Cabotegravir (CBG) + Rilpivirine (RPV)

DOSAGE

Adult dosage (in three phases)

ORAL LEAD-IN

1 tablet of cabotegravir 30 mg DIE with 1 tablet of rilpivirine 25 mg DIE for the first month (at least 28 days).

Oral rilpivirine should be taken with food.

INITIATION INTRAMUSCULAR INJECTIONS

1 injection of 3 mL (600 mg) of cabotegravir and 1 injection of 3 ml (900 mg) of rilpivirine for a dose to be administered on the same day as the last oral doses of cabotegravir and rilpivirine.

CONTINUATION INTRAMUSCULAR INJECTIONS

1 injection of 2 mL (400 mg) of cabotegravir and 1 injection of 2 mL (600 mg) of rilpivirine every 4 weeks (to start 4 weeks after the initial intramuscular injections).

The dose can be administered within 7 days before up to 7 days after the date of the scheduled monthly injection.

If it is not possible for the patient to receive their injections within this interval, they should take oral rilpivirine (25 mg die) and oral cabotegravir (30 mg die) as an alternative, to be started approximately 1 month after the last IM dose. The return to IM doses should start on the day the patient takes his last oral doses. If the oral alternative is taken for more than two months, when returning to IM doses, the initial IM doses should be re-administered (600 mg of cabotrgravir and 900 mg of rilpivirine for one dose then move on to subsequent doses).

Pediatric dosage

Safety and efficacy have not been established in pediatric population.

Adjustment in renal impairment

CrCl ≥ 15 mL/min : No adjustment required

CrCl < 30 mL/min or patients on dialysis: Since there are no data for this population, a closer monitoring of adverse effects is recommended.

Adjustment in hepatic impairment

Child-Pugh A or B : No adjustment required

Child-Pugh C : Caution during administration (not studied in this population)

COMPARATIVE EFFICIENCY

Cabenuva^® has been studied in patients naïve to antiretroviral treatment as well as in patients changing treatment with virologic suppression.

Study in patients who have never received antiretrovirals

Studies in patients with virological suppression

*CAR : Current ART regimen containing 2 NRTIs associated with either an INI, an NNRTI or a PI (excluding ABC + 3TC + DTG-based regimen)

ADVERSE REACTIONS

In short

• Headache
• Nausea, diarrhea
• Pain at the injection site

N/A : not applicable

Regarding the adverse reactions that were considered to be related to the treatment (excluding reactions at the injection site), they were present in 28% of participants in the CBG LA + RPV LA group compared to 10% of participants in the DTG/ABC/3TC group. Besides pain at the injection site, the most common adeverse reactions considered to be associated with CBG LA + RPV LA were headache, pyrexia, increased body temperature, asthenia and malaise. The most common adeverse reactions considered to be associated with DTG / ABC / 3TC were nausea and fatigue.

Discontinuation of treatment secondary to adverse reactions was necessary in 2.8% and 0.7% of patients on CBG LA + RPV LA and DTG/ABC/3TC, respectively, at 48 weeks.

N/A : not applicable
*CAR : Current ART regimen containing 2 NRTIs associated with either an INI, an NNRTI or a PI (excluding regimen with ABC + 3TC + DTG)

Discontinuation of treatment secondary to adverse reactions was necessary in 5% and 2% of patients on CBG LA + RPV LA and CAR, respectively, at 48 weeks. The most common side effects leading to discontinuation of injectable therapy were pain at the injection site, viral hepatitis, and headache.

For management of adverse reactions associated with antiretrovirals, see section management of adverse reactions.

Rare adverse reactions

Hypersensitivity reactions

Hypersensitivity reactions have been associated with integrase inhibitors. This reaction presented with a rash, constitutional symptoms, multi-organ and hepatic damage. Skin and hypersensitivity reactions have also been reported when taking therapy containing rilpivirine. The product monograph therefore recommends that Cabenuva^® or Vocabria^®/Edurant^® be stopped immediately in the presence of signs or symptoms that may suggest a hypersensitivity reaction (severe rash or accompanied by fever, general malaise, fatigue, muscle or joint pain, vesicles, mouth sores, conjunctivitis, facial edema , hepatitis, eosinophilia or angioedema) and closely monitor the patient’s clinical condition.

Hepatotoxicity

Acute hepatitis or hepatotoxicity has been reported in patients who had no pre-existing liver disease or other identifiable risk factors. Therefore, it is recommended to monitor for the appearance of hepatotoxicity during treatment. It is important to note that the dual therapy of cabotegravir and rilpivirine should not be considered as antiretroviral therapy in a patient with concomitant chronic hepatitis B.

Immune reconstitution inflammatory syndrome (IRIS)

This effect can be seen with any antiretroviral therapy. An inflammatory response to poorly progressive or residual opportunistic infections (e.g. Mycobacterium avium complex, cytomegalovirus, Pneumocystis jirovecii pneumonia or tuberculosis) which may require treatment. Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been observed.

Depressive disorders

Depressive disorders have been reported with the use of rilpivirine. Patients who present with depressive symptoms (depressed mood, depression, dysphoria, major depression, mood alteration, negative thoughts, suicide attempt, suicidal ideation) following initiation of therapy containing rilpivirine should be evaluated adequately to determine if the drug may be involved. Insomnia, depression and suicidality have been reported with integrase inhibitors, more in patients with pre-existing psychiatric conditions.

RESISTANCE

This dual therapy should not be used in patients with known or possible resistance to cabotegravir or rilpivirine.

In the FLAIR study, at 48 weeks, there were three confirmed virologic failures in the CBG LA + RPV LA group. Following these virological failures, the following mutations were detected on genotyping on the reverse transcriptase E138E/A/K/T, K101E, E138K and on the integrase Q148R (n=2), G140R (n=1) and N155H (n=1).

All three patients already had the L74I mutation in the pretreatment genotype (when alone, this mutation has very little effect on susceptibility to integrase inhibitors). Three participants had virologic failure in the comparator group (DTG/ABC/3TC), and no mutations were detected.

In the ATLAS study, at 48 weeks, there were three confirmed virologic failures in the CBG LA + RPV LA group. One patient developed the N155H mutation on integrase and the E138E/K mutation on reverse transcriptase (mutations not detected in the basic genotype). The following mutations were detected in some of these patients in the baseline genotype and at the time of virological failure : integrase L74I; reverse transcriptase E138A, V108I, E138K.

MECHANISM OF ACTION

Cabotegravir

Integrase inhibitor

Rilpivirine

Non-nucleoside reverse transcriptase inhibitor (NNRTI) of the diarylpyrimidine class

PHARMACOKINETICS

Bioavailability

Cabotegravir : Absolute bioavailability is not known
Rilpivirine : Absolute bioavailability is not known
It is recommended that oral rilpivirine be taken with a meal. When taken with a meal, the absorption of rilpivirine is increased.
Indeed, a moderate fat meal increases the AUC and Cmax of rilpivirine by 57% and 89%, respectively.

Tmax

Cabotegravir : 3 hours (oral), 7 days (injectable)
Rilpivirine : 4 hours (oral), 3 to 4 days (injectable)

Elimination T½ (plasma)

Cabotegravir : 41 hours (oral), ~40 days (injectable)
Rilpivirine : 45 hours (with a single dose and a moderate fat meal*) (oral), ~90 days (IM long acting)
* ~625 kcal : 125 kcal of protein (20 %), 300 kcal of carbohydrates (48 %) et 200 kcal of fat (32 %)

Metabolism

Cabotegravir : UGT1A1 and UGT1A9 minor (oral and injectable)
Rilpivirine : CYP3A4 (oral and injectable)

Blood-plasma ratio

Cabotegravir : 0.5 (oral and injectable)
Rilpivirine : 0.7 (oral and injectable)

Elimination

Cabotegravir : in faeces 59% (47% as unchanged drug) and urinary excretion 27% (0% as unchanged drug) (oral and injectable)
Rilpivirine : in faeces 85% (25% unchanged) and urinary excretion 6.1% (< 1% unchanged) (oral and injectable)

Binding to plasma proteins

Cabotegravir : > 99.8% (oral and injectable)
Rilpivirine : ~99.7% (oral and injectable)

Pregnancy

Cabotegravir : There are no pharmacokinetic data for cabotegravir during pregnancy.
Rilpivirine : Orally, there is a decrease in total rilpivirine exposure during pregnancy in the 2nd and 3rd trimesters compared to the postpartum period, representing a 21%, 29% and 35% decrease in Cmax, AUC and Cmin respectively. For free (active) rilpivirine, the decrease in pharmacokinetic parameters observed between pregnancy and the postpartum period was less pronounced.

PREGNANCY AND BREAST FEEDING

There are not enough data to assess the safety and efficacy of Cabenuva^® in pregnant or breastfeeding women. Mothers treated with Cabenuva^® should be advised not to breast-feed because of the risk of transmitting HIV-1 to their infants.

Professionals are encouraged to report pregnancy cases with a view to adding them to the register: :
www.apregistry.com/  Telephone : 1-800-258-4263 Fax : 1-800-800-1052.

PRECAUTIONS AND CONTRAINDICATIONS

Contraindications

• Hypersensitivity to the active or inactive molecules (see product monograph for further details).

Rilpivine per os (Edurant^®) in association with cabotegravir (Vocabria^®)

• Co-administration with drugs that induce CYP3A enzymes or increase gastric pH as it could lead to loss of virological response and possible resistance to cabotegravir (Vocabria^®) and/or to rilpivirine (Edurant^®) : carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifabutin, rifapentine, systemic dexamethasone (more than a single dose), St. John’s Wort (Hypericum perforatum), proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole)

Cabotegravir/rilpivirine IM (Cabenuva^®)

• Co-administration with drugs that induce CYP3A enzymes as it could lead to loss of virological response and possible resistance to cabotegravir/rilpivirine IM (Cabenuva®) : carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifabutin, rifapentine, systemic dexamethasone (more than a single dose), St. John’s Wort (Hypericum perforatum).

See the interaction module for further details.

FURTHER INFORMATION

Oral administration

Rilpivirine and cabotegravir tablets should be swallowed whole.

According to written communication with the company ViiV reported in a publication in 2016, crushed rilpivirine, added to a small amount of soft food or liquid is not expected to cause any change in the quality of the drug product if the drug is consumed immediately after crashing it. However, this has not been studied. There is no information on whether the cabotegravir tablet can be crushed.

Based on clinical judgment, if the tablets are to be crushed, they should be crushed and added to a small amount of liquid or semi-solid food and consumed whole immediately with a meal. In the absence of detailed data on this method of administration, the clinician may consider performing a therapeutic drug monitoring (TDM) for rilpivirine.

Intramuscular administration

A healthcare professional should give intramuscular injections of cabotegravir and rilpivirine into the buttock muscle exclusively, at two separate points in the buttock muscle (gluteus medius). For each dose of antiretrovirals, two injections should be given: one injection of cabotegravir and one injection of rilpivirine. For patients with a higher BMI (BMI > 30 kg/m²), a longer needle should be considered in order to ensure that the injection is made into the muscle.

Storage

Store cabotegravir and rilpivirine tablets at room temperature 15-30 °C. Edurant^® product monograph recommends storing the tablets in the original packaging and protected from light.

Store the rilpivirine and cabotegravir injections in the original carton, in the refrigerator between 2-8 °C. Before administration, they must be brought back to room temperature (maximum stability at room temperature: 6 hours).

REFERENCES

• Cabotegravir/rilpivirine (Cabenuva) and cabotegravir (Vocabria), ViiVHealthcare, Quebec, Canada, march 18 2020.

• Rilpivirine (Edurant), Janssen Inc., Ontario, Canada, July 26, 2017.

• U.S. Department of Health and Human Services (DHHS). Antiretroviral Dosing Recommendations in Patients with Renal or Hepatic Insufficiency. Publié le 10 juillet 2019. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/44/arv-dosing-for-renal-or-hepatic-insufficiency Consulté le 30 novembre 2019.

• M. Foisy, Pharm.D., AAHIVP, Northern Alberta Program, Royal Alexandra Hospital Site, Edmonton, C. Hughes, Pharm.D., AAHIVP, Northern Alberta Program, KEC Site,Edmonton, Alberta, Sarah Lamb, PharmD Student (2017 updates), and A. Tseng, Pharm.D, AAHIVP, Toronto General Hospital. ORAL ANTIRETROVIRAL ADMINISTRATION: INFORMATION ON CRUSHING AND LIQUID DRUG FORMULATIONS.

• Swindells S, Andrade-Villanueva JF, Richmond GJ, Rizzardini G, Baumgarten A et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. New England Journal of Medicine, 2020 Mar 19; 382(12): 1112-1123.

• Orkin C, Arasteh K, Górgolas Hernández-Mora M, Pokrovsky V, Overton ET et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. New England Journal of Medicine, 2020 Mar 19; 382(12), 1124-1135.

• La pharmacométrie clinique des antirétroviraux et l’individualisation de la thérapie antirétrovirale chez les adultes et les enfants vivant avec le VIH – Guide pour les professionnels de la santé du Québec: https://publications.msss.gouv.qc.ca/msss/fichiers/2013/13-308-06W.pdf

ABBREVIATIONS

CBG, cabotegravir; RPV, rilpivirine; DIE, once daily; IM, intramuscular; CrCl, creatinine clearance; LA, long acting; DTG, dolutegravir; ABC, abacavir; 3TC, lamivudine; CAR, current ART regimen; VL, viral load; NRTI, nucleoside reverse transcriptase inhibitor, InI, integrase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; IP, protease inhibitor; AUC, area under the curve; Cmax, maximum concentration; Cmin, minimum concentration.