Cabenuva®
Cabotegravir 30 mg (Vocabria®)
Rilpivirine 25 mg (Edurant®)
Cabotegravir 600 mg/3mL - Rilpivirine 900 mg/3mL
Cabotegravir 400 mg/2mL - Rilpivirine 600 mg/2mL
Fabricant : ViiV Healthcare
OPTIONNAL 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. For missed doses, the product monograph recommends an interval of 12 hours.
Take the missed dose as soon as possible, unless there are only 12 hours or less before the next dose. Do not double the dose.
EVERY 2-MONTH INTRAMUSCULAR INJECTION DOSING
Initiation intramuscular injections (first and second month)
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.
One month later, a second set of 3mL initiation injections should be administered.
Continuation intramuscular injections (from the fourth month)
1 injection of 3 mL (600 mg) of cabotegravir and 1 injection of 3 mL (900 mg) of rilpivirine Month 4 and every 2-months onwards.
The dose can be administered within 7 days before up to 7 days after the date of the scheduled injection.
MISSED INJECTIONS
Patients who miss a scheduled injection visit should be clinically reassessed to ensure resumption of therapy remains appropriate. Refer to Cabenuva® product monograph for details on dosing recommendations after missed injections.
Safety and efficacy have not been established in pediatric population.
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.
Child-Pugh A or B : No adjustment required
Child-Pugh C : Caution during administration (not studied in this population)
Cabenuva® has been studied in patients naïve to antiretroviral treatment as well as in patients changing treatment with virologic suppression.
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL in intention to treat) |
Type of patients |
|
FLAIR |
Induction phase : DTG/ABC/3TC x 20 weeks for subjects which then pass into the group DTG/ABC/3TC per os DTG/ABC/3TC x 16 weeks and CBG per os + RPV per os x 4 weeks for subjects who then move on to CBG LA + RPV LA IM Maintenance phase : |
Noninferiority of CBG LA + RPV LA IM vs DTG/ABC/3TC per os Lack of response (VL ≥ 50 copies/ml) observed in 2.1% and 2.5% of patients, respectively for CBG LA + RPV LA IM and the DTG/ABC/3TC per os group at week 48 and 3.2% and 2.5% at week 96 |
Median age 34 years, 78% male, 74% white, 92% CD4+ ≥ 350 cells/mm3. |
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL) in intention to treat |
Types of patients |
|
ATLAS |
CBG LA + RPV LA IM (N=308) vs CAR* (N=308) |
Week 48 |
Taking the same CAR* since > 6 months; viral load < 50 copies/mL since > 6 months; no histoiry of virological failure; without resistance to INIs or NNRTIs (except the K103N reverse transcriptase mutation). Patients not requiring treatment for hepatitis B. Median age 42 years, 67% male, 68% white, 92% CD4+ ≥ 350 cells/mm3. |
|
ATLAS 2M |
CBG-RPV LA IM |
FDA Snapshot Analysis (ITT) Lack of response (VL ≥ 50 copies/mL) observed in 1.7% (Q8wk) and 1.0% (Q4wk). Week 152 : 87% et 86%. Lack of response (VL ≥ 50 copies/mLl) observed in 3.0% (Q8wk) and 1.0% (Q4wk). |
Subjects of ATLAS study with VL <50 copies/mL at 52 weeks and subjects on CAR* outside the ATLAS study with VL <50 copies/mL for > 6 months; without histoiry of virological failure; without resistance INIs or NNRTIs (except the K103N reverse transcriptase mutation). Patients not requiring treatment for hepatitis B. Median 42 years, 74% male, 73% white, 94% CD4+ ≥ 350 cells/mm3. |
|
CARISEL |
CBG + RPV LA IM |
FDA Snapshot Analysis (ITT) Lack of response (VL ≥ 50 copies/mL) observed in 0.7%. |
Patients with virologic suppression who switched from daily oral therapy to CAB+RPV LA Q8wk; no documented or suspected resistance to CBG or RPV. Median age 44, 75% male, 18% black. |
*CAR : Current ART regimen containing 2 NRTIs associated with either an INI, an NNRTI or a PI (excluding ABC + 3TC + DTG-based regimen)
FLAIR Study
|
||
| CBG LA + RPV LA (N=283) |
DTG/ABC/3TC (N=283) |
|
|
Headache |
14% |
7% |
|
Diarrhea |
11% |
9% |
|
Vitamin D deficiency |
8% |
5% |
|
Back pain |
8% |
5% |
|
Pyrexia |
8% |
1% |
|
Hemorrhoids |
6% |
1% |
|
Nausea |
6% |
4% |
|
Dizziness |
5% |
1% |
|
Pain at injection site |
80% |
N/A |
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.
In this single-arm study of 430 virologically suppressed PLHIV who switched from daily oral treatment with CAB+RPV LA Q8Wk, 6% of participants experienced Grade ≥3 drug-related adverse events. The most reported side effect was injection site reactions in 86% of participants and 98% were mild or moderate in severity. 10% of patients discontinued study treatment due to adverse effects (6% due to injection site reactions).
ATLAS Study
|
||
| CBG LA + RPV LA (N=308) |
CAR* (N=308) |
|
|
Headache |
11% (4%) |
6% (0%) |
|
Diarrhea |
7% (1%) |
5% (0%) |
|
Back pain |
7% (1%) |
3% (0%) |
|
Pyrexia |
7% (4%) |
3% (0%) |
|
Pain at injection site |
75% |
N/A |
|
Flu-like reaction |
6% (2%) |
5% (0%) |
|
Fatigue |
7% (4%) |
2% (0%) |
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.
ATLAS-2M Study
|
||
| CBG + RPV LA Q8Wk (N=522) |
CBG + RPV LA Q4Wk (N=523) |
|
|
Pyrexia |
7% |
8% |
|
Pain at injection site |
75% |
75% |
|
Fatigue |
5% |
6% |
In the ATLAS-2M study at 48 weeks, 2% of patients in both groups discontinued study treatment due to adverse effects. The most common adverse reactions leading to discontinuation of injectable therapy were injection site reactions, fatigue, pyrexia, headache, presyncope, acute hepatitis B, and abnormal dreams.
At week 152, adverse reactions observed other than injection site reactions were fatigue and fever.
There were approximately 2% discontinuations due to injection site reactions and these were somewhat higher in individuals receiving the injectable therapy every 4 weeks vs. 8 weeks.
Serious but very rare side effects have been reported such as hepatotoxicity, pancreatitis and cellulitis at the injection site..
For management of adverse reactions associated with antiretrovirals, see section management of 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.
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. All 3 patients had subtype A1 viruses. 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). One shows resistance to cabotegravir and 2 to rilpivirine.
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 in patients with subtype A, A1 and AG viruses. One patient developed the N155H mutation on integrase which decreases the susceptibility to cabotegravir and the E138E/K mutation on reverse transcriptase (mutations not detected in the basic genotype). All 3 demonstrates resistance to rilpivirine. 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.
In the ATLAS-2M study, at 152 weeks, there is still a low rate of virological failure of 1% or 13/1045 participants. There are slightly more failures in the arm with injections every 8 weeks (2%) vs every 4 weeks (less than 1%). Most failures (10/13) occurred before the 48th week. 8 subjects (1.5%) in the arm with injections every 8 weeks and 2 subjects (0.4%) with injections every 4 weeks. Moreover, 8/10 of the failures occurred before the 24th week.
At baseline in the Q8W arm, 5 subjects had rilpivirine resistance-associated mutations of Y181Y/C + H221H/Y, Y188Y/F/H/L, Y188L, E138A or E138E/A and 1 subject contained cabotegravir resistance mutation, G140G/R (in addition to the above Y188Y/F/H/L rilpivirine resistance-associated mutation).
At the suspected virologic failure (SVF) timepoint in the Q8W arm, 6 subjects had rilpivirine resistance-associated mutations with 2 subjects having an addition of K101E and 1 subject having an addition of E138E/K from Baseline to SVF timepoint. Rilpivirine FC was above the clinical cut-off for 7 subjects and ranged from 2.4 to 15. Five of the 6 subjects with rilpivirine resistance-associated substitution, also had INI resistance-associated substitutions, N155H (n=2); Q148R; Q148Q/R+N155N/H (n=2). INI substitution, L74I, was seen in 4/7 subjects.
The integrase genotype and phenotype assay failed for one subject and cabotegravir phenotype was unavailable for another. FCs for the Q8W subjects ranged from 0.6 to 9.1 for cabotegravir, 0.8 to 2.2 for dolutegravir and 0.8 to 1.7 for bictegravir.
In the Q4W arm, neither subject had any rilpivirine or INI resistance-associated substitutions at baseline. One subject had the NNRTI substitution, G190Q, in combination with the NNRTI polymorphism, V189I. At SVF timepoint, one subject had on-treatment rilpivirine resistance-associated mutations, K101E + M230L and the other retained the G190Q + V189I NNRTI substitutions with the addition of V179V/I. Both subjects showed reduced phenotypic susceptibility to rilpivirine. Both subjects also had INI resistance-associated mutations, either Q148R + E138E/K or N155N/H at SVF and 1 subject had reduced susceptibility to cabotegravir. Neither subject had the INI substitution, L74I. FCs for the Q4W subjects were 1.8 and 4.6 for cabotegravir, 1.0 and 1.4 for dolutegravir and 1.1 and 1.5 for bictegravir.
Integrase inhibitor
Non-nucleoside reverse transcriptase inhibitor (NNRTI) of the diarylpyrimidine class
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.
Cabotegravir : 3 hours (oral), 7 days (injectable)
Rilpivirine : 4 hours (oral), 3 to 4 days (injectable)
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 %)
Cabotegravir : UGT1A1 and UGT1A9 minor (oral and injectable)
Rilpivirine : CYP3A4 (oral and injectable)
Cabotegravir : 0.5 (oral and injectable)
Rilpivirine : 0.7 (oral and injectable)
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)
Cabotegravir : > 99.8% (oral and injectable)
Rilpivirine : ~99.7% (oral and injectable)
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.
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.
Rilpivine per os (Edurant®) in association with cabotegravir (Vocabria®)
Cabotegravir/rilpivirine IM (Cabenuva®)
See the interaction module for further details.
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.
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.
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).
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.
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