or 4 hours after oral cabotegravir. Risk D: Consider therapy modification
Primidone: May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Reverse Transcriptase Inhibitors (Non-Nucleoside): May enhance the adverse/toxic effect of other Reverse Transcriptase Inhibitors (Non-Nucleoside). Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of other Reverse Transcriptase Inhibitors (Non-Nucleoside). Specifically, efavirenz and nevirapine may decrease the serum concentrations of other non-nucleoside reverse transcriptase inhibitors. Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of other Reverse Transcriptase Inhibitors (Non-Nucleoside). Specifically, delavirdine may increase the serum concentration of etravirine. Risk X: Avoid combination
Rifabutin: May decrease the serum concentration of Rilpivirine. Management: Increase rilpivirine dose to 50 mg/day during rifabutin treatment. Use of rifabutin with emtricitabine/rilpivirine/tenofovir alafenamide product is not recommended. Use with IV cabotegravir/rilpivirine is contraindicated. Risk D: Consider therapy modification
Rifabutin: May decrease the serum concentration of Cabotegravir. Additionally, rifabutin may decrease rilpivirine concentrations, a drug often coadministered with IV cabotegravir. Management: Do not use long-acting injectable cabotegravir (Cabenuva) with rifabutin. Cabotegravir dose adjustments required if extended-release suspension (Apretude) is coadministered with rifabutin. No interaction expected with cabotegravir tablets. Risk D: Consider therapy modification
RifAMPin: May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
Rifapentine: May decrease the serum concentration of Cabotegravir. Risk X: Avoid combination
Rifapentine: May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
Saquinavir: Rilpivirine may enhance the arrhythmogenic effect of Saquinavir. Saquinavir may increase the serum concentration of Rilpivirine. Risk X: Avoid combination
St John's Wort: May decrease the serum concentration of Rilpivirine. Risk X: Avoid combination
UGT1A1 Inducers: May decrease the serum concentration of Cabotegravir. Risk X: Avoid combination
The cabotegravir/rilpivirine injection is not currently recommended for use in patients planning to become pregnant (HHS [adult] 2021).
Cabotegravir and rilpivirine can be detected in the plasma for ≥12 months after the last injection.
Refer to individual monographs for additional information.
The cabotegravir/rilpivirine injection is not currently recommended for use in patients who are pregnant. Patients who became pregnant during clinical trials were changed to alternative therapy (HHS [adult] 2021).
Cabotegravir and rilpivirine can be detected in the plasma for ≥12 months after the last injection.
Refer to individual monographs for additional information.
It is not known if cabotegravir or rilpivirine are present in breast milk.
Cabotegravir and rilpivirine can be detected in the plasma for ≥12 months after the last injection.
Refer to individual monographs for additional information.
Liver chemistries; signs/symptoms of hypersensitivity and/or skin reactions; injection-related reactions; mood changes.
Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration.
Rilpivirine is a non-nucleoside reverse transcriptase inhibitor; activity is mediated by noncompetitive inhibition of HIV-1 reverse transcriptase.
Distribution: CSF:plasma concentration ratio: Cabotegravir: Range: 0.002 to 0.004; Rilpivirine: Range: Not quantifiable to 0.02.
Protein binding: Cabotegravir: >99.8%; Rilpivirine: 99.7%.
Metabolism: Cabotegravir: UGT1A1, UGT1A9 (minor); Rilpivirine: CYP3A.
Half-life elimination: Cabotegravir: 5.6 to 11.5 weeks; Rilpivirine: 13 to 28 weeks.
Time to peak: Cabotegravir: 7 days; Rilpivirine: 3 to 4 days.
Excretion:
Cabotegravir: Urine: 27% (0% as unchanged drug); Feces: 59% (47% as unchanged drug).
Rilpivirine: Urine: 6% (<1% as unchanged drug); Feces: 85% (26% as unchanged drug).
