Apretude Drug Information
Generic name: CABOTEGRAVIR
Uses of Apretude
APRETUDE is indicated for 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 APRETUDE (with or without an oral lead-in with oral cabotegravir) for HIV-1 PrEP.
Dosage & Administration of Apretude
Dosage and Administration Overview •
APRETUDE contains cabotegravir extended-release injectable suspension in a single-dose vial. • APRETUDE must be administered by a healthcare provider by gluteal intramuscular injection. • 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.
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.
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.
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. No safety and efficacy data are available for use of APRETUDE without an oral lead-in. 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.
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. 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 ).
Table 1. Recommended Dosing Schedule (with Oral Lead-In) for Pre-Exposure Prophylaxis in Adults and Adolescents Weighing at Least 35 kg Table 2. Recommended Dosing Schedule (Direct to Injection) for Pre-Exposure Prophylaxis in Adults and Adolescents Weighing at Least 35 kg
Recommended Dosing Schedule for Missed Injections Adherence to the injection dosing schedule is strongly recommended. Individuals who miss a scheduled injection visit should be clinically reassessed to ensure resumption of APRETUDE remains appropriate. 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.
If the injection dosing schedule will be continued, see Table 3 for dosing recommendations. Table 3. Injection Dosing
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., >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 ).
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.
| 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) |
| 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) |
| 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. |
Side Effects of Apretude
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. 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 most common adverse reactions regardless of severity reported in at least intramuscular injection every 2 months and 4% of participants receiving oral TRUVADA 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 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: 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. 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. 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. 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 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). Table 6. Table 7.
Fasting Lipid Values, Median Change from Baseline a at Week 57, Reported in 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.
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).
Skin and Subcutaneous Tissue Disorders Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).
| 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% |
| 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 |
| 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% |
| 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 |
Warnings & Cautions for Apretude
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. 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. 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; 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. • 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. Some individuals, such as adolescents, may benefit from frequent visits and counseling to support adherence to the dosing and testing schedule.
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. 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.
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.
Hypersensitivity Reactions Serious or severe hypersensitivity reactions have been reported with cabotegravir and include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). 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.
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, 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.
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. Clinical and laboratory monitoring should be considered and APRETUDE should be discontinued if hepatotoxicity is suspected and individuals managed as clinically indicated.
Depressive Disorders
Depressive disorders (including depression, depressed mood, major depression, persistent depressive disorder, suicidal ideation, suicide attempt) have been reported with APRETUDE. 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.
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. 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.
Drug Interactions with Apretude
Use of Other Antiretroviral
Drugs after Discontinuation of APRETUDE Residual concentrations of cabotegravir may remain in the systemic circulation of individuals 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 APRETUDE.
Potential for Other Drugs to Affect APRETUDE Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease cabotegravir plasma concentrations; therefore, coadministration of APRETUDE with these drugs is contraindicated.
Established and Other Potentially Significant Drug Interactions Information regarding potential drug interactions with cabotegravir is provided in Table 8. These recommendations are based on either drug interaction trials following oral administration of cabotegravir or predicted interactions due to the expected magnitude of the interaction. Table 8 includes potentially significant interactions but is not all inclusive.
Table 8. Drug Interactions with APRETUDE
Drugs without Clinically Significant Interactions with Cabotegravir Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals) 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.
| ↑ = Increase, ↓ = Decrease, ↔ = No change. | ||
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment |
| Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital Phenytoin | ↓Cabotegravir | Coadministration is contraindicated with APRETUDE due to potential for significant decreases in plasma concentration of APRETUDE. |
| Antimycobacterials: Rifampin Rifapentine | ↓Cabotegravir | |
| Antimycobacterial: Rifabutin | ↓Cabotegravir | When rifabutin is started before or concomitantly with the first initiation injection of APRETUDE, the recommended dosing of APRETUDE is one 600-mg (3-mL) injection, followed 2 weeks later by a second 600‑mg (3-mL) initiation injection and monthly thereafter while on rifabutin. When rifabutin is started at the time of the second initiation injection or later, the recommended dosing schedule of APRETUDE is 600‑mg (3 mL) monthly while on rifabutin. After stopping rifabutin, the recommended dosing schedule of APRETUDE is 600-mg (3 mL) every 2 months. |
Pregnancy Safety for Apretude
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to APRETUDE during pregnancy. Healthcare providers are encouraged to register individuals by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of APRETUDE during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage.
Discuss the benefit-risk of using APRETUDE with individuals of childbearing potential or during pregnancy. Cabotegravir use in pregnant individuals has not been evaluated. APRETUDE should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
The APR has been established to monitor for birth defects following prenatal exposure to antiretrovirals. The rate of miscarriage is not reported in the APR. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%.
The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates mothers and infants from a limited geographic area and does not include outcomes for births that occurred at <20 weeks’ gestation.
In animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at >28 times the exposure at the recommended human dose (RHD). No evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (>28 times or similar to the exposure at the RHD, respectively) given during organogenesis (see Data). Clinical Considerations Cabotegravir is detected in systemic circulation for up to 12 months or longer after discontinuing injections of APRETUDE; therefore, consideration should be given to the potential for fetal exposure during pregnancy.
Data Animal Data: Cabotegravir was administered orally to pregnant rats at mg/kg/day from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. There were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD). No drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD), and no drug-related fetal malformations were observed at any dose.
Cabotegravir was administered orally to pregnant rabbits at mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD). In a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at mg/kg/day from Gestation Day 6 to Lactation Day 21.
A delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (>28 times the exposure in humans at the RHD); there were no alterations to growth and development of surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. There was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers.
A lower dose of 5 mg/kg/day (13 times the exposure at the RHD) was not associated with delayed parturition or neonatal mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue.
Pediatric Use of Apretude
Pediatric Use The safety and effectiveness of APRETUDE for HIV-1 PrEP in adolescents weighing at least 35 kg who are at risk for HIV-1 acquisition is supported by data from 2 adequate and well-controlled trials of APRETUDE for HIV-1 PrEP in adults with additional safety and pharmacokinetic data from studies in adults with HIV-1 who were administered CABENUVA, and in adolescent participants with HIV-1 who were administered separate components of CABENUVA in addition to their current antiretroviral therapy. Sixty-four adolescents were enrolled. Of these, 62 adolescent participants received one or more injections.
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. While using APRETUDE, HIV-1 testing should be conducted prior to initiating APRETUDE (with or without an oral lead-in with oral cabotegravir) and prior to each injection of APRETUDE. Adolescents may benefit from more frequent visits and counseling to support adherence to the dosing and testing schedule.
The safety, efficacy, and pharmacokinetics of APRETUDE in pediatric participants younger than 12 years of age or weighing <35 kg have not been established.
Contraindications for Apretude
- APRETUDE is contraindicated in individuals:
- With unknown or positive HIV-1 status.
- With previous hypersensitivity reaction to cabotegravir.
- 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 reduced effectiveness: o Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin o Antimycobacterials: Rifampin, rifapentine
- Coadministration with drugs where significant decreases in cabotegravir plasma concentrations may occur.
Overdosage Information for Apretude
There is no known specific treatment for overdose with APRETUDE. If overdose occurs, monitor the individual and apply standard supportive treatment as required as well as observation of the clinical status of the individual. As APRETUDE is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
Consider the prolonged exposure to APRETUDE following an injection when assessing treatment needs and recovery.
Clinical Studies of Apretude
Clinical Trials in Adults for HIV-1 Pre-Exposure Prophylaxis
The safety and efficacy of APRETUDE to reduce the risk of acquiring HIV-1 infection were evaluated in 2 randomized, double-blind, controlled, multinational trials, HPTN 083 in men and transgender women without HIV-1 who have sex with men and have evidence of high-risk behavior for HIV-1 infection and HPTN 084 in cisgender women without HIV-1 at risk of acquiring HIV-1. Participants randomized to receive APRETUDE initiated oral lead-in dosing with 1 oral cabotegravir 30-mg tablet and a placebo daily for up to 5 weeks, followed by APRETUDE 600‑mg (3-mL) intramuscular injection at months 1 and 2 and every 2 months thereafter and a daily placebo tablet. The primary endpoint was the rate of incident HIV-1 infections among participants randomized to daily oral cabotegravir and intramuscular injections of APRETUDE every 2 months compared with daily oral TRUVADA (corrected for early stopping).
The primary analysis demonstrated the superiority of APRETUDE compared with TRUVADA with a 66% reduction in the risk of acquiring HIV-1 infection, hazard ratio (95% CI) 0.34; further testing revealed 1 of the infections on APRETUDE to be prevalent then yielding a 69% reduction in the risk of HIV-1 incident infection relative to TRUVADA ( Table 14 ). Table 14. HIV-1 Infection Results During Randomized Phase in HPTN 083: Extended Retrospective Virologic Testing with Readjudicated Endpoints a a mITT from Supplemental Virology Report. b Following the primary analysis, extended retrospective virologic testing was performed to better characterize the timing of HIV-1 infections.
The original hazard ratio (95% CI) from the primary analysis is Figure 1. Cumulative Incidence of HIV-1 Infections in HPTN 083 Results from all subgroup analyses were consistent with the overall protective effect. A lower rate of incident HIV‑1 infections was observed for participants randomized to APRETUDE compared with participants randomized to TRUVADA ( Table 15 ).
Table 15. Table 16. Table 17.
Incident of HIV-1 Infections by Subgroup in HPTN 084: Extended Retrospective Virologic Testing with Readjudicated Endpoints a Figure 1 Figure 2
| a mITT from Supplemental Virology Report. | |||
| b Following the primary analysis, extended retrospective virologic testing was performed to better characterize the timing of HIV-1 infections. As a result, 1 of the 13 HIV-1 incident infections in participants receiving APRETUDE was determined to be a prevalent infection. The original hazard ratio (95% CI) from the primary analysis is 0.34 (0.18, 0.62). | |||
| APRETUDE (N = 2,278) | TRUVADA (N = 2,281) | Superiority P Value | |
| Person-years | 3,211 | 3,193 | |
| HIV-1 infections (incidence rate per 100 person-years) | 12 b (0.37) | 39 (1.22) | |
| Hazard ratio (95% CI) | 0.31 (0.16, 0.58) | 0.0003 | |
| a mITT from Supplemental Virology Report. b Cisgender men who have sex with men. c Transgender women who have sex with men. | |||||
| Subgroup | APRETUDE Incidence per 100 Person-Years | APRETUDE Person-Years | TRUVADA Incidence per 100 Person-Years | TRUVADA Person-Years | Hazard Ratio (95% CI) |
| Age | |||||
| <30 years | 0.47 | 2,110 | 1.66 | 1,987 | 0.29 |
| (0.15, 0.59) | |||||
| ≥30 years | 0.18 | 1,101 | 0.50 | 1,206 | 0.39 |
| (0.08, 1.84) | |||||
| Gender | |||||
| MSM b | 0.35 | 2,836 | 1.14 | 2,803 | 0.32 |
| (0.16, 0.64) | |||||
| TGW c | 0.54 | 371 | 1.80 | 389 | 0.34 |
| (0.08, 1.56) | |||||
| Race (US) | |||||
| Black | 0.58 | 691 | 2.28 | 703 | 0.26 |
| (0.09, 0.76) | |||||
| Non-Black | 0.00 | 836 | 0.50 | 801 | 0.11 |
| (0.00, 2.80) | |||||
| Region | |||||
| US | 0.26 | 1,528 | 1.33 | 1,504 | 0.21 |
| (0.07, 0.60) | |||||
| Latin America | 0.49 | 1,020 | 1.09 | 1,011 | 0.47 |
| (0.17, 1.35) | |||||
| Asia | 0.35 | 570 | 1.03 | 581 | 0.39 |
| (0.08, 1.82) | |||||
| Africa | 1.08 | 93 | 2.07 | 97 | 0.63 |
| (0.06, 6.50) | |||||
| a mITT from Supplemental Virology Report. | |||
| b Following the primary analysis, extended retrospective virologic testing was performed to better characterize the timing of HIV-1 infections. As a result, 1 of the 4 HIV-1 incident infections in participants receiving APRETUDE was determined to be a prevalent infection. The original hazard ratio (95% CI) from the primary analysis is 0.12 (0.05, 0.31). | |||
| APRETUDE (N = 1,613) | TRUVADA (N = 1,610) | Superiority P Value | |
| Person-years | 1,960 | 1,946 | |
| HIV-1 incident infections (incidence rate per 100 person-years) | 3 b (0.15) | 36 (1.85) | |
| Hazard ratio (95% CI) | 0.10 (0.04, 0.27) | <0.0001 | |
| a mITT from Supplemental Virology Report. | |||||
| Subgroup | APRETUDE Incidence per 100 Person-Years | APRETUDE Person-Years | TRUVADA Incidence per 100 Person-Years | TRUVADA Person-Years | Hazard Ratio (95% CI) |
| Age | |||||
| <25 years | 0.23 | 868 | 2.34 | 853 | 0.12 |
| (0.03, 0.46) | |||||
| ≥25 years | 0.09 | 1,093 | 1.46 | 1,093 | 0.09 |
| (0.02, 0.49) | |||||
| Body Mass Index | |||||
| <30 | 0.22 | 1,385 | 1.88 | 1,435 | 0.12 |
| (0.04, 0.38) | |||||
| ≥30 | 0.00 | 575 | 1.76 | 511 | 0.04 |
| (0.00, 0.93) | |||||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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