Summary Basis of Decision for Vocabria/Cabenuva
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Vocabria/Cabenuva is located below.
Recent Activity for Vocabria/Cabenuva
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Vocabria/Cabenuva
Date SBD issued: 2020-06-12
The following information relates to the new drug submission for Vocabria/Cabenuva.
Vocabria: Cabotegravir (supplied as cabotegravir sodium)
Cabenuva: Cabotegravir and rilpivirine
Drug Identification Number (DIN):
- DIN 02497204 (Vocabria) - 30 mg, tablet, oral administration
- DIN 02497247 (Cabenuva) - 200 mg/mL (600 mg/3 mL) cabotegravir and 300 mg/mL (900 mg/3 mL) rilpivirine, suspensions (extended-release), intramuscular administration
- DIN 02497220 (Cabenuva) - 200 mg/mL (400 mg/2 mL) cabotegravir and 300 mg/mL (600 mg/2 mL) rilpivirine, suspensions (extended-release), intramuscular administration
ViiV Healthcare ULC
New Drug Submission Control Number: 227315
On March 18, 2020, Health Canada issued a Notice of Compliance to ViiV Healthcare ULC for the drug products Vocabria and Cabenuva.
The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review:
- The benefit-harm-uncertainty profile of Vocabria is favourable in combination with Edurant (rilpivirine tablets), as a complete regimen for short‑term treatment of human immunodeficiency virus type 1 (HIV‑1) infection in adults who are virologically stable and suppressed (HIV‑1 ribonucleic acid [RNA] less than 50 copies/mL) as:
- an oral lead‑in to assess tolerability of cabotegravir prior to initiating Cabenuva.
- oral bridging therapy for missed Cabenuva injections.
- The benefit-harm-uncertainty profile of Cabenuva is favourable as a complete regimen for the treatment of HIV‑1 infection in adults to replace the current antiretroviral regimen in patients who are virologically stable and suppressed (HIV‑1 RNA less than 50 copies/mL).
1 What was approved?
Vocabria and Cabenuva are antiretroviral agents. These two drugs represent one treatment regimen for human immunodeficiency virus type 1 (HIV‑1) infection in virologically suppressed patients.
Vocabria was authorized in combination with Edurant (rilpivirine tablets), as a complete regimen for short‑term treatment of HIV‑1 infection in adults who are virologically stable and suppressed (HIV-1 ribonucleic acid [RNA] less than 50 copies/mL) as:
- an oral lead‑in to assess tolerability of cabotegravir prior to initiating Cabenuva.
- oral bridging therapy for missed Cabenuva injections.
Cabenuva was authorized as a complete regimen for the treatment of HIV‑1 infection in adults to replace the current antiretroviral regimen in patients who are virologically stable and suppressed (HIV‑1 RNA less than 50 copies/mL).
Dosing consists of three distinct phases: an oral lead‑in with Vocabria taken together with Edurant (rilpivirine tablets), initiation injections of Cabenuva (cabotegravir 3 mL and rilpivirine 3 mL), and continuation injections with Cabenuva (cabotegravir 2 mL and rilpivirine 2 mL).
The safety and efficacy of Vocabria and Cabenuva have not been established in pediatric patients (younger than 18 years of age).
Clinical studies of Vocabria and Cabenuva did not include sufficient numbers of geriatric patients (aged 65 years and older) to determine whether they respond differently than adult patients under 65 years of age.
Vocabria and Cabenuva are contraindicated in patients who are hypersensitive to cabotegravir or rilpivirine or to any ingredient in the formulations, including any non‑medicinal ingredient, or component of the containers.
Vocabria is additionally contraindicated in combination with the following:
- Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, and phenytoin
- Antimycobacterials: rifampin, rifapentine
Prior to initiation of Vocabria, healthcare professionals should be aware that use of Cabenuva with rifabutin is contraindicated.
As Vocabria is taken in combination with Edurant (rilpivirine tablets), the prescribing information for Edurant should be consulted for additional contraindications.
Cabenuva is additionally contraindicated in combination with the following:
- Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, and phenytoin
- Antimycobacterials: rifabutin, rifampin, rifapentine
- Glucocorticoid: systemic dexamethasone (more than a single dose)
- St. John's wort (Hypericum perforatum)
Vocabria and Cabenuva were approved for use under the conditions stated in their Product Monograph taking into consideration the potential risks associated with the administration of these drug products.
Vocabria (30 mg cabotegravir, supplied as cabotegravir sodium) is presented as tablets. In addition to the medicinal ingredient, the tablets contain hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
Cabenuva (200 mg/mL cabotegravir and 300 mg/mL rilpivirine) is presented as extended‑release injectable suspensions, with each medicinal ingredient in a separate vial. The Cabenuva initiation kit includes 3 mL vials of both the cabotegravir and rilpivirine suspensions. The Cabenuva maintenance kit includes 2 mL vials of both the cabotegravir and rilpivirine suspensions. In addition to the medicinal ingredient, the cabotegravir suspension contains mannitol, polysorbate 20, polyethylene glycol (PEG) 3350, and water for injection. The rilpivirine suspension contains citric acid monohydrate, glucose monohydrate, poloxamer 338, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Vocabria and Cabenuva Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Vocabria/Cabenuva approved?
Health Canada considers that the benefit‑harm‑uncertainty profiles of Vocabria and Cabenuva are favourable for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection in virologically suppressed patients. Together, Vocabria and Cabenuva represent one treatment regimen.
Vocabria (cabotegravir tablets) was authorized in combination with Edurant (rilpivirine tablets), as a complete regimen for short‑term treatment of HIV‑1 infection in adults who are virologically stable and suppressed (HIV‑1 ribonucleic acid [RNA] less than 50 copies/mL) as:
- an oral lead‑in to assess tolerability of cabotegravir prior to initiating Cabenuva.
- oral bridging therapy for missed Cabenuva injections.
Cabenuva (cabotegravir and rilpivirine extended‑release injectable suspensions) was authorized as a complete regimen for the treatment of HIV‑1 infection in adults to replace the current antiretroviral regimen in patients who are virologically stable and suppressed (HIV‑1 RNA less than 50 copies/mL).
Human immunodeficiency virus type 1 (HIV‑1) is a retrovirus that targets the immune system. If left untreated, HIV‑1 infection causes the progressive loss of CD4+ T‑cells and a wide range of immunological abnormalities that may ultimately lead to acquired immunodeficiency syndrome (AIDS). Patients with AIDS have increased susceptibility to opportunistic infections and cancer. Additionally, HIV‑1 infection contributes to cardiovascular disease, bone disease, renal and hepatic dysfunction, and several other common morbidities. According to national estimates, there were 63,000 HIV‑1‑infected people in Canada at the end of 2016.
The current standard of care in Canada for HIV‑infected patients includes combination antiretroviral therapy (cART) with the goal to suppress viral replication to below detectable limits, increase CD4+ cell counts, and stop disease progression. At this time, there are six classes of antiretroviral drugs that can be used for cART: nucleos(t)ide reverse transcriptase inhibitors (NRTIs), non‑nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), fusion inhibitors, and co receptor antagonists.
Vocabria and Cabenuva have been developed as one therapeutic regimen for the treatment of HIV‑1 infection in adult patients who are virologically suppressed (plasma level of HIV‑1 RNA less than 50 copies/mL). Cabotegravir, a medicinal ingredient in both Vocabria and Cabenuva, is a new active substance in Canada. Rilpivirine, a medicinal ingredient in Cabenuva, has already been approved in Canada as a single agent as well as in several fixed‑dose combination products. Cabotegravir is an INSTI that acts by inhibiting HIV DNA integration into host genomic DNA. Rilpivirine is an NNRTI that acts by inhibiting the HIV reverse transcriptase enzyme.
The market authorizations for Vocabria and Cabenuva were based primarily on evidence from two Phase III pivotal studies. The FLAIR study was conducted in antiretroviral treatment‑naïve patients with HIV‑1, while the ATLAS study was conducted in antiretroviral treatment‑experienced patients with HIV‑1. Both studies demonstrated the non‑inferiority of Vocabria and Cabenuva relative to the current antiretroviral regimen in virologically suppressed patients with HIV‑1, and are described in further detail in the Clinical Efficacy section.
The main risks and uncertainties associated with Vocabria and Cabenuva treatment are related to long‑acting properties of Cabenuva. Residual concentrations of cabotegravir and rilpivirine injections may remain in the patient's systemic circulation for prolonged periods (12 months or longer). Patients to be treated with Vocabria and Cabenuva must therefore agree to the required monthly injection dosing schedule. Non‑adherence to monthly injections could lead to the loss of virologic response and the development of resistance.
Cases of hepatotoxicity have been reported in patients receiving cabotegravir (a medicinal ingredient in both Vocabria and Cabenuva) with or without known pre‑existing hepatic disease or other identifiable risk factors. Therefore, the Product Monograph recommends monitoring of liver chemistries.
A Risk Management Plan (RMP) for Vocabria and Cabenuva was submitted by ViiV Healthcare ULC to Health Canada. The RMP includes drug resistance as an important identified risk, and hypersensitivity reactions and medication errors as important potential risks. These are expected to be monitored post‑market. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Vocabria and Cabenuva Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look‑alike Sound‑alike brand name assessment was performed and the proposed names Vocabria and Cabenuva were accepted.
Vocabria and Cabenuva have acceptable safety profiles based on the non‑clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Vocabria and Cabenuva Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Vocabria/Cabenuva?
The sponsor filed a request for the review of the new drug submission (NDS) for Vocabria and Cabenuva to be carried out under the Priority Review Policy. To be reviewed through this pathway, sufficient evidence must be provided that the drug provides:
- an effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada, or
- a significant increase in efficacy and/or significant decrease in risk such that the overall benefit‑risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.
An assessment was conducted, and it was determined that this NDS did not meet the criteria for Priority Review Status according to the policy. Specifically, it was determined that as the pivotal studies were non‑inferiority studies, the sponsor had not definitively established improved compliance and superior efficacy for the product, compared to available therapies. The request for Priority Review Status was therefore denied, and the NDS was reviewed through a regular pathway.
Submission Milestones: Vocabria/Cabenuva
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2019-02-21 |
| Request for priority status | |
| Filed: | 2019-02-28 |
| Rejection issued by Director, Bureau of Medical Sciences: | 2019-04-02 |
| Submission filed: | 2019-04-29 |
| Screening | |
| Screening Acceptance Letter issued: | 2019-05-24 |
| Review | |
| Quality Evaluation complete: | 2020-03-13 |
| Clinical/Medical Evaluation complete: | 2020-03-17 |
| Review of Risk Management Plan complete: | 2020-02-18 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2020-03-17 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2020-03-18 |
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post‑market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Cabotegravir, a medicinal ingredient in both Vocabria and Cabenuva, inhibits the human immunodeficiency virus (HIV) integrase enzyme. It binds to the integrase active site and blocks the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration, which is essential for the HIV replication cycle.
Rilpivirine, a medicinal ingredient in Cabenuva, is a diarylpyrimidine non‑nucleoside reverse transcriptase inhibitor of HIV‑1. Rilpivirine activity is mediated by non‑competitive inhibition of HIV‑1 reverse transcriptase. Rilpivirine does not inhibit the human cellular DNA polymerases α, β, and γ.
The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Vocabria and Cabenuva have been well characterized in patients and healthy volunteers.
No dosage adjustment of Vocabria or Cabenuva is required for patients with mild to moderate renal impairment. No dosage adjustment of Vocabria is required for patients with severe renal impairment. Cabenuva has not been studied in patients with severe renal impairment or end stage renal disease, or in patients on dialysis. Increased monitoring for adverse events is therefore recommended in patients meeting these criteria.
No dosage adjustment of Vocabria or Cabenuva is required in patients with mild or moderate hepatic insufficiency. Vocabria and Cabenuva have not been studied in patients with severe hepatic insufficiency.
At their recommended doses, Vocabria or Cabenuva are not expected to prolong the corrected QT (QTc) interval.
Vocabria and Cabenuva are contraindicated with drugs that may reduce the exposure to cabotegravir or rilpivirine, and thus cause a loss of therapeutic effect and possible development of resistance.
Based on their in vitro and clinical drug interaction profiles, cabotegravir and rilpivirine are not expected to alter concentrations of other antiretroviral medications including protease inhibitors, nucleoside reverse transcriptase inhibitors, non‑nucleoside reverse transcriptase inhibitors, integrase inhibitors, entry inhibitors, and ibalizumab.
For further details, please refer to the Vocabria and Cabenuva Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Evidence of the clinical efficacy of Vocabria and Cabenuva was provided through two Phase III non‑inferiority studies in virologically suppressed patients with HIV‑1 infection: FLAIR (201584) and ATLAS (201585).
The FLAIR study aimed to demonstrate the non‑inferiority of Vocabria and Cabenuva relative to continuation of a patient's current antiretroviral regimen in 629 antiretroviral treatment‑naïve patients with HIV‑1. All patients were treated according to a standard‑of‑care dolutegravir (integrase strand transfer inhibitor [INSTI])‑containing antiretroviral regimen) for 20 weeks. Patients who were virologically suppressed (defined as a plasma level of HIV‑1 ribonucleic acid [RNA] <50 copies/mL; number of patients [n] = 566) were then randomized to receive the Vocabria and Cabenuva regimen, or to remain on the standard‑of‑care regimen. The Vocabria and Cabenuva regimen consisted of daily oral lead‑in dosing with one tablet of Vocabria plus one 25 mg tablet of Edurant (rilpivirine) for at least 4 weeks, followed by monthly intramuscular injections of Cabenuva for 44 weeks.
The ATLAS study aimed to demonstrate the non‑inferiority of Vocabria and Cabenuva relative to continuation of a patient's current antiretroviral regimen in 616 antiretroviral treatment‑experienced patients with HIV‑1. All patients were virologically suppressed (plasma level of HIV‑1 RNA <50 copies/mL for at least 6 months) and were randomized to receive the Vocabria and Cabenuva regimen, or to remain on their current antiretroviral regimen. The patients' current antiretroviral regimens consisted of one of the following combinations:
- one non‑nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs),
- a protease inhibitor and two NRTIs, or
- an INSTI and two NRTIs.
The primary endpoint in both the FLAIR and ATLAS studies was the proportion of patients with plasma levels of HIV‑1 RNA ≥50 copies/mL at Week 48.
A pooled analysis of FLAIR and ATLAS demonstrated that Cabenuva was non‑inferior to the control antiretroviral regimens (CAR), with 1.9% and 1.7% of patients, respectively, having plasma levels of HIV‑1 RNA ≥50 copies/mL at Week 48. Additionally, Cabenuva was non‑inferior to the control antiretroviral regimens with respect to the proportion of subjects having plasma levels of HIV‑1 RNA <50 copies/mL at Week 48, with 93% of patients in the pooled FLAIR and ATLAS studies compared to 94% of patients on CAR. Treatment differences across baseline characteristics in the FLAIR and ATLAS studies were comparable. Patients in FLAIR and ATLAS were virologically suppressed prior to Day 1 or study entry, respectively. No clinically relevant change from baseline was observed in either study with respect to CD4+ cell counts.
Indication
| Sponsor's proposed indication | Health Canada-approved indication |
Vocabria (cabotegravir tablets) is indicated:
Cabenuva (cabotegravir injection and rilpivirine injection) is indicated:
| Vocabria (cabotegravir tablets) is indicated, in combination with Edurant (rilpivirine tablets), as a complete regimen for short‑term treatment of human immunodeficiency virus type 1 (HIV‑1) infection in adults who are virologically stable and suppressed (HIV‑1 RNA less than 50 copies/mL) as:
Cabenuva (cabotegravir and rilpivirine extended‑release injectable suspensions) is indicated:
|
For more information, refer to the Vocabria and Cabenuva Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety evaluation of Vocabria and Cabenuva was based on data from the two pivotal studies, FLAIR and ATLAS, which are described in the Clinical Efficacy section.
The most common adverse reactions in the pooled analysis of the two pivotal studies were injection site reactions (83%), pyrexia (8%), fatigue (5%) and headache (4%). The severity of injection site reactions was generally mild (Grade 1) or moderate (Grade 2), reported in 75% and 36% of patients, respectively. Severe (Grade 3) injection site reactions were reported in 4% of patients. There were no Grade 4 injection site reactions. The median duration of all injection site reaction events was three days. Adverse events leading to discontinuation include injection site reactions, hepatitis A, acute hepatitis B, headache, and diarrhea.
The main risks and uncertainties associated with Vocabria and Cabenuva treatment are related to long‑acting properties of Cabenuva. Residual concentrations of cabotegravir and rilpivirine injections may remain in the patient's systemic circulation for prolonged periods (12 months or longer). Patients to be treated with Vocabria and Cabenuva must therefore agree to the required monthly injection dosing schedule. Non‑adherence to monthly injections could lead to the loss of virologic response and the development of resistance.
Cases of hepatotoxicity have been reported in patients receiving cabotegravir, a medicinal ingredient in both Vocabria and Cabenuva. This has been observed in patients with or without known pre‑existing hepatic disease or other identifiable risk factors. Therefore, the Product Monograph recommends monitoring of liver chemistries.
Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Vocabria and Cabenuva, and to promote their safe and effective use. Overall, the benefit‑harm‑uncertainty profile of Vocabria and Cabenuva are favourable for the approved indication.
For more information, refer to the Vocabria and Cabenuva Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non‑clinical data submitted in this New Drug Submission (NDS) are acceptable with respect to regulatory requirements for the development of antiretroviral drugs. The majority of non‑clinical studies were conducted with cabotegravir, which is a new active substance in Canada. The non‑clinical data for rilpivirine have been reviewed by Health Canada in earlier submissions for oral rilpivirine‑containing products. For this NDS, only a few new studies were conducted with injectable rilpivirine.
The non‑clinical pharmacology studies supported development of cabotegravir as an antiretroviral agent. There were no clinically relevant safety effects of cabotegravir (oral and injectable) or rilpivirine (injectable) in the general toxicology, genotoxicity, carcinogenicity or fertility studies.
Cabotegravir was not teratogenic when studied in pregnant rats and rabbits, but caused decreased fetal weight, a delay in the onset of parturition and increased stillbirths and neonatal deaths in rats at 28 times the therapeutic exposure. These effects were not seen at cabotegravir exposure comparable to 10 times the therapeutic exposure.
The results of the non‑clinical studies as well as the potential risks to humans have been included in the Vocabria and Cabenuva Product Monograph. Considering the intended use of Vocabria and Cabenuva, no pharmacological or toxicological issues have been identified within this submission to preclude authorization of the products.
For more information, refer to the Vocabria and Cabenuva Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Vocabria and Cabenuva has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable for both Vocabria and Cabenuva. Vocabria must be stored up to 30ºC. Cabenuva must be stored at 2°C to 8ºC, and must not be frozen. Special handling instructions for Cabenuva are included in the Product Monograph.
All sites involved in production are compliant with Good Manufacturing Practices.
All non‑medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VOCABRIA | 02497204 | VIIV HEALTHCARE ULC | CABOTEGRAVIR (CABOTEGRAVIR SODIUM) 30 MG |
| CABENUVA | 02497220 | VIIV HEALTHCARE ULC | CABOTEGRAVIR 200 MG / ML RILPIVIRINE 300 MG / ML |
| CABENUVA | 02497247 | VIIV HEALTHCARE ULC | CABOTEGRAVIR 200 MG / ML RILPIVIRINE 300 MG / ML |