FDA Approves Cabenuva and Vocabria for the Treatment of HIV-1 Infection

FDA approved CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use. This is the first FDA-approved injectable, complete regimen for HIV-1 infected adults that is administered once a month. FDA also approved VOCABRIA (cabotegravir) 30 mg tablets which should be taken in combination with oral rilpivirine (EDURANT) for one month prior to starting treatment with Cabenuva to ensure the medications are well-tolerated before switching to the extended-release injectable formulation. Additionally, changes to the EDURANT (rilpivirine) tablet label was revised to reflect the oral lead-in recommendations for use with VOCABRIA. VOCABRIA is a human immunodeficiency virus type-1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with EDURANT (rilpivirine) for short-term treatment of HIV-1 infection in adults who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as: oral lead-in to assess the tolerability of cabotegravir prior to administration of CABENUVA (cabotegravir; rilpivirine) extended-release injectable suspensions. oral therapy for patients who will miss planned injection dosing with CABENUVA. 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. Dosing and Administration: The recommended dosing is as follows: The recommended oral lead-in daily dose is one 30-mg tablet of VOCABRIA (cabotegravir) and one 25-mg tablet of EDURANT (rilpivirine). Intramuscular Injection Dosing with CABENUVA Initiation Injections (CABENUVA 600-mg/900-mg Kit) Initiate injections on the last day of oral lead-in. CABENUVA contains cabotegravir and rilpivirine extended-release injectable suspensions. The recommended initial injection doses of CABENUVA in adults are a single 600-mg (3-mL) gluteal intramuscular injection of cabotegravir and a single 900-mg (3-mL) gluteal intramuscular injection of rilpivirine. Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or 2 cm apart) during the same visit. Continuation injections should be initiated a month after the initiation injections. Continuation Injections (CABENUVA 400-mg/600-mg Kit) After the initiation injections, the recommended monthly continuation injection doses of CABENUVA in adults are a single 400-mg (2-mL) gluteal intramuscular injection of cabotegravir and a single 600‑mg (2-mL) gluteal intramuscular injection of rilpivirine at each visit. Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or 2 cm apart) during the same visit. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive monthly injections. Missed Injections Adherence to the monthly injection dosing schedule is strongly recommended. Patients who miss a scheduled injection visit should be clinically reassessed to ensure resumption of therapy remains appropriate. Planned Missed Injections (Oral Dosing to Replace Up to 2 Consecutive Monthly Injections) If a patient plans to miss a scheduled injection visit by more than 7 days, take daily oral therapy to replace up to 2 consecutive monthly injection visits. The recommended oral daily dose is one 30-mg tablet of VOCABRIA (cabotegravir) and one 25-mg tablet of EDURANT (rilpivirine). The first dose of oral therapy should be taken approximately 1 month after the last injection dose of CABENUVA and continued until the day injection dosing is restarted. Unplanned Missed Injections If monthly injections are missed or delayed by more than 7 days and oral therapy has not been taken in the interim, clinically reassess the patient to determine if resumption of injection dosing remains appropriate Injection Dosing Recommendations after Missed Injections Less than or equal to 2 months since last injection: Resume with 400-mg (2-mL) cabotegravir and 600-mg (2-mL) rilpivirine intramuscular monthly injections as soon as possible. Greater than 2 months since last injection: Re-initiate the patient with 600-mg (3-mL) cabotegravir and 900-mg (3 mL) rilpivirine intramuscular injections then continue to follow the 400 mg (2 mL) cabotegravir and 600-mg (2-mL) rilpivirine intramuscular monthly injection dosing schedule  Summary of Clinical Studies: The efficacy of CABENUVA has been evaluated in two Phase 3 randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials: Trial 201584 (FLAIR, [NCT02938520]), (n = 629): HIV-1–infected, antiretroviral treatment (ART)-naive subjects received a dolutegravir INSTI-containing regimen for 20 weeks (either dolutegravir/abacavir/lamivudine or dolutegravir plus 2 other NRTIs if subjects were HLA-B*5701 positive). Subjects who were virologically suppressed (HIV-1 RNA less than 50 copies/mL, n = 566) were then randomized (1:1) to receive either a cabotegravir plus rilpivirine regimen or remain on the current antiretroviral regimen. Subjects randomized to receive cabotegravir plus rilpivirine initiated treatment with daily oral lead-in dosing with one 30-mg VOCABRIA (cabotegravir) tablet plus one 25-mg EDURANT (rilpivirine) tablet for at least 4 weeks followed by monthly injections with CABENUVA for an additional 44 weeks. Trial 201585 (ATLAS, [NCT02951052]), (n = 616): HIV-1–infected, ART-experienced, virologically-suppressed (for at least 6 months; median prior treatment duration was 4.3 years) subjects (HIV-1 RNA less than 50 copies/mL) were randomized and received either a cabotegravir plus rilpivirine regimen or remained on their current antiretroviral regimen. Subjects randomized to receive cabotegravir plus rilpivirine initiated treatment with daily oral lead-in dosing with one 30-mg VOCABRIA (cabotegravir) tablet plus one 25-mg EDURANT (rilpivirine) tablet for at least 4 weeks followed by monthly injections with CABENUVA for an additional 44 weeks. The primary analysis was conducted after all subjects completed their Week 48 visit or discontinued the trial prematurely. The primary endpoint of FLAIR and ATLAS was the proportion of subjects with plasma HIV-1 RNA greater than or equal to 50 copies/mL at Week 48. In FLAIR the proportion of subjects with HIV-1 RNA > 50 copies/mL was 2% for each cabotegravir plus rilpivirine arm and the remained on current antiretroviral regimen arm [treatment difference -0.4% (95% CI: -2.8%, 2.1%). In ATLAS the proportion of subjects with HIV-1 RNA > 50 copies/mL was 2% for the cabotegravir plus rilpivirine arm and 1% for remained on current antiretroviral regimen arm [treatment difference -0.7% (95% CI: -1.2%, 2.5%). CONTRAINDICATIONS CABENUVA is contraindicated in patients: with previous hypersensitivity reaction to cabotegravir or rilpivirine receiving the following coadministered drugs for which significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur due to uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 and/or cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response o          Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin o          Antimycobacterials: Rifabutin, rifampin, rifapentine o          Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) o          Herbal product: St John's wort (Hypericum perforatum) Summary of WARNINGS AND PRECAUTIONS: Hypersensitivity reactions have been reported with rilpivirine-containing regimens and in association with other integrase inhibitors. Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop. Serious post-injection reactions with rilpivirine were reported. Monitor and treat as clinically indicated. Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine. Monitoring of liver chemistries is recommended. Discontinue CABENUVA if hepatotoxicity is suspected Depressive disorders have been reported with CABENUVA. Immediate medical evaluation is recommended for depressive symptoms. 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. Adverse Reactions: 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. 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. 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.  Please refer to the full prescribing information Manage Subscriptions  |  Unsubscribe All  |  Help This email was sent to ooseims.archieves@blogger.com using GovDelivery Communications Cloud on behalf of: U.S. Food and Drug Administration ·  10903 New Hampshire Ave · Silver Spring, MD ·  20993-0002 ·  1-888-INFO-FDA