CABOTEGRAVIR: 8,304 Adverse Event Reports & Safety Profile

VOCABRIA contains cabotegravir, as cabotegravir sodium, an HIV integrase strand transfer inhibitor (INSTI). The chemical name of cabotegravir sodium is sodium ( 3S,11aR )-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido [1,2-d]pyrazine-8-carboxamide. The empirical formula is C 19 H 16 F 2 N 3 NaO 5 and the molecular weight is 427.34 g/mol. It has the following structural formula: Cabotegravir sodium is a white to almost white crystalline solid that is slightly soluble in water. Each immediate-release film-coated tablet of VOCABRIA for oral administration contains 30 mg of cabotegravir (equivalent to 31.62 mg cabotegravir sodium) and the inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablet film-coating contains hypromellose, polyethylene glycol, and titanium dioxide. Cabotegravir sodium chemical structure

AND USAGE HIV-1 Treatment: VOCABRIA is an HIV-1 integrase strand transfer inhibitor (INSTI) indicated in combination with EDURANT (rilpivirine) for short-term treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA <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. ( 1.1 ) HIV-1 Pre-Exposure Prophylaxis: VOCABRIA is indicated for short-term pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition. Individuals must have a negative HIV-1 test prior to initiating VOCABRIA for HIV-1 PrEP. ( 1.2 ) VOCABRIA may be used as:

• oral lead-in to assess the tolerability of cabotegravir prior to administration of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) for HIV-1 treatment or APRETUDE (cabotegravir extended-release injectable suspension) for HIV-1 PrEP. ( 1.1 , 1.2 )
• oral therapy for patients who will miss planned injection dosing with CABENUVA for HIV-1 treatment or APRETUDE for HIV-1 PrEP. ( 1.1 , 1.2 )

1.1 Treatment of HIV-1 Infection VOCABRIA is indicated in combination with EDURANT (rilpivirine) tablets for short-term treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA &lt;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 <span class="opacity-50 text-xs">[see Microbiology ( 12.4 ), Clinical Studies ( 14.1 )]</span> :

• oral lead-in to assess the tolerability of cabotegravir prior to administration of cabotegravir extended-release injectable suspension, a component of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension).
• oral therapy for patients who will miss planned injection dosing with CABENUVA.

1.2 HIV-1 Pre-Exposure Prophylaxis VOCABRIA is indicated for short-term pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition. Individuals must have a negative HIV-1 test prior to initiating VOCABRIA for HIV-1 PrEP. VOCABRIA may be used as <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Clinical Studies ( 14.2 )]</span> :

• oral lead-in to assess the tolerability of cabotegravir prior to administration of APRETUDE (cabotegravir extended-release injectable suspension).
• oral PrEP for patients who will miss planned injection dosing with APRETUDE.

AND ADMINISTRATION

• HIV-1 Screening: Screen all individuals for HIV-1 infection immediately prior to initiating APRETUDE for HIV-1 PrEP and prior to each injection while taking APRETUDE. ( 2.2 )
• Prior to initiating APRETUDE, an oral lead-in dosing may be used for approximately 1 month with the recommended dosage to assess the tolerability of APRETUDE. ( 2.4 )
• For gluteal intramuscular injection only. ( 2.5 , 2.7 )
• Recommended Dosing Schedule: Initiate APRETUDE with a single 600-mg (3-mL) injection given 1 month apart for 2 consecutive months on the last day of an oral lead-in if used or within 3 days and continue with the injections every 2 months thereafter. ( 2.5 )

2.1 Dosage and Administration Overview

• APRETUDE contains cabotegravir extended-release injectable suspension in a single-dose vial [see Dosage Forms and Strengths ( 3 )] .
• APRETUDE must be administered by a healthcare provider by gluteal intramuscular injection [see Dosage and Administration ( 2.7 )] .
• APRETUDE may be initiated with oral cabotegravir prior to the intramuscular injections or the patient may proceed directly to injection of APRETUDE without an oral lead-in [see Dosage and Administration ( 2.4 )] .

2.2 HIV-1 Screening for Individuals Receiving APRETUDE for HIV-1 Pre-Exposure Prophylaxis Individuals must be tested for HIV-1 infection prior to initiating APRETUDE or oral cabotegravir, and with each subsequent injection of APRETUDE, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. If an antigen/antibody-specific test is used and provides negative results, then such negative results should be confirmed using an RNA-specific assay, even if the results of the RNA-assay are available after APRETUDE or oral cabotegravir administration <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )]</span> .

2.3 Adherence to APRETUDE Prior to starting APRETUDE, healthcare providers should carefully select individuals who agree to the required injection dosing and testing schedule and counsel individuals about the importance of adherence to scheduled dosing visits to help reduce the risk of acquiring HIV-1 infection and development of resistance <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.1 , 5.3 ), Microbiology ( 12.4 )]</span> .

2.4 Optional Oral Lead-In Dosing to Assess Tolerability of APRETUDE The healthcare provider and individual may decide to use an oral lead-in with oral cabotegravir prior to the initiation of APRETUDE to assess the tolerability of cabotegravir or the healthcare provider and individual may proceed directly to injection of APRETUDE without the use of an oral lead-in <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> . No safety and efficacy data are available for use of APRETUDE without an oral lead-in <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 )]</span>. However, in HIV-1 treatment clinical trials, data show that an oral lead-in is not needed to ensure adequate plasma cabotegravir exposure upon initiation of injections and that the safety and efficacy results of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) were similar when administered with and without an oral lead-in.

2.5 Gluteal Intramuscular Injection Dosing with APRETUDE Initiation Injections If an oral lead-in is used, initiation injections should be administered on the last day of oral lead‑in or within 3 days thereafter. The recommended initiation injection doses of APRETUDE in individuals is a single 600‑mg (3-mL) intramuscular injection of APRETUDE given 1 month apart for 2 consecutive months ( Table 1 and Table 2 ). Individuals may be given the second APRETUDE initiation injection up to 7 days before or after the date the individual is scheduled to receive the injections.

Continuation Injections

After the 2 initiation injection doses given consecutively 1 month apart, the recommended continuation injection dose of APRETUDE is a single 600-mg (3-mL) intramuscular injection of APRETUDE every 2 months ( Table 2 ). Individuals may be given APRETUDE up to 7 days before or after the date the individual is scheduled to receive the injections.

Table

1.

Recommended Dosing

Schedule (with Oral Lead-In) for Pre-Exposure Prophylaxis in Adults and Adolescents Weighing at Least 35 kg a Should be administered on the last day of oral lead-in or within 3 days thereafter. b Individuals may be given APRETUDE up to 7 days before or after the date the individual is scheduled to receive the injections.

Oral

Lead-In (at Least 28 Days) (Month Prior to Starting Injections) Intramuscular (Gluteal)

Initiation

Injection (Month 1 and Month 2) Intramuscular (Gluteal)

Continuation

Injection (Month 4 and Every 2 Months Onwards) Oral cabotegravir 30 mg by mouth once daily for 28 days APRETUDE a 600-mg (3 mL) APRETUDE b 600-mg (3 mL)

Table

2.

Recommended Dosing

Schedule (Direct to Injection) for Pre-Exposure Prophylaxis in Adults and Adolescents Weighing at Least 35 kg a Individuals may be given APRETUDE up to 7 days before or after the date the individual is scheduled to receive the injections. Intramuscular (Gluteal)

Initiation

Injection (Month 1 and Month 2) Intramuscular (Gluteal)

Continuation

Injection (Month 4 and Every 2 Months Onwards) APRETUDE a APRETUDE a 600-mg (3 mL) 600-mg (3 mL)

2.6 Recommended Dosing Schedule for Missed Injections Adherence to the injection dosing schedule is strongly recommended <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> . Individuals who miss a scheduled injection visit should be clinically reassessed to ensure resumption of APRETUDE remains appropriate <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 )]</span> . Refer to Table 3 for dosing recommendations after missed injections.

Planned Missed

Injections If an individual plans to miss a scheduled every-2-month continuation injection visit by more than 7 days, take daily oral cabotegravir for up to 2 months to replace 1 missed scheduled every-2-month injection. The recommended oral daily dose is one 30-mg tablet of oral cabotegravir. The first dose of oral cabotegravir (or alternative oral PrEP regimen) should be taken approximately 2 months after the last injection dose of APRETUDE. Restart injection with APRETUDE on the day oral cabotegravir dosing completes or within 3 days, thereafter, as recommended in Table 3 . For oral PrEP durations greater than 2 months, an alternative regimen to oral cabotegravir is recommended.

Unplanned Missed

Injections If a scheduled injection visit is missed or delayed by more than 7 days and oral dosing has not been taken in the interim, clinically reassess the individual to determine if resumption of injection dosing remains appropriate [see Warnings and Precautions ( 5.1 )] . If the injection dosing schedule will be continued, see Table 3 for dosing recommendations.

Table

3.

Injection Dosing

Recommendations after Missed Injections Time since Last Injection Recommendation If second injection is missed and time since first injection is: Less than or equal to 2 months Administer 600-mg (3-mL) gluteal intramuscular injection of APRETUDE as soon as possible, then continue to follow the every-2-month injection dosing schedule. Greater than 2 months Restart with 600-mg (3-mL) gluteal intramuscular injection of APRETUDE, followed by a second 600-mg (3-mL) initiation injection dose 1 month later. Then continue to follow the every-2-month injection dosing schedule thereafter. If third or subsequent injection is missed and time since prior injection is: Less than or equal to 3 months Administer 600-mg (3-mL) intramuscular injection of APRETUDE as soon as possible, then continue with the every-2-month injection dosing schedule. Greater than 3 months Restart with 600-mg (3-mL) gluteal intramuscular injection of APRETUDE, followed by the second 600-mg (3-mL) initiation injection dose 1 month later. Then continue with the every-2-month injection dosing schedule thereafter.

2.7 Administration Instructions 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. APRETUDE is a suspension for gluteal intramuscular injection that does not need further dilution or reconstitution. The ventrogluteal site is recommended for injection. 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 individual 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 individuals with higher BMI (e.g., &gt;30 kg/m 2 ) to ensure that the injection is administered intramuscularly as opposed to subcutaneously. If the pack has been stored in the refrigerator, the vial should be brought to room temperature prior to administration (not to exceed 30°C [86°F]). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The APRETUDE vial has a brown tint to the glass that may limit visual inspection. Discard the vial if the medicine exhibits particulate matter or discoloration. Shake the vial vigorously so that the suspension looks uniform before injecting. Small air bubbles are expected and acceptable. Once the suspension has been drawn into the syringe, the injection should be administered as soon as possible, but may remain in the syringe for up to 2 hours. The filled syringe should not be placed in the refrigerator. If the medicine remains in the syringe for more than 2 hours, the filled syringe and needle must be discarded <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling ( 16 )]</span>.

Treatment of HIV-1 Infection VOCABRIA is contraindicated in patients:

• with previous hypersensitivity reaction to cabotegravir [see Warnings and Precautions ( 5.2 )] .
• receiving the following coadministered drugs for which significant decreases in cabotegravir plasma concentrations may occur due to uridine diphosphate glucuronosyltransferase (UGT)1A1 enzyme induction, which may result in loss of virologic response [see Drug Interactions ( 7.2 , 7.3 ), Clinical Pharmacology ( 12.3 )] : o Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin o Antimycobacterials: Rifampin, rifapentine Prior to initiation of VOCABRIA, note that use of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated. Since VOCABRIA is taken in combination with EDURANT tablets, the prescribing information for EDURANT should be consulted for additional contraindications. HIV-1 Pre-Exposure Prophylaxis VOCABRIA is contraindicated in individuals:
• with unknown or positive HIV-1 status [see Warnings and Precautions ( 5.1 )] .
• with previous hypersensitivity reaction to cabotegravir [see Warnings and Precautions ( 5.2 )] .
• receiving the following coadministered drugs for which significant decreases in cabotegravir plasma concentrations may occur due to UGT1A1 enzyme induction, which may result in loss of efficacy [see Drug Interactions ( 7.2 , 7.3 ), Clinical Pharmacology ( 12.3 )] : o Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin o Antimycobacterials: Rifampin, rifapentine
• Previous hypersensitivity reaction to cabotegravir. ( 4 )
• Coadministration with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, and rifapentine. ( 4 )
• Positive HIV-1 status for HIV-1 PrEP. ( 4 )

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

• Hypersensitivity reactions [see Warnings and Precautions ( 5.4 )]
• Hepatotoxicity [see Warnings and Precautions ( 5.5 )]
• Depressive disorders [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (all grades) observed in at least 1% of participants receiving APRETUDE were injection site reactions, diarrhea, headache, pyrexia, fatigue, sleep disorders, nausea, dizziness, flatulence, abdominal pain, vomiting, myalgia, rash, decreased appetite, somnolence, back pain, and upper respiratory tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

Clinical Trials

Experience in Adults The safety assessment of APRETUDE is based on the analysis of data from 2 international, multicenter, double-blind trials, HPTN 083 and HPTN 084 [see Clinical Studies ( 14.1 )] . Adverse reactions were reported while on blinded study product following exposure to APRETUDE extended-release injectable suspension and oral cabotegravir tablets as oral lead-in. The median time on blinded study product in HPTN 083 was 65 weeks and 2 days (range: 1 day to 156 weeks and 1 day), with a total exposure on cabotegravir of 3,231 person‑years. The median time on blinded study product in HPTN 084 was 64 weeks and 1 day (range: 1 day to 153 weeks and 1 day), with a total exposure on cabotegravir of 2,009 person‑years. The most common adverse reactions regardless of severity reported in at least 1% of participants in HPTN 083 or HPTN 084 are presented in Table 4 . In HPTN 083, 6% of participants in the group receiving APRETUDE intramuscular injection every 2 months and 4% of participants receiving oral TRUVADA [emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF)] once daily discontinued due to adverse events (all causality). Non-injection-site–associated adverse events leading to discontinuation and occurring in ≥1% of participants were increased alanine aminotransferase with APRETUDE and TRUVADA. In HPTN 084, 1% of participants receiving APRETUDE and 1% of participants receiving TRUVADA discontinued due to adverse events. The most commonly reported adverse event (all causality) leading to discontinuation was increased alanine aminotransferase (<1%) with APRETUDE and TRUVADA. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trials.

Table

4.

Adverse Drug

Reactions a (All Grades) Reported in at Least 1% of Participants Receiving APRETUDE in Either HPTN 083 or HPTN 084 a Adverse reactions defined as “treatment-related” as assessed by the investigator, with exception of injection site reactions, where all injection site reactions were reported regardless of causality. b Participants who received injection: HPTN 083, APRETUDE (n = 2,117) and TRUVADA (n = 2,081); HPTN 084, APRETUDE (n = 1,519) and TRUVADA (n = 1,516). c Pyrexia includes pyrexia, feeling hot, chills, influenza-like illness. d Fatigue includes fatigue, malaise. e Sleep disorders includes insomnia, abnormal dreams. f Abdominal pain includes abdominal pain, upper abdominal pain. g Rash includes rash, erythema, pruritis, macular, papular, maculopapular.

Adverse

Reactions HPTN 083 HPTN 084 APRETUDE Every 2 Months (n = 2,281)

Truvada

Once Daily (n = 2,285)

Apretude

Every 2 Months (n = 1,614)

Truvada

Once Daily (n = 1,610) Injection site reactions b 82% 35% 38% 11% Diarrhea 4% 5% 4% 4% Headache 4% 3% 12% 13% Pyrexia c 4% <1% <1% <1% Fatigue d 4% 2% 3% 3% Sleep disorders e 3% 3% 1% 1% Nausea 3% 5% 4% 8% Dizziness 2% 3% 4% 6% Flatulence 1% 1% <1% <1% Abdominal pain f 1% 1% 2% 2% Vomiting <1% 1% 2% 5% Myalgia <1% <1% 2% 1% Rash g <1% <1% 2% 1% Decreased appetite <1% <1% 2% 4% Somnolence <1% <1% 2% 2% Back pain <1% <1% 1% <1% Upper respiratory tract infection 0 <1% 4% 4% Injection-Associated Adverse Reactions: Local Injection Site Reactions (ISRs) with APRETUDE: The most frequent adverse reactions associated with the intramuscular administration of APRETUDE in HPTN 083 were ISRs.

After

20,286 injections, 8,900 ISRs were reported. Of the 2,117 participants who received at least one injection of APRETUDE, 1,740 (82%) participants experienced at least one ISR, of which a total of 3% of participants discontinued APRETUDE because of ISRs. Among the participants who received APRETUDE and experienced at least one ISR, the maximum severity of reactions was mild (Grade 1) in 41% of participants, moderate (Grade 2) in 56% of participants, and severe (Grade 3) in 3% of participants. The median duration of overall ISR events was 4 days. The proportion of participants reporting ISRs at each visit and the severity of the ISRs decreased over time. The most commonly reported ISRs (all causality and grades) in at least 1% of participants who received APRETUDE and experienced at least one ISR from HPTN 083 are presented in Table 5 . The most frequent adverse reactions associated with the intramuscular administration of APRETUDE in HPTN 084 were ISRs.

After

13,068 injections, 1,171 ISRs were reported. Of the 1,519 participants who received at least one injection of APRETUDE, 578 (38%) participants experienced at least one ISR. No participants discontinued APRETUDE because of ISRs. Among the participants who received APRETUDE and experienced at least one ISR, the maximum severity of reactions was mild (Grade 1) in 66% of participants, moderate (Grade 2) in 34% of participants, and severe (Grade 3) in less than 1% of participants. The median duration of overall ISR events was 8 days. The proportion of participants reporting ISRs at each visit and the severity of the ISRs generally decreased over time. The most commonly reported ISRs (all causality and grades) in at least 1% of participants who received APRETUDE and experienced at least one ISR from HPTN 084 are presented in Table 5 .

Table

5.

Injection Site

Reactions (All Grades) Reported in at Least 1% of Participants Who Experienced at Least One Injection Site Reaction (All Causality) with APRETUDE in Either HPTN 083 or HPTN 084 a Placebo injectable suspension: intralipid 20% fat emulsion.

Injection Site

Reactions HPTN 083 HPTN 084 APRETUDE (n = 1,740) TRUVADA a (n = 724) APRETUDE (n = 578) TRUVADA a (n = 166) Pain/tenderness 98% 95% 90% 87% Nodules 15% 2% 14% 2% Induration 15% <1% 12% 2% Swelling 12% 1% 18% 3% Bruising 4% 4% 1% 0 Erythema 4% 2% 5% 2% Pruritus 3% 3% 6% 11% Warmth 3% 1% <1% 0 Anesthesia 1% 2% 1% 2% Abscess <1% 0 2% 3% Discoloration <1% 0 1% 0 Other Injection-Associated Adverse Reactions: In the HPTN 083 clinical trial, an increased incidence of pyrexia (including pyrexia, feeling hot, chills, influenza-like illness) (4%) was reported by participants receiving APRETUDE compared with participants receiving TRUVADA (<1%). There were no differences reported in the incidence of pyrexia between groups in HPTN 084. Vasovagal or pre-syncopal reactions considered treatment related were reported in <1% of participants after injection with APRETUDE in HPTN 083. None were reported as treatment related by the investigators in HPTN 084.

Less Common Adverse

Reactions: The following select adverse reactions (regardless of severity) occurred in <1% of participants receiving APRETUDE in HPTN 083 or HPTN 084.

Hepatobiliary

Disorders: Hepatotoxicity. Investigations: Weight increase (see below).

Psychiatric

Disorders: Depression; suicidal ideation, and suicide attempt (these events were observed primarily in participants with a pre‑existing history of depression or other psychiatric illness).

Weight

Increase: At the Week 41 and Week 97 timepoints in HPTN 083, participants who received APRETUDE gained a median of 1.2 kg (Interquartile Range [IQR]; -1.0, 3.5; n = 1,623) and 2.1 kg (IQR; -0.9, 5.9; n = 601) in weight from baseline. Those who received TRUVADA gained a median of 0 kg (IQR; -2.1, 2.4; n = 1,611) and 1 kg (IQR; -1.9, 4.0; n = 598) in weight from baseline, respectively. At the Week 41 and 97 timepoints in HPTN 084, participants who received APRETUDE gained a median of 2 kg (IQR; 0.0, 5.0; n = 1,151) and 4 kg (IQR; 0.0, 8.0; n = 216) in weight from baseline, respectively. Those who received TRUVADA gained a median of 1 kg (IQR; -1.0, 4.0; n = 1,131) and 3 kg (IQR; -1.0, 6.0; n = 218) in weight from baseline, respectively.

Laboratory

Abnormalities: Grade 3 or 4 post-baseline maximum toxicity laboratory abnormalities for HPTN 083 or HPTN 084 are summarized in Table 6 .

Table

6.

Laboratory

Abnormalities (Grades 3 to 4) in ≥1% of Participants in Either HPTN 083 or HPTN 084 ALT = Alanine transaminase, ULN = upper limit of normal, AST = Aspartate aminotransferase.

Laboratory

Parameter HPTN 083 HPTN 084 APRETUDE Every 2 Months (n = 2,281)

Truvada

Once Daily (n = 2,285)

Apretude

Every 2 Months (n = 1,614)

Truvada

Once Daily (n = 1,610) ALT (≥5.0 x ULN) 2% 2% <1% 1% AST (≥5.0 x ULN) 3% 3% <1% <1% Creatine phosphokinase (≥10.0 x ULN) 15% 14% 2% 2% Lipase (≥3.0 x ULN) 3% 3% <1% <1% Creatinine (>1.8 x ULN) or increase to ≥1.5 x baseline) 3% 3% 5% 4% Serum Lipids: Changes from baseline to Month 15 in total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol to HDL ratio in HPTN 083 and HPTN 084 are presented in Table 7 .

Table

7.

Fasting Lipid

Values, Median Change from Baseline a at Week 57, Reported in HPTN 083 and HPTN 084 a Nearly 60% of participants with baseline data available had Week 57 data available in both arms of both trials. Within each trial, baseline values were comparable among participants receiving APRETUDE and TRUVADA. HPTN 083 HPTN 084 APRETUDE TRUVADA APRETUDE TRUVADA Total cholesterol (mg/dL) +1.0 -10.0 +0.2 -3.9 LDL cholesterol (mg/dL) +1.0 -6.0 -1.1 -5.0 HDL cholesterol (mg/dL) -0.2 -3.0 -0.8 -2.6 Triglycerides (mg/dL) +2.7 0.0 +3.1 +0.7 Total cholesterol: HDL cholesterol ratio +0.1 +0.0 +0.1 +0.1 Clinical Trials Experience in Adolescents In adolescents receiving APRETUDE for HIV-1 PrEP, the safety data were comparable to the safety data reported in adults receiving APRETUDE for HIV-1 PrEP [see Use in Specific Populations ( 8.4 )].

6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of APRETUDE or cabotegravir-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 ( 5.4 )] . Skin and Subcutaneous Tissue Disorders Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) [see Warnings and Precautions ( 5.4 )] .

AND PRECAUTIONS

• Comprehensive management to reduce the risk of HIV-1 acquisition. ( 5.1 )
• Potential risk of developing resistance to APRETUDE if an individual acquires HIV-1 either before or while taking APRETUDE or following discontinuation of APRETUDE. Reassess risk of HIV-1 acquisition and test before each injection to confirm HIV-1 negative status. ( 5.2 )
• Residual concentrations of cabotegravir may remain in the systemic circulation of individuals up to 12 months or longer. ( 5.3 )
• Serious or severe hypersensitivity reactions have been reported with cabotegravir and include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Discontinue APRETUDE immediately if signs or symptoms of hypersensitivity reactions develop. ( 5.4 )
• Hepatotoxicity has been reported in individuals receiving cabotegravir. Clinical and laboratory monitoring should be considered. Discontinue APRETUDE if hepatotoxicity is suspected. ( 5.5 )
• Depressive disorders have been reported with APRETUDE. Prompt evaluation is recommended for depressive symptoms. ( 5.6 )

5.1 Comprehensive Management to Reduce the Risk of HIV-1 Infection Use APRETUDE for HIV-1 PrEP to reduce the risk of HIV-1 infection as part of a comprehensive prevention strategy including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). APRETUDE is not always effective in preventing HIV-1 acquisition <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> . The time from initiation of APRETUDE for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including, but not limited to, condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network. Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use; knowledge of partner(s)’ HIV-1 status, including viral suppression status; regular testing for STIs that can facilitate HIV-1 transmission). Inform individuals about and support their efforts in reducing sexual risk behavior. Use APRETUDE to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV‑1 negative <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV‑1 infection who are taking only APRETUDE, because APRETUDE alone does not constitute a complete regimen for HIV-1 treatment <span class="opacity-50 text-xs">[see Microbiology ( 12.4 )]</span> ; therefore, care should be taken to minimize the risk of initiating or continuing APRETUDE before confirming the individual is HIV-1 negative.

• Prior to initiating APRETUDE for HIV-1 PrEP, ask seronegative individuals about recent (in past month) potential exposure events (e.g., condomless sex or condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, a recent STI), and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash).
• If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection. When using APRETUDE for HIV-1 PrEP, HIV-1 testing should be repeated prior to each injection and upon diagnosis of any other STIs [see Dosage and Administration ( 2.2 , 2.5 )] .
• If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following an exposure event, additional HIV testing to determine HIV status is needed. If an individual has confirmed HIV-1 infection, then the individual must be transitioned to a complete HIV-1 treatment regimen. Counsel individuals without HIV-1 to strictly adhere to the recommended dosing and testing schedule for APRETUDE in order to reduce the risk of HIV-1 acquisition and the potential development of resistance [see Dosage and Administration ( 2.3 , 2.5 ), Microbiology ( 12.4 )] . Some individuals, such as adolescents, may benefit from frequent visits and counseling to support adherence to the dosing and testing schedule [see Use in Specific Populations ( 8.4 ), Microbiology ( 12.4 ), Clinical Studies ( 14 )] .

5.2 Potential Risk of Resistance with APRETUDE There is a potential risk of developing resistance to APRETUDE if an individual acquires HIV-1 either before or while taking APRETUDE or following discontinuation of APRETUDE <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.3 )]</span> . To minimize this risk, it is essential to clinically reassess individuals for risk of HIV-1 acquisition and to test before each injection to confirm HIV-1 negative status. Individuals who are confirmed to have HIV-1 infection must transition to a complete HIV-1 treatment regimen. Alternative forms of PrEP should be considered following discontinuation of APRETUDE for those individuals at continuing risk of HIV-1 acquisition and initiated within 2 months of the final injection of APRETUDE.

5.3 Long-Acting Properties and Potential Associated Risks with APRETUDE Residual concentrations of cabotegravir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer). It is important to carefully select individuals who agree to the required every-2-month injection dosing schedule because non-adherence to every‑2-monthly injections or missed doses could lead to HIV-1 acquisition and development of resistance. Healthcare providers should take the prolonged-release characteristics of cabotegravir into consideration when APRETUDE is prescribed <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 , 5.2 ), Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.1 , 8.2 ), Overdosage ( 10 )]</span> .

5.4 Hypersensitivity Reactions Serious or severe hypersensitivity reactions have been reported with cabotegravir and include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Administration of cabotegravir oral lead-in dosing was used in clinical studies to help identify participants who may be at risk of a hypersensitivity reaction. Remain vigilant and discontinue APRETUDE if a hypersensitivity reaction is suspected <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ), Contraindications ( 4 ), Adverse Reactions ( 6 )]</span> . Discontinue APRETUDE 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 APRETUDE <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> .

5.5 Hepatotoxicity Hepatotoxicity has been reported in a limited number of individuals receiving cabotegravir with or without known pre-existing hepatic disease or identifiable risk factors <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Clinical and laboratory monitoring should be considered and APRETUDE should be discontinued if hepatotoxicity is suspected and individuals managed as clinically indicated. For information regarding the long-acting properties of APRETUDE <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> .

5.6 Depressive Disorders Depressive disorders (including depression, depressed mood, major depression, persistent depressive disorder, suicidal ideation, suicide attempt) have been reported with APRETUDE <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Promptly evaluate individuals with depressive symptoms to assess whether the symptoms are related to APRETUDE and to determine whether the risks of continued therapy outweigh the benefits.

5.7 Risk of Reduced Drug Concentration of APRETUDE Due to Drug Interactions The concomitant use of APRETUDE and other drugs may result in reduced drug concentration of APRETUDE <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Drug Interactions ( 7.2 , 7.3 )]</span> .

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 use of, and after discontinuation of APRETUDE; review concomitant medications during use of APRETUDE [see Drug Interactions ( 7.3 , 7.4 )] .

INTERACTIONS

• Refer to the full prescribing information for important drug interactions with VOCABRIA. ( 4 , 5.5 , 7 )
• VOCABRIA in combination with EDURANT is a complete regimen for HIV-1 treatment. Coadministration with other antiretroviral medications for PrEP is not recommended. ( 7.1 )
• Drugs that induce uridine diphosphate glucuronosyltransferase (UGT)1A1 may decrease the plasma concentrations of cabotegravir. ( 4 , 7.2 , 7.3 )

7.1 Concomitant Use with Other Antiretroviral Medicines VOCABRIA in combination with EDURANT (rilpivirine) is a complete regimen for the treatment of HIV-1 infection. Refer to the prescribing information for EDURANT for relevant information on rilpivirine. Coadministration of VOCABRIA with other antiretroviral medications for PrEP is not recommended <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.3 )]</span> . Prior to initiating dosing with VOCABRIA, the prescribing information for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) or APRETUDE should be consulted to ensure use of CABENUVA or APRETUDE will be appropriate for either the treatment of HIV-1 infection or HIV-1 PrEP, respectively.

7.2 Potential for Other Drugs to Affect VOCABRIA 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 efficacy; therefore, coadministration of VOCABRIA with these drugs is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Coadministration of oral cabotegravir with polyvalent cation-containing products may lead to decreased absorption of cabotegravir <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span> .

7.3 Established and Other Potentially Significant Drug Interactions Information regarding potential drug interactions with cabotegravir are provided in Table 1 . These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for loss of efficacy <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.3 )]</span> .

Table

1 includes potentially significant interactions but is not all inclusive. Refer to the prescribing information for EDURANT (rilpivirine) for established or potentially significant interactions that should be considered during concomitant administration of VOCABRIA and EDURANT for HIV-1 treatment.

Table

1.

Drug

Interactions with VOCABRIA ↓ = Decrease; PrEP = Pre-exposure prophylaxis. a Rifabutin can be coadministered with cabotegravir; however, it is contraindicated with CABENUVA for HIV-1 treatment. Dosage modification is recommended with APRETUDE for HIV-1 PrEP.

Concomitant Drug

Class: Drug Name Effect on Concentration Clinical Comment Antacids containing polyvalent cations (e.g., aluminum or magnesium hydroxide, calcium carbonate) ↓Cabotegravir Administer antacid products at least 2 hours before or 4 hours after taking VOCABRIA. Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital Phenytoin ↓Cabotegravir Coadministration is contraindicated with VOCABRIA due to potential for loss of efficacy and development of resistance [see Contraindications ( 4 )] . Antimycobacterials a : Rifampin Rifapentine ↓Cabotegravir Antimycobacterial: Rifabutin ↓Cabotegravir Dose modification is not required for VOCABRIA. Dose modification is recommended for APRETUDE for HIV-1 PrEP. Coadministration is contraindicated with CABENUVA for HIV-1 treatment.

7.4 Drugs without Clinically Significant Interactions with Cabotegravir Based on drug interaction study results, the following drugs can be coadministered with cabotegravir without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, rifabutin, and rilpivirine <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Prior to initiating oral therapy, note that use of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated for the treatment of HIV-1 infection. Dosage modification is recommended when APRETUDE is used with rifabutin for HIV-1 PrEP.