Regulatory Decision Summary for Apo-Levothyroxine

This Abbreviated New Drug Submission (ANDS) for Apo-Levothyroxine (100 mcg and 300 mcg levothyroxine sodium) tablets by Apotex Inc. was filed to obtain market authorization for a generic formulation of levothyroxine tablets.

Levothyroxine is the levo isomer of the naturally occurring thyroid hormone thyroxine (T4), and Apo-Levothyroxine tablets are indicated as a replacement or supplemental therapy in patients with hypothyroidism. The Canadian reference product (CRP) for this subsequent-entry product is Synthroid (25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200 and 300 mcg levothyroxine sodium tablets), manufactured by BGP Pharma ULC.

The determination of applicable bioequivalence standards for levothyroxine requires special considerations due to endogenous background levels of the drug and its narrow therapeutic index. Doses of levothyroxine administered to patients must be carefully and precisely titrated to achieve and maintain the euthyroid state clinically and biochemically, thus avoiding the adverse consequences of under- and over-treatment.

In consideration of the above, while levothyroxine does not meet the definition of a critical dose drug (CDD) as outlined in the currently published Health Canada Guidance Document “Comparative Bioavailability Standards: Formulations Used for Systemic Effects” (2018), it is considered that the bioequivalence assessment standards for levothyroxine-based products should be more stringent than those applied for uncomplicated drugs.

Health Canada Bioequivalence Standards for Levothyroxine Generic Products

To establish bioequivalence between a proposed levothyroxine sodium product (T) and a Canadian reference product (R), the following studies should be provided using either a partial (RTR, TRR, RRT) or full (TRTR, RTRT) replicate two-treatment crossover design:

1. 2 x 300 mcg in healthy subjects under both fasting and fed conditions. Of note, a single dose of 600 mcg is recommended to be given to reliably detect T4 above baseline levels. Doses greater than 600 mcg are not recommended as they may increase the risk of cardiac complications.

2. For a proposed product line containing twelve proportionally formulated tablet strengths, testing of the highest strength as well as one of the lower strengths is recommended while maintaining a dose of 600 mcg. Therefore, in addition to the above studies, a study using 6 x 100 mcg in healthy subjects under fasting conditions should be conducted. Of note, the assessment of comparable food effect on the highest strength is considered to be sufficient, and the demonstration of bioequivalence under fed conditions on a lower strength is therefore not considered to be a requirement.

The following standards should be met:

1. The 90% confidence interval of the relative mean area under curve (AUC_0-48h) of the test to reference products should be within the following limits:

s_WR ≥ 0.15 (i.e., CV ≥ 15%): (exp[-0.76s_WR] x 100.0%) – (exp[0.76s_WR] x 100.0%)

s_WR: within-subject standard deviation of log-transformed AUC values of the reference product; a minimum value of 0.15 may be used in determining the acceptance limits.

1. The 90% confidence interval of the relative mean C_max of the test to reference products should be between 80.0% and 125.0% (inclusive).

In addition to the above, the following should be considered in the design of the bioequivalence studies for a subsequent-entry levothyroxine sodium product:

1. The comparative bioavailability assessment is to be based on total (free and bound) levothyroxine (T4).

2. The study must be designed so as to accurately and reliably measure T4 levels taking into account baseline levels of endogenous T4. Three appropriately spaced pre-dose samples are recommended for baseline correction for endogenous T4.

3. The bioequivalence standards should be met for baseline corrected data.

4. The blood sampling should be truncated to 48 hours, in part because of the reduced suppression of endogenous levels after that time and the reduced reliability of the recommended baseline correction method over a longer sampling period.

5. The washout period should be at least 35 days.

Biopharmaceutics Evaluation Summary

The clinical component of the material provided to support this ANDS included two blinded single dose, three-way crossover, partially replicated comparative bioavailability studies comparing a 600 mcg dose of levothyroxine sodium administered as 2 x 300 mcg tablets with Apo-Levothyroxine versus the CRP Synthroid (BGP Pharma ULC, Canada) in healthy male subjects under fasting (Study LY17406) and fed (Study LY17407) conditions. In addition, a similarly designed study (Study LY17408) comparing a 600 mcg dose of levothyroxine sodium administered as 6 x 100 mcg tablets under fasting conditions was provided.

No critical concerns with regard to the design, conduct or data from Studies LY17406, LY17407 and LY17408 were noted during review. The above detailed bioequivalence assessment criteria were met between Apo-Levothyroxine and Synthroid 100 mcg and 300 mcg tablets, when administered under fasting (100 mcg and 300 mcg) and fed (300 mcg) conditions.

Quality and Manufacturing Evaluation Summary

Adequate characterization data and comparative analysis were provided to support that the generic product and innovator product are essentially the same. Apo-Levothyroxine has the identical medicinal ingredient, dosage form, route of administration and conditions of use as those of the CRP.

The drug substance and drug product are manufactured in a consistent manner.

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