Regulatory Decision Summary for Viagra

This Supplement to a New Drug Submission (SNDS-COMP/C & M, Control #274068) for Viagra (sildenafil citrate) was filed to obtain an approval of a change in manufacturing process of the active pharmaceutical ingredient (API, i.e. a new route of API synthesis) and obtain market authorization for a new dosage form (orodispersible film, 50 mg, ODF). In addition, the Product Monograph (PM) has been migrated to the 2020 template.

A new rapidly disintegrating oral film (Viagra orodispersible film, 50 mg, ODF) formulation of sildenafil for erectile dysfunction (ED) has been developed. Viagra ODF offers an advantage, over ordinary oral dosage formulations given the lack of requirement for drinking water. In addition, a new manufacturing process of API synthesis has also been introduced.

No new non-clinical studies were conducted on Sildenafil Orodispersible Film (ODF). A comprehensive non-clinical package were reviewed and approved by Health Canada as part of the original New Drug Submission (NDS) (control #053606) for Viagra 25, 50 and 100 mg tablets. These studies are considered sufficient to support this SNDS regarding ODF.

Additionally, two new supporting studies for orodispersible tablets (ODT) were submitted in this SNDS including a 14-day dose-repeated study of local tolerance of the ODT formulation on oral mucosa of male dogs, and a 6-month treatment and 4-month recovery rats and dogs study. The results of these studies showed that 1) regarding local tolerance in dogs, there was mild erythema during the first week of dosing but it was not observed in the second week; 2) There were neither relevant clinical pathology nor organ macroscopic findings at any dose levels in the 6-month treatment period or 4-month recovery period in rats and dogs.

The New Drugs Quality Division (NDQD) requested a toxicology consultation regarding four impurities identified in the new route of API synthesis. The Reproduction and Urology Division (RUD) at the Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS) reviewed relevant data and concluded that the ICH M7 classification of Class 5 for impurities (i.e. PF-6238455, PF-61502320, PF-05300496 and PF-06230452), is acceptable, and the proposed limits of these impurities (NMT 0.10%) are considered qualified for the drug substance.

The Division of Biopharmaceutics Evaluation 2 (DBE2) reviewed two bioavailability studies comparing the 50 mg tablets and the 50 mg ODF. DBE2 concluded in their Manager Memo (MM) that the rate and extent of sildenafil absorption can be considered equivalent after dosing with the proposed 50 mg orodispersible film (ODF) administered with or without water when compared to the same dose of the currently marketed Viagra oral tablets.

No clinical phase 3 studies were conducted to evaluate the efficacy and safety of Viagra 50 mg ODF in the patient population because the comparative bioequivalence has been established between the proposed sildenafil 50 mg ODF and the currently marketed sildenafil 50 mg tablet. There are no changes to the approved indication and recommended dosing regimen.

The clinical efficacy of sildenafil 50 mg tablet has been demonstrated in phase 3 clinical trials on which previous regulatory approval was granted in by Health Canada (NDS Control #053606).

The sildenafil 50 mg in a new orodispersible film (ODF) formulation as an additional dosage form was approved in Japan in September 2016, and it is currently submitted for regulatory approval in Europe and Taiwan. Since the approval of sildenafil 50 mg ODF in Japan, there were 3 completed PSURs for all sildenafil formulations, covering the reporting periods five years (2017 to 2021). Overall, adverse events (AEs) reported in post-marketing surveillance systems were consistent with that of known safety profile of sildenafil already characterized in the product monograph (PM) of Viagra, and no new significant safety signals were identified during the 3 PSUR reporting periods.

Additionally, the sponsor carried out a search and review of post-marketing surveillance data on sildenafil 50 mg ODF currently marketed in Japan and concluded that the ODF formulation appeared to be well tolerated and safe. No serious adverse events (SAEs) or severe AEs observed.

One hundred and sixty-two (n = 162) subjects received sildenafil citrate ODF across the four bioequivalence studies. No deaths and no discontinuations due to AEs were observed in any of the bioequivalence studies. Sildenafil 50 mg ODF appeared to be well tolerated and safe. There were no serious adverse events (SAEs) or severe AEs observed in the studies. As expected, and according to the safety profile of sildenafil citrate, NDQD in BPS reviewed quality data submitted in this SNDS and recommends a Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations from a Quality perspective.

The overall benefit-risk profile of Viagra for the recommended indication and dosage recommendation remains favorable.

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