Regulatory Decision Summary for Tirosint

The active ingredient, levothyroxine sodium, is well-established to be efficacious for the indications of replacement or supplemental therapy of hypothyroidism and TSH suppression in thyroid cancer through a multitude of studies. This New Drug Submission for Tirosint soft gelatin capsules was filed using the Health Canada Guidance on “Drug Submissions Relying on Third-Party Data (Literature and Market Experience)”. No new safety or efficacy studies were provided in support of the proposed Tirosint capsules finished product.

The soft gelatin capsules were developed to create a levothyroxine sodium formulation with improved swallowability, protection of the encapsulated compound against oxygen and light, and ability to readily dissolve in the gastrointestinal tract. The sole oral dosage formulation of levothyroxine sodium currently available on the Canadian market is an immediate-release tablet.

The Sponsor conducted a bioequivalence study to show that Tirosint has comparative bioavailability to the US product Synthroid, which is identical to the Canadian Synthroid. However, the Division of Biopharmaceutics Evaluation 2 (DBE2) concluded that since the formulation of Tirosint capsules was modified in 2007, and the bioequivalence study was conducted with the older formulation of Tirosint, this cannot be considered a pivotal study.

The bioequivalence study to the European product Euthyrox (levothyroxine sodium tablets) was reviewed as pivotal. DBE2 concluded that the safety and efficacy profiles of the proposed Tirosint capsules can be expected to be similar to those described in the literature for the reference product. Therefore, the safety and efficacy of Tirosint are based on over 400 literature references on levothyroxine tablets, as well as Tirosint’s market experience in other countries. The pivotal efficacy and safety studies identified by the Sponsor from the Synthroid Product Monograph (PM) were no longer considered pivotal since Synthroid was no longer the reference product; thus, no pivotal studies for safety and efficacy were identified for this submission; efficacy and safety were based on the totality of the evidence from the entire literature review.

The Sponsor proposed to use Tirosint as replacement and supplemental therapy in adult and pediatric patients 6 years and older for primary, secondary, and tertiary hypothyroidism of any etiology in any state (including pregnancy). They provided evidence that Tirosint, at a dose of approximately 1.7 mcg/kg/day administered once daily, is efficacious for younger (under 50), healthy adults. The Sponsor also provided evidence that Tirosint will be beneficial in children with congenital or acquired hypothyroidism, as long as they are able to swallow the capsule. Thus, Tirosint is indicated in children over the age of 6 who can swallow the capsule. There is also evidence that Tirosint is efficacious for the treatment of hypothyroidism in pregnancy, provided the dose is adjusted appropriately.

The efficacy of using Tirosint for aftercare following surgery or radioactive iodine therapy on a differentiated thyroid carcinoma with TSH suppression has been shown. Review of the literature suggests that using levothyroxine in these patients reduces the likelihood of development of metastases.

The Sponsor had proposed to indicate Tirosint for the treatment or prevention of various types of euthyroid goitres, including thyroid nodules, and multinodular goiter with TSH suppression. In these patients, suppressive therapy results in subclinical hyperthyroidism. Therefore, the treated patients are at increased risk of decreased bone density, fractures, atrial fibrillation and other cardiac abnormalities. Additionally, efficacy of suppressive therapy in euthyroid goiters is controversial. Therefore, the benefit-risk of Tirosint for TSH suppression in the treatment or prevention of various types of euthyroid goitres, including thyroid nodules, and multinodular goiter, is not considered favorable. Following an internal consult with the Bureau of Medical Sciences this indication was not granted. Further, a class labelling action is already initiated to revise the indications of all levothyroxine products in Canada with respect to euthyroid goitres.

Levothyroxine is considered a narrow therapeutic index (NTI) drug. However, since it has a long history of use, extensive published literature, and is endogenous, the safety profile of this active ingredient is well established. The more serious adverse effects only occur in situations of overdosage. The most common adverse events, such as cardiovascular effects, osteoporosis in menopausal women, worsening of diabetes, hypersensitivity reactions, are well described in the PM for Tirosint. Mitigating strategies, such as adjusting the dose in patients older than 50, patients with cardiovascular predispositions, as well as warnings again the use of Tirosint for the treatment of obesity, or in patients with myxedema, are also described in the proposed PM.

The drug-drug interactions involving levothyroxine that may be potentially dangerous are also reflected in the PM. To avoid the well-known effects of food on the absorption of Tirosint, it is recommended, that Tirosint be administered as a single daily oral dose, on an empty stomach, one-half to one hour before breakfast.

In conclusion, when Tirosint is used appropriately, there is a favourable benefit/risk ratio for the proposed treatment of hypothyroidism and TSH suppression in thyroid cancer. The benefit-risk ratio for the treatment of subacute thyroiditis and for TSH suppression in treatment or prevention of various types of euthyroid goitres, including thyroid nodules, and multinodular goiter, is not favorable and these indications were not granted. The benefit-risk ratio in children over the age of 6, who can swallow the capsule and pregnant women is favourable, provided the dosage is adjusted as described in the PM.