Regulatory Decision Summary for Vitamin D3 Oral Solution

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:

Drug

Medicinal ingredient(s):

Vitamin D3

Therapeutic area:

Vitamins

Type of submission:

New Drug Submission

Control number:

219321
What was the purpose of this submission?

 

This New Drug Submission (NDS) was filed to obtain market authorization for Vitamin D3 Oral Solution (cholecalciferol) for the prevention and treatment of vitamin D deficiency. Based on the clinical review, a Notice of Deficiency (NOD) was issued. Upon review of the response to the NOD, the modified indication for the initial treatment of vitamin D deficiency in adults when 25-hydroxyvitamin D levels are ≥ 5 ng/mL and ≤ 20 ng/mL was approved.

 

Why was the decision issued?

 

Health Canada considers that the benefit-harm-uncertainty profile of Vitamin D3 Oral Solution (cholecalciferol) (25,000 IU) is favorable for the initial treatment of vitamin D deficiency in adults when 25-hydroxyvitamin D levels are ≥ 5 ng/mL and ≤ 20 ng/mL.

The indication for the treatment of vitamin D deficiency is supported by the results from a phase IV, interventional, randomized, parallel, double-blinded study (Study D-CURE-IV-12-2) conducted in Belgium in 150 patients with 25-hydroxyvitamin D concentrations ≥ 5 ng/mL and ≤ 20 ng/mL. In this study, 50 patients were treated with 100,000 IU vitamin D, 50 patients were treated with 200,000 IU vitamin D, and 50 patients were treated with 400,000 IU vitamin D. The objectives were to determine an adapted regime for vitamin D supplementation in patients with deficiency in vitamin D concentration and to estimate the dose-response effect of Vitamin D3 Oral Solution in these patients. This study was not designed to demonstrate the safety and efficacy of vitamin D; however, it was considered the main source of evidence of efficacy of vitamin D3 supplementation to bring 25-hydroxyvitamin D levels to the desired levels. The clinical review concluded that the design of this study was appropriate for evaluating the dose-response relationship between the dose of Vitamin D3 Oral Solution and the achievement of desired levels of 25-hydroxyvitamin D. A post-hoc analysis was requested to provide further support. Based on the results of the primary analysis, secondary analyses, and sensitivity analysis, a statistically significant dose-response relationship was demonstrated. The results of the post-hoc analysis supported the main results and specifically demonstrated that a higher proportion of subjects who received a total dose of 400,000 IU achieved 25-hydroxyvitamin D concentrations above 20 ng/mL and above 30 ng/mL in comparison to subjects who were administered a total dose of 200,000 IU or 100,000 IU (> 20 ng/mL: 100%, 68.42%, and 41.66%, in the 400,000 IU, 200,000 IU, and 100,000 IU treatment groups, respectively; > 30 ng/mL: 57.14%, 21.05%, and 0%, in the 400,000 IU, 200,000 IU, and 100,000 IU treatment groups, respectively). Given that only severe cases of vitamin D deficiency are associated with clinical symptoms, evaluation of clinical symptoms was not performed. No additional supportive studies evaluating efficacy of this dosing regimen have been conducted.

Vitamin D3 Oral Solution was well tolerated in the pivotal trial. No clinically relevant adverse events were reported. The Sponsor performed a review of the published literature to better understand the tolerability of high doses of vitamin D administration. The main safety concerns identified included hypercalcemia, hypercalciuria, hyperphosphatemia, nephrolithiasis, nephrocalcinosis, hypersensitivity, hypervitaminosis D, malabsorption syndrome, pseudo hypoparathyroidism, and sarcoidosis, which have all been adequately addressed in the Product Monograph and the Risk Management Plan.

Overall, the anticipated benefits of Vitamin D3 Oral Solution are expected to outweigh its risks under the conditions of use recommended in the Vitamin D3 Oral Solution (cholecalciferol) (25,000 IU) Product Monograph at this time.

 

Decision issued

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