Regulatory Decision Summary for Teva-Sapropterin

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.

Product type:


Medicinal Ingredient(s):

Sapropterin dihydrochloride

Control Number:


Brand/Product Name:


Therapeutic Area:

Various alimentary tract and metabolism products

Type of Submission:

Abbreviated New Drug Submission

Decision Issued:

Authorized; issued a Notice of Compliance in accordance with the Food and Drug Regulations

What was the purpose of this submission?

This Abbreviated New Drug Submission (ANDS) for Teva-Sapropterin was filed by Teva Canada Limited to obtain market authorization for a generic formulation of Sapropterin tablets containing 100 mg of sapropterin dihydrochloride.

Sapropterin is a synthetic form of the endogenous cofactor, tetrahydrobiopterin and Teva-Sapropterin tablets are indicated in conjunction with a phenylalanine (Phe)-restricted diet for the reduction of blood Phe levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin-(BH4)-responsive Phenylketonuria (PKU). Teva-Sapropterin is intended as a generic alternative to the Canadian Reference Product (CRP) Kuvan (sapropterin dihydrochloride 100 mg tablets) manufactured by BioMarin International Limited.

The determination of applicable bioequivalence assessment standards for Sapropterin requires special considerations due to endogenous background levels of the drug and because food enhances absorption.

In consideration of the above, the bioequivalence assessment standards for subsequent-entry, immediate-release sapropterin products are different than those applied to uncomplicated drugs.

Why was the decision issued?

Sapropterin dihydrochloride is considered to be a drug with uncomplicated pharmacokinetic characteristics; however, it is recommended to be administered under fed conditions given that food enhances absorption. Thus, a single-dose, crossover, comparative bioavailability study should be conducted in healthy subjects under fed conditions to establish bioequivalence between a proposed immediate-release sapropterin product and the CRP.

The following standards should be met:

1. The 90% confidence interval of the relative mean AUCT of the test to the reference product should be within 80.0% - 125.0% inclusive.

2. The relative mean Cmax of the test to the reference product should be within 80.0% - 125.0% inclusive.


Correction for individual endogenous levels should be done by subtracting the estimated endogenous baseline concentration from each post-dose concentration in the profile. It is recommended that individual baseline levels be calculated in each period as the mean of three concentrations during an interval prior to dosing that is appropriate given the known fluctuations in endogenous concentrations. Negative concentrations should be set to zero. Baseline-corrected plasma concentrations should be used in statistical analyses.

Furthermore, given that endogenous plasma biopterin levels suggest a circadian rhythm, test and reference products should be administered at the same time of day to reduce the potential contribution of diurnal variation to observed differences between products.

The clinical component of the material provided to support this ANDS included a single-dose, crossover, comparative bioavailability study (Study BE-2098-20) comparing the proposed Teva-Sapropterin 100 mg tablets to an European Union (EU)-sourced Reference Product, Kuvan 100 mg tablets (BioMarin International Limited, Germany). In Study BE-2098-20, the study drugs were administered as single oral doses of 7 x 100 mg (sapropterin dihydrochloride) tablets dissolved in 120 mL of water to healthy adult male subjects under fed conditions.

A foreign-sourced reference product (Kuvan 100 mg tablets from BioMarin International Limited, Germany) was used in Study BE-2098-20. The use of Kuvan 100 mg tablets from BioMarin International Limited (Germany) as the Canadian reference product in Study BE-2098-20 is considered to be acceptable as per criteria listed in the Health Canada Guidance Document Use of a Foreign-sourced Reference Product as a Canadian Reference Product (2017).

The dosing administration for sapropterin dihydrochloride states that tablets can be swallowed whole or dissolved in water or apple juice and taken within 15 minutes of dissolution. Generally, comparative bioavailability studies conducted with tablets swallowed whole would be considered the more discriminating method of detecting differences between test and reference products. However, for Study BE-2098-20, the dose administered as tablets dissolved in 120 mL of water is acceptable due to the following:

  1. Sapropterin dihydrochloride is highly soluble across the physiological pH range,

  2. The test product has a rapid disintegration time, and

  3. Both the CRP and test product displayed very rapid (≥ 85% for the mean percent dissolved in ≤ 15 minutes) in vitro dissolution.

Furthermore, considering that sapropterin dihydrochloride degrades in aqueous environments and it is possible that different excipients could impact degradation rate, administering the dose as tablets dissolved in water as opposed to swallowing the tablets whole is potentially the more sensitive administration condition to detect differences between test and reference products.

No critical concerns with regard to the design, conduct or data from Study BE-2098-20 were noted during review. The above detailed bioequivalence assessment criteria were met between Teva-Sapropterin and Kuvan 100 mg tablets, when administered under fed conditions.

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

Date of Decision:



Teva Canada Limited

Drug Identification Number(s) Issued:


Prescription Status:

Available by prescription only

Date Filed: