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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
CABENUVA KIT (NDA-212888)
(CABOTEGRAVIR; RILPIVIRINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
04/11/2025 (SUPPL-16)
5 Warnings and Precautions
5.1 Hypersensitivity ReactionsAdditions and/or revisions underlined:
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) [see Adverse Reactions (6.2)]. Reactions associated with rilpivirine-containing regimens include cases of drug reaction with eosinophilia and systemic symptoms (DRESS) [see Adverse Reactions (6.1, 6.2)]. 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.
…
6 Adverse Reactions
6.2 Postmarketing ExperienceAdditions and/or revisions underlined:
…
Skin and Subcutaneous Tissue Disorders
Severe skin and hypersensitivity reactions, including DRESS, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) [see Warnings and Precautions (5.1)].
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
…
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 Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) or drug reaction with eosinophilia and systemic symptoms (DRESS): 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)].
09/20/2024 (SUPPL-15)
6 Adverse Reactions
6.1 Clinical Trials ExperienceAdditions and/or revisions underlined:
…
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 greater than or equal to 35 kg) was consistent with the safety profile established with cabotegravir plus rilpivirine in adults [see Clinical Studies (14.2)].
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 equal or less than 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).
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
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 [see Clinical Studies (14.1)]
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) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].
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 [see Adverse Reactions (6.1)]. 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 [see Clinical Pharmacology (12.3), Clinical Studies (14.2)].
The safety, efficacy, and pharmacokinetics of CABENUVA have not been established in pediatric patients younger than 12 years of age or weighing <35 kg.
12/13/2023 (SUPPL-11)
5 Warnings and Precautions
5.1 Hypersensitivity Reactions
(Additions and/or revisions underlined)
Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and during postmarketing experience with rilpivirine-containing regimens where reactions include cases of drug reaction with eosinophilia and systemic symptoms (DRESS) [see Adverse Reactions (6.1, 6.2)]. 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…
5.4 Depressive Disorders
(Additions and/or revisions underlined)
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 [see Adverse Reactions (6.1)]…
6 Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions underlined)
Clinical Trials Experience in Adults
…
Psychiatric Disorders: Anxiety (including anxiety and irritability), depression, abnormal dreams.; suicidal ideation, and suicide attempt (these events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness).
…
8 Use in Specific Populations
8.2 Lactation
(Additions and/or revisions underlined)
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 (see Data). 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 [see Warnings and Precautions (5.6)].
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
Advise the patient to read the FDA-approved patient labeling (Patient Information).
…
Depressive Disorders
Inform patients that depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, unusual mood, negative thoughts, suicidal ideation, suicide attempt) have been reported with at least one of the components of CABENUVA. Advise patients to seek prompt medical evaluation if they experience depressive symptoms [see Warnings and Precautions (5.4), Adverse Reactions (6.1)].
…
Lactation
Inform individuals with HIV-1 infection that the 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 [see Use in Specific Populations (8.2)].
02/27/2023 (SUPPL-8)
6 Adverse Reactions
6.2 Postmarketing ExperienceAdditions and revisions underlined:
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) [see Warnings and Precautions (5.1)].
Renal and Genitourinary Disorders
Nephrotic Syndrome.
Skin and Subcutaneous Tissue Disorders
Severe skin and hypersensitivity reactions, including DRESS [see Warnings and Precautions (5.1)].
03/29/2022 (SUPPL-5)
6 Adverse Reactions
6.1 Clinical Trials ExperienceAdditions underlined
…
Clinical Trial Experience in Adolescents
Based on data from the Week 16 analysis of the MOCHA study in 23 adolescents (aged 12 to younger than 18 years and weighing ?35 kg) receiving background antiretroviral therapy, the safety profile in adolescents with the addition of either oral cabotegravir followed by injectable cabotegravir (n = 8) or oral rilpivirine (n = 15) followed by injectable rilpivirine (n = 13) was consistent with the safety profile established with cabotegravir plus rilpivirine in adults. Adverse reactions were reported in 61% of adolescent subjects receiving either cabotegravir or rilpivirine. The majority of these subjects (86%) had a Grade 1 or Grade 2 adverse reaction. The adverse reactions reported by more than one subject (regardless of severity) were injection site pain
(n = 13) and insomnia (n = 2). Two subjects had Grade 3 adverse reactions of hypersensitivity (n = 1) and insomnia (n = 1). The Grade 3 adverse reaction of drug hypersensitivity led to discontinuation of rilpivirine during oral lead-in. Sixty-two percent of subjects who received at least 1 injection of cabotegravir or rilpivirine reported at least 1 ISR. All ISRs were Grade 1 or Grade 2.
…
8 Use in Specific Populations
8.4 Pediatric UseSubsection revised, additions and/or revisions underlined
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 [see Clinical Studies (14.1)]
MOCHA (NCT03497676) trial in adolescents MOCHA Trial
The safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing Phase 1/2 multicenter, open-label,
non-comparative study, MOCHA (IMPAACT 2017). Data are available from the Week 16 interim analysis from MOCHA. The primary objective at Week 16 was to confirm the use of the adult dose, through the evaluation of safety and pharmacokinetics, for oral and injectable cabotegravir and injectable rilpivirine in HIV-1–infected virologically suppressed adolescents.
Twenty-three HIV-1–infected and virologically suppressed adolescents aged 12 to younger than 18 years and weighing at least 35 kg were assigned to 1 of 2 cohorts, 1C or 1R, based on their background antiretroviral regimen. In cohort 1C, participants (n = 8) received one 30-mg cabotegravir tablet daily for 1 month, followed by monthly cabotegravir injections (Month 1: 600-mg injection, Months 2 and 3: 400-mg injection) for an additional 3 months, while continuing background antiretroviral therapy. In cohort 1R, participants received one 25-mg rilpivirine tablet (n = 15) daily for 1 month, followed by monthly rilpivirine injections (n = 13) (Month 1: 900-mg injection, Months 2 and 3: 600-mg injection) for an additional 3 months, while continuing background antiretroviral therapy.
At baseline, in cohort 1C, the median age of participants was 14.5 years; the median weight was57.2 kg (range: 43.0, 73.5); 25% were female; 100% were non-White; and no participant had a CD4+ cell count <350 cells per mm3. At baseline, median CD4+ cell count was 725 cells per mm3 (range: 629 to 924). In cohort 1R, the median age of participants was 17 years; the median weight was 63.0 kg (range: 44.1, 98.5); 53% were female; 73% were non-White; and no participant had a CD4+ cell count <350 cells per mm3. At baseline, median CD4+ cell count was 827 cells per mm3 (range: 439 to 1,509).
The safety of CABENUVA in adolescents is expected to be similar to adults, as there was no clinically significant difference in drug exposure for the components of CABENUVA [see Adverse Reactions (6.1)]. The efficacy of CABENUVA in adolescents is extrapolated from adults with support from pharmacokinetic analyses showing similar drug exposure [see Clinical Pharmacology (12.3)]. The safety, efficacy, and pharmacokinetics of CABENUVA have not been established in pediatric patients younger than 12 years of age or weighing <35 kg.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONAdditions underlined
CABENUVA is a prescription medicine that is used without other human immunodeficiency virus-1 (HIV-1) medicines to treat HIV-1 infection in people 12 years of age and older who weigh at least 77 pounds (35 kg) to replace their current HIV-1 medicines when their healthcare provider determines that they meet certain requirements.
…
It is not known if CABENUVA is safe and effective in children younger than 12 years of age or weighing less than 77 pounds (35 kg).
…03/29/2022 (SUPPL-6)
6 Adverse Reactions
6.1 Clinical Trials ExperienceAdditions underlined
…
Clinical Trial Experience in Adolescents
Based on data from the Week 16 analysis of the MOCHA study in 23 adolescents (aged 12 to younger than 18 years and weighing ?35 kg) receiving background antiretroviral therapy, the safety profile in adolescents with the addition of either oral cabotegravir followed by injectable cabotegravir (n = 8) or oral rilpivirine (n = 15) followed by injectable rilpivirine (n = 13) was consistent with the safety profile established with cabotegravir plus rilpivirine in adults. Adverse reactions were reported in 61% of adolescent subjects receiving either cabotegravir or rilpivirine. The majority of these subjects (86%) had a Grade 1 or Grade 2 adverse reaction. The adverse reactions reported by more than one subject (regardless of severity) were injection site pain
(n = 13) and insomnia (n = 2). Two subjects had Grade 3 adverse reactions of hypersensitivity (n = 1) and insomnia (n = 1). The Grade 3 adverse reaction of drug hypersensitivity led to discontinuation of rilpivirine during oral lead-in. Sixty-two percent of subjects who received at least 1 injection of cabotegravir or rilpivirine reported at least 1 ISR. All ISRs were Grade 1 or Grade 2.
…
8 Use in Specific Populations
8.4 Pediatric UseSubsection revised, additions and/or revisions underlined
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 [see Clinical Studies (14.1)]
MOCHA (NCT03497676) trial in adolescents MOCHA Trial
The safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine are being assessed in an ongoing Phase 1/2 multicenter, open-label,
non-comparative study, MOCHA (IMPAACT 2017). Data are available from the Week 16 interim analysis from MOCHA. The primary objective at Week 16 was to confirm the use of the adult dose, through the evaluation of safety and pharmacokinetics, for oral and injectable cabotegravir and injectable rilpivirine in HIV-1–infected virologically suppressed adolescents.
Twenty-three HIV-1–infected and virologically suppressed adolescents aged 12 to younger than 18 years and weighing at least 35 kg were assigned to 1 of 2 cohorts, 1C or 1R, based on their background antiretroviral regimen. In cohort 1C, participants (n = 8) received one 30-mg cabotegravir tablet daily for 1 month, followed by monthly cabotegravir injections (Month 1: 600-mg injection, Months 2 and 3: 400-mg injection) for an additional 3 months, while continuing background antiretroviral therapy. In cohort 1R, participants received one 25-mg rilpivirine tablet (n = 15) daily for 1 month, followed by monthly rilpivirine injections (n = 13) (Month 1: 900-mg injection, Months 2 and 3: 600-mg injection) for an additional 3 months, while continuing background antiretroviral therapy.
At baseline, in cohort 1C, the median age of participants was 14.5 years; the median weight was57.2 kg (range: 43.0, 73.5); 25% were female; 100% were non-White; and no participant had a CD4+ cell count <350 cells per mm3. At baseline, median CD4+ cell count was 725 cells per mm3 (range: 629 to 924). In cohort 1R, the median age of participants was 17 years; the median weight was 63.0 kg (range: 44.1, 98.5); 53% were female; 73% were non-White; and no participant had a CD4+ cell count <350 cells per mm3. At baseline, median CD4+ cell count was 827 cells per mm3 (range: 439 to 1,509).
The safety of CABENUVA in adolescents is expected to be similar to adults, as there was no clinically significant difference in drug exposure for the components of CABENUVA [see Adverse Reactions (6.1)]. The efficacy of CABENUVA in adolescents is extrapolated from adults with support from pharmacokinetic analyses showing similar drug exposure [see Clinical Pharmacology (12.3)]. The safety, efficacy, and pharmacokinetics of CABENUVA have not been established in pediatric patients younger than 12 years of age or weighing <35 kg.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONAdditions underlined
CABENUVA is a prescription medicine that is used without other human immunodeficiency virus-1 (HIV-1) medicines to treat HIV-1 infection in people 12 years of age and older who weigh at least 77 pounds (35 kg) to replace their current HIV-1 medicines when their healthcare provider determines that they meet certain requirements.
…
It is not known if CABENUVA is safe and effective in children younger than 12 years of age or weighing less than 77 pounds (35 kg).
…03/23/2022 (SUPPL-3)
5 Warnings and Precautions
5.1 Hypersensitivity ReactionsAdditions and/or revisions underlined:
… Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.3), Contraindications (4)]. Remain vigilant and discontinue CABENUVA if a hypersensitivity reaction is suspected.
6 Adverse Reactions
6.1 Clinical Trials ExperienceAdditions and/or revisions underlined:
… 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 subjects in the group receiving CABENUVA and 2% of subjects in the control group in FLAIR and ATLAS discontinued due to adverse events …
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or revisions underlined:
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 injection visit and that oral therapy with VOCABRIA and EDURANT may be used up to 2 months to replace missed injection visits, or any other fully suppressive oral antiretroviral regimen may be used until injections are resumed. 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 (2.2, 2.8), Warnings and Precautions (5.6)].
01/31/2022 (SUPPL-1)
5 Warnings and Precautions
5.1 Hypersensitivity Reactions
Additions and/or revisions for references have been underlined:
… Administer oral lead-in dosing prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction [see Dosage and Administration (2.3), Contraindications (4)].
5.2 Post-Injection Reactions
Additions and/or revisions underlined:
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 less than 1% of subjects 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 [see Adverse Reactions (6.1)].
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 [see Dosage and Administration (2.9)].
5.5 Risk of Adverse Reactions or Loss of Virological Response Due to Drug Interactions
Additions and/or revisions underlined:
… Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times the recommended oral dosage) in healthy adults prolonged the QTc interval with mean steady-state Cmax values 4.4- and 11.6-fold 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 higher than Cmax values associated with the recommended 900-mg every-2-month dose of rilpivirine extended-release injectable suspension [see Clinical Pharmacology (12.2)] …
… 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 [see Drug Interactions (7.4)].
5.6 Long-Acting Properties and Potential Associated Risks with CABENUVA
Additions and/or revisions underlined:
… 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 [see Dosage and Administration (2.2), Adverse Reactions (6.1), Drug Interactions (7.4)].
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.
6 Adverse Reactions
Table 6. Injection Site Reactions (Grades 1 to 3) Reported in at Least 1% of Subjects in FLAIR and ATLAS (Pooled Analysis) and ATLAS-2M Trials (Week 48 Analysis) (Newly added table; please refer to label for complete information).
Anesthesia, abscess, cellulitis, and hemorrhage at the injection site were each reported in <1% of subjects.
Other Injection-Associated Adverse Reactions: In the ATLAS and FLAIR clinical trials, an increased incidence of pyrexia (8%) was reported by subjects receiving cabotegravir plus rilpivirine injections compared with no events among subjects 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 subject in each arm reported pyrexia which led to withdrawal.
In ATLAS and FLAIR, reports of musculoskeletal pain (3%) and less frequently, sciatica, were also more common in subjects receiving cabotegravir plus rilpivirine compared with the current antiretroviral regimen and some events had a temporal association with injection.
Weight Increase
Additions and/or revisions underlined:
… In the FLAIR trial, the median weight gain in subjects 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 in the ATLAS trial in subjects 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, subjects 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.
Table 7. Selected Laboratory Abnormalities (Grades 3 to 4, Week 48) in FLAIR and ATLAS (Pooled Analyses) and ATLAS-2M Trials
Additions and/or revisions underlined:
… The safety assessment of CABENUVA is based on the analysis of pooled 48-week data from 1,182 virologically suppressed subjects with HIV-1 infection in 2 international, multicenter, open-label pivotal trials, FLAIR and ATLAS, and 1,045 virologically suppressed subjects from the ATLAS-2M trial [see Clinical Studies (14.1)] …
… 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) …
… 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 greater than or equal to 2% of adult subjects from FLAIR and ATLAS are presented in Table 5. Selected laboratory abnormalities are included in Table 7.
Overall, 4% of subjects in the group receiving CABENUVA and 2% of subjects 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 subject were headache, diarrhea, hepatitis A, and acute hepatitis B (all with an incidence <1%). In ATLAS-2M, 2% of subjects in both treatment groups discontinued due to adverse events. Non-injection-site–related adverse events leading to discontinuation and occurring in more than 1 subject in ATLAS-2M were fatigue, pyrexia, headache, presyncope, acute hepatitis B, hyperhidrosis, and abnormal dreams that occurred with an incidence of less than or equal to 1% in either treatment group.
Table 5. Adverse Reactions (Grades 1 to 4) Reported in at Least 2% of Subjects 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 subjects 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 subjects reported any injection site reaction with the monthly dosing regimen, with 1% of subjects 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 subjects) or moderate (Grade 2: 36% of subjects). Four percent (4%) subjects experienced severe (Grade 3) ISRs, and no subject 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 subjects reported any injection site reaction in both the monthly and every-2-month dosing regimens, with <1% of subjects 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 subjects) or moderate (Grade 2: 28% and 27% of subjects) in monthly and every-2-month dosing regimens, respectively. Four percent (4%) subjects in the monthly group and 3% of subjects in the every-2-month group experienced severe (Grade 3) ISRs, and no subject 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 subjects without prior exposure to CABENUVA.
The most commonly reported ISR (Grades 1 to 3) in at least 1% of adult subjects 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.
7 Drug Interactions
7.3 Potential for Other Drugs to Affect CABENUVA
Additions and/or revisions underlined:
Refer to the prescribing information for VOCABRIA (cabotegravir) and EDURANT (rilpivirine) for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively …
7.4 Established and Other Potentially Significant Drug Interactions
Additions and/or revisions underlined:
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.
Table 8. Drug Interactions with CABENUVA
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
The safety and efficacy of CABENUVA have not been established in pediatric patients.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdverse Reactions Following Injections
Additions and/or revisions underlined:
… Serious post-injection reactions were reported within minutes after the injection of rilpivirine, including dyspnea, bronchospasm, agitation, abdominal cramping, rash/urticaria, dizziness, flushing, sweating, oral numbness, changes in blood pressure, and back pain (e.g., back and chest). These events began to resolve within minutes after the injection.
Newly added information following Adherence to CABENUVA:
Two Options for Dosing Frequency
Advise the patient that CABENUVA can be injected monthly or every 2 months after oral lead-in with cabotegravir and rilpivirine to assess tolerability. Discuss the two injection dosing frequency options with the patient prior to starting CABENUVA and decide which injection dosing frequency would be the most appropriate option for the patient [see Dosage and Administration (2.1)].
Missed Dose
Additions and/or revisions underlined:
… 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 (2.2, 2.8), Warnings and Precautions (5.6)].
Additions and/or revisions underlined:
How will I receive CABENUVA?
You will receive CABENUVA as 2 injections (cabotegravir and rilpivirine), either one time every month or one time every 2 months.
What are the possible side effects of CABENUVA?
CABENUVA may cause serious side effects including:
Post-injection reactions. Post-injection reaction symptoms have happened within minutes in some people after receiving their rilpivirine injection. Most symptoms resolved within minutes after the injection. Symptoms of post-injection reactions may include:
Newly added information:
narrowing of airways
pain (e.g., back and chest)
rash