CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use

 

Initial U.S. Approval: 2021 

 

 

 INDICATIONS AND USAGE

 

 CABENUVA, a 2-drug co-packaged product of cabotegravir, a human immunodeficiency virus type-1 (HIV-1) integrase strand transfer inhibitor (INSTI), and rilpivirine, an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. (1) 

 

 DOSAGE AND ADMINISTRATION 

 

 • Prior to initiating treatment with CABENUVA, oral lead-in dosing should be used for approximately 1 month to assess the tolerability of cabotegravir and rilpivirine.

 

 • For intramuscular (IM) gluteal injection only. (2.3, 2.5)

 

• Recommended Dosing Schedule: Initiate injections of CABENUVA (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of oral lead-in and continue with injections of CABENUVA (400 mg of cabotegravir and 600 mg of rilpivirine) every month thereafter. (2.3) 

 

 DOSAGE FORMS AND STRENGTHS-

 

 Cabotegravir extended-release injectable suspension and rilpivirine extendedrelease injectable suspension, co-packaged as follows: (3) CABENUVA 400-mg/600-mg Kit: • single-dose vial of 400 mg/2 mL (200 mg/mL) cabotegravir  • single-dose vial of 600 mg/2 mL (300 mg/mL) rilpivirine  CABENUVA 600-mg/900-mg Kit: • single-dose vial of 600 mg/3 mL (200 mg/mL) cabotegravir • single-dose vial of 900 mg/3 mL (300 mg/mL) rilpivirine 

 

------------------------------ CONTRAINDICATIONS ------------------------------ 

 • Previous hypersensitivity reaction to cabotegravir or rilpivirine. (4)  • Coadministration with drugs where significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur, which may result in loss of virologic response. (4) 

 

----------------------- WARNINGS AND PRECAUTIONS ------------------------ 

 • Hypersensitivity reactions have been reported with rilpivirine-containing regimens and in association with other integrase inhibitors. Discontinue 

------------------------------ ADVERSE REACTIONS ------------------------------ 

 The most common adverse reactions (Grades 1 to 4) observed in =2% of subjects receiving CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. (6.1) 

To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 

 

 

CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop. (5.1) • Serious post-injection reactions with rilpivirine were reported. Monitor and treat as clinically indicated. (5.2) • Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine. Monitoring of liver chemistries is recommended. Discontinue CABENUVA if hepatotoxicity is suspected. (5.3) • Depressive disorders have been reported with CABENUVA. Immediate medical evaluation is recommended for depressive symptoms. (5.4) • Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients up to 12 months or longer. It is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA. If virologic failure is suspected, prescribe an alternative regimen as soon as possible. (5.6)  

 

------------------------------ ADVERSE REACTIONS ------------------------------ 

 The most common adverse reactions (Grades 1 to 4) observed in =2% of subjects receiving CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. (6.1) 

To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 

 

------------------------------ DRUG INTERACTIONS------------------------------- 

 • Refer to the full prescribing information for important drug interactions with CABENUVA. (4, 5.5, 7) • Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. (7.1) • Drugs that induce uridine diphosphate glucuronosyltransferase (UGT)1A1 or cytochrome P450 (CYP)3A4 may decrease the plasma concentrations of the components of CABENUVA. (4, 7.3, 7.4)  • CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes. (7.3)  

 

----------------------- USE IN SPECIFIC POPULATIONS ----------------------- 

 • Pregnancy: After oral use of rilpivirine, exposures were generally lower during pregnancy compared with the postpartum period. (8.1) • Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2) 

------------------------------ CONTRAINDICATIONS ------------------------------ 

 • Previous hypersensitivity reaction to cabotegravir or rilpivirine. (4)  • Coadministration with drugs where significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur, which may result in loss of virologic response. (4) 

 

----------------------- WARNINGS AND PRECAUTIONS ------------------------ 

 • Hypersensitivity reactions have been reported with rilpivirine-containing regimens and in association with other integrase inhibitors. Discontinue 

17 PATIENT COUNSELING INFORMATION 

 

Advise the patient to read the FDA-approved patient labeling (Patient Information).

 

Hypersensitivity Reactions-                                                                                              Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking CABENUVA and seek medical attention if they develop a rash associated with any of the following symptoms, as it may be a sign of a more serious reaction such as DRESS or severe hypersensitivity: fever; generally ill feeling; extreme tiredness; muscle or joint aches; blisters; oral blisters or lesions; eye inflammation; facial swelling; swelling of the eyes, lips, tongue, or mouth; difficulty breathing; and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes; dark or tea-colored urine; pale-colored stools or bowel movements; nausea; vomiting; loss of appetite; or pain, aching, or sensitivity on the right side below the ribs).

 

Advise patients that if hypersensitivity occurs, they will be closely monitored, laboratory tests will be ordered, and appropriate therapy will be initiated [see Warnings and Precautions (5.1)]

 

Adverse Reactions Following Injection-                                                                 Advise patients that injection site reactions have been reported in the majority of patients receiving CABENUVA. These local reactions typically consist of one or more of the following: pain, erythema, tenderness, pruritus, and local swelling. Systemic reactions have also been reported, such as fever, musculoskeletal pain, and sciatica pain [see Adverse Reactions (6.1)].

 

Serious post-injection reactions were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events began to resolve within a few minutes after the injection. Advise patients that they will be observed briefly (approximately 10 minutes) after the injection. If they experience a post-injection reaction, they will be monitored, and appropriate treatment administered [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients that hepatotoxicity has been reported with cabotegravir and rilpivirine, components of CABENUVA [see Warnings and Precautions (5.3), Adverse Reactions (6.1)]. Inform patients that monitoring for liver transaminases is recommended. 

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Depressive Disorders  Inform patients that depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, unusual mood, feeling tense, negative thoughts, suicidal ideation or attempt) have been reported with at least one of the components of CABENUVA. Advise patients to seek immediate medical evaluation if they experience depressive symptoms [see Warnings and Precautions (5.4), Adverse Reactions (6.1)]. Drug Interactions  CABENUVA may interact with other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort. CABENUVA is an extended-release injectable which may be systemically present for 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 Contraindications (4), Drug Interactions (7)]. Adherence to CABENUVA Counsel patients about the importance of continued medication adherence and scheduled visits to help maintain viral suppression and to reduce risk of loss of virologic response and development of resistance [see Dosage and Administration (2.1), Warnings and Precautions (5.6)]. Missed Dose Inform patients that CABENUVA can remain in the body for up to 12 months or longer after receiving their last injection. Advise patients that they should contact their healthcare provider if they miss or plan to miss a scheduled monthly injection visit and that oral therapy may be used to replace up to 2 consecutive monthly injections. Advise patients that if they stop treatment with CABENUVA, they will need to take other medicines to treat their HIV-1 infection [see Dosage and Administration (2.1, 2.5), Warnings and Precautions (5.6)]. Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to CABENUVA during pregnancy. Patients who are of reproductive potential should be informed of the long duration of exposure of CABENUVA and that there is very limited clinical experience in human pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)]. Lactation Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)]. CABENUVA and VOCABRIA are trademarks owned by or licensed to the ViiV Healthcare group of companies. 

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The other brand listed is a trademark owned by or licensed to its respective owner and is not a trademark owned by or licensed to the ViiV Healthcare group of companies. The maker of this brand is not affiliated with and does not endorse the ViiV Healthcare group of companies or its products. 

 

Manufactured for: 

 

ViiV Healthcare Research Triangle Park, NC 27709 

 

by: GlaxoSmithKline Research Triangle Park, NC 27709 ©2021 ViiV Healthcare group of companies or its licensor

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action CABENUVA contains 2 long-acting HIV-1 antiretroviral drugs, cabotegravir and rilpivirine [see Microbiology (12.4)]. 12.2 Pharmacodynamics Cardiac Electrophysiology At a dose of cabotegravir 150 mg orally every 12 hours (10 times the recommended total daily oral leadin dosage for CABENUVA), the QT interval is not prolonged to any clinically relevant extent. Administration of 3 doses of cabotegravir 150 mg orally every 12 hours resulted in a geometric mean Cmax approximately 2.8-fold and 5.4-fold above the geometric mean steady-state Cmax associated with the recommended 30-mg dose of oral cabotegravir and the recommended 400-mg monthly dose of cabotegravir extended-release injectable suspension, respectively. At the recommended dose of rilpivirine 25 mg orally once daily, the QT interval is not prolonged to any clinically relevant extent. The rilpivirine 25-mg once-daily mean steady-state Cmax was 247 ng/mL, which is 1.7-fold higher than the mean steady-state Cmax observed with the recommended 600-mg monthly dose of rilpivirine extended-release injectable suspension. When rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times the recommended oral lead-in dosage) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval were 10.7 (15.3) and 23.3 (28.4) msec, respectively, after baseline and placebo adjustment. Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 4.4-fold and 11.6-fold, respectively, higher than the mean steady-state Cmax observed with the recommended 600-mg monthly dose of rilpivirine extended-release injectable suspension. The corresponding Cmax ratios are 2.6 and 6.7 when compared with the recommended oral rilpivirine dosage [see Warnings and Precautions (5.5)]. 12.3 Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic properties of the components of CABENUVA are provided in Table 6. The multiple-dose pharmacokinetic parameters are provided in Table 7. For the pharmacokinetic properties of oral cabotegravir and oral rilpivirine, refer to the full prescribing information for VOCABRIA and EDURANT, respectively. 

Table 6. Pharmacokinetic Properties of the Components of CABENUVA  Cabotegravir Rilpivirine  Absorptiona   Tmax (days), median 7 3 to 4  Distribution   

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% Bound to human plasma proteins >99.8 99.7 Blood-to-plasma ratio 0.52 0.7 CSF-to-plasma concentration ratio (median [range])b 0.003 (0.002 to 0.004) 0.01 (BLQ to 0.02) Elimination   t1/2 (weeks) meanc 5.6 to 11.5 13 to 28 Metabolism Metabolic pathways UGT1A1 UGT1A9 (minor) CYP3A Excretion   Major route of elimination Metabolism Metabolism % of dose excreted as total 14C (unchanged drug) in urined 27 (0) 6 (<1) % of dose excreted as total 14C (unchanged drug) in fecesd 59 (47) 85 (26) a When taken orally with a high-fat meal versus fasted, the AUC(0-inf) (geometric mean ratio [90% CI] of cabotegravir and rilpivirine are 1.14 [1.02, 1.28] and 1.72 [1.36, 2.16]), respectively. b The clinical relevance of CSF-to-plasma concentration ratios is unknown. Concentrations were measured at steady-state one week after administration of cabotegravir and rilpivirine extended-release injectable suspensions given monthly or every 2 months. c Elimination half-life driven by slow absorption rate from the injection site. d Dosing in mass balance studies: single-dose oral administration of [14C] cabotegravir; single-dose oral administration of [14C] rilpivirine. BLQ = Below limit of quantification. 

Table 7. Pharmacokinetic Parameters following Once-Daily Oral Cabotegravir and Rilpivirine and following Initiation and Monthly Continuation Intramuscular Injections of the Components of CABENUVA 

Drug Dosing Phase 

Dosage Regimen 

Geometric Mean (5th, 95th Percentile)a AUC(0-tau)b (mcg•h/mL) Cmax (mcg/mL) Ctau (mcg/mL) 

Cabotegravir 

Oral Lead-Inc 

30 mg  once daily 

145 (93.5, 224) 

8.0 (5.3, 11.9) 

4.6 (2.8, 7.5) 

Initial Injectiond 

600 mg IM initial dose 

1,591 (714, 3,245) 

8.0 (5.3, 11.9) 

1.5 (0.65, 2.9) 

Monthly Injectione 

400 mg IM monthly 

2,415 (1,494, 3,645) 

4.2 (2.5, 6.5) 

2.8 (1.7, 4.6) 

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Drug Dosing Phase 

Dosage Regimen 

Geometric Mean (5th, 95th Percentile)a AUC(0-tau)b (ng•h/mL) Cmax (ng/mL) Ctau (ng/mL) 

Rilpivirine 

Oral Lead-Inb,f 

25 mg  once daily 

2,083 (1,125, 3,748) 

116 (48.6, 244) 

78.9 (32.2, 180) 

Initial Injectiond 

900 mg IM initial dose 

41,069  (20,062, 76,855) 

139 (87.6, 219) 

37.2 (19.4, 69.2) 

Monthly Injectione 

600 mg IM monthly 

65,603 (37,239, 113,092) 

116 (66.8, 199) 

82.2 (47.5, 140) a Pharmacokinetic parameter values based on individual post-hoc estimates from separate cabotegravir and rilpivirine population pharmacokinetic models (pooled FLAIR and ATLAS, n = 581), except for oral rilpivirine (see footnote e). b tau is dosing interval: 24 hours for oral cabotegravir and rilpivirine; 1 month for cabotegravir and rilpivirine extended-release injectable suspensions. c Oral lead-in pharmacokinetic parameter values represent steady-state. d Initial injection AUC(0-tau) and Cmax values primarily reflect values following oral dosing because the initial injection was administered on the same day as the last oral dose; however, the Ctau value at Week 4 reflects the initial injection. e Monthly injection pharmacokinetic parameter values represent Week 48 data. f Oral rilpivirine: AUC(0-tau) based on population pharmacokinetic estimates of rilpivirine 25 mg once daily from pooled Phase 3 trials with EDURANT (rilpivirine); Ctau based on observed data from FLAIR and ATLAS; Cmax based on observed data for rilpivirine 25 mg once daily from a pharmacokinetic substudy in pooled Phase 3 trials with EDURANT. IM = Intramuscular. Specific Populations No clinically significant differences in the pharmacokinetics of cabotegravir or rilpivirine were observed based on age, sex, race/ethnicity, body mass index, or UGT1A1 polymorphisms. The effect of hepatitis B and C virus co-infection on the pharmacokinetics of cabotegravir is unknown. No clinically relevant differences in the pharmacokinetics of oral rilpivirine have been observed with hepatitis B and/or C virus co-infection. The pharmacokinetics of cabotegravir (oral or injectable) and of injectable rilpivirine have not been studied in pediatric patients and data are limited in subjects aged 65 years or older [see Use in Specific Populations (8.4, 8.5)]. Patients with Renal Impairment: With oral cabotegravir, no clinically significant differences in the pharmacokinetics of cabotegravir are expected in patients with mild, moderate, or severe renal impairment. Cabotegravir has not been studied in patients with end-stage renal disease not on dialysis. 

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As cabotegravir is greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir [see Use in Specific Populations (8.6)]. Population pharmacokinetic analyses indicated that mild renal impairment had no clinically relevant effect on the exposure of oral rilpivirine. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment, or end-stage renal disease not on dialysis. As rilpivirine is greater than 99% protein bound, dialysis is not expected to alter exposures of rilpivirine [see Use in Specific Populations (8.6)]. Patients with Hepatic Impairment: No clinically significant differences in the pharmacokinetics of cabotegravir are expected in mild to moderate (Child-Pugh A or B) hepatic impairment. The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir has not been studied [see Use in Specific Populations (8.7)]. No clinically significant differences in the pharmacokinetics of rilpivirine were observed in mild to moderate (Child-Pugh A or B) hepatic impairment. The effect of severe hepatic impairment (Child-Pugh C) has not been studied [see Use in Specific Populations (8.7)]. Drug Interaction Studies Cabotegravir is not a clinically relevant inhibitor of the following enzymes and transporters: CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B15, and 2B17; P-glycoprotein (P-gp); breast cancer resistance protein (BCRP); bile salt export pump (BSEP); organic cation transporter (OCT)1, OCT2; organic anion transporter polypeptide (OATP)1B1, OATP1B3; multidrug and toxin extrusion transporter (MATE) 1, MATE 2-K; multidrug resistance protein (MRP)2 or MRP4. In vitro, cabotegravir inhibited renal OAT1 (IC50 = 0.81 microM) and OAT3 (IC50 = 0.41 microM). Based on physiologically based pharmacokinetic (PBPK) modeling, cabotegravir may increase the AUC of OAT1/3 substrates up to approximately 80%. In vitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Simulations using PBPK modeling show that no clinically significant interaction is expected during coadministration of cabotegravir with drugs that inhibit UGT1A1. In vitro, cabotegravir was not a substrate of OATP1B1, OATP1B3, or OCT1. Cabotegravir is a substrate of P-gp and BCRP in vitro; however, because of its high permeability, no alteration in cabotegravir absorption is expected with coadministration of P-gp or BCRP inhibitors. Rilpivirine is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes. Drug interaction studies were not conducted with injectable cabotegravir or injectable rilpivirine. Drug interaction studies with oral cabotegravir or oral rilpivirine are summarized in Tables 8, 9, 10, and 11. 

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Table 8. Effect of Coadministered Drugs on the Pharmacokinetics of Cabotegravir 

Coadministered Drug(s) and Dose(s) 

Dose of Cabotegravir n 

Geometric Mean Ratio (90% CI) of Cabotegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 Cmax AUC C? or C24 

Etravirine  200 mg twice daily 

30 mg once daily 

12 1.04  (0.99, 1.09) 

1.01  (0.96, 1.06) 

1.00  (0.94, 1.06) 

Rifabutin  300 mg once daily 

30 mg once daily 

12 0.83 (0.76, 0.90) 

0.77 (0.74, 0.83) 

0.74 (0.70, 0.78) 

Rifampin  600 mg once daily 

30-mg single dose 

15 0.94  (0.87, 1.02) 

0.41  (0.36, 0.46) 

0.50 (0.44, 0.57) 

Rilpivirine  25 mg once daily 

30 mg once daily 

11 1.05 (0.96, 1.15) 

1.12  (1.05, 1.19) 

1.14  (1.04, 1.24) CI = Confidence Interval; n = Maximum number of subjects with data; NA = Not available. 

Table 9. Effect of Coadministered Drugs on the Pharmacokinetics of Rilpivirine 

Coadministered Drug(s) and Dose(s) 

Dose of Rilpivirine n 

Geometric Mean Ratio (90% CI) of Rilpivirine Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 Cmax AUC Cmin 

Acetaminophen 500-mg single dose 

150 mg once dailya 

16 1.09 (1.01 to 1.18) 

1.16 (1.10 to 1.22) 

1.26 (1.16 to 1.38) 

Atorvastatin 40 mg once daily 

150 mg once dailya 

16 0.91 (0.79 to 1.06) 

0.90 (0.81 to 0.99) 

0.90 (0.84 to 0.96) 

Chlorzoxazone 500-mg single dose taken 2 hours after rilpivirine 

150 mg once dailya 

16 1.17 (1.08 to 1.27) 

1.25 (1.16 to 1.35) 

1.18 (1.09 to 1.28) 

Darunavir/ritonavir 800/100 mg once daily 

150 mg  once dailya 

14 1.79 (1.56 to 2.06) 

2.30 (1.98 to 2.67) 

2.78 (2.39 to 3.24) 

Didanosine 400 mg once daily delayed release capsules taken 2 hours before rilpivirine 

150 mg  once dailya 

21 1.00 (0.90 to 1.10) 

1.00 (0.95 to 1.06) 

1.00 (0.92 to 1.09) 

Ethinylestradiol/ Norethindrone 0.035 mg once daily/ 1 mg once daily 

25 mg once daily 

15 ?b ?b ?b 

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8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women 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. While there are insufficient human data to assess the risk of neural tube defects (NTDs) with exposure to CABENUVA during pregnancy, NTDs were associated with dolutegravir, another integrase inhibitor. 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 [see Warnings and Precautions (5.6), Drug Interactions (7.2)]. Cabotegravir use in pregnant women 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 

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birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). 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 Metropolitan Atlanta Congenital Defects Program (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 women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 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 greater than 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 (greater than 28 times or similar to the exposure at the RHD, respectively) given during organogenesis (see Data). 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 (see Data). 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 [see Warnings and Precautions (5.6)]. Data Human Data: Cabotegravir: Data from an observational study in Botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of NTDs when administered at the time of conception and in early pregnancy. Data from clinical trials are insufficient to address this risk with cabotegravir. Rilpivirine: Based on prospective reports to the APR of over 390 exposures to oral rilpivirine-containing regimens during the first trimester of pregnancy and over 170 during second/third trimester of pregnancy, the prevalence of birth defects in live births was 1.3% (95% CI: 0.4% to 3.0%) and 1.1% (95% CI: 0.1% to 4.0%) 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 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 

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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 (greater than 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 (greater than 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. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known if the components of CABENUVA are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rats, cabotegravir and rilpivirine were present in milk (see Data). If cabotegravir and/or rilpivirine are present in human milk, residual exposures may remain for 12 months or longer after the last injections have been administered [see Warnings and Precautions (5.6)]. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), (3) adverse reactions in a breastfed infant similar to those seen in adults, and (4) detectable cabotegravir and rilpivirine concentrations in systemic circulation for up to 12 

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months or longer after discontinuing injections of CABENUVA, instruct mothers not to breastfeed if they are receiving CABENUVA. Data Animal 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.  Rilpivirine: Animal lactation studies with rilpivirine have not been conducted. However, rilpivirine was detected in the plasma of nursing pups on Lactation Day 7 in the rat pre- and postnatal development study. 8.4 Pediatric Use The safety and efficacy of CABENUVA have not been evaluated in pediatric patients. 8.5 Geriatric Use Clinical trials of CABENUVA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. 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 (12.3)]. 8.6 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 greater than or equal to 60 to less than 90 mL/min) or moderate renal impairment (creatinine clearance greater than or equal to 30 to less than 60 mL/min). In patients with severe renal impairment (creatinine clearance 15 to less than 30 mL/min) or end-stage renal disease (creatinine clearance less than 15 mL/min), increased monitoring for adverse effects is recommended [see Clinical Pharmacology (12.3)]. In patients with end-stage renal disease not on dialysis, effects on the pharmacokinetics of cabotegravir or rilpivirine are unknown. As cabotegravir and rilpivirine are greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir or rilpivirine. 8.7 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 [see Clinical Pharmacology (12.3)]. 

10 OVERDOSAGE There is no known specific treatment for overdose with cabotegravir or rilpivirine. If overdose occurs, monitor the patient and apply standard supportive treatment as required, including monitoring of vital 

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signs and ECG (QT interval) as well as observation of the clinical status of the patient. As both cabotegravir and rilpivirine are highly bound to plasma proteins, it is unlikely that either would be significantly removed by dialysis. Consider the prolonged exposure to cabotegravir and rilpivirine (components of CABENUVA) following an injection when assessing treatment needs and recovery [see Warnings and Precautions (5.6)]. 

11 DESCRIPTION CABENUVA contains cabotegravir extended-release injectable suspension, an HIV INSTI, co-packaged with rilpivirine extended-release injectable suspension, an HIV NNRTI. Cabotegravir: The chemical name for cabotegravir is (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8carboxamide