Apretude®
Cabotegravir tablets
They may be used before initiating the injectable form to assess patient tolerance.
The recommended daily dose of Apretude® tablets is 30 mg with or without food for 28 days.
Cabotegravir injectable
The first injection of Apretude® should be given on the last day of tablet-taking or within the following three days. It can also be initiated directly without going through an oral phase.
The recommended initial dose is a single intramuscular injection into the gluteal muscle of 3 mL (600 mg) of Apretude®.
One month later the patient should receive a second injection of 3 mL (600 mg). A 7-day delay before and after the injection date is tolerated.
After the second injection, the patient should receive an intramuscular injection of 3 mL (600 mg) of Apretude® every 2 months. A 7-day gap before and after the scheduled injection date is also tolerated.
The patient’s body mass index should be taken into consideration to ensure that the needle length is sufficient to reach the gluteal muscle.
Missed doses
The prescriber should be experienced in prescribing PreP and should discuss with the individual who wishes to receive Apretude® the importance of adherence.
Tablets
For missed doses of tablets, the product monograph recommends taking the tablet unless it is 12 hours or less until the next dose.
Injections
For missed doses of injection, by a gap of more than 2 months and 7 days, individuals should be clinically evaluated to determine if resuming injections remains appropriate.
Postponed injections with or without a schedule
Postponed injections with a schedule
If an individual plans to miss a scheduled injection visit by more than 7 days, Apretude® tablets may be used once daily for up to 2 months to replace a missed injection.
– The first dose of Apretude® tablets should be taken approximately 2 months (+/- 7 days) after the last Apretude® injection.
– Injection administration should resume on the last day of Apretude® tablet dosing or within 3 days.
Postponed injections without a schedule
If a scheduled injection visit is missed or delayed by more than 7 days and oral dosing has not been taken in the meantime, individuals should be clinically reassessed to determine whether resuming injections is still appropriate.
How to restart injections when they have been interrupted
Less than 3 months
If clinically appropriate, restart with a 3 mL injection of Apretude® as soon as possible. If the person was taking Apretude® in tablet form, the injections should be restarted on the same day as the last day of oral treatment or within 3 days. Then continue with the dosing schedule of injections every 2 months.
More than 3 months
If clinically appropriate, restart with a 3 mL injection of Apretude®, followed one month later by the second 3 mL injection. If the person was taking Apretude® in tablet form, the injection should be on the same day as the last dose or within 3 days. Then continue with the dosing schedule of injections every 2 months.
When stopping injections
Residual concentrations of cabotegravir injection may remain in the systemic circulation of individuals for extended periods of time, therefore healthcare professionals should consider the extended-release of IM cabotegravir when stopping cabotegravir.
Efficacy and safety not established in pediatric population < 12 years or < 35 kg.
No adjustment necessary for patients with mild to severe renal impairment.
Child-Pugh A or B : No adjustment required
Child-Pugh C : Caution during administration (not studied in this population)
Study |
Comparator groups |
Efficacy results (Incidence of HIV-1 infections) |
Type of patients |
|
HPTN 083 |
Cabotegravir (N=2278) VS TDF/FTC (N=2281) |
Incidence rate per 100 person-years: |
Cisgender men (88%) and transgender women (12%) who have sex with men, median age 26 years, 72% non-white. |
|
HPTN 84 |
Cabotegravir (N=1613) VS TDF/FTC (N=1610) |
Incidence rate per 100 person-years: |
Cisgender women (99%), median age 25 years, >99% non-white. |
1 Following the primary analysis, an in-depth retrospective virological analysis was performed, which confirmed that 13 infections in the cabotegravir group were found to be prevalent infections.
2 After the primary analysis, an in-depth retrospective virological analysis was performed, which confirmed that 4 infections in the cabotegravir group were found to be prevalent infections.
Hepatotoxicity presenting as elevated serum transaminase levels has been reported in individuals receiving Apretude® with or without a history of pre-existing liver disease.
Depressive disorders, including depression, depressed mood, major depression, suicidal ideation, and suicide attempt have been reported with Apretude®. Individuals with depressive disorders should be promptly evaluated to determine if they are related to treatment.
Hypersensitivity reactions have been observed with integrase inhibitors and may therefore occur with Apretude®. Clinical studies have been conducted to identify participants who may be at risk for a hypersensitivity reaction. These reactions are characterized by rash, systemic symptoms, and sometimes organ dysfunction, including liver damage. If signs or symptoms of hypersensitivity develop, Apretude® should be discontinued immediately.
HPTN 083 Study
|
||
| Apretude® Every 2 months (n=2281) |
Truvada® Once a day (n=2285) |
|
|
Injection site reactions |
82% |
35% * |
|
Diarrhea |
4% |
5% |
|
Headache |
4% |
3% |
|
Pyrexia |
4% |
<1% |
|
Fatigue |
4% |
2% |
|
Sleep disorders |
3% |
3% |
|
Nausea |
3% |
5% |
|
Dizziness |
2% |
3% |
|
Flatulence |
1% |
1% |
|
Abdominal pain |
1% |
1% |
|
Vomiting |
<1% |
1% |
|
Myalgia |
<1% |
<1% |
|
Rash |
<1% |
<1% |
|
Decreased appetite |
<1% |
<1% |
|
Somnolence |
<1% |
<1% |
|
Back pain |
<1% |
<1% |
|
Upper respiratory tract infection |
0% |
<1% |
* Placebo injectable suspension: intralipid 20% fat emulsion
HPTN 084 Study
|
||
| Apretude® Every 2 months (n=1614) |
Truvada® Once a day (n=1610) |
|
|
Injection site reactions |
38% |
11% * |
|
Diarrhea |
4% |
4% |
|
Headache |
12% |
13% |
|
Pyrexia |
<1% |
<1% |
|
Fatigue |
3% |
3% |
|
Sleep disorders |
1% |
1% |
|
Nausea |
4% |
8% |
|
Dizziness |
4% |
6% |
|
Flatulence |
<1% |
<1% |
|
Abdominal pain |
2% |
2% |
|
Vomiting |
2% |
5% |
|
Myalgia |
2% |
1% |
|
Rash |
<1% |
<1% |
|
Decreased appetite |
2% |
4% |
|
Somnolence |
2% |
2% |
|
Back pain |
1% |
<1% |
|
Upper respiratory tract infection |
4% |
4% |
During the study, no participants withdrew due to adverse events. Among participants who experienced at least one adverse event during the Apretude® injection, the severity of reactions was mild in 66% of participants, moderate in 34% of participants, and severe in less than 1%. The median duration of adverse events was 8 days. The proportion of participants reporting adverse events and their severity decreased over time.
Drug-resistant HIV-1 variants have been identified with the use of Apretude® by HIV-1 infected individuals. HIV-1 testing should be performed before starting Apretude® and also before each subsequent injection.
Integrase inhibitor
Absolute bioavailability is not known
3 hours (oral), 7 days (injectable)
41 hours (oral), 5.6 – 11.5 weeks (injectable)
UGT1A1 and UGT1A9 minor (oral and injectable)
0.5 (oral and injectable)
In faeces 59% (47% as unchanged drug) and urinary excretion 27% (0% as unchanged drug) (oral and injectable)
> 99,8% (oral and injectable)
Cabotegravir injection exhibits limited absorption kinetics (flip-flop model). Its slow absorption from the gluteal muscle to the systemic circulation results in a constant plasma concentration. The plasma concentration of cabotegravir is detectable from the day of injection and then increases to reach its maximum value with a median Tmax of 7 days.
Initial safety assessment of injectable cabotegravir (CAB-LA) during pregnancy in the open-label extension HPTN 084
|
|||
| CAB-LA injections during pregnancy | CAB-LA injections before pregnancy only | No exposition to CAB-LA | |
|
Incidence of maternal adverse effects |
45.7% |
47.1% |
37.5% |
|
Poor pregnancy outcomes* |
33.0% |
38.0% |
27.0% |
|
Maternal death |
0% |
0% |
0% |
| Major congenital anomaly |
1.0% |
0% |
0% |
* Composite outcome of spontaneous abortion <20 weeks, intrauterine fetal death or stillbirth ≥20 weeks, preterm birth <37 weeks, or small for gestational age.
A median of 4 injections (IQR 2-4) were received by participants using CAB-LA during pregnancy. CAB-LA was well tolerated in pregnant women, with pregnancy and infant outcomes similar to those estimated for the general population.
The data highlight that no dose modification is required for CAB-LA during pregnancy. To date, none of the pregnant women who continued treatment with CAB-LA had a positive HIV test during pregnancy. In summary, the pharmacokinetics of cabotegravir have not changed and no cases of HIV positivity have been observed.
These data provide reassurance regarding the use of CAB-LA during pregnancy.
Based on animal studies, cabotegravir may be present in human milk. Therefore, women are advised to breastfeed only if the benefit outweighs the potential risk.
Concomitant administration of cabotegravir tablets with antacids results in chelation and loss of efficacy. It is therefore recommended that antacids containing polyvalent ions be administered at least 2 hours before or 4 hours after taking Apretude® tablets.
See interaction module for further details.
Modified presentation of HIV infection
When patients receive CAB-LA PrEP, a modified presentation of acute HIV infection, called Long-Acting Early Viral inhibition, has been observed (LEVI).
LEVI is characterized by :
– A low or undetectable HIV viral load
– Decreased or delayed production of HIV antibodies
– Levels close to the detection threshold of tests complicating diagnosis
HIV RNA testing can detect infection earlier than standard HIV screening tests, so current “Centers for Disease Control and Prevention” guidelines recommend HIV RNA testing in people receiving CAB-LA PrEP.
| Classic acute HIV infection | Acute HIV infection involving LEVI | |
|
Context |
No antiretroviral therapy |
Long-acting antiretroviral PrEP (CAB-LA prototype) |
|
Beginning |
New infection |
Infection during PrEP or starting PrEP during early infection |
|
Symptoms |
Fevers, chills, itching, rash, night sweats, muscle aches, fatigue, sore throat, swollen glands |
Minimal symptoms varied and often non-existent |
|
Viral replication |
Very high |
Low to undetectable |
|
Detection |
Antigen and antibody testing, RNA testing (including less sensitive point-of-care testing) |
Ultrasensitive RNA analysis (often low or undetectable, low or undetectable DNA, decreased or delayed antibody production) |
|
Duration |
1 to 2 weeks |
Several months |
|
Resistance to treatment |
No |
Yes |
For safer use of these drugs used concomitantly with cabotegravir, consult the product monograph.
Cabotegravir tablets and injections should be stored below 30°C and should not be frozen. The suspension can be stored for up to 2 hours at 25°C.
CAB, cabotegravir; LA, long-acting, TDF, tenofovir disoproxyl furamate; FTC, emtricitabine.
Search interactions