4 )] The most common adverse reactions (Grades 1 to 4) observed in ≥2% of participants receiving CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.
gov/medwatch . 1 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.
1 )] . 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. 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.
Table 5. Adverse Reactions a (Grades 1 to 4) Reported in at Least 2% of Participants with HIV-1 Infection in FLAIR and ATLAS Trials (Week 48 Pooled Analyses) a Adverse reactions defined as “treatment-related” as assessed by the investigator.
b See Injection-Associated Adverse Reactions for additional information. c Pyrexia: includes pyrexia, feeling hot, chills, influenza-like illness, body temperature increased. d Fatigue: includes fatigue, malaise, asthenia. e Musculoskeletal pain: includes musculoskeletal pain, musculoskeletal discomfort, back pain, myalgia, pain in extremity.
f Sleep disorders: includes insomnia, poor quality sleep, somnolence. g Rash: includes erythema, pruritus, pruritus generalized, purpura, rash, rash- erythematous, generalized, macular. Adverse Reactions Cabotegravir plus Rilpivirine Once Monthly (n = 591) Current Antiretroviral Regimen (n = 591) All Grades At Least Grade 2 All Grades At Least Grade 2 Injection site reactions b 83% 37% 0 0 Pyrexia c 8% 2% 0 0 Fatigue d 5% 1% <1% <1% Headache 4% <1% <1% <1% Musculoskeletal pain e 3% 1% <1% 0 Nausea 3% <1% 1% <1% Sleep disorders f 2% <1% <1% 0 Dizziness 2% <1% <1% 0 Rash g 2% <1% 0 0 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.
Table 6. 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) Anesthesia, abscess, cellulitis, and hemorrhage at the injection site were each reported in <1% of participants.
Injection Site Reactions FLAIR and ATLAS ATLAS-2M Cabotegravir plus Rilpivirine Once Monthly (n = 591) Cabotegravir plus Rilpivirine Once Every 2 Months (n = 522) Cabotegravir plus Rilpivirine Once Monthly (n = 523) Any injection site reaction 83% 75% 75% Pain/discomfort 79% 73% 71% Nodules 14% 10% 17% Induration 12% 8% 7% Swelling 8% 6% 5% Erythema 4% 2% 3% Pruritus 4% 5% 5% Bruising/discoloration 3% 2% 2% Warmth 2% 1% 2% Hematoma 2% <1% 3% 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. 0 kg (pooled analysis). 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.
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 ALT = Alanine Aminotransferase, ULN = Upper limit of normal, AST = Aspartate Transaminase. 0 x ULN) 5% 3% 3% 2% Changes in Total Bilirubin: Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed with cabotegravir plus rilpivirine.
3 )]. 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. 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 ≤ 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).
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.
1 )] . Renal and Genitourinary Disorders Nephrotic syndrome. 1 )] .