APRETUDE SIDE EFFECTS
- Generic Name: cabotegravir extended-release injectable suspension
- Brand Name: Apretude
SIDE EFFECTS
The following adverse reactions are described below and in other sections of the labeling:
- Hypersensitivity reactions
- Hepatotoxicity
- Depressive disorders
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect rates observed in practice.
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 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 1: Adverse Drug Reactionsa (All Grades) Reported in at Least 1% of Participants Receiving APRETUDE in Either HPTN 083 or HPTN 084
| 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 reactionsb | 82% | 35% | 38% | 11% |
| Diarrhea | 4% | 5% | 4% | 4% |
| Headache | 4% | 3% | 12% | 13% |
| Pyrexiac | 4% | <1% | <1% | <1% |
| Fatigued | 4% | 2% | 3% | 3% |
| Sleep disorderse | 3% | 3% | 1% | 1% |
| Nausea | 3% | 5% | 4% | 8% |
| Dizziness | 2% | 3% | 4% | 6% |
| Flatulence | 1% | 1% | <1% | <1% |
| Abdominal painf | 1% | 1% | 2% | 2% |
| Vomiting | <1% | 1% | 2% | 5% |
| Myalgia | <1% | <1% | 2% | 1% |
| Rashg | <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 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-likeillness. 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. |
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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 2.
Table 2: 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
| Injection Site Reactions | HPTN 083 | HPTN 084 | ||
| APRETUDE (n = 1,740) |
TRUVADAa (n = 724) |
APRETUDE (n = 578) |
TRUVADAa (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 |
| a Placeboinjectablesuspension:intralipid20%fatemulsion. | ||||
Other Injection-Associated Adverse Reactions
In the HPTN 083 clinical trial, an increased incidence of pyrexia (including pyrexia, feelinghot, chills, influenza-likeillness) (4%) was reported by participants receiving APRETUDE compared with participants receiving TRUVADA (<1%).Therewere 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.Nonewerereportedastreatment 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.
Weight Increase
At the Week 41 and Week 97 time points 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 time points in HPTN 084, participants who received APRETUDE gained amedian of 2kg(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 Table3.
Table 3: Laboratory Abnormalities (Grades 3 to 4) in ≥1 % of participants in Either HPTN 083 or HPTN 084
| 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% |
| ALT = Alanine transaminase, ULN = upper limit of normal, AST = Aspartate aminotransferase. | ||||
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 4.
Table 4: Fasting Lipid Values, Median Change from Baselinea at Week 57, Reported in HPTN 083 and HPTN 084
| 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 |
| 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. | ||||
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.
SRC: NLM .