Summary Basis of Decision for Zemplar
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:
Zemplar
Paricalcitol, 5 mcg/mL, Solution for Injection, Intravenous
Abbott Laboratories Ltd.
Submission control no: 087818
Date issued: 2005-11-18
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), ZEMPLAR*, Paricalcitol, 5 mcg/mL, solution, Laboratoires Abbott Limitée, No de contrôle de la présentation 087818
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02266202
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
*Trademark of Abbott Laboratories Limited, all trademark rights used under licence.
2 Notice of decision
On March 31, 2005, Health Canada issued a Notice of Compliance to Abbott Laboratories Limited for the drug product Zemplar*. Zemplar* contains the medicinal ingredient paricalcitol which is a synthetic vitamin D analogue.
Zemplar* is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease. Patients with chronic kidney disease produce less Vitamin D which can result in high levels of parathyroid hormone (PTH) contributing to renal osteodystrophy. Paricalcitol appears to correct the Vitamin D deficiency and reduces parathyroid hormone (PTH) levels; directly inhibiting the pre-pro-PTH mRNA synthesis by the parathyroid glands and providing an anti-proliferative effect on the parathyroid cells.
The market authorization was based on submitted Chemistry and Manufacturing information, as well as adequate preclinical and clinical studies. The safety of Zemplar* was investigated in 660 patients in Phase II/III/IV clinical trials. The data submitted demonstrate that Zemplar* can be administered safely when used under the conditions stated in the Product Monograph.
Zemplar* (5 mcg/mL paricalcitol) is presented in ampoules or flip-top vials containing 1 mL or 2 mL each. The recommended initial dose of Zemplar* is 0.04 mcg/kg to 0.1 mcg/kg (2.8 to 7 mcg) administered as a bolus dose at any time during dialysis, via the haemodialysis line, no more than every other day. If a satisfactory response is not observed, the dose may be increased by 2 to 4 mcg at every 2- to 4-week intervals. Frequent monitoring of serum calcium and phosphorous levels is required. Dosing guidelines are available in the Product Monograph.
Zemplar* is contraindicated for patients with evidence of Vitamin D toxicity, hypercalcemia, or hypersensitivity to any of its ingredients.
Detailed conditions for the use of Zemplar* are described in the Product Monograph. Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Zemplar* is favourable for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Manufacturing Process and Process Controls
The drug substance, paricalcitol, is synthetically derived. The method of manufacturing, the control during manufacturing, and the control of reagents/solvents/intermediates are considered acceptable.
Characterisation
Elucidation/characterization data is considered acceptable. The primary reference standard has been appropriately characterised. Test results demonstrate that the methods are capable of differentiating between potential isomers and the product, and show that none of the chemical transformations cause a loss of chirality.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterised. These products were found to be within ICH established limits and/or were qualified from batch analysis and therefore considered to be acceptable.
Control of Drug Substance
Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of paricalcitol. The specifications are considered acceptable for the drug substance.
Test results for 15-20 batches were provided. Data from the batch analyses were reviewed and considered to be acceptable according to the specifications.
The proposed packaging components are considered acceptable.
Stability
Stability study results based on accelerated and long-term testing show that paricalcitol is a stable compound when packaged as proposed over the proposed storage period. The bulk drug is also stable under the proposed storage conditions.
3.1.2 Drug Product
Description and Composition
Zemplar* is a clear, colourless, sterile, pyrogen-free solution. It comprises of 5 mcg/mL of paricalcitol in a cosolvent system of ethanol (20% v/v), propylene glycol (30% v/v) and Water for Injection (qs). The formulations are identical in the 1 mL and 2 mL filled 2 mL vials, as well as in the 1 mL and 2 mL fill volumes in the 1 mL and 2 mL ampoules respectively. The proposed formulations are considered acceptable based on the drug substance solubility data.
Vials and ampoules are of glass, USP Type I. The vial (bottle) comes with a flip-top stopper, and a flip-top closure (green for the 1 mL volume and dark blue for the 2 mL volume). The ampoules have no markings; the sizes of the ampoules differ for the 1 mL volume and the 2 mL volume. Packaging consists of cartons of 25 vials or 5 ampoules.
Pharmaceutical Development
Experiments were performed to determine the solubility of paricalcitol as a function of the composition of cosolvent systems composed of water, ethanol and propylene glycol. The drug substance solubility/compatibility data with the proposed excipients were noted. The formulation developmental data of the drug product is considered acceptable.
Studies evaluated the suitability of the container closure systems, for vials and ampoules. Based on the developmental data for the packaging components, the proposed packaging appears to be satisfactory for the product.
A microbiological protocol was undertaken to evaluate the bactericidal/fungicidal properties of Zemplar*. Studies showed that 2 mcg/mL paricalcitol was both bacteriostatic and fungistatic for up to 48 hours. The hold time of 42 hours for Zemplar* is considered acceptable.
Manufacturing Process and Process Controls
The specifications for all of the ingredients are either approved in accordance with USP/NF or Ph. Eur standards.
The manufacturing process is basic and involves terminal sterilization. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
The validation data for the bulk hold-time, the packaging components sterilization/depyrogenation, and the terminal sterilization of the finished product are considered acceptable.
Control of Drug Product
Zemplar* is tested to verify its potency, identity, clarity, sterility, volume, and the presence of impurities, particulate matter, and bacterial endotoxins. The validation data for all are considered acceptable.
Data from final batch analyses were reviewed and considered to be acceptable according to the specifications of the drug product.
Stability
Stability data show that the ampoules and the vials with the proposed closure system are acceptable for the finished product.
Based upon the real-time and accelerated stability data submitted, the proposed shelf-life of 12 months is considered acceptable for the product when packaged in vials and 24 months when packaged in ampoules. All packages should be stored at 15-25°C and protected from light, freezing, and excessive heat.
3.1.3 Facilities and Equipment
The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the products manufactured at the site.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Summary and Conclusion
This New Drug Submission is considered to meet the requirements of Division C.08.002 of the Food and Drug Regulations insofar as the Quality (Chemistry and Manufacturing) information is concerned.
The Chemistry and Manufacturing information submitted for Zemplar* has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
In vitro and in vivo studies were conducted to study the pharmacodynamic activities of paricalcitol compared to the approved vitamin D analogue, calcitriol. In vitro studies used various concentrations of paricalcitol and calcitriol with bovine parathyroid cells, and in vivo studies used various doses of the two drugs in partially nephrectomized rats.
Paricalcitol showed the following primary pharmacodynamic activities:
- Significantly decreased the levels of parathyroid hormone (PTH) in a concentration-dependent manner similar to calcitriol.
- Significantly decreased the levels of pre-pro-PTH messenger RNA, and parathyroid gland weights. Calcitriol produced similar results.
- Slightly increased levels of calcium (Ca) and phosphate (PO4) when administered to rats in high doses (16 mcg/kg). Calcitriol, at high does (8 ngs/rat/dose), caused significant increases of Ca and PO4 levels. High doses of calcitriol also increased levels of Vitamin D receptor in the intestine; paricalcitrol did not have this effect.
Secondary pharmacodynamic studies assessed the effect of paricalcitol on bone. Paricalcitol was seven times less effective than calcitrol in promoting bone mobilization.
Three-month toxicity studies were performed on dogs with paricalcitol doses that yielded plasma concentrations of 317 pg/mL and 1,081 pg/mL (peak human concentrations are between 300 and 450 pcg/mL). Results showed no evidence of effects on cardiac, lung or central nervous system (CNS) function.
3.2.2 Pharmacokinetics
Absorption
No absorption studies were performed since the intended route for clinical use is intravenous.
Distribution
A quantitative tissue distribution study was performed following a single 3 mcg/kg intravenous dose of paricalcitol to male and female rats. Paricalcitol distributed rapidly throughout the body and did not appear to be selectively concentrated in any specific tissue. Plasma concentration at 30 minutes was approximately 18 ng eq/mL; at 2 hours, approximately 9 ng eq/mL; at 6 hours, 2.1 ng eq/mL; and at 24 hours, 0.14 ng eq/mL. At 2 hours, the concentration in the liver was 8.4 ng eq/g; adrenals, 6.9 ng eq/g; lungs, 6.7 ng eq/g; kidney, 5.3 ng eq/g; and pancreas, 4.0 ng eq/g. By 72 hours, the drug was virtually undetectable.
In the circulation, paricalcitol was extensively bound to protein. In vitro studies of plasma from mice, rats, dogs, monkeys and humans, all showed 99.9% to 100% protein binding of paricalcitol over a wide of range of concentrations (1-100 ng/mL).
Metabolism
Studies in biliary cannulated rats showed that 90-95% of the intravenous dose appeared in the faeces in the succeeding 24 hours. Urinary excretion accounted for 1% in male rats and 9% in female rats. In bile, less than 4% was identified as the parent drug; the remainder were unidentified metabolites. One of these metabolites, designated as M3, constituted 50% of the total. This metabolite was identical to 75% of the urinary metabolite excretion in female rats. Half-life of the parent drug was approximately 3 hours and only the parent drug was detected in the plasma. Similar experiments in dogs showed that a number of metabolites were produced. The M3 metabolite was the only common product between rats and dogs and contributed to 50% of the total metabolite in dogs. Again, only the parent drug was detected in the plasma of dogs. The metabolic pathways and the characterization of the metabolites were not defined.
The pharmacokinetic experiments did not include drug interaction studies.
Excretion
Within three days of dosing rats, 97 to 100 % of the administered dose was eliminated and 88 to 99% was excreted in the faeces. In female rats, 9% of the dose was excreted in the urine. In dogs, there were no gender differences in the excretion profile; 95% of the dose was eliminated over a similar period of 72 hours and was excreted in the faeces.
3.2.3 Toxicology
The animal toxicology assessment was based on acute single-dose studies, repeat-dose studies, as well as mutagenic, carcinogenic, reproductive and development studies.
Single-Dose Toxicity
The acute IV no-toxic-effect dose was 16 mcg/kg in rats, and > 24 mcg/kg in mice. Dosing was limited by the vehicle for paricalcitol (ethanol). Human dosing of paricalcitol is < 0.24 mcg/kg.
Repeat-Dose Toxicity
Doses of 0.1, 0.5, 3.0, and 10.0 mcg/kg were administered to mice 3 times per week for 3 months. Leucopenia was observed with doses ≥ 0.5 mcg/kg in female mice, and in male mice with doses of 10 mcg/kg. High doses of paricalcitol also significantly increased serum Ca, PO4, and PTH levels.
Similar 3-month studies were conducted in rats but the highest dose was 3.0 mcg/kg. Male rats failed to gain weight at the highest dose. At post-mortem, there was widespread tissue calcification. These effects were somewhat less in female rats.
Rats in a 6-month study received doses of 0.1, 0.5, and 3.0 mcg/kg, 3 times per week. High doses of paricalcitol slightly lowered haemoglobin concentrations in female rats. In male rats, the high doses slightly lowered levels of Activated Partial Prothrombin Time (APPT), reduced PTH levels, and increased serum Ca and PO4 levels. Skeletal calcium deposition was also noted with high doses of paricalcitol.
Dogs were considerably more sensitive than rodents to the calcemic actions of PTH. In a 6 week study (4 weeks of active treatment), doses of 0.1, 0.3, 0.6, and 1.0 mcg/kg paricalcitol were administered 3 times per week. Results showed reduced food consumption in male dogs with the 0.6 mcg/kg dose, and in both male and female dogs with the 1.0 mcg/kg dose. In all dogs, the PTH was reduced. Doses of 1.0 mcg/kg paricalcitol increased serum Ca and PO4 levels, and reports of renal tubular degeneration, and thymus and parathyroid gland atrophy were noted with high doses of paricalcitol.
During the 3-month dog studies, dogs that received the 0.3 mcg/kg dose had to be prematurely euthanized; the dogs suffered from "failure to gain weight" (an effect of hypercalcemia). Results from the 6- and 12-month studies with doses of 0.02, 0.10, and 0.20 mcg/kg showed decreases in white blood cell counts and immunoreactive parathyroid hormone (iPTH) levels; and increases in APPT, Ca, and PO4 levels. Parathyroid atrophy and mild nephrocalcinosis were also observed.
Genotoxicity
Standard genetic toxicity tests were negative. Mutation tests were negative and no chromosomal aberrations were noted.
Carcinogenicity
Two-year carcinogenicity tests were performed in mice using paricalcitol doses of 1, 3, and 10 mcg/kg. There was no evidence of tumourigenesis. Similar two-year studies were performed in rats with doses of 0, 0.15, 0.50 and 1.50 mcg/kg. Increases in benign and malignant pheochromocytomas were noticed in female rats with the highest dose. These conditions were attributed to high calcium absorption in the rats, a calcemic effect of paricalcitol.
Reproductive and Development Toxicity
Paricalcitol had no effect on reproductive capabilities of male and female rats or on development up to 13 days at doses up to 20 mcg/kg.
Female rats were dosed daily with 0.3, 1.0, or 3.0 mcg/kg per dose for gestation days 6 to 17. Food consumption and weight were decreased in the high-dose group. No other effects were noted in the adult rats and there were no drug-related changes in fetal viability and growth. Perinatal and post-natal studies in rats showed a no-effect level at 3.0 mcg/kg per day.
Rabbits were tested for maternal and developmental fetal toxicity. Gravid female rabbits were given 0.03, 0.10, and 0.30 mcg/kg per day for gestation days 6 to 18. The does were euthanized at day 29. No maternal mortality was noted before that day. Some of the does that received 0.10 mcg/kg and all does that received 0.30 mcg/kg had decreased weight gain. Thus, the no-effect level for maternal toxicity was 0.03 mcg/kg per day. The fetal no-effect toxicity was 0.10 mcg/kg per day.
3.2.4 Summary and Conclusion
In the animal studies, paricalcitol was shown to reduce parathyroid hormone levels. Safety studies showed no evidence of effects on cardiac, lung or central nervous function.
Toxicity testing revealed unexpected toxicity (leukopenia and increased APPT) only at the high doses, however these conditions have not occurred in humans at therapeutic dosing levels. High doses also caused widespread tissue calcification. Tissue calcinosis arises from the therapeutic activity of the drug, but only with doses that produce hypercalcemia.
In the initial submission, neither the metabolites nor the metabolic pathways were identified. However, in a subsequent clarifax, 50% of the metabolites were identified and some P450 pathways postulated. Studies on possible drug interactions are lacking, but the drug has been used widely in humans on haemodialysis and post marketing surveillance has not revealed any interactions of concern.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Renal osteodystrophy is a debilitating condition that occurs with chronic renal failure. The condition is caused by a combination of factors including chronic retention of phosphate which in turn causes excess secretion of parathormone. In addition, there is reduced formation of 1,25 dihydroxy vitamin D consequent to reduced renal mass associated with chronic renal failure.
Vitamin D causes suppression of parathormone secretion but, unfortunately, also causes increased calcium absorption from the gut and consequent hypercalcemia. This latter action limits dosing with Vitamin D. Various analogues of vitamin D including paricalcitol and various dosing strategies (parenteral bolus doses, daily oral doses etc.) have been investigated to allow maximum suppression of PTH with minimal effects on serum calcium. So far, there is no consensus on the best approach to this problem.
3.3.2 Pharmacokinetics
Paricalcitol was administered intravenously in healthy subjects. During the first 24 hours, only the parent drug was detected in the blood; no metabolites were present. At 21 hours, approximately half of the parent drug was detected.
In the Phase II and III studies, estimates of Cmax and T1/2 were performed on a small number of subjects and the decline in drug concentrations were shown to be log linear. Similar results were obtained in multi-dose studies indicating no significant accumulation between doses when they were administered at either two- or three-day intervals. Equilibrium dialysis experiments with human blood showed 99% protein binding (similar to the animal studies).
Results from radioactive isotope labelling indicated that approximately 85% of the dose was eliminated by biliary excretion and the remainder in the urine.
Studies with haemodialysis patients indicated that haemodialysis had no impact on the drug pharmacokinetics.
Studies with patients with mild and moderate hepatic impairment (Child-Pugh Grades A and B) showed that patients with moderate hepatic impairment had slightly lower concentrations of paricalcitol than patients with mild hepatic impairment. Protein binding was also reduced, hence effective concentrations of paricalcitol remained unchanged. Therefore, it is recommended that no dosage change is necessary for patients with mild and moderate hepatic impairment. Information regarding patients with severe hepatic impairment was not available.
3.3.3 Clinical Efficacy
Eight trials were conducted to assess efficacy. Four small Phase II trials were double-blind, randomized, and placebo-controlled but only involved 8-22 patients on the active drug; numbers were too small to contribute significantly to the efficacy data. Two larger trials (the pivotal studies) were double-blind and randomized and had an active comparator (calcitriol) rather than placebo. The remaining two trials had one as an active control equivalent study with two different starting doses and the other was an open-label long-term study for a duration of 13 months.
Patients in these studies received haemodialysis three times a week. At baseline, the iPTH levels were greater than 300 pg/mL and the CaXPO4 product (calcium level multiplied by the phosphate level) was <5.6 (not hypercalcemic). Patients were excluded if they had significant liver disease, malignancy, pregnancy, or questionable survival rate. Most patients had significant comorbidity.
Primary endpoints for evaluating efficacy were decreased levels of iPTH (30% or 50%), and increased values of serum Ca, PO4, and CaXPO4.product.
The starting dose varied in the different trials. In the two major pivotal trials, the starting dose was 0.04 mcg/kg for paricalcitol and 0.01 mcg/kg for calcitriol. Both drugs were administered intravenously.
Pivotal Trial 1
Pivotal Trial 1 was a good design: a multicentre, randomized, double-blind, active comparator study. The treatment phase had 263 haemodialysis patients: 130 received 0.4 mcg/kg paricalcitol, and the remainder received 0.01 mcg/kg calcitriol (an acceptable comparator). Both drugs were administered intravenously in an escalating dose. The treated population was 57% male and 74% black with a mean age of 56.6 years. This study population had a far greater representation of Blacks than what would occur in Canada, but the age and the sex profiles were similar. Diabetes, hypertension and focal segmental glomerulosclerosis (FSGS) were the most common causes of renal failure (causes similar to those seen in Canada). Dose escalation continued until iPTH levels fell by 50% or until Ca or CaXPO4 levels exceeded the upper limits of safety. It was noted that 16 of the calcitriol-treated subjects, and 23 of the paricalcitol subjects were treated but not evaluated. The primary efficacy endpoint was a single incident of hypercalcemia (Ca ≥2.88 mm/L) and/or increased levels of CaXPO4 product (> 5.6). Secondary endpoints included a 50% reduction in iPTH as well as the length of treatment time to achieve this endpoint
Results showed that 108 (83%) of the patients treated with paricalcitol and 111 (83%) of the patients treated with calcitriol achieved a 50% reduction in iPTH at least once. Results also showed that 83 (64%) of the patients in the paricalcitol group became hypercalcemic or had CaXPO4 product > 5.6 compared to 90 (68%) in the calcitriol group. These percentages show no significant difference between the two drugs. When the criteria was changed to 2 consecutive hypercalcemic results and/or 4 incidences of increased levels of CaXPO4, the results were 24 (18%) in the paricalcitol group and 44 (33%) in the calcitriol group. It was therefore concluded that paricalcitol is a safer drug to use than calcitriol when doses are comparable in terms of efficacy.
The most that can be concluded from this trial is that paricalcitol and calcitriol are similar with respect to efficacy and that no difference was proven with respect to incidence of hypercalcemia. The efficacy endpoint used to support the claim that paricalcitol was superior to calcitriol was not defined as such in the initial protocol. Selecting an endpoint that involved consecutive readings of hypercalcemia or increased levels of CaXPO4 could merely reflect the time course of drug action rather than a decreased propensity to cause hypercalcemia. The incidence of hypercalcemia was also quoted as a percentage of the total patients treated rather than the total evaluable subjects, which does not appear to be consistent.
Pivotal Trial 2
Pivotal Trial 2 was very similar to the first pivotal study. The second study compared paricalcitol with calcitriol to determine whether the incidence of hypercalcemia and/or increased levels of CaXPO4 were lower in haemodialysis patients when dosing was increased until iPTH decreased by 50% from the baseline. In this study, 330 patients were enrolled: 197 patients were randomized and treated intravenously (98 patients received paricalcitol and 99 received calcitriol) and 180 was similar to the dialysis population in Canada except that there was a preponderance of Blacks (79%). The primary efficacy endpoints were hypercalcemia with levels of Ca >2.88 mm/L or CaXPO4 product >6.1 (slightly higher than the 5.7 endpoint in the first pivotal study) following a >50% reduction in iPTH concentration compared with baseline.
The incidence of hypercalcemia was the same for each drug (31% for paricalcitol and 32% for calcitriol). There was an increased incidence of increased levels of CaXPO4 in the paricalcitol group (72 incidents or 73.5%) as compared to the calcitriol group (58 incidents or 58.6%). The efficacy assessment in this trial slightly favoured calcitriol.
Additional Studies
One of the studies involved 125 patients with two different dosing regimens of paricalcitol: 61 patients received 0.04 mcg/kg (the reference dose), and 64 had dosing tailored to their iPTH level. It took less time for the latter group to achieve a 30% fall in iPTH than the group that were receiving the reference dosing regime of 0.04 mcg/kg. The incidence of hypercalcemia was similar in both groups.
The long-term open-label study consisted of 164 patients taking paricalcitol for 13 months. Control of iPTH was obtained in 52% of the patients at 13 months, and there were 101 incidences of hypercalcemia during the study.
Conclusion
Paricalcitol, the active ingredient in Zemplar*, is more effective than placebo in reducing PTH concentrations in haemodialysis patients but there is no evidence that paricalcitol is more effective than calcitriol in this function.
Comparative clinical trials were performed in an attempt to show that paricalcitol did not cause as much hypercalcemia as calcitriol for the same degree of suppression of PTH secretion. Though the FDA accepted this statement in their labelling, it has not been accepted for the Canadian labelling for the following reasons:
- Two almost identical trials were performed and only one supported the hypothesis of less hypercalcemia.
- In the positive trial, the primary endpoint of one episode of hypercalcemia showed no difference between paricalcitol and calcitriol and it was only when an "ad hoc" analysis where two consecutive measures of serum calcium was used did a favourable result appear for paricalcitol.
- The definition of hypercalcemia used in the trials was higher than that used in current clinical practice (11%).
3.3.4 Clinical Safety
In all the trials, paricalcitol was administered to 660 haemodialysis patients. Haemodialysis patients have a high morbidity rate and hence adverse events were common in the placebo, active comparator groups as well as in the group treated with paricalcitol. There were no new concerns with respect to adverse reactions with paricalcitol as compared to the comparator drug.
Premature discontinuation of the drug similarly did not reveal any significant trends. Hypercalcemia was the most common and expected adverse effect and arose from the mode of action of the drug.
Post-marketing Experience
Paricalcitol was approved in the USA in April 1998. It has since been approved in a number of other jurisdictions. Between August 2002 and Feb 2003, the company estimated that 425,300 doses were administered amounting to the equivalence of 1,164 patient treatment years. During that period, there were 15 Periodic Safety Update Reports. Two reports involved serious adverse reactions and the remainder were non-serious. It was determined that the serious events were not related to the drug. In the non-serious category, two cases of taste perversion occurred and these were thought to be possibly related to the drug.
Conclusion
The clinical trials showed no common (>2%) toxicity effects with paricalcitol. Extensive post-marketing surveillance also revealed no serious adverse effects. Hypercalcemia which occurs as part of the pharmacological activity of the drug was the most common significant adverse effect.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Zemplar* is effective with respect to lowering PTH in chronic renal failure patients. It can, however cause a rise in serum calcium and phosphate concentrations. So far, there is no evidence that Zemplar* is more effective than alternative preparations in lowering PTH while simultaneously producing less adverse events. As with all Vitamin D analogues, Zemplar* has the potential to produce hypercalcemia and hyperphophatemia, and therefore must be accompanied by a program to monitor serum concentrations of these parameters.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Zemplar* is favourable in the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease. The 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.
4 Submission Milestones
Submission Milestones: Zemplar
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2003-11-05 |
| Screening 1 | |
| Screening Deficiency Notice issued: | 2003-11-19 |
| Response filed: | 2004-01-12 |
| Screening Acceptance Letter issued: | 2004-01-14 |
| Review 1 | |
| Clinical Evaluation complete: | 2004-11-03 |
| Quality Evaluation complete: | 2005-03-09 |
| Labelling Review complete: | 2005-03-23 |
| NOC issued by Director General: | 2005-03-31 |