Regulatory Decision Summary for Rifapentine Tablets

The purpose of this New Drug Submission (NDS)-New Active Substance (NAS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Rifapentine Tablets, filed by Macleods Pharmaceuticals Limited.

This submission was filed for Rifapentine Tablets, 150 mg, oral, for the treatment of latent tuberculosis infection (LTBI) caused by Mycobacterium tuberculosis in combination with isoniazid in patients 2 years of age and older at high risk of progression to tuberculosis disease. Upon review of the submitted data package, Health Canada authorized Rifapentine Tablets as filed.

This is a Submission Relying on Third-Party Data (SRTD). The Sponsor has provided comparative bioavailability data to bridge this product to the United Sates Food and Drug Administration (FDA)-approved product, Priftin (rifapentine), in addition to published clinical and non-clinical studies from the literature.

Rifapentine is a rifamycin antibiotic with antimycobacterial activity. Once-weekly rifapentine and isoniazid for three months is one of the first-line latent tuberculosis (TB) infection (LTBI) treatment regimens recommended by the Public Health Agency of Canada (PHAC), as per the Canadian Tuberculosis Standards, 8^th edition (2022).

Rifapentine Tablets NDS-NAS was reviewed as a Submission Relying on Third-Party Data (SRTD). The Sponsor provided comparative bioavailability data to bridge this product to the United States FDA-approved rifapentine product, Priftin, manufactured by Sanofi, in addition to published clinical and non-clinical studies from the literature. The review also leveraged the United States (US) Prescribing Information and the FDA review reports for Priftin (rifapentine).

The clinical literature studies consisted of one pharmacokinetic study in patients with active TB, one pivotal clinical trial in LTBI patients aged 2 years and older, one supportive clinical trial in adult LTBI patients, one supportive clinical trial in adult male silicosis patients at risk of developing active TB, and two supportive clinical trials in patients with active TB.

The results of the pharmacokinetic (PK) study in patients with active TB demonstrate that the proposed dose of 900 mg once-weekly Rifapentine Tablets is expected to maintain total (protein-bound and free, active) concentrations above the MIC (0.05 µg/mL) for rifapentine-susceptible M. tuberculosis for more than 48 hours following administration.

The results of the pivotal clinical trial demonstrated that 3 months of once-weekly rifapentine plus isoniazid (combination therapy) given under direct observation and 9 months of daily self-administered isoniazid (isoniazid-only therapy) were both efficacious in preventing progression to active TB in LTBI patients aged 2 years and older, within 33 months of enrollment. Without treatment, the risk of TB in the first 2 years after M. tuberculosis infection was estimated to be 5%. In the combination (n = 3,074) and isoniazid-only (n = 3,074) modified intention-to-treat groups, TB developed in 0.16% and 0.32% of patients, respectively. The combination therapy was consistently found to be non-inferior to the isoniazid-only therapy, with a non-inferiority margin of 0.75%. There was a trend toward superior effectiveness of the combination therapy by 33 months of follow-up. Patients receiving combination therapy were more likely to complete treatment than those receiving isoniazid-only therapy.

The most relevant adverse reactions observed in the pivotal clinical trial with respect to incidence and severity were hypersensitivity reactions and hepatotoxicity. The safety profile for Rifapentine Tablets is acceptable for the LTBI indication.

Two (2) bioequivalence studies were conducted with Rifapentine Tablets against the US Reference Listed Drug (Priftin) under fasting and high-fat, high-calorie fed conditions. The results of both studies demonstrated that both drugs were bioequivalent.

The submitted non-clinical package for Rifapentine Tablets was comprised of published literature, US Priftin labelling, and FDA review reports of Priftin. Rifapentine has a long half-life which enables a once weekly dosing regimen. It is not extensively metabolized and rat studies showed distribution to the lungs, which are the site of TB infection. The non-clinical data indicated a potential for neurological effects, hepatotoxicity, teratogenicity, and drug-drug interactions due to hepatic enzyme induction. Rifapentine was not genotoxic. Carcinogenicity studies showed increased hepatocellular carcinomas and nasal cavity adenomas in mice and rats, respectively; however, these findings are of unclear relevance to humans. The Product Monograph (PM) is adequately labeled with respect to the non-clinical risks identified.

As with all antibiotics, there is a potential risk of resistance development with rifapentine. There is a high degree of cross-resistance between rifapentine and other rifamycins. Antimicrobial resistance (AMR) standard statements and C. difficile associated disease (CDAD) safety risk statements have been included in the Canadian Product Monograph (PM). In addition to the standard AMR statements, the PM states that rifapentine should be administered through directly observed therapy, should only be used in combination with isoniazid, and should not be used for individuals exposed to rifamycin- or isoniazid-resistant TB.

The rifapentine-specific nitrosamine impurity 1-Cyclopentyl-4- Nitrosopiperazine (CPNP) is known to be present in all rifapentine drug products. A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

The chemistry and manufacturing information submitted for Rifapetine Tablets has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

A Risk Management Plan (RMP) review was conducted by the Marketed Health Products Directorate (MHPD). The Sponsor proposed routine pharmacovigilance activities and noted that routine risk minimization measures are sufficient to manage the safety concerns for the evaluation of the effectiveness of the risk minimization measures. This was considered to be acceptable given the vast post-authorization experience of rifapentine worldwide. The RMP was considered to be acceptable with no revisions.

Overall, the benefit-harm-uncertainty profile is favourable for Rifapentine Tablets, 150 mg, for the proposed indication when used under the conditions of use recommended in the Product Monograph. Therefore, a Notice of Compliance (NOC) is recommended.

For further details about Rifapentine Tablets, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.