Cabenuva kit Kit Uses, Dosage & Side Effects

The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of CABENUVA, and possible development of viral resistance [see Contraindications (4), Drug Interactions (7.4)].

Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times, respectively, the recommended oral dosage) in healthy adults prolonged the QTc interval with mean steady-state C_max values 4.4- and 11.6-fold, respectively, higher than C_max values associated with the recommended 600-mg monthly dose of rilpivirine extended-release injectable suspension and 4.1- and 10.7-fold, respectively, higher than C_max values associated with the recommended 900-mg every-2-month dose of rilpivirine extended‑release injectable suspension [see Clinical Pharmacology (12.2)]. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes [see Drug Interactions (7.3, 7.4)].

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)].

The following adverse reactions are described below and in other sections of the labeling:

1. •Hypersensitivity reactions [see Warnings and Precautions (5.1)]
2. •Post-injection reactions [see Warnings and Precautions (5.2)]
3. •Hepatotoxicity [see Warnings and Precautions (5.3)]
4. •Depressive disorders [see Warnings and Precautions (5.4)]

• 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). Reactions associated with rilpivirine-containing regimens include cases of drug reaction with eosinophilia and systemic symptoms (DRESS). Discontinue 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. Prompt 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 injections of CABENUVA when dosed monthly and no later than 2 months after the final injections when dosed every 2 months. If virologic failure is suspected, prescribe an alternative regimen as soon as possible. (5.6) 5.1 Hypersensitivity Reactions

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. 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 [see Contraindications (4), Adverse Reactions (6)].

Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. For information regarding the long-acting properties of CABENUVA, [see Warnings and Precautions (5.6)]. 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

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 <1% of participants 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)]. Observe patients briefly (approximately 10 minutes) after the injection. If a patient experiences a post-injection reaction, monitor and treat as clinically indicated. 5.3 Hepatotoxicity

Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors [see Adverse Reactions (6.1)].

Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations.

Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected. For information regarding the long-acting properties of CABENUVA, [see Warnings and Precautions (5.6)]. 5.4 Depressive Disorders

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)]. Promptly evaluate patients with depressive symptoms to assess whether the symptoms are related to CABENUVA and to determine whether the risks of continued therapy outweigh the benefits. 5.5 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of CABENUVA, and possible development of viral resistance [see Contraindications (4), Drug Interactions (7.4)].

Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times, respectively, the recommended oral dosage) in healthy adults prolonged the QTc interval with mean steady-state Cmax values 4.4- and 11.6-fold, respectively, 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, respectively, 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)]. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes [see Drug Interactions (7.3, 7.4)].

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

Residual concentrations of both cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). 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.

• Refer to full prescribing information for detailed information on dosage and administration recommendations. (2) • Prior to initiating treatment with CABENUVA, oral lead-in dosing may be considered to assess the tolerability of cabotegravir and rilpivirine with the recommended dosage used for approximately 1 month. (2.3) • For gluteal intramuscular injection only. (2.4, 2.5, 2.9) • Recommended Monthly Dosing Schedule: Initiate injections of CABENUVA (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of current antiretroviral therapy or oral lead-in and continue with injections of CABENUVA (400 mg of cabotegravir and 600 mg of rilpivirine) every month thereafter. (2.4) • Recommended Every-2-Month Dosing Schedule: Initiate injections of CABENUVA (600 mg of cabotegravir and 900 mg of rilpivirine) on the last day of current antiretroviral therapy or oral lead-in for 2 consecutive months and continue with injections of CABENUVA every 2 months thereafter. (2.5) 2.1 Dosage and Administration Overview • CABENUVA contains cabotegravir extended-release injectable suspension in a single-dose vial and rilpivirine extended-release injectable suspension in a single-dose vial [see Dosage Forms and Strengths (3)]. • CABENUVA must be administered by a healthcare provider by gluteal intramuscular injection [see Dosage and Administration (2.9)]. • CABENUVA may be initiated with oral cabotegravir and oral rilpivirine prior to the intramuscular injections or the patient may proceed directly to injection of CABENUVA without an oral lead-in [see Dosage and Administration (2.3)]. • CABENUVA can be injected monthly or every 2 months [see Dosage and Administration (2.4, 2.5)]. Healthcare providers should discuss these 2 dosing options with the patient prior to starting CABENUVA and decide which injection dosing frequency would be the most appropriate option for the patient [see Adverse Reactions (6.1), Microbiology (12.4), Clinical Studies (14.1)]. 2.2 Adherence to CABENUVA Prior to starting CABENUVA, healthcare providers should carefully select patients who agree to the required monthly or every‑2-month injection dosing schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance with missed doses [see Dosage and Administration (2.1), Warnings and Precautions (5.6), Microbiology (12.4)]. 2.3 Optional Oral Lead-In Dosing to Assess Tolerability of CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kg The healthcare provider and patient may decide to use an oral lead-in with oral cabotegravir and oral rilpivirine prior to the initiation of CABENUVA to assess the tolerability of cabotegravir and rilpivirine, or the healthcare provider and patient may proceed directly to injection of CABENUVA without the use of an oral lead-in. If oral lead-in is used, the recommended oral lead-in daily dose is one 30-mg tablet of VOCABRIA (cabotegravir) and one 25-mg tablet of EDURANT (rilpivirine) taken with a meal for approximately 1 month (at least 28 days), followed by intramuscular initiation injections of CABENUVA. See Tables 1 and 2 for recommended oral lead-in and monthly or every-2-month intramuscular injection dosing schedule for CABENUVA [see Dosage and Administration (2.4, 2.5)]. 2.4 Recommended Monthly Gluteal Intramuscular Injection Dosing with CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kg Initiation Injections (CABENUVA 600-mg/900-mg Kit) Initiate injections on the last day of current antiretroviral therapy or oral lead-in, if used [see Dosage and Administration (2.3)]. The recommended initiation injection doses of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine. Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit [see Dosage and Administration (2.9)]. 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 are a single 400-mg (2-mL) intramuscular injection of cabotegravir and a single 600-mg (2-mL) intramuscular injection of rilpivirine at each visit (Table 1). Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit [see Dosage and Administration (2.9)]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive monthly injections. Table 1. Recommended Dosing Schedule with Optional Oral Lead-In or Direct to Injection for Monthly Injection a The optional oral therapy should be continued until the day the first injection is administered. b Given on the last day of current antiretroviral therapy or oral lead-in if used. Drug Optional Oral Lead-Ina (at Least 28 Days) Intramuscular (Gluteal) Initiation Injections (One-Time Dosing) Intramuscular (Gluteal) Continuation Injections (Once-Monthly Dosing) Month (at Least 28 Days) Prior to Starting Injections Initiate Injections at Month 1b One Month after Initiation Injection and Monthly Onwards Cabotegravir 30 mg once daily with a meal 600 mg (3 mL) 400 mg (2 mL) Rilpivirine 25 mg once daily with a meal 900 mg (3 mL) 600 mg (2 mL) 2.5 Recommended Every-2-Month Gluteal Intramuscular Injection Dosing with CABENUVA in Adults and Adolescents 12 Years of Age and Older and Weighing at Least 35 kg Initiation Injections (CABENUVA 600-mg/900-mg Kit) Initiate injections on the last day of current antiretroviral therapy or oral lead-in, if used [see Dosage and Administration (2.3)]. The recommended initiation injection doses of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine 1 month apart for 2 consecutive months (Table 2). Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit [see Dosage and Administration (2.9)]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive the second initiation injections. Continuation Injections (CABENUVA 600-mg/900-mg Kit) After the 2 initiation doses given consecutively 1 month apart (Months 1 and 2), the recommended continuation injection doses (Month 4 onwards) of CABENUVA are a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine administered every 2 months (Table 2). Administer cabotegravir and rilpivirine at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit [see Dosage and Administration (2.9)]. Patients may be given CABENUVA up to 7 days before or after the date the patient is scheduled to receive the injections. Table 2. Recommended Dosing Schedule with Optional Oral Lead-In or Direct to Injection for Every-2-Month Injection a The optional oral therapy should be continued until the day the first injection is administered. b For the every-2-month injection dosing schedule in adults, Initiation Injections are injections administered at Month 1 and Month 2 and Continuation Injections are injections administered every 2 months onwards (starting Month 4). c Given on the last day of current antiretroviral therapy or oral lead-in if used. Drug Optional Oral Lead-Ina (at Least 28 Days) Intramuscular (Gluteal) Injectionsb Month (at Least 28 Days) Prior to Starting Injections Initiate Injectionsc at Month 1, Month 2, and then Every 2 Months Onwards (Starting at Month 4) Cabotegravir 30 mg once daily with a meal 600 mg (3 mL) Rilpivirine 25 mg once daily with a meal 900 mg (3 mL) 2.6 Dosing Recommendations When Switching from Monthly to Every-2-Month Intramuscular Injections Patients switching from a monthly continuation injection schedule (a single 400-mg [2-mL] gluteal intramuscular injection of cabotegravir and a single 600-mg [2-mL] intramuscular injection of rilpivirine) to an every-2-month continuation injection dosing schedule should receive a single 600-mg (3-mL) intramuscular injection of cabotegravir and a single 900-mg (3-mL) intramuscular injection of rilpivirine administered 1 month after the last monthly continuation injections and then every 2 months thereafter. Cabotegravir and rilpivirine injections should be administered at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit [see Dosage and Administration (2.9)]. 2.7 Dosing Recommendations When Switching from Every-2-Month to Monthly Intramuscular Injections Patients switching from an every-2-month continuation injection schedule (a single 600-mg [3-mL] intramuscular injection of cabotegravir and a single 900-mg [3-mL] intramuscular injection of rilpivirine) to a monthly continuation dosing schedule should receive a single 400-mg (2-mL) intramuscular injection of cabotegravir and a single 600-mg (2-mL) intramuscular injection of rilpivirine 2 months after the last every-2‑month continuation injection and then monthly thereafter. Cabotegravir and rilpivirine injections should be administered at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit [see Dosage and Administration (2.9)]. 2.8 Recommended Dosing Schedule for Missed Injections Adherence to the injection dosing schedule is strongly recommended [see Dosage and Administration (2.2)]. Patients who miss a scheduled injection visit should be clinically reassessed to ensure resumption of therapy remains appropriate. Refer to Table 3 for dosing recommendations after missed injections. Planned Missed Injections for Patients on the Monthly Dosing Schedule If a patient plans to miss a scheduled injection visit by more than 7 days, VOCABRIA in combination with EDURANT once daily may be used for up to 2 months to replace missed injection visits, or any other fully suppressive oral antiretroviral regimen may be used until injections are resumed. The recommended oral daily dose is one 30-mg tablet of VOCABRIA (cabotegravir) and one 25-mg tablet of EDURANT (rilpivirine). Take VOCABRIA with EDURANT at approximately the same time each day with a meal. The first dose of oral therapy should be taken 1 month (+/-7 days) after the last injection dose of CABENUVA and continued until the day injection dosing is restarted. Refer to Table 3 for injection dosing recommendations. For oral therapy with VOCABRIA and EDURANT of durations greater than 2 months, an alternative oral regimen is recommended. Unplanned Missed Injections for Patients on the Monthly Dosing Schedule 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 [see Warnings and Precautions (5.6)]. If injection dosing will be continued, see Table 3 for dosing recommendations. Table 3. Injection Dosing Recommendations after Missed Injections for Patients on the Monthly Dosing Schedulea a Refer to oral dosing recommendations if a patient plans to miss a scheduled injection visit. Time since Last Injection Recommendation Less than or equal to 2 months Resume with 400-mg (2-mL) cabotegravir and 600-mg (2-mL) rilpivirine gluteal intramuscular monthly injections as soon as possible. Greater than 2 months Re-initiate the patient with 600-mg (3-mL) cabotegravir and 900-mg (3‑mL) rilpivirine gluteal intramuscular injections then continue to follow the 400‑mg (2‑mL) cabotegravir and 600-mg (2-mL) rilpivirine gluteal intramuscular monthly injection dosing schedule. Planned Missed Injections for Patients on the Every-2-Month Dosing Schedule If a patient plans to miss a scheduled injection visit by more than 7 days, VOCABRIA in combination with EDURANT once daily may be used for up to 2 months to replace 1 missed injection visit, or any other fully suppressive oral antiretroviral regimen may be used until injections are resumed. The recommended oral daily dose is one 30‑mg tablet of VOCABRIA (cabotegravir) and one 25‑mg tablet of EDURANT (rilpivirine). Take VOCABRIA with EDURANT at approximately the same time each day with a meal. The first dose of oral therapy should be taken approximately 2 months after the last injection dose of CABENUVA and continued until the day injection dosing is restarted. Refer to Table 4 for injection dosing recommendations. For oral therapy with VOCABRIA and EDURANT of durations greater than 2 months, an alternative oral regimen is recommended. Unplanned Missed Injections for Patients on the Every-2-Month Dosing Schedule If a scheduled every-2-month injection visit is 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 [see Warnings and Precautions (5.6)]. If the every-2‑month dosing schedule will be continued, see Table 4 for dosing recommendations. Table 4. Injection Dosing Recommendations after Missed Injections for Patients on the Every-2-Month Dosing Schedule Missed Injection Visit Time since Last Injection Recommendation Injection 2 (Month 2) Less than or equal to 2 months Resume with 600-mg (3-mL) cabotegravir and 900‑mg (3‑mL) rilpivirine intramuscular injections as soon as possible, then continue to follow the every-2-month injection dosing schedule. Greater than 2 months Re-initiate the patient with 600-mg (3-mL) cabotegravir and 900-mg (3‑mL) rilpivirine intramuscular injections, followed by the second initiation injection dose 1 month later. Then continue to follow the every-2-month injection dosing schedule thereafter. Injection 3 or later (Month 4 onwards) Less than or equal to 3 months Resume with 600-mg (3-mL) cabotegravir and 900‑mg (3‑mL) rilpivirine intramuscular injections as soon as possible and continue with the every‑2‑month injection dosing schedule. Greater than 3 months Re-initiate the patient with 600-mg (3-mL) cabotegravir and 900-mg (3‑mL) rilpivirine intramuscular injections, followed by the second initiation injection dose 1 month later. Then continue with the every-2-month injection dosing schedule thereafter. 2.9 Administration Instructions for Injections Refer to the Instructions for Use for complete administration instructions with illustrations. Carefully follow these instructions and ensure that the vial adaptor is used correctly when preparing the suspension for injection to avoid leakage. A complete dose requires 2 injections: 1 injection of cabotegravir and 1 injection of rilpivirine [see Dosage and Administration (2.4, 2.5)]. Cabotegravir and rilpivirine are suspensions for gluteal intramuscular injection that do not need further dilution or reconstitution. Administer each injection at separate gluteal injection sites (on opposite sides or at least 2 cm apart) during the same visit. The ventrogluteal site is recommended. A dorsogluteal approach (upper outer quadrant) is acceptable, if preferred by the healthcare professional. Do not administer by any other route or anatomical site. Consider the body mass index (BMI) of the patient to ensure that the needle length is sufficient to reach the gluteus muscle. Longer needle lengths (not included in the dosing kit) may be required for patients with higher BMI (example: >30 kg/m2) to ensure that injections are administered intramuscularly as opposed to subcutaneously. The administration order of cabotegravir and rilpivirine injections is not important. Before preparing the injections, remove CABENUVA from the refrigerator and wait at least 15 minutes to allow the medicines to come to room temperature. The vials may remain in the carton at room temperature for up to 6 hours; do not put back into the refrigerator. If not used within 6 hours, the medication must be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The cabotegravir vial has a brown tint to the glass that may limit visual inspection. Discard CABENUVA if either medicine exhibits particulate matter or discoloration. Shake each vial of CABENUVA vigorously so that the suspensions look uniform before injecting. Small air bubbles are expected and acceptable. Once the suspensions have been drawn into the respective syringes, the injections should be administered as soon as possible, but may remain in the syringes for up to 2 hours. The filled syringes should not be placed in the refrigerator. If the medicine remains in the syringes for more than 2 hours, the filled syringes and needles must be discarded [see How Supplied/Storage and Handling (16)].

1. •CABENUVA contains cabotegravir extended-release injectable suspension in a single-dose vial and rilpivirine extended-release injectable suspension in a single-dose vial [see Dosage Forms and Strengths (3)].
2. •CABENUVA must be administered by a healthcare provider by gluteal intramuscular injection [see Dosage and Administration (2.9)].
3. •CABENUVA may be initiated with oral cabotegravir and oral rilpivirine prior to the intramuscular injections or the patient may proceed directly to injection of CABENUVA without an oral lead-in [see Dosage and Administration (2.3)].
4. •CABENUVA can be injected monthly or every 2 months [see Dosage and Administration (2.4, 2.5)]. Healthcare providers should discuss these 2 dosing options with the patient prior to starting CABENUVA and decide which injection dosing frequency would be the most appropriate option for the patient [see Adverse Reactions (6.1), Microbiology (12.4), Clinical Studies (14.1)].

Injection:

1. •Kit of single-dose vials of 400 mg/2 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 600 mg/2 mL (300 mg/mL) of rilpivirine extended-release injectable suspension. (3)
2. •Kit of single-dose vials of 600 mg/3 mL (200 mg/mL) of cabotegravir extended-release injectable suspension and 900 mg/3 mL (300 mg/mL) of rilpivirine extended-release injectable suspension. (3)

The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of CABENUVA, and possible development of viral resistance [see Contraindications (4), Drug Interactions (7.4)].

Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times, respectively, the recommended oral dosage) in healthy adults prolonged the QTc interval with mean steady-state C_max values 4.4- and 11.6-fold, respectively, higher than C_max values associated with the recommended 600-mg monthly dose of rilpivirine extended-release injectable suspension and 4.1- and 10.7-fold, respectively, higher than C_max values associated with the recommended 900-mg every-2-month dose of rilpivirine extended‑release injectable suspension [see Clinical Pharmacology (12.2)]. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes [see Drug Interactions (7.3, 7.4)].

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)].

• 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, 7.4) 7.1 Concomitant Use with Other Antiretroviral Medicines Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1)]. 7.2 Use of Other Antiretroviral Drugs after Discontinuation of CABENUVA Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 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 Warnings and Precautions (5.6), Drug Interactions (7.4), Clinical Pharmacology (12.3)]. 7.3 Potential for Other Drugs to Affect CABENUVA Refer to the prescribing information for VOCABRIA (cabotegravir) and EDURANT (rilpivirine) for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively. Cabotegravir Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations and may result in loss of virologic response; therefore, coadministration of CABENUVA with these drugs is contraindicated [see Contraindications (4)]. Rilpivirine Rilpivirine is primarily metabolized by CYP3A. Coadministration of CABENUVA and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs [see Contraindications (4), Drug Interactions (7.4)]. Coadministration of CABENUVA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine [see Drug Interactions (7.4), Clinical Pharmacology (12.3)]. QT-Prolonging Drugs: At mean steady-state Cmax values 4.4- and 11.6-fold higher than those with the recommended 600‑mg dose of rilpivirine extended-release injectable suspension, rilpivirine may prolong the QTc interval [see Clinical Pharmacology (12.2)]. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes [see Warnings and Precautions (5.5), Drug Interactions (7.4)]. 7.4 Established and Other Potentially Significant Drug Interactions 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. These recommendations are based on either drug interaction trials following oral administration of cabotegravir or rilpivirine or predicted interactions due to the expected magnitude of the interaction and potential for loss of virologic response [see Contraindications (4), Warnings and Precautions (5.5), Clinical Pharmacology (12.3)]. Table 8 includes potentially significant interactions but is not all inclusive. Table 8. Drug Interactions with CABENUVA ↑ = Increase, ↓ = Decrease, ↔ = No change. a See Clinical Pharmacology (12.3) for magnitude of interaction. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital Phenytoin ↓Cabotegravir ↓Rilpivirine Coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance [see Contraindications (4)]. Antimycobacterials: Rifampina Rifapentine ↓Cabotegravir ↓Rilpivirine Antimycobacterial: Rifabutina ↓Cabotegravir ↔Rifabutin ↓Rilpivirine Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) ↓Rilpivirine Herbal product: St John’s wort ( Hypericum perforatum ) ↓Rilpivirine Macrolide or ketolide antibiotics: Azithromycin Clarithromycin Erythromycin ↔Cabotegravir ↑Rilpivirine Macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes [see Warnings and Precautions (5.5)]. Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides. Narcotic analgesic: Methadonea ↔Cabotegravir ↓Methadone ↔Rilpivirine No dose adjustment of methadone is required when starting coadministration of methadone with CABENUVA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. 7.5 Drugs without Clinically Significant Interactions Cabotegravir Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals and rilpivirine) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine [see Clinical Pharmacology (12.3)]. Rilpivirine Based on drug interaction study results, the following drugs can be coadministered with rilpivirine (non-antiretrovirals and cabotegravir) or given after discontinuation of rilpivirine (antiretrovirals and non-antiretrovirals): acetaminophen, atorvastatin, cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, sildenafil, tenofovir alafenamide, and tenofovir disoproxil fumarate [see Clinical Pharmacology (12.3)]. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.

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. These recommendations are based on either drug interaction trials following oral administration of cabotegravir or rilpivirine or predicted interactions due to the expected magnitude of the interaction and potential for loss of virologic response [see Contraindications (4), Warnings and Precautions (5.5), Clinical Pharmacology (12.3)]. Table 8 includes potentially significant interactions but is not all inclusive.

Cabotegravir

Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals and rilpivirine) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine [see Clinical Pharmacology (12.3)].

Rilpivirine

Based on drug interaction study results, the following drugs can be coadministered with rilpivirine (non-antiretrovirals and cabotegravir) or given after discontinuation of rilpivirine (antiretrovirals and non-antiretrovirals): acetaminophen, atorvastatin, cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, sildenafil, tenofovir alafenamide, and tenofovir disoproxil fumarate [see Clinical Pharmacology (12.3)]. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.