CABENUVA SIDE EFFECTS
- Generic Name: cabotegravir; rilpivirine extended-release injectable suspension
- Brand Name: Cabenuva
- Drug Class: HIV, NNRTIs, HIV, Integrase Inhibitors
SIDE EFFECTS
The following adverse reactions are described below and in other sections of the labeling:
- Hypersensitivity reactions
- Post-injection reactions
- Hepatotoxicity
- Depressive disorders
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.
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. 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: 54 weeks) and data from VOCABRIA (cabotegravir) tablets and EDURANT (rilpivirine) tablets administered in combination as oral lead-in therapy (median time exposure: 5.3 weeks). 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 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 in the pooled analyses from FLAIR and ATLAS are presented in Table 1. Selected laboratory abnormalities are included in Table 2.
Overall, 4% of subjects in the group receiving CABENUVA and 2% of subjects in the control group 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 less than 1%).
Table 1. Adverse Reactionsa (Grades 1 to 4) Reported in at Least 2% of Subjects with HIV-1 Infection in FLAIR and ATLAS Trials (Week 48 Pooled Analyses)
| Adverse Reactions | Cabotegravir plus Rilpivirine (n = 591) |
Current Antiretroviral Regimen (n = 591) |
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| All Grades | At Least Grade 2 | All Grades | At Least Grade 2 | |
| Injection site reactionsb | 83% | 37% | 0 | 0 |
| Pyrexiac | 8% | 2% | 0 | 0 |
| Fatigued | 5% | 1% | <1% | <1% |
| Headache | 4% | <1% | <1% | <1% |
| Musculoskeletal paine | 3% | 1% | <1% | 0 |
| Nausea | 3% | <1% | 1% | <1% |
| Sleep disordersf | 2% | <1% | <1% | 0 |
| Dizziness | 2% | <1% | <1% | 0 |
| Rash g | 2% | <1% | 0 | 0 |
| 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. |
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Injection-Associated Adverse Reactions
Local Injection Site Reactions (ISRs)
The most frequent adverse reactions associated with the intramuscular administration of CABENUVA were ISRs. After 14,682 injections, 3,663 ISRs were reported. One percent (1%) of subjects discontinued treatment with CABENUVA because of ISRs. Most ISRs were mild (Grade 1, 75%) or moderate (Grade 2, 36%). Four percent (4%) of subjects experienced severe (Grade 3) ISRs, and no subjects experienced Grade 4 ISRs. The most commonly reported ISR was localized pain/discomfort (79%) regardless of severity or relatedness. Other manifestations of ISRs reported in more than 1% of subjects over the duration of the analysis period included nodules (14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising (3%), warmth (2%), and hematoma (2%). Abscess and cellulitis at the injection site were each reported in less than 1% of subjects. The median duration of ISR events was 3 days.
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. No cases were serious or led to withdrawal and the occurrences of pyrexia may represent a response to administration of CABENUVA via intramuscular injection.
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.
Vasovagal or pre-syncopal reactions were reported in less than 1% of subjects after injection with rilpivirine or cabotegravir.
Less Common Adverse Reactions
The following select adverse reactions (regardless of severity) occurred in less than 2% of subjects 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.
Skin and Hypersensitivity Reactions: Hypersensitivity reactions.
Weight Increase
At Week 48, subjects 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 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.
Laboratory Abnormalities
Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in Table 2.
Table 2. Selected Laboratory Abnormalities (Grades 3 to 4; Week 48 Pooled Analyses) in FLAIR and ATLAS Trials
| Laboratory Parameter | Cabotegravir plus Rilpivirine (n = 591) |
Current Antiretroviral Regimen (n = 591) |
| ALT (≥5.0 x ULN) | 2% | <1% |
| AST (≥5.0 x ULN) | 2% | <1% |
| Total bilirubin (≥2.6 x ULN) | <1% | <1% |
| Creatine phosphokinase (≥10.0 x ULN) | 8% | 4% |
| Lipase (≥3.0 x ULN) | 5% | 3% |
| ULN = Upper limit of normal. | ||
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) micrograms/dL in the group receiving EDURANT compared with -0.02 (-0.48, 0.44) micrograms/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.
Postmarketing Experience
The following adverse reactions have been identified during postmarketing experience in patients receiving an oral rilpivirine-containing regimen. 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.
Renal And Genitourinary Disorders
Nephrotic syndrome.
Skin And Subcutaneous Tissue Disorders
Severe skin and hypersensitivity reactions, including DRESS.
SRC: NLM .