Cabotegravir and rilpivirine (co-packaged)

Cabotegravir and rilpivirine (co-packaged)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]

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Overview

Cabotegravir and rilpivirine (co-packaged) is an HIV-1 integrase strand transfer inhibitor (INSTI), and rilpivirine, an HIV-1 non‑nucleoside reverse transcriptase inhibitor that is FDA approved 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 <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.. Common adverse reactions include injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• CABENUVA is indicated as 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 <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.

Dosage and Administration Overview

• CABENUVA contains cabotegravir extended-release injectable suspension in a single-dose vial and rilpivirine extended-release injectable suspension in a single-dose vial.
• CABENUVA must be administered by a healthcare provider by gluteal intramuscular injection.
• CABENUVA may be initiated with oral cabotegravir and oral rilpivirine prior to the intramuscular injections or the patient may proceed directly to injection of CABENUVA without an oral lead-in.
• CABENUVA can be injected monthly or every 2 months.
• Healthcare providers should discuss these 2 dosing options with the patient prior to starting CABENUVA and decide which injection dosing frequency would be the most appropriate option for the patient.

• Kit of single-dose vials of 400 mg/2 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 600 mg/2 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.
• Kit of single-dose vials of 600 mg/3 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 900 mg/3 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Cabotegravir and rilpivirine (co-packaged) in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Cabotegravir and rilpivirine (co-packaged) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

The safety and effectiveness of CABENUVA have been established in adolescents aged 12 to younger than 18 years and weighing at least 35 kg.

• Kit of single-dose vials of 400 mg/2 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 600 mg/2 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.
• Kit of single-dose vials of 600 mg/3 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 900 mg/3 mL (300 mg/mL) of rilpivirine extended-release injectable suspension.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Cabotegravir and rilpivirine (co-packaged) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Cabotegravir and rilpivirine (co-packaged) in pediatric patients.

Contraindications

CABENUVA is contraindicated in patients:

• with previous hypersensitivity reaction to cabotegravir or rilpivirine

• receiving the following coadministered drugs for which significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur due to uridine diphosphate glucuronosyltransferase (UGT)1A1 and/or cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response:
• Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• Antimycobacterials: Rifabutin, rifampin, rifapentine
• Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment)
• Herbal product: St John’s wort (Hypericum perforatum)

Warnings

Hypersensitivity Reactions

• Serious or severe hypersensitivity reactions have been reported with cabotegravir- and rilpivirine-containing regimens. Reactions associated with cabotegravir include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).

• Reactions associated with rilpivirine-containing regimens include cases of drug reaction with eosinophilia and systemic symptoms (DRESS).

• While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. Administration of cabotegravir and rilpivirine oral lead-in dosing was used in clinical studies to help identify patients who may be at risk of a hypersensitivity reaction.

• Remain vigilant and discontinue CABENUVA if a hypersensitivity reaction is suspected

• Discontinue CABENUVA 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 CABENUVA.
• Administer oral lead-in dosing prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction .

Post-Injection Reactions

• In clinical trials, 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 participants and began to resolve within minutes after the injection, with some patients receiving supportive care. These events may have been associated with accidental intravenous administration during the intramuscular injection procedure

• Carefully follow the Instructions for Use when preparing and administering CABENUVA. The suspensions should be injected slowly via intramuscular injection, and care should be taken to avoid accidental intravenous administration.

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• Observe patients briefly (approximately 10 minutes) after the injection. If a patient experiences a post-injection reaction, monitor and treat as clinically indicated.

Hepatotoxicity

• Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors.

• 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.
• Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected. For information regarding the long-acting properties of CABENUVA.

Depressive Disorders

• Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation, suicide attempt) have been reported with CABENUVA or the individual drug products.

• Promptly evaluate patients with depressive symptoms to assess whether the symptoms are related to CABENUVA and to determine whether the risks of continued therapy outweigh the benefits.

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

• The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of CABENUVA, and possible development of viral resistance.

• Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times, respectively, the recommended oral dosage) in healthy adults prolonged the QTc interval with mean steady-state Cmax values 4.4- and 11.6-fold, respectively, higher than Cmax values associated with the recommended 600-mg monthly dose of rilpivirine extended-release injectable suspension and 4.1- and 10.7-fold, respectively, higher than Cmax values associated with the recommended 900-mg every-2-month dose of rilpivirine extended release injectable suspension.

• CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes.

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 therapy with, and after discontinuation of, CABENUVA; review concomitant medications during therapy with CABENUVA.

Long-Acting Properties and Potential Associated Risks with CABENUVA

• Residual concentrations of both cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). It is important to carefully select patients who agree to the required monthly or every-2-month injection dosing schedule because non-adherence to monthly or every-2-month injections or missed doses could lead to loss of virologic response and development of resistance.

• To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injections of CABENUVA when dosed monthly and no later than 2 months after the final injections of CABENUVA when dosed every 2 months. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect rates observed in practice.

Clinical Trials Experience in Adults

• The safety assessment of CABENUVA is based on the analysis of pooled 48-week data from 1,182 virologically suppressed participants with HIV-1 infection in 2 international, multicenter, open-label pivotal trials, FLAIR and ATLAS, and 1,045 virologically suppressed participants from the ATLAS-2M trial.
• Additional safety information from other ongoing or earlier clinical trials in the cabotegravir and rilpivirine program have been considered in assessing the overall safety profile of CABENUVA.

Adverse reactions were reported following exposure to CABENUVA extended-release injectable suspensions (median time exposure at the time of analysis: 54 weeks in FLAIR and ATLAS, and 64 weeks in ATLAS-2M) and data from VOCABRIA (cabotegravir) tablets and EDURANT (rilpivirine) tablets administered in combination as oral lead-in therapy (median time exposure: 5.3 weeks in FLAIR and ATLAS, and 5.6 weeks in ATLAS-2M). Adverse reactions included those attributable to both the oral and injectable formulations of cabotegravir and rilpivirine administered as a combination regimen. Refer to the prescribing information for EDURANT (rilpivirine) for other adverse reactions associated with oral rilpivirine.

• The most common adverse reactions regardless of severity reported in ≥2% of adult participants from FLAIR and ATLAS at Week 48 are presented in TABLE 5. Selected laboratory abnormalities are included in TABLE 7. At Week 96, the overall safety profile for FLAIR was consistent with that observed at Week 48, with no new safety findings identified.

In the extension phase of the FLAIR study at Week 124, the overall safety profile was consistent with that observed at Week 48 and when injection therapy with CABENUVA was initiated directly without the oral lead-in phase.

• Overall, 4% of participants in the group receiving CABENUVA and 2% of participants in the control group in FLAIR and ATLAS discontinued due to adverse events. Non-injection-site-related adverse events leading to discontinuation and occurring in more than 1 participant were headache, diarrhea, hepatitis A, and acute hepatitis B (all with an incidence <1%). In ATLAS-2M, 2% of participants in both treatment groups discontinued due to adverse events. Non-injection-site–related adverse events leading to discontinuation and occurring in more than 1 participant in ATLAS-2M were fatigue, pyrexia, headache, presyncope, acute hepatitis B, hyperhidrosis, and abnormal dreams that occurred with an incidence of ≤1% in either treatment group.

Adverse Reactionsa (Grades 1 to 4) Reported in at Least 2% of Participants with HIV-1 Infection in FLAIR and ATLAS Trials (Week 48 Pooled Analyses)

• In ATLAS-2M, the type and frequency of adverse reactions reported in participants receiving CABENUVA once monthly or CABENUVA once every 2 months for 48 weeks were similar. Differences between treatment arms were reported for the types of injection-associated adverse reactions (see Injection-Associated Adverse Reactions for additional information).

Injection-Associated Adverse Reactions:

• Local Injection Site Reactions (ISRs): In the 3 Phase 3 studies, FLAIR, ATLAS, and ATLAS 2M, the most frequent adverse reactions associated with the intramuscular administration of CABENUVA were ISRs.

• In the pooled analysis of FLAIR and ATLAS, 83% of participants reported any injection site reaction with the monthly dosing regimen, with 1% of participants who discontinued treatment with CABENUVA because of ISRs. After 14,682 injections, 3,663 ISRs were reported. The severity of ISRs was generally mild (Grade 1: 75% of participants) or moderate (Grade 2: 36% of participants). Four percent (4%) of participants experienced severe (Grade 3) ISRs, and no participant experienced Grade 4 ISRs. The median duration of overall ISR events was 3 days. The most commonly reported ISR in FLAIR and ATLAS was pain/discomfort, with 79% reported in the group receiving CABENUVA.
• In ATLAS-2M, 75% of participants reported any injection site reaction in both the monthly and every 2 month dosing regimens, with <1% of participants who discontinued treatment with CABENUVA because of ISRs. When dosing monthly, after 15,711 injections, 3,152 ISRs were reported. When dosing every 2 months, after 8,470 injections, 2,507 ISRs were reported. The severity of ISRs was generally mild (Grade 1: 70% and 71% of participants) or moderate (Grade 2: 28% and 27% of participants) in monthly and every 2 month dosing regimens, respectively. Four percent (4%) of participants in the monthly group and 3% of participants in the every 2 month group experienced severe (Grade 3) ISRs, and no participant experienced Grade 4 ISRs. The median duration of overall ISR events was 3 days for both dosing regimens. The most commonly reported ISR in ATLAS 2M was pain/discomfort, with 71% and 73% reported in the monthly and every 2 month dosing regimens, respectively. The severity and duration of ISRs, including pain/discomfort, were similar for both dosing regimens and in participants without prior exposure to CABENUVA.
• The most commonly reported ISR (Grades 1 to 3) in at least 1% of adult participants in the pooled analyses from FLAIR and ATLAS, and from ATLAS 2M, are presented in TABLE 6. The side by side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trials.

Anesthesia, abscess, cellulitis, and hemorrhage at the injection site were each reported in <1% of participants.

Injection Site Reactions (Grades 1 to 3) Reported in at Least 1% of Participants in FLAIR and ATLAS (Pooled Analysis) and ATLAS-2M Trials (Week 48 Analysis)

           Other Injection-Associated Adverse Reactions: In the ATLAS and FLAIR clinical trials, an increased incidence of pyrexia (8%) was reported by participants receiving cabotegravir plus rilpivirine injections compared with no events among participants receiving current antiretroviral regimen. In ATLAS and FLAIR, no cases were serious or led to withdrawal and the occurrences of pyrexia may represent a response to administration of CABENUVA via intramuscular injection. In ATLAS-2M, 1 participant in each arm reported pyrexia that led to withdrawal.

In ATLAS and FLAIR, reports of musculoskeletal pain (3%) and less frequently, sciatica, were also more common in participants receiving cabotegravir plus rilpivirine compared with the current antiretroviral regimen and some events had a temporal association with injection. Vasovagal or pre-syncopal reactions were reported in <1% of participants after injection with rilpivirine or cabotegravir.

Less Common Adverse Reactions:

• The following select adverse reactions (regardless of severity) occurred in <2% of participants receiving cabotegravir plus rilpivirine.

           ====Gastrointestinal Disorders:====

• Abdominal pain (including upper abdominal pain), gastritis, dyspepsia, vomiting, diarrhea, and flatulence.

           ====Hepatobiliary Disorders:====

• Hepatotoxicity.

           ====Investigations:====

• Weight increase (see below).

           ====Psychiatric Disorders====

• Anxiety (including anxiety and irritability), depression, abnormal dreams, suicidal ideation, and suicide attempt (these events were observed primarily in participants with a pre-existing history of depression or other psychiatric illness).

           ====Skin and Hypersensitivity Reactions:====

• Hypersensitivity reactions.

Weight Increase: At Week 48, participants in FLAIR and ATLAS who received cabotegravir plus rilpivirine had a median weight gain of 1.5 kg; those in the current antiretroviral regimen group had a median weight gain of 1.0 kg (pooled analysis). In the FLAIR trial, the median weight gain in participants receiving cabotegravir plus rilpivirine or a dolutegravir-containing regimen was 1.3 kg and 1.5 kg, respectively, compared with 1.8 kg and 0.3 kg, respectively, in the ATLAS trial in participants receiving either cabotegravir plus rilpivirine or a protease inhibitor-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or integrase strand transfer inhibitor (INSTI)-containing regimen, respectively. At Week 48, participants in ATLAS-2M who received cabotegravir plus rilpivirine in both the monthly and every-2-month treatment arms had a median weight gain of 1.0 kg. Laboratory Abnormalities: Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in TABLE 7. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trials.

Selected Laboratory Abnormalities (Grades 3 to 4, Week 48) in FLAIR and ATLAS (Pooled Analyses) and ATLAS-2M Trials

           *Changes in Total Bilirubin: Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed with cabotegravir plus rilpivirine. These changes are not considered clinically relevant as they likely reflect competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1).
           *Serum Cortisol: In pooled Phase 3 trials of EDURANT (rilpivirine), the overall mean change from baseline in basal cortisol was -0.69 (-1.12, 0.27) mcg/dL in the group receiving EDURANT compared with -0.02 (-0.48, 0.44) mcg/dL in the control group. Abnormal responses to ACTH stimulation tests were also higher in the group receiving EDURANT. The clinical significance of the higher abnormal rate of ACTH stimulation tests in the group receiving EDURANT is not known. Refer to the prescribing information for EDURANT for additional information.

Clinical Trial Experience in Adolescents

• Based on data from the Week 16 (cohort 1) and Week 24 (cohort 2) analyses of the MOCHA study, the safety profile in adolescents (aged 12 to younger than 18 years and weighing ≥35 kg) was consistent with the safety profile established with cabotegravir plus rilpivirine in adults.

• In cohort 1, 55 virologically suppressed adolescents with HIV-1 received background antiretroviral therapy in addition to either oral cabotegravir (n = 30) followed by injectable cabotegravir (n = 29), or oral rilpivirine (n = 25) followed by injectable rilpivirine (n = 23). Adverse reactions were reported in 38% of adolescents receiving either cabotegravir or rilpivirine. Thirty-three percent of participants reported at least 1 ISR. All ISRs were Grade 1 or Grade 2. Two participants had Grade 3 adverse reactions of hypersensitivity (n = 1, oral rilpivirine) and insomnia (n = 1, injectable cabotegravir). The Grade 3 adverse reaction of drug hypersensitivity led to discontinuation of rilpivirine during oral lead-in. The adverse reactions reported by more than one participant (regardless of severity) were injection site pain (n = 18), headache (n = 2), hypersensitivity (n = 2), insomnia (n = 2), and nausea (n = 2).
• In cohort 2, 144 virologically suppressed adolescents with HIV-1 received oral cabotegravir plus oral rilpivirine followed by injectable cabotegravir plus injectable rilpivirine. Adverse reactions were reported in 35% of adolescents receiving cabotegravir plus rilpivirine. Thirty-four percent of participants reported at least 1 ISR. The majority of these participants experienced Grade 1 or Grade 2 ISRs. Two participants had Grade 3 ISRs consisting of injection site abscess (n = 2) and injection site pain in one of these two participants (symptoms resolved in both participants). All non-ISR adverse reactions were ≤ Grade 2. Non-injection-site associated adverse reactions reported by more than one participant (regardless of severity) were headache (n = 3), nausea (n = 2), rash (n = 2) and rash pruritic (n = 2).

Postmarketing Experience

• The following adverse reactions have been identified during postmarketing experience in patients receiving cabotegravir- or oral-rilpivirine-containing regimens. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders

• Hypersensitivity reactions (including angioedema and urticaria).

Renal and Genitourinary Disorders

• Nephrotic syndrome.

Skin and Subcutaneous Tissue Disorders

• Severe skin and hypersensitivity reactions, including DRESS, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).

Drug Interactions

Concomitant Use with Other Antiretroviral Medicines

• Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

Use of Other Antiretroviral Drugs after Discontinuation of CABENUVA

• 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 CABENUVA [see Warnings and Precautions.

Potential for Other Drugs to Affect CABENUVA

• Refer to the prescribing information for VOCABRIA (cabotegravir) and EDURANT (rilpivirine) for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively.

Cabotegravir

• 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 virologic response; therefore, coadministration of CABENUVA with these drugs is contraindicated.

Rilpivirine

• Rilpivirine is primarily metabolized by CYP3A. Coadministration of CABENUVA and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs Coadministration of CABENUVA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine .

QT-Prolonging Drugs:

• At mean steady-state Cmax values 4.4- and 11.6-fold higher than those with the recommended 600 mg dose of rilpivirine extended-release injectable suspension, rilpivirine may prolong the QTc interval.CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes.

Established and Other Potentially Significant Drug Interactions

• Refer to the prescribing information for VOCABRIA (cabotegravir) and EDURANT (rilpivirine) for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively.
• Information regarding potential drug interactions with cabotegravir and rilpivirine is provided in TABLE 8. These recommendations are based on either drug interaction trials following oral administration of cabotegravir or rilpivirine or predicted interactions due to the expected magnitude of the interaction and potential for loss of virologic response.TABLE 8 includes potentially significant interactions but is not all inclusive.

Drug Interactions with CABENUVA

Drug Interactions with CABENUVA

Drugs without Clinically Significant Interactions

Cabotegravir

Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals and rilpivirine) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine.

Rilpivirine

• Based on drug interaction study results, the following drugs can be coadministered with rilpivirine (non-antiretrovirals and cabotegravir) or given after discontinuation of rilpivirine (antiretrovirals and non-antiretrovirals): acetaminophen, atorvastatin, cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, sildenafil, tenofovir alafenamide, and tenofovir disoproxil fumarate.
• Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Pregnancy Exposure Registry

• There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to CABENUVA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

• There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. Discuss the benefit-risk of using CABENUVA with individuals of childbearing potential or during pregnancy.
• Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy.

• Cabotegravir use in pregnant individuals has not been evaluated. Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in a United States (U.S.) reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).

• The rate of miscarriage is not reported in the APR. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the MACDP is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates mothers and infants from a limited geographic area and does not include outcomes for births that occurred at <20 weeks’ gestation.
• In animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at >28 times the exposure at the recommended human dose (RHD). No evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (>28 times or similar to the exposure at the RHD, respectively) given during organogenesis.

• No adverse developmental outcomes were observed when rilpivirine was administered orally at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD.

Clinical Considerations

• Lower exposures with oral rilpivirine were observed during pregnancy. Viral load should be monitored closely if the patient remains on CABENUVA during pregnancy. Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy.

Data

Human Data:

           ====Rilpivirine: ====

• Based on prospective reports to the APR of over 580 exposures to oral rilpivirine-containing regimens during the first trimester of pregnancy and over 200 during second/third trimester of pregnancy, the prevalence of birth defects in live births was 1.5% (95% CI: 0.7% to 2.9%) and 1.5% (95% CI: 0.3% to 4.2%) following first and second/third trimester exposures, respectively, compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. In a clinical trial, total oral rilpivirine exposures were generally lower during pregnancy compared with the postpartum period. Refer to the prescribing information for EDURANT (rilpivirine) for additional information on rilpivirine.

Animal Data:

Cabotegravir:

• Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. There were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD). No drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD), and no drug-related fetal malformations were observed at any dose.

Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD).

• In a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. A delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD); there were no alterations to growth and development of surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. There was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 times the exposure at the RHD) was not associated with delayed parturition or neonatal mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue.

           ====Rilpivirine:====

• Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on Gestation Days 6 through 17 and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans at the RHD.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cabotegravir and rilpivirine (co-packaged) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Cabotegravir and rilpivirine (co-packaged) during labor and delivery.

Nursing Mothers

Risk Summary

• Based on limited data after oral administration, rilpivirine is present in human breast milk. The data do not allow determination of the amount of rilpivirine that is transferred to milk. There are no data on the presence of cabotegravir in human milk. Cabotegravir is present in animal milk

• When a drug is present in animal milk, it is likely that the drug will be present in human milk. It is not known if the components of CABENUVA affect human milk production or have effects on the breastfed infant. Residual exposures in human milk of cabotegravir (if present) and rilpivirine may remain for 12 months or longer after the last injections have been administered.

• Potential risks of breastfeeding include: (1) HIV 1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults.

Data

Cabotegravir:

• Animal lactation studies with cabotegravir have not been conducted. However, cabotegravir was detected in the plasma of nursing pups on Lactation Day 10 in the rat pre- and postnatal development study.

Pediatric Use

• The safety and effectiveness of CABENUVA have been established in adolescents aged 12 to younger than 18 years and weighing at least 35 kg, which is supported by the following:

Trials in adults

• MOCHA (NCT03497676) trial in adolescents, in which virologically suppressed adolescents with HIV-1 (aged 12 to younger than 18 years and weighing at least 35 kg) received either cabotegravir or rilpivirine in addition to their background antiretroviral regimen (cohort 1), or cabotegravir plus rilpivirine as a complete regimen (cohort 2).

• The safety and efficacy in adolescents (aged 12 to younger than 18 years and weighing at least 35 kg) were similar to that in adults and there was no clinically significant change in exposure for the components of CABENUVA

• The efficacy of CABENUVA in adolescents is extrapolated from adults with support from pharmacokinetic analyses showing similar drug exposure and additional supportive efficacy data from the MOCHA study.

• The safety, efficacy, and pharmacokinetics of CABENUVA have not been established in pediatric patients younger than 12 years of age or weighing <35 kg.

Geriatic Use

Clinical trials of CABENUVA did not include sufficient numbers of participants aged 65 years and older to determine whether they respond differently from younger participants. In general, caution should be exercised in administration of CABENUVA in elderly patients, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see Clinical Pharmacology.

Gender

There is no FDA guidance on the use of Cabotegravir and rilpivirine (co-packaged) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Cabotegravir and rilpivirine (co-packaged) with respect to specific racial populations.

Renal Impairment

• Based on studies with oral cabotegravir and population pharmacokinetic analyses of oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild (creatinine clearance ≥60 to <90 mL/min) or moderate renal impairment (creatinine clearance ≥30 to <60 mL/min).
• In patients with severe renal impairment (creatinine clearance 15 to <30 mL/min) or end-stage renal disease (creatinine clearance <15 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 >99% protein bound, dialysis is not expected to alter exposures of cabotegravir or rilpivirine.

Hepatic Impairment

• Based on separate studies with oral cabotegravir and oral rilpivirine, no dosage adjustment of CABENUVA 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 or rilpivirine is unknown.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Cabotegravir and rilpivirine (co-packaged) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Cabotegravir and rilpivirine (co-packaged) in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Administration in the drug label.

Monitoring

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Cabotegravir and rilpivirine (co-packaged) and IV administrations.

Overdosage

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Mechanism of Action in the drug label.

Structure

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Structure in the drug label.

Pharmacodynamics

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Clinical Studies in the drug label.

How Supplied

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) How Supplied in the drug label.

Storage

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Cabotegravir and rilpivirine (co-packaged) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

CABENUVA

Look-Alike Drug Names

There is limited information regarding Cabotegravir and rilpivirine (co-packaged) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.