Summary Basis of Decision for Rayaldee

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Rayaldee is located below.

Recent Activity for Rayaldee

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

 

The following table describes post-authorization activity for Rayaldee, a product which contains the medicinal ingredient calcifediol. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

 

Updated: 2024-06-14

 

Drug Identification Number (DIN):

DIN 02478498 – 30 mcg calcifediol, capsule, oral administration

 

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NDS # 271071

2022-12-30

Issued NOC 2023-02-09

Submission filed to transfer ownership of the drug product from Vifor Fresenius Medical Care Renal Pharma Ltd. to Eirgen Pharma Limited. An NOC was issued.

NDS # 205392

2017-05-09

Issued NOC 2018-07-10

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Rayaldee

Date SBD issued: 2018-11-27

The following information relates to the New Drug Submission for Rayaldee.

Calcifediol
30 mcg, capsule, oral

Drug Identification Number (DIN):

  • 02478498

Vifor Fresenius Medical Care Renal Pharma Ltd.

New Drug Submission Control Number: 205392

 

On July 10, 2018, Health Canada issued a Notice of Compliance to Vifor Fresenius Medical Care Renal Pharma Ltd for the drug product Rayaldee.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Rayaldee is favourable for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease and low serum 25-hydroxyvitamin D levels (less than 75 nmol/L [30 ng/mL] at initiation).

Rayaldee is not indicated for the treatment of secondary hyperparathyroidism in patients with stage 5 chronic kidney disease or in patients with end-stage renal disease on dialysis.

 

1 What was approved?

 

Rayaldee, a vitamin D3 analogue, was authorized for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease and low serum 25-hydroxyvitamin D levels (less than 75 nmol/L [30 ng/mL] at initiation).

Rayaldee is not indicated for the treatment of secondary hyperparathyroidism in patients with stage 5 chronic kidney disease or in patients with end-stage renal disease on dialysis.

The safety and effectiveness of Rayaldee in pediatric patients (<18 years of age) have not been established. Therefore, Rayaldee should not be used in this population.

Evidence from clinical studies and experience suggests that use of Rayaldee in the geriatric patients (≥65 years of age) was not associated with differences in safety or effectiveness.

Rayaldee is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. Rayaldee is also contraindicated in patients with hypercalcemia or evidence of vitamin D toxicity.

Rayaldee was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Rayaldee (calcifediol) is presented as a capsule. In addition to the medicinal ingredient calcifediol, the capsule also contains the following non-medicinal ingredients, butylated hydroxytoluene, carrageenan, dehydrated alcohol, dibasic sodium phosphate, FD&C blue #1, hypromellose, lauroyl polyoxylglycerides, medium chain triglycerides, mineral oil, modified corn starch, mono- and di-glycerides, paraffin, propylene glycol, sorbitol sorbitan solution, titanium dioxide, and water.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Rayaldee Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Rayaldee approved?

 

Health Canada considers that the benefit-risk profile of Rayaldee is favourable for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease and low serum 25-hydroxyvitamin D levels (less than 75 nmol/L [30 ng/mL] at initiation).

Secondary hyperparathyroidism is a condition commonly associated with chronic kidney disease. In Canada, the prevalence of chronic kidney disease during the period from 2007 to 2009 was approximately 12.5%, representing about three million Canadian adults. The estimated prevalence of stage 3-5 disease was approximately 3.1% (about 730,000 adults).

The two leading causes of chronic kidney disease in Canada are diabetes and renal vascular disease, including hypertension. Patients with stage 3 or 4 chronic kidney disease have a decreased glomerular filtration rate, which is between 60 and 30 mL/min/1.73m2 for stage 3 and between 30 and 15 mL/min/1.73m2 for Stage 4. As kidney function declines, there is a disruption of normal serum and tissue concentrations of phosphorus and calcium, and changes in circulating levels of parathyroid hormone and vitamin D metabolites. Beginning in chronic kidney disease Stage 3, a disruption in the normal regulation of bone and mineral physiology occurs, leading to elevated parathyroid hormone, and decreased 1,25-dihydroxyvitamin D3, and disturbances in calcium and phosphate.

The conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 is impaired, reducing intestinal calcium absorption and increasing parathyroid hormone. The kidney fails to respond adequately to the parathyroid hormone, which normally promotes phosphaturia and calcium reabsorption. In addition, there is evidence at the tissue level of a downregulation of vitamin D receptor and of resistance to the actions of the parathyroid hormone. This results in the development of secondary hyperparathyroidism. Secondary hyperparathyroidism is a condition in which the parathyroid glands secrete excessive amounts of parathyroid hormone. It requires prompt and effective treatment, as prolonged elevation of parathyroid hormone causes excessive calcium and phosphorus to be released from bone, leading to metabolic bone disease and calcification of cardiovascular and renal tissues. In the absence of effective therapy, secondary hyperparathyroidism becomes progressively more severe and unresponsive to treatment.

Currently, vitamin D supplementation using daily, weekly, or monthly vitamin D doses or therapy with a vitamin D receptor activator is recommended for secondary hyperparathyroidism arising from vitamin D insufficiency. Alfacalcidol (One-Alpha) is approved for this indication in Canada. Vitamin D receptor activators effectively lower parathyroid hormone plasma levels; however, they leave serum 25-hydroxyvitamin D potentially lower, depriving extrarenal tissues of adequate substrate for local hormone production. Moreover, they produce supraphysiological surges in blood vitamin D hormone levels associated with increased risk of hypercalcemia.

Rayaldee is formulated as an extended-release capsule for oral use containing 30 mcg of calcifediol, a vitamin D3 analogue, synthetically manufactured as calcifediol monohydrate. The capsules were designed to release calcifediol over a prolonged period, thereby raising serum 25-hydroxyvitamin D in a gradual manner to the desired levels of 75 to 250 nmol/L while avoiding excessive induction of cytochrome P450 (CYP) 24A1. Calcifediol is also known as calcidiol, 25-hydroxycholecalciferol or 25-hydroxyvitamin D3. It is a prohormone of the active form of vitamin D3, which is converted to calcitriol (1,25-dihydroxyvitamin D3), by CYP27B1 primarily in the kidney. Calcitriol binds to the vitamin D receptor in target tissues and activates vitamin D responsive pathways that result in increased intestinal absorption of calcium and phosphorus and reduced parathyroid hormone synthesis.

Rayaldee has been shown to be efficacious for the treatment of secondary hyperparathyroidism in adult patients with stage 3 or 4 chronic kidney disease and low serum 25-hydroxyvitamin D levels (less than 75nmol/L [30 ng/mL] at initiation). The market authorization was based on two Phase III clinical studies (CTAP101-CL-3001 and CTAP101-CL-3002) which figured significantly in Health Canada's evaluation of the safety and effectiveness of Rayaldee.

The primary efficacy endpoint in both clinical trials was the number of subjects from the Intent-to-Treat population who attained a mean decrease in plasma intact parathyroid hormone levels (iPTH) of ≥30% from pre-treatment baseline in the efficacy assessment phase, which encompassed weeks 20 through 26. A larger proportion of patients randomized to Rayaldee experienced at least a 30% reduction in plasma iPTH from baseline compared to placebo in both trials [33% versus 8% in the first trial (P<0.001) and 34% versus 7% in the second trial (P<0.001)].

The secondary efficacy endpoints were the number of subjects in the Per protocol population who attained a mean 30% decrease in plasma iPTH from pre-treatment baseline in the efficacy assessment phase, and the number of patients with adequate serum total 25-hydroxyvitamin D (≥30 ng/mL or 75 nmol/L) in the efficacy assessment phase. The proportion of PP subjects with mean plasma iPTH reduction of ≥30% from baseline was higher in the Rayaldee treated group (40% vs 8% in the placebo patients for both pivotal trials).

Results from both clinical trials revealed that total 25-hydroxyvitamin D serum levels increased to at least 75 nmol/L (30 ng/mL) in 80% and 83% of patients treated with Rayaldee versus 3% and 7% of patients treated with placebo, respectively. In addition, the average steady-state of 25-hydroxyvitamin D levels were 125 and 140 nmol/L (50 and 56 ng/mL) for patients receiving 30 mcg daily, and 167 and 172 nmol/L (67 and 69 ng/mL) for patients receiving 60 mcg daily, in the first and second studies, respectively.

Adverse events reported were consistent with known pharmacology of vitamin D analogues and with expected class specific side effects (e.g., elevated serum calcium, elevated serum phosphate, and a potential for oversuppression of parathyroid hormone). Serious adverse reactions of chronic heart failure and increase in serum creatinine were more frequent in patients randomized to receive Rayaldee. They were found to be unlikely related to study drug and resolved while continuing treatment; however, they are considered uncertainties.

A Risk Management Plan (RMP) for Rayaldee was not provided in this submission, as agreed upon with Health Canada, since the safety profile of calcifediol is well known. Rather, Vifor Fresenius Medical Care Renal Pharma Ltd. submitted an outline of their pharmacovigilance monitoring and reporting plan. Upon review, the submitted plan was considered acceptable.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Rayaldee Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Rayaldee was accepted.

Overall, the efficacy of Rayaldee for the treatment of secondary hyperparathyroidism (SHPT), in adult subject with Stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency (total 25-hydroxyvitamin D levels less than 30 ng/mL or 75 nmol/L) has been shown. The proposed initial dose is 30 mcg orally at bedtime. The dose may be increased to 60 mcg orally once daily at bedtime after approximately 3 months, if intact PTH remains above the desired therapeutic range. Rayaldee has an acceptable safety profile based on the non-clinical data and clinical trials. The identified safety issues regarding Rayaldee are adequately described in the Rayaldee Product Monograph, and appropriate recommendations for risk mitigation are included. Considering the efficacy of Rayaldee in managing secondary hyperparathyroidism in adult patients with stage 3 or 4 chronic kidney disease and vitamin D insufficiency, the overall benefit-risk assessment is considered favourable.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Rayaldee?

 

Submission Milestones: Rayaldee

Submission Milestone Date
Pre-submission meeting: 2016-01-18
Submission filed: 2017-05-09
Screening  
Screening Deficiency Notice issued: 2017-06-26
Response filed: 2017-08-09
Screening Acceptance Letter issued: 2017-09-14
Review  
Biopharmaceutics Evaluation complete: 2018-07-01
Quality Evaluation complete: 2018-07-01
Clinical Evaluation complete: 2018-07-10
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-07-10
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2018-07-10

 

The Canadian regulatory decision on the quality (chemistry and manufacturing) non-clinical and clinical review of Rayaldee was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) were used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Rayaldee?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Rayaldee is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Calcifediol (the medicinal ingredient in Rayaldee) is a prohormone of the active form of vitamin D3, calcitriol (1,25-dihydroxyvitamin D3). Calcifediol is converted to calcitriol by cytochrome P450 27B1 (CYP27B1) primarily in the kidney. Calcitriol binds to the vitamin D receptor in target tissues and activates vitamin D responsive pathways that result in increased intestinal absorption of calcium and phosphorus and reduced parathyroid hormone synthesis.

Calcifediol is an endogenous molecule and its metabolism, distribution and excretion are well understood. Specific trials were not conducted by the sponsor. Calcifediol is readily absorbed in the intestine and does not require further metabolism in the liver.

The effect of food on the pharmacokinetics of calcifediol was evaluated in an open-label, randomized, parallel-group study in healthy adult subjects under fasted and under fed conditions (Study CTAP101-CL-1016). The results demonstrate that food (high-fat, high-caloric meal) has a significant impact on the rate and extent of absorption of calcifediol. Administration of calcifediol at a supratherapeutic dose of 450 mcg, with a high-fat, high-caloric meal increases the maximum serum concentration by approximately 5-fold and the area under the plasma drug concentration-time curve by approximately 3.5-fold. Dosing at bedtime is expected to decrease the likelihood of regular co-administration of Rayaldee with such meals. Inevitable occasional dosing with meals is unlikely to pose a risk to patients since a single 30 or 60 mcg dose of calcifediol results in a small incremental increase in serum total 25-hydroxyvitamin D.

Co-administration with cytochrome P450 inhibitors, such as ketoconazole, may alter serum levels of calcifediol. A complete drug-drug interaction table has been provided in the Rayaldee Product Monograph.

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

Clinical Efficacy

The efficacy of Rayaldee was evaluated in two identical multicentre, randomized, placebo-controlled, double-blind trials (CTAP101-CL-3001 and CTAP101-CL-3002) in adult patients with secondary hyperparathyroidism, stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D levels between 25 and 75 nmol/L (10 and 30 ng/mL).

A total of 429 patients stratified by chronic kidney disease stage were randomized in a 2:1 ratio to receive a daily 30 mcg oral dose of Rayaldee or matching placebo for 12 weeks at bedtime followed by an additional 14 weeks of treatment with daily doses of either 30 or 60 mcg of Rayaldee (or a placebo). The dose was increased to 60 mcg at the start of week 13 if the plasma intact parathyroid hormone (iPTH) level was greater than 7.4 pmol/L (70 pg/mL), the serum 25-hydroxyvitamin D level was less than 162 nmol/L (65 ng/mL) and the serum calcium level was less than 2.4 mmol/L (9.8 mg/dL).

The patients' mean age was 66 years (range 25-85); 50% were male, 65% White, 32% African-American or Black and 3% Other. At baseline, patients had secondary hyperparathyroidism, and stage 3 (52%) or stage 4 (48%) chronic kidney disease without macroalbuminuria. The most common causes of chronic kidney disease were diabetes and hypertension and the mean estimated glomerular filtration rate was 31 mL/min/1.73m2. Mean baseline iPTH was 13.7 pmol/L (130 pg/mL) for patients with stage 3 disease (number of patients [n] = 222) and 17.6 pmol/L (166 pg/mL) for patients with stage 4 disease (n = 207). Mean serum calcium was 2.3 mmol/L (9.2 mg/dL), mean serum phosphorus was 1.2 mmol/L (3.7 mg/dL) and mean serum 25-hydroxyvitamin D was 50 nmol/L (20 ng/mL). Of the 429 patients randomized, 354 (83%) completed the clinical trials.

The primary efficacy endpoint in both clinical trials was the number of subjects from the intent-to-treat population who attained a mean decrease in iPTH of ≥30% from pre-treatment baseline in the efficacy assessment phase, which encompassed weeks 20 through 26. The secondary efficacy endpoints were the number of subjects from the per protocol population who attained a mean 30% decrease in plasma iPTH from pre-treatment baseline in the efficacy assessment phase, and the number of patients with adequate serum total 25-hydroxyvitamin D (≥30 ng/mL or 75 nmol/L) in the efficacy assessment phase.

Study Results

The primary analysis in both clinical trials demonstrated the following in terms of the proportion of individuals who experienced at least 30% reduction in plasma iPTH from baseline to end of study (average of weeks 20, 22, 24 and 26).

Thirty three percent 33% of patients in the Rayaldee group versus 8% of patients in the placebo (p<0.001) in clinical trial CTAP101-CL-3001 and 34% of patients in the Rayaldee-treated group versus 7% of patients in the placebo-treated group (p<0.001) in the clinical trial CTAP101-CL-3002 experienced a ≥30% reduction in plasma iPTH from baseline to end of study.

The proportion of per protocol subjects with mean plasma iPTH reduction of ≥30% from baseline (secondary end point) was higher in the Rayaldee treated group (40% vs 8% in the placebo patients for both pivotal studies).

Serum total 25-hydroxyvitamin D levels increased to at least 75 nmol/L in 80% and 83% of subjects treated with Rayaldee vs. 3% and 7% of subjects treated with placebo (P<0.001) in the two studies, respectively. Average steady-state 25-hydroxyvitamin D levels were 125 and 140 nmol/L for subjects receiving 30 mcg daily, and 167 and 172 nmol/L for subjects receiving 60 mcg daily, in the first and second studies, respectively.

The results from both clinical trials indicate that Rayaldee effectively treats secondary hyperparathyroidism in subjects with Stage 3 and Stage 4 chronic kidney disease and low serum vitamin D levels as soon as 12 weeks after initiation of treatment.

Indication

The New Drug Submission for Rayaldee was filed by the sponsor with the following indication:

Rayaldee (calcifediol modified-release capsules, 30 mcg) is a vitamin D3 analogue indicated for the treatment of secondary hyperparathyroidism in stage 3 or 4 chronic kidney disease patients with vitamin D insufficiency.

To ensure effective use of the product, Health Canada approved the following indication:

Rayaldee (calcifediol modified-release capsules, 30 mcg) is a vitamin D3 analogue indicated for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease and low serum 25-hydroxyvitamin D levels (less than 75 nmol/L [30 ng/mL] at initiation).

Overall Analysis of Efficacy

Overall, the submitted trials provide evidence that the benefit of Rayaldee (calcifediol modified-release capsules, 30 mcg), a vitamin D3 analogue, for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D levels less than 30 ng/mL (75 nmol/L) outweighs the risks.

For more information, refer to the Rayaldee Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The evaluation of the clinical safety of Rayaldee was based primarily on the two pivotal Phase III clinical trials (CTAP101-CL-3001 and CTAP101-CL-3002) previously described in the Clinical Efficacy section. Additional safety data was also obtained from an open-label extension of the CTAP101-CL-3001 and CTAP101-CL-3002 trials. A total of 324 patients were treated with Rayaldee for >6 months and 169 patients were treated with Rayaldee for >12 months.

Approximately 70% of patients in the Phase III trials experienced at least one treatment-emergent adverse event (TEAE) and the incidence of TEAEs was comparable between treatment groups and chronic kidney disease stages. The most common adverse events associated with the use of Rayaldee in the pooled placebo-controlled trials that were not present at baseline, occurred more commonly on Rayaldee than on placebo, and occurred in at least 1.4% of patients treated with Rayaldee, include anemia (Rayaldee 4.9%; placebo 3.5%), nasopharyngitis (Rayaldee 4.9%; placebo 2.8%), dyspnea (Rayaldee 4.2%; placebo 2.8%), cough (Rayaldee 3.5%; placebo 2.1%), constipation (Rayaldee 3.2%; placebo 2.8%), bronchitis (Rayaldee 2.8%; placebo 0.7%); hyperkalemia (Rayaldee 2.5%; placebo 0.7%), osteoarthritis (Rayaldee 2.1%; placebo 0.7%), and hyperuricemia (Rayaldee 1.8%; placebo 0.7%).

In the two Phase III trials, treatment-emergent serious adverse events were reported by 16% of placebo-treated patients and 18% of Rayaldee-treated patients. In the open-label Phase III extension study, 17.5% and 21.5% of patients experienced a serious TEAE in the 26-week and 52-week groups, respectively.

Two serious TEAEs, chronic heart failure and increased blood creatinine were noted to occur more frequently in Rayaldee-treated patients compared to placebo patients. Both of these TEAEs were considered as unlikely related to study drug and resolved while continuing treatment. Therefore, congestive heart failure and increased blood creatinine were considered as uncertainties and were included in the Adverse Reaction section of the Product Monograph. Twelve patients (2/175 placebo [1.1%] and 10/435 Rayaldee [2.3%]) died during the Phase III studies; none of the deaths was considered related to Rayaldee.

Overall, the safety issues were consistent with exaggerated pharmacology and with expected class specific side effects of vitamin D analogues and consisted of increase in serum calcium and phosphorus levels. The incidence of confirmed cases of increases in serum calcium and phosphorus levels in Rayaldee patients across the Phase III trials was low.

As discussed at the January 2016 pre-submission meeting, a thorough QT study was not performed since Rayaldee is an endogenous compound and the plasma concentrations of calcifediol (medicinal ingredient in Rayaldee) achieved with the therapeutic doses of Rayaldee are not higher than the upper limit of the normal physiological range.

Overall, treatment with Rayaldee was safe, well tolerated and consistent with known pharmacology and with expected class specific side effects of vitamin D analogues. The review of pooled safety data did not result in new safety findings or trends that have not been previously seen with other Vitamin D therapies. In addition, any identified risk has been addressed through appropriate labelling in the Rayaldee Product Monograph. The Product Monograph provides warnings pertaining to the significant adverse events reported in clinical trials, and recommendations to the prescriber regarding treatment monitoring and dose modifications that may be required to manage adverse events.

For more information, refer to the Rayaldee Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical pharmacology, pharmacokinetic, and toxicology trials have characterized the non-clinical profile of calcifediol (the medicinal ingredient in Rayaldee) in sufficient detail to support the intended clinical indication.

The primary pharmacodynamic effects of calcifediol and its role in parathyroid hormone regulation, calcium homeostasis, and bone metabolism are well established. For this reason, additional pharmacology trials were not performed to evaluate the primary pharmacodynamic effects of Rayaldee. Rather, a study in vitamin D deficient rats was performed to evaluate the pharmacodynamic properties of the extended-release formulation of calcifediol. When compared with a bolus intravenous dose of calcifediol, extended-release calcifediol exhibited a gradual increase in serum calcifediol and calcitriol. Correspondingly, the absorption profile of Rayaldee is characterized by a lower maximum plasma concentration and a longer time to achieve maximum plasma concentration compared to immediate-release calcifediol. The sponsor did not evaluate the distribution, metabolism or excretion profile of calcifediol. Considering that Rayaldee consists of calcifediol that exhibits extended-release properties, there is no reason to expect the distribution, metabolism and excretion profile to differ when compared to immediate-release calcifediol.

A full toxicology program was not performed for Rayaldee as a substantial body of data exists in the public domain. The toxicity profile of Rayaldee was therefore characterized by performing only select toxicology studies in order to identify toxicities relevant to the extended-release formulation of calcifediol. The data was then bridged to information in the literature. The effects of calcifediol administered at high doses to humans or animals are those associated with vitamin D toxicity (hypercalciuria, hypercalcemia, calcification of soft tissues following prolonged administration). Indeed, in a 13-week repeat-dose toxicity study performed in beagle dogs at 0, 2.5, 12.5, 50 and 100 mcg/kg/day, Rayaldee exhibited a chronic toxicity profile that is similar to other vitamin D analogues.

Genotoxicity studies were not performed with Rayaldee. There is sufficient information in the literature to conclude that calcifediol likely does not exhibit mutagenic or genotoxic potential. The carcinogenic potential of Rayaldee was evaluated in a 26-week study conducted in rasH2 transgenic mice treated with 3, 10 and 33 mcg/kg/day of calcifediol by subcutaneous injection. There were no calcifediol-related neoplastic findings at the high-dose level. A 2-year rat carcinogenicity study was not performed.

Reproductive and developmental toxicity studies were not performed with Rayaldee. This was considered acceptable as there is sufficient reproductive and developmental toxicity data for calcifediol from various sources. The totality of the data suggests that calcifediol does not exhibit an adverse effect on fertility and postnatal development. Calcifediol was not teratogenic in rats, but was teratogenic in rabbits at doses ≥25 mcg/kg (8-16 times the human dose). Mechanistically, the teratogenic effect of calcifediol in rabbits may be driven by the expected pharmacological effect of hypercalcemia at high doses as calcitriol (the pharmacologically active metabolite of calcifediol) was also found to be teratogenic in rabbits (and not rats) at exaggerated doses. Importantly, data from several published studies have indicated that doses up to 4,000 IU (100 mcg) of vitamin D are not associated with adverse pregnancy outcomes.

For more information, refer to the Rayaldee Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Rayaldee has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 12 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

Neither the drug substance nor the reagents are obtained from sources that are at risk of transmitting bovine spongiform encephalopathy (BSE) / transmissible spongiform encephalopathy (TSE).

 

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