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Contact: Tara Bower
May 13, 2004
Our file number: 04-108734-850
Summary Basis of Decision: Publication of Pilot Exercises
Further to the Notice entitled "HPFB to publish Summary Basis of Decision documents" (March 11, 2004), the Health Products and Food Branch (HPFB)is pleased to provide the results of two pilot exercises. Publication of the pilot exercises is consistent with Health Canada's commitment to developing appropriate transparent measures to provide Canadians with timely information on the benefits and risks of approved products.
The two Summary Basis of Decision (SBD) pilot documents highlight the scientific and benefit/risk-based reasons for Health Canada's decision to grant market authorization, including regulatory, safety, efficacy and quality considerations.
The New Drug Submissions selected for the pilot exercises are:
- Crestor® (rosuvastatin calcium) filed by AstraZeneca Canada Inc., Notice of Compliance issued February 18, 2003; and
- Fabrazyme® (agalsidase beta) filed by Genzyme Canada Inc., Notice of Compliance issued January 23, 2004.
A draft SBD template for drugs was developed, and the content and format tested for suitability under the pilot exercises. The resultant pilot SBDs were written with input from the respective submission sponsors. Results of the pilot exercises are being disclosed with the expectation that the content and format of the SBDs may subsequently evolve as a result of June consultations with all affected stakeholders, including patient groups, consumer associations and industry. As such, results of the pilots will not be precedent setting.
Canadian health professionals frequently rely on approval packages/basis for decision disseminated by the United States or European Union as there has previously been no similar information disseminated in Canada. These information sources may be inconsistent with regulatory decisions made in Canada and may not provide information appropriate to the Canadian context. The Summary Basis of Decision initiative is developed to address this gap and to provide Canadian health professionals and consumers with more information to support informed treatment choices.
Any comments regarding the pilot exercises or consultations should be directed to Tara Bower, Policy Bureau, Therapeutic Products Directorate, at the coordinates below.
By Mail
1600 Scott Street,
Holland Cross, Tower 'B',
2nd Floor, Address Locator 3102C5,
Ottawa, Ontario, K1A 1B6,
Fax to 613-941-6458
E-mail to tara_bower@hc-sc.gc.ca
SUMMARY BASIS OF DECISION (SBD)
CRESTOR®
Rosuvastatin calcium, 10, 20 and 40 mg tablets
AstraZeneca Canada Inc.
Control No. 072326
| Dated Issued | 2004/05/13 |
Health Products and Food Branch
Our mission is to help the people of Canada maintain and improve their health. Health Canada
HPFB's Mandate is to take an integrated approach to the management of the risks and benefits to health related to health products and food by:
- Minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and,
- Promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.
Health Products and Food Branch
Également disponible en français sous le titre : SOMMAIRE DES MOTIFS DE LA DÉCISION (SMD) Crestor® Rosuvastatine calcique, comprimés de 10, 20 et 40 mg N° de contrôle 072326
TABLE OF CONTENTS
1 PRODUCT AND SUBMISSION INFORMATION
2 SCIENTIFIC AND REGULATORY BASIS FOR DECISION
2.1 Introduction
2.2 Quality Basis for Decision
2.2.1 Drug Substance (Medicinal Ingredient)
Manufacturing Process and Process Controls
Characterisation
Control of Drug Substance
Stability
2.2.2 Drug Product
Description and Composition
Pharmaceutical Development
Manufacturing Process and Process Controls
Control of Drug Product
Stability
2.2.3 Facilities and Equipment
2.2.4 Adventitious Agents Safety Evaluation
2.2.5 Summary and Conclusion
2.3 Pre-clinical Basis for Decision
2.3.1 Pharmacodynamics
2.3.2 Pharmacokinetics
2.3.3 Toxicology
2.3.4 Summary and conclusion
2.4 Clinical Basis for Decision
2.4.1 Pharmacodynamics
2.4.2 Pharmacokinetics
2.4.3 Special Populations
2.4.4 Interactions
2.4.5 Clinical Efficacy (analysis of main studies)
2.4.6 Clinical Safety
2.4.7 Additional Considerations
2.5 Benefit/risk Assessment and Recommendation
2.5.1 Benefit/risk assessment
2.5.2 Recommendation
1 PRODUCT AND SUBMISSION INFORMATION
| Brand Name | CRESTOR® |
| Manufacturer/Sponsor | AstraZeneca Canada Inc. |
| Medicinal ingredient | rosuvastatin calcium |
| International Nonproprietary Name | |
| Strength(s) | 10, 20 and 40 mg |
| Dosage form(s) | tablets |
| Route(s) | oral |
| DIN(s) | 02247162, 02247163, 02247164 |
| Pharmaco-therapeutic group (ATC Code) | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor |
| Non-medicinal ingredients | calcium phosphate, crospovidone, glycerol triacetate,hydroxypropyl methylcellulose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, ferric oxide red and titanium dioxide |
| Submission Type and Control No. | New Drug Submission Control No. 072326 |
| Date of Submission | July 24, 2001 |
| Date of Approval | February 18, 2003 |
| Overview of submission | The New Drug Submission (NDS)for Crestor® was given a Notice of Compliance (NOC) on February 18, 2003. Crestor® is approved as an adjunct to diet for the reduction of elevated total cholesterol, LDL-C, apoB, total C/HDL-C, triglycerides (TG) and increasing HDL-C (high density lipoprotein cholesterol) in patients with hypercholesterolemia or dyslipidemia when the response to diet and exercise alone has been inadequate. The NOC for Crestor® covers 10, 20 and 40 mg strengths of rosuvastatin calcium, intended for once daily oral administration. |
2 SCIENTIFIC AND REGULATORY BASIS FOR DECISION
2.1 Introduction
On February 18th, 2003, Health Canada issued a Notice of Compliance to AstraZeneca Canada for the drug product Crestor®. Crestor® contains the active medicinal ingredient rosuvastatin, also known as ZD4522 and S4522, which is a selective competitive inhibitor of 3-hydroxyl-3methylglutaryl coenzyme A (HMG CoA) reductase. This enzyme plays an important role in the synthetic pathway generating endogenous cholesterol. Inhibition of HMG CoA reductase effectively affects plasma concentration of circulating lipid components and, in particular, reduces plasma levels of low-density lipoprotein cholesterol (LDL-C)1. Rosuvastatin is the seventh medication in the pharmacological class commonly known as statins to be approved in Canada. The other statins are lovastatin, pravastatin, simvastatin, cerivastatin (now off market), fluvastatin and atorvastatin.
The approval was based on data from adequate pre-clinical studies and more than 65 controlled/uncontrolled Phase I, II and III clinical studies involving more than 11,600 patients of which over 5,300 received rosuvastatin (over 6,500 in controlled and uncontrolled Phase II and III studies). The studies investigated the efficacy, effectiveness and safety of rosuvastatin in healthy volunteers, special populations and patients with various lipid disorders. These trials conclusively demonstrated that rosuvastatin effectively reduced plasma levels of LDL-C, total cholesterol and to a lesser degree reduced triglycerides as well as, increased to a certain extent high-density lipoprotein cholesterol, all in a dose-dependant manner. The data submitted demonstrated that rosuvastatin can be administered safely when used under the conditions stated in the Product Monograph.
Crestor® is indicated as an adjunct to diet, at least
equivalent to the Adult Treatment Panel III (ATP III TLC diet), for the
reduction of elevated total cholesterol, LDL-C, apoB, total C/HDL-C ratio
and triglycerides (TG) and for increasing HDL-C (high density lipoprotein
cholesterol) in hyperlipidemic and dyslipidemic conditions, when the response
to diet and exercise alone has been inadequate. Crestor® is indicated in patients with: (1) primary hypercholesterolemia (type
IIa including heterozygous familial hypercholesterolemia and severe non-familial
hypercholesterolemia),
(2) combined (mixed) dyslipidemia (type IIb) and
(3) homozygous familial hypercholesterolemia where Crestor® is used either alone or as an adjunct to diet and other lipid lowering
treatment such as apheresis.
Tablets of 10, 20 or 40 mg are to be administered orally once daily. The majority of patients are controlled at the 10 mg dose. If needed the dose can be increased at 2 week-intervals up to a maximum of 40 mg. The maximum dose should not be larger than 10 mg in patients with severe renal impairment and 20 mg for patients with severe liver impairment. Crestor® is contraindicated for: (1) patients with hypersensitivity to any of its ingredients, (2) patients with active liver disease or unexplained persistent 'liver' enzymes (transaminases) exceeding 3 times the upper limit of normal, (3) pregnant and nursing women and (4) patients on cyclosporine.
Detailed conditions for the use of Crestor® are described in the Product Monograph (Section 3: "Information to the Patient" attached).
2.2 Quality Basis for Decision
2.2.1 Drug Substance (Medicinal Ingredient)
Manufacturing Process and Process Controls
Rosuvastatin calcium is manufactured by a series of synthetic chemical reactions. Adequate measures are in place to ensure that the starting materials are of acceptable quality, and reagents and solvents meet widely accepted standards. Intermediates are isolated and tested to ensure their purity, and reaction yields are calculated at each step. The final drug substance is processed to control particle size. Each step of the manufacturing process was considered to be controlled within acceptable limits.
Characterisation
There are two chiral centres present in the rosuvastatin molecule, but the optical purity is well controlled during the manufacturing process and release testing of the drug substance.
Limits for other impurities (process-related and/or degradation products) are considered acceptable, according to Health Canada requirements, which are harmonized with internationally recognized standards [International Conference on Harmonization (ICH), Q3A].
Control of Drug Substance
The drug substance is tested to verify its identity, ascertain its potency, and limit the impurities. All analytical procedures were validated according to internationally accepted criteria [ICH, Q2A and Q2B], and the acceptance limits on the tests were scientifically justified.
All the results from the batch analysis were well within the limits set out in the drug substance specification.
The following is a complete list of tests conducted on the drug substance: description, identification, assay, calcium content, organic impurities, optical impurities, residual solvents, water, inorganic impurities, and particle size.
Stability
Health Canada has granted an18-month expiry period for bulk rosuvastatin calcium when it is stored under approved storage conditions in a double-layer polyethylene bag inside a foil-lined fibreboard container.
1 Different strategies are used for the
control and treatment of elevated 'cholesterol'. Diet and maintenance
of body weight are the mainstay. Aggravating factors should also be eliminated
or controlled to reduce risk factors (physical exercise, cessation of
smoking, control of blood glucose and blood pressure). When not sufficient,
drug treatment is required. The most commonly used class of agents in
this respect is the statins. Statins inhibit the rate-controlling enzyme
for cholesterol synthesis in the liver, i.e., the
3-hydroxyl-3methylglutaryl
coenzyme A reductase (most often abbreviated as HMG CoA reductase). The
statins are very effective in lowering the so-called "bad cholesterol"
(low density lipoprotein cholesterol or LDL-C) and to a lesser extent
in raising "good' cholesterol" (high density lipoprotein cholesterol or
HDL-C). Lipoproteins are globular particles of different sizes that contain
cholesteryl esters or triglycerides surrounded by a polar (more avid of
water) coat.
2.2.2 Drug Product
Description and Composition
Crestor® tablets are approved in three strengths:
10 mg, pink film-coated, round, biconvex intagliated
tablet, engraved with "ZD4522 10"
20 mg, pink film-coated, round, biconvex intagliated tablet, engraved
with "ZD4522 20"
40 mg, pink film-coated, oval, biconvex intagliated tablet, engraved with
"ZD4522 40"
Each strength is approved in blister packages (7s or 10s) or bulk pharmacy bottles of 100 tablets.
Pharmaceutical Development
Phase I and II trials were conducted using oral capsules, but the sponsor wanted to develop a formulation which was stable, robust and suitable for high throughput manufacture for their Phase III studies, so a tablet was formulated. Other desired attributes of the tablet included stability in the presence of light, oxygen, and moisture and good dissolution characteristics.
The final commercial formulation chosen for Crestor® tablets meets all the desired criteria outlined above (refer to sections 2.4.2 and 2.4.7 for assessment of bioequivalence).
Manufacturing Process and Process Controls
The manufacturing process for Crestor® tablets incorporates standard pharmaceutical practices.
Manufacturing occurs at sites which meet Health Canada's Good Manufacturing Practice (GMP) standards, [GMP Guidelines, 2002 Edition], and critical manufacturing steps have been properly validated [Validation Guideline for Pharmaceutical Dosage Forms, 2000].
Note that all excipients meet Ph. Eur. standards, and sufficient in-process testing is in place to ensure a finished product of consistently high quality.
Control of Drug Product
The specification for Crestor® tablets includes tests for the following characteristics: description, identification, assay, degradation products, content uniformity, dissolution, and water content.
Analytical methods were validated according to internationally recognized standards [ICH, Q2A and Q2B] with respect to accuracy, precision, linearity and other relevant criteria. The limits set for assay and impurities were in line with those in compendial monographs for similar products and/or Health Canada and ICH standards [ICH, Q3B] .
Batch results for commercial-scale drug product lots met the specification of the drug product. No test results fell out of the range of acceptable limits.
Note that, although impurities (process-related and degradants) were present in the drug product, they are found at levels which have been deemed to be safe based on internationally recognized standards or toxicity studies conducted on animals.
Stability
Stability studies included the following tests: appearance, assay, impurities, dissolution testing, water content, diastereomers, enantiomers content, crystalline hydrate content, microbiological testing, hardness, and disintegration time.
During the review of the NDS, results from the 18-month test station were submitted. The reviewer noted that these results supported the requested 24 month expiry period.
An expiry period of 24 months was granted for Crestor® tablets, in both the blister packaging and the high density polyethylene bottles. The recommended storage temperature is between 15-30°C, in a tightly sealed container.
On-going stability studies will be conducted on one lot of drug product each year, as outlined in GMP guidelines [GMP Guidelines, 2002 Edition].
2.2.3 Facilities and Equipment
The proposed manufacturing sites for Crestor® tablets all meet Health Canada's GMP guidelines and currently have a rating of "C" (conforms).
2.2.4 Adventitious Agents Safety Evaluation
N/A
2.2.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Crestor® 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.
2.3 Pre-clinical Basis for Decision
2.3.1 Pharmacodynamics
The usual in vitro animal models such as isolated human and rat hepatic microsomes, isolated human recombinant HMG-CoA reductase and rat hepatocyte culture, as well as in vivo models such as plasma cholesterol levels in rats, dogs, monkeys and transgenic mice established that rosuvastatin caused effects qualitatively similar to those of other statins. Quantitative differences were observed with the testing of different animal models, however in general, rosuvastatin was found to be more potent than other statins to which it was compared. Some differences in vitro might have been due to the hydrophilic properties of rosuvastatin (like pravastatin) relative to other more lipohilic statins (e.g. atorvastatin). Rosuvastatin did not inhibit cholesterol synthesis from mevalonate indicating that it had no effect on the pathway downstream from the HMG-CoA reductase step. Other animal studies showed that rosuvastatin has minimal potential to cause extraneous pharmacological effects in humans when administered orally at therapeutic doses.
2.3.2 Pharmacokinetics
Rosuvastatin was rapidly and extensively absorbed by the intestine. The estimated bioavailability was rather low (< 25%) indicating an important first-pass probably by the liver. Rosuvastatin was in fact, found mainly in the liver where it undergoes extraction. Protein binding was moderate (80-90% in animals; 88% in humans).
Most of the rosuvastatin administered orally to animals was excreted unchanged in the faeces. Low concentrations were found in the foetuses of rats and rabbits and rat milk contained rosuvastatin-related metabolites. The main metabolite was the N-desmethyl rosuvastatin metabolite and it was the only metabolite capable of a notable inhibition of HMG-CoA reductase though 2-7 times less potent than the parent compound. Excretion was multi-exponential with a terminal half-life of approximately 7 hours in the monkey and 12 hours in the dog (19 hours in man). Rosuvastatin did not accumulate upon repeated administration.
2.3.3 Toxicology
Toxicity was low (<2 g/kg) in acute trials in rats and dogs. In chronic dosage, 100 mg/kg or more caused toxicity mainly in the forestomach, liver, and gallbladder in mice, liver and forestomach in rats, eye and testes effects in dogs, kidney, muscle, heart, gallbladder and liver in rabbits, and testes in monkeys. The toxicological profile conformed with that observed for other statins presently on the market. In animal models the data was not sufficient to provide conclusive evidence of the effect of rosuvastatin on liver and testes. For this reason and because of inherent uncertainties in preclinical studies, i.e. extrapolating animal studies to humans, one has to rely largely on clinical data to assess the safety of rosuvastatin.
No antigenic or sensitizing potentials were detected.
Reproductive studies showed reduced pup survival, litter size and litter weight in the rat as expected with this class of drug, however rosuvastatin was not teratogenic.
Standard mutagenicity and genotoxicity tests were negative.
An increase in the number of hepatocellular adenomas and carcinomas were observed at hepatotoxic doses only in the mouse carcinogenicity study. This was a species specific effect and raised no concern for carcinogenicity in man. Similarly, uterine stromal polyps observed in rats did not translate to a significant concern in man.
2.3.4 Summary and conclusion
It can be concluded that the animal toxicity is consistent with that found for other statins. No new and unexpected serious adverse events can be predicted in man from these animal studies, i.e., one cannot foresee that rosuvastatin safety in man will be qualitatively different from that of the other statins presently on the Canadian market. An accurate assessment of the safety margins for rosuvastatin will have to be based mainly on the results obtained in clinical trials as calculations in animal data incorporate several inherent uncertainties i.e. extrapolating to humans, and did not provide conclusive evidence of product safety.
2.4 Clinical Basis for Decision
The sponsor provided an extensive number of studies2 to support the efficacy and safety of rosuvastatin in man. Single and repeated doses were used to investigate absorption, distribution, metabolism, excretion, bioavailability, pharmacokinetics and pharmacodynamics interactions in volunteers and special populations, and effects on electrocardiogram parameters.
The clinical experience in Phase II and III studies included 4 pivotal trials (placebo-controlled and active drug-controlled) and 11 non-pivotal trials. Some of these clinical trials also included a pharmacokinetic component.
Various types of dyslipidemic patients were enrolled in these Phase II and III trials. Specifically, patients with mild, moderate and severe hypercholesterolemia (Fredrickson Type IIa/IIb) with or without diabetes mellitus, hypertriglyceridemia, severe non-familial and familial heterozygous hypercholesterolemia, homozygous familial hypercholesterolemia, dyslipidemia (Fredrickson Type IIb/IV) with and without diabetes and Fredrickson Type IV dyslipidemia. The sponsor filed additional studies subsequent to filing the original submission, bringing the total number of subjects to 5,319 patients (768 in placebo-controlled trials) in Controlled Phase II and III trials, and 646 subjects, mainly healthy volunteers, in Phase I and early Phase II trials. Long-term exposure (at or over 48 weeks) of rosuvastatin at the 20 and 40 mg doses included 194 and 140 subjects respectively.
2 The clinical pharmacology included the results of more than 50 Phase I or early Phase II trials.
| Type | Lipoprotein Elevated | Major | Minor |
|---|---|---|---|
| I (rare) | Chylomicrons | TG | ↑ → C |
| IIa | LDL | C | ---- |
| IIb | LDL, VLDL | C | TG |
| III (rare) | IDL | C/TG | ---- |
| IV | VLDL | TG | ↑ → C |
| V (rare) | Chylomicrons | TG | ↑ → C |
Chylomicron = a microscopic lipid particle common in the blood during
fat digestion or assimilation. Lipoprotein = conjugated protein composed
of a complex of protein and lipid
C = cholesterol, LDL = low density lipoprotein (moderate proportion of
protein with little TG and high proportion of C), VLDL = very low density
lipoprotein , IDL = intermediate density lipoprotein
2.4.1 Pharmacodynamics
Studies in volunteers have established that rosuvastatin in the range
of 10 to 80 mg reduced plasma and urinary mevalonic acid (a building block
for endogenous3 cholesterol synthesis).
In early Phase II studies in Fredrickson Type IIa/IIb patients, all doses
of rosuvastatin from 1 to 80 mg significantly reduced LDL-C in a dose-related
manner ranging from 33 to 65% relative to baseline. Changes from dose
to dose were also statistically significant compared to placebo. As observed
with other statins, doubling the dose generally resulted in an additional
reduction in LDL-C of 5 to 6%. Decreases in total-C and triglycerides
were also dose-related as were increases in
HDL-C. Similar results were
obtained in patients with Fredrickson type IIb/IV dyslipidemia. Other
lipid parameters varied as expected from a statin.
Phase II trial results led to the sponsor's selection of the minimal doses of 5 and 10mg in phase III trials. Eventually, the sponsor recommended 10 mg as the minimal starting dose although 5mg also caused significant effects. This was based on the observations that there were no significant differences in adverse events between the dose of 5 and 10 mg and that there was a significantly greater number of responders4 with 10 mg.
Acknowledging hesitation from medical professionals to up-titrate patients, it was agreed that 10 mg was the best choice.
3 Approximately 80% of the cholesterol
in the human body is derived from endogenous synthesis which occurs mainly
in the liver. The initial chemicals during the formation of cholesterol
are simple 2-carbon molecules such as acetic acid or acetates which are
derived from sugars and fats. An acetate associated with an enzyme called
acetyl-CoA forms the building blocks of a
6-carbon molecule called HMG
CoA. The latter becomes associated with a reductase enzyme to form mevalonate,
a more complex building block of cholesterol. Statins inhibit the reductase
(HMG CoA reductase) and thus reduce the amount of cholesterol synthesized.
Acetyl-CoA is also involved in the syntheses of many substances essential
for life in animals and plants.
4 Patients attaining target LDL-C level.
2.4.2 Pharmacokinetics
Maximum plasma levels of rosuvastatin were obtained 3-5 hours after administration with rosuvastatin being absorbed by the intestine. A slight delay in peak levels was observed when administration was done together with food, whether of low or high caloric intake. Secondary peaks in plasma levels were seen due to enterohepatic circulation (intestinal absorption, secretion via the biliary gland and reabsorption by the intestine).
The absolute bioavailability was 20% due to an important first-pass effect. Total exposure to rosuvastatin did not change significantly when taken under fasting or fed conditions or when administered in the morning or in the evening. The circulating drug was extensively but reversibly bound (90%) mostly to plasma albumin. The degree of binding however, was largely independent of the blood concentration of rosuvastatin. Absorbed rosuvastatin was found mainly in the liver. No accumulation of the drug was seen after repeated once-daily dosing. Blood levels of rosuvastatin, measured at peak level, and leveled over a given time period, were directly proportional to the dose administered. Inter-subject variability was found to be 50-65% while intra-subject variability was 20-30%. Blood levels did not predict the effect on LDL-C.
A steady state was obtained following repeated daily dosing for at least 5 days. Within 72 hours, 9% of the rosuvastatin administered was found in urine and 70% in faeces while after 10 days 10% of the dose was recovered in urine and 90% in the faeces. Approximately 80% of the rosuvastatin radioactivity5 recovered in the faeces was that of the parent compound. Following intravenous administration, 30% of the drug administered was recovered in urine and the rest was found in faeces, the major route of elimination being the liver. Thus, metabolism was not a major route for clearance of rosuvastatin. Renal clearance was approximately 13 L/h indicating some renal tubular excretion because this renal clearance is greater than the glomerular filtration rate. The terminal half-life of rosuvastatin is approximately 19 hours.
In vitro studies showed that rosuvastatin was mainly metabolized via the CYP2C9 isoenzyme of the cytochrome P450 system while other isoenzymes (i.e. CYP2C19, 3A4 and 2D6) played only minor roles. Rosuvastatin did not significantly inhibit P450 isoenzymes. The main metabolites were a lactone derivative (inactive) and a N-desmethyl derivative (at 26% of the parent drug and half of its activity). Most of the activity was accounted for by the parent drug while the desmethyl metabolite would account for approximately 13% of the effects.
Pharmacokinetic studies established that formulation(s) used in pivotal clinical studies were bioequivalent to the formulation intended for the Canadian market.
5 Refers to standard radioactivity assay. Therapeutic doses of rosuvastatin do not contain any radioactivity.
2.4.3 Special Populations
Patients versus healthy subjects: Pharmacokinetics in dyslipidemic patients indicated that they did not significantly differ from healthy volunteers.
Renal Impairment: Pharmacokinetics in patients with mild to moderate renal impairment (creatinine clearance ≥30 ml/min/1.73 m2) were not significantly different from that of healthy individuals. However, severe impairment resulted in a 2-3 fold increased exposure. This, therefore, led to the recommendation that the maximal dose in these patients be limited to 10 mg per day. In patients on hemodialysis, Cmax and AUC values were similar to those obtained in 'normal' patients.
Hepatic Impairment: Only severe hepatic impairment increased significantly the exposure to rosuvastatin and the daily dose in these patients should not exceed 20 mg.
Age and sex: Age (from young and older adult) and sex did not play a significant role and, therefore, dose adjustment for sex and age was not required. Pharmacokinetics were not evaluated in children.
Race: Bioavailability in Japanese living in Japan was higher (29%) compared to Caucasians (20%) probably due to a lower clearance. Subjects from other ethnic origins were not investigated.
2.4.4 Interactions
A number of drug interactions were investigated.
No significant effects were observed in or between rosuvastatin and the following: ketoconazole, fluconazole, and erythromycin, which inhibit a number of CYP isoenzymes; or digoxin.
Warfarin did not significantly affect rosuvastatin. In contrast, rosuvastatin caused a clinically significant increase in the anticoagulant effect of warfarin in patients on a stable warfarin regimen (INR from 2-3 to >4); the higher the dose of rosuvastatin the more likely was the increase in INR. The cause of the latter change was probably pharmacodynamic in origin because no significant changes in pharmacokinetics of either drug can account for this difference.
Cyclosporine exposure was not affected by rosuvastatin but cyclosporine increased exposure to rosuvastatin by 7-fold and, therefore, concomitant use of these two drugs is contraindicated.
Ethynyl estradiol and norgestrel levels were increased by approximately 30% with concomitant use of rosuvastatin; a finding which should be considered when prescribing contraceptives.
Antacids containing aluminum and magnesium hydroxide (co-magaldrox) reduced plasma levels of rosuvastatin by 50%. When the antacid was taken 2 hours after rosuvastatin, exposure was decreased by only 20%. Consequently, the Product Monograph recommends that frequent antacid users should take rosuvastatin at a time of day when they are less likely to need the antacid. Other types of antacids were not investigated.
Gemfibrozil caused a 2-fold increase in exposure to rosuvastatin and consequently the dose of rosuvastatin should be reduced by half when these drug are indicated to be used concomitantly. Less rosuvastatin was metabolized to the active desmethyl metabolite in the presence of gemfibrozil. The mechanism of this phenomenon was not known but may be related to transport. Unlike gemfibrozil, fenofibrate or niacin did not appear to affect rosuvastatin plasma levels.
To conclude, it was estimated that the pharmacokinetics of rosuvastatin had been sufficiently investigated if one also takes into account that rosuvastatin was administered concomitantly with many other medications in the course of clinical trials in dyslipidemic patients and that no specific interactions were observed to be clinically significant.
2.4.5 Clinical Efficacy (analysis of main studies)
The clinical efficacy of rosuvastatin was demonstrated by its ability to lower LDL-C. This was the primary efficacy parameter for most of the studies submitted. Although LDL-C plasma level is a surrogate marker, it has been accepted by the Canadian, American, European, Australian and Japanese Regulatory Agencies as a validated surrogate endpoint. Thus, it has been demonstrated that there is a strong, independent and consistent association between a lowering in LDL-C and clinical outcomes (morbidity and mortality).
All trials were preceded by a 6-week dietary run-in period. Patients were equally randomized to parallel groups during double-blind treatment periods. A 4-week drug free follow-up period was done in two trials (8 and 23) to determine the time-course for lipid blood levels to return to baseline. For most trials, the primary efficacy endpoint was LDL-C plasma levels with other lipid variables used as secondary efficacy endpoint. Safety was also a secondary endpoint.
Exclusion criteria were generally the same in all trials: liver disease or dysfunction, elevated creatine kinase, uncontrolled hypertension, active arterial disease, history of malignancy, uncontrolled diabetes or other metabolic endocrine diseases known to alter plasma lipids, known homozygous familial hypercholesterolemia in all but one trial, Type III hyperlipoproteinemia, any contraindication, medications interfering with lipid levels (eg., hormone replacement therapy), alcohol abuse and unstable medical or psychological conditions. The baseline characteristics between treatment groups in each study were, in general, comparable and where differences existed, these differences were not important enough to invalidate the results. Statistical analyses were adequate and properly used.
Table 2 provides an overview of the design of the trials. An assessment of the results follows.
Lipid levels entry criteria were, depending on the trial:
Type IIa/IIb patients LDL-C ≥ 4.14 to < 6.2 or < 6.5 mmol/L
and TG <3.39 or 4.5 mmol/L;
Type IIb or IV TG ≥2.26 or 3.4 to ≤9.0 mmol/L, total cholesterol
≥5.17 mmol/L and HDL-C <1.16 mmol/L;
Familial and non-familial heterozygous hypercholesterolemia LDL-C 5.69
to12.93 mmol/L and TG < 4.52 mmol/L;
Homozygous familial hypercholesterolemia TG <6.77 mmol/L.
| Study | Design | N | Rosuvastatin | Comparator (mg/day) |
Duration (weeks) |
|---|---|---|---|---|---|
| 8 | R/DB/placebo and active-drug controlled dose-ranging | 142 | 1, 2.5, 5, 10, 20, 40 | atorvastatin 10, 80, placebo | 6 |
| 23 | R/DB/placebo dose-ranging | 64 | 40, 80 | placebo | 6 |
| 24 | R/DB/placebo and active controlled | 519 | 5, 10 | atorvastatin 10, placebo | 12 |
| 25 | R/DB/active controlled force titration | 383 | 5, 10, 20, 40, 80 | atorvastatin 10, 40, 80 | 24 |
| 26 | R/DB/active controlled, titration to NCEP II goals (52 weeks but primary endpoint at 12 weeks) | 412 | 5, 10, 20, 40, 80 | atorvastatin 10, 20, 40 ,80 | 12 |
| 27 | R/DB/active controlled | 502 | 5, 10 | pravastatin 20 simvastatin 20 | 12 |
| 28 | R/DB/active controlled titrated to NCEP II goals (52 weeks but primary endpoint at 12 weeks) | 477 | 5, 10, 20, 40, 80 | pravastatin 20, 40 simvastatin 20, 40, 80 | 12 |
| 33 | R/DB/active control | 374 | 5, 10, 20, 40, 80 | atorvastatin 10, 20, 40, 80 | 6 |
| 29 | R/force-titration | 270 (162 IIb, 101 IV) | 4 groups: (1) rosu. 10-40 mg, (2) niacin 0.5 to 2.0 g, (3) rosu. 10-40 + niacin 0.5-1.0 g and (4) rosu. 10 mg + niacin 0.5-2.0 g | 24 LDL-C6 | |
| 35 | R/DB/placebo controlled dose-ranging | 156 (65 IIb, 88 IV) | 5, 10, 20, 40, 80 | placebo | 6 TG6 |
| 36 | R/6 weeks DB placebo-controlled with 2 placebo groups and 2 groups on each on rosuvastatin 5 and 10 mg | 216 | see below | see below | 24 TG6 |
| Trial 36 | group 1 | group 2 | group 3 | group 4 |
| 6 weeks DB | pbo | pbo | rosu. 5 mg | rosu. 10 mg |
| 16 weeks open-label | rosu. Force-titrated 10-40 mg | fenofibrate force-titrated from 67 mg od to 67 mg bid to 67 mg tid | rosu. 5 mg + fenofibrate force-titrated from 67 mg od to 67 mg bid to 67 mg tid |
rosu. 10 mg + fenofibrate force-titrated from 67 mg od to 67 mg bid to 67 mg tid |
| 30 | R/DB/active controlled, forced titration | 623 | 20, 40, 80 | atorvastatin 20, 40, 80 | 18 |
| 31 | R/open-label/after 6 weeks on rosu. 40 mg, randomized to 2 groups: rosu. alone 80 mg and concomitantly with cholestyramine | 153 | 40, 80 | 80 mg + 16 g/day cholestyramine | 6 |
DB - double blind; pbo = placebo; R = randomized; rosu. = rosuvastatin;
od/bid/tid = once, twice and three time daily.
A trial (34) not listed in Table 2 was an open-label extension of the
trials above in Type IIa/IIb, Type IIb or IV, and homozygous familial
hypercholesterolemic patients. This extension was ongoing when the NDS
was originally filed in July 2001 and included up to 3500 patients.
The results of these studies demonstrated that rosuvastatin across the range of 1 to 80 mg once daily produced a dose-related decrease in LDL-C and TG plasma levels. The decrease in LDL-C (from 35 to 65% relative to baseline7) produced by each dose of rosuvastatin, including the lowest dose of 1 mg, was statistically significant compared to placebo. The highest dose of 80 mg caused, however, only a 2-4% fall in LDL-C above the reduction produced by 40 mg indicating that a near maximal effectiveness had been reached.8
The proportion of patients reaching NCEP targets9 for LDL-C was calculated for trial 24 since there was a sufficient number of patients for such a parameter to be meaningful. The results are shown in Table 3. The use of responders is considered more clinically meaningful than a simple change in cholesterol plasma levels since it also takes into account the condition of the patients (presence or absence of cardiovascular disease and other risk factors).
7A 15% decrease from baseline in LDL-C is considered to be clinically meaningful.
8 A 5-7% difference is expected with doubling the dose of a statin.
9According to the 2nd report of the National Cholesterol Education Program
| NCEP risk category | Placebo | Rosuvastatin 5 mg |
Rosuvastatin 10 mg |
Atorvastatin 10 mg |
||||
|---|---|---|---|---|---|---|---|---|
| N | % | N | % | N | % | N | % | |
| Week 2 Low Medium High Total |
63 49 20 132 |
19 2 0 10 |
80 28 19 127 |
88 75 26 76 |
69 40 19 128 |
97 85 42 85 |
72 39 16 127 |
92 69 25 76 |
| Week 6 Low Medium High Total |
61 46 19 126 |
15 0 0 7 |
75 27 18 120 |
92 70 33 78 |
68 39 19 126 |
99 87 53 88 |
71 39 16 126 |
94 77 13 79 |
| Week 12 Low Medium High Total |
63 49 20 132 |
27 0 0 13 |
80 28 19 127 |
93 86 42 84 |
69 40 19 128 |
93 88 47 84 |
72 39 16 127 |
86 72 19 73 |
N = number of patients in a category; % = percent of patients in that category reaching NCEP target; CHD = coronary heart disease; PVD = peripheral vascular disease.
| NCEPII Risk categories10 | |
| Low risk: No CHD/PVD and ≤1 risk factor | Target LDL-C: <4.14 mmol/L |
| Medium risk: No CHD/PVD and ≥2 risk factors | Target LDL-C: <3.36 " |
| High risk: Clinically evident CHD/PVD or diabetes | Target LDL-C: ≤2.59 " |
As mentioned above, secondary endpoints in these trials included lipid variables and safety, which are affected by drugs regulating lipid metabolism. As expected from a statin, it was found that rosuvastatin produced highly significant dose-related decreases in plasma levels of total cholesterol, non-HDL-C and Apolipoprotein B, and increases in HDL-C and ApolipoproteinA-I.
Studies clearly demonstrated that rosuvastatin is an effective statin. They also showed that the effects of rosuvastatin are maintained. The effect of rosuvastatin on LDL-C plasma levels was near maximal by week 2. It was found that the same maximal effect was still present after 6 and 12 weeks of treatment in the studies mentioned above. In at least two trials where the treatment lasted for 52 weeks, there was no evidence that the effect of rosuvastatin diminished with time.
Other studies have clearly established that rosuvastatin was not only effective in Type IIa/IIb patients but also in severe non-familial and familial heterozygous hypercholesterolemia and in homozygous familial hypercholesterolemia (see table Clinical Trial design: Overview).
10 NCEP II targets are shown above since these were the goals at the time the studies were conducted. However, note that NCEP III targets are currently used <www.nhlbi.nih.gov/guidelines/cholesterol/index.htm>.
2.4.6 Clinical Safety
The total safety database originally filed included 30 Phase I and 15 Phase II/III studies. Two other studies were ongoing at submission time (July 2001). Trials completed at submission time included 4393 patients who received at least one dose of rosuvastatin.
During the review, the sponsor withdrew the 80 mg rosuvastatin strength. As a result, data for the 20 mg and 40 mg strengths was not sufficiently robust to reach a conclusion as to the safety profile of rosuvastatin. Furthermore, potential safety concerns related to outcomes of the higher 80 mg dose in phase II trials, necessitated the provision of additional safety data to support 20 and 40 mg11 strengths and allow for proper evaluation of the long-term risk-benefit ratios. For this purpose, the sponsor submitted in 2002 additional safety data which brought long-term exposure numbers (at or over 48 weeks) for rosuvastatin at the 20 and 40 mg doses to 194 and 140 subjects respectively. The number of patients on rosuvastatin in all controlled Phase II/III trials was 5,319 and in controlled and uncontrolled trials 6523. Controlled trials also included 2,945 patients on atorvastatin, 1457 on simvastatin and 1281 on pravastatin. The adverse events of all observed doses were taken into account in evaluating the overall safety of rosuvastatin.
11 For long-term treatment of a non life-threatening condition, ICH guidelines suggest exposure of 300 to 600 patients for 6 months and at least 100 for one year.
Adverse Events
The incidences of adverse events on the different body systems were similar for all doses across the 5 to 40 mg rosuvastatin range. No significant differences were observed between doses, nor between doses and placebo with the exception of myalgia (in placebo-controlled trials the incidences of myalgia were 3.6% and 1.4% in rosuvastatin- and placebo-treated patients, respectively). Similarly, no significant differences were observed in incidences between rosuvastatin and statins used as comparator drugs (atorvastatin, pravastatin and simvastatin). The presence or absence of hypertension, coronary heart disease or mild to moderate renal impairment, did not affect the incidences of adverse events. Moreover, the incidence of adverse events, which led to discontinuation in the rosuvastatin group, was not significantly different from those leading to discontinuation in placebo-treated patients.
The frequencies of adverse events observed in rosuvastatin-treated patients were similar across the range of 5 to 40 mg and were not significantly different from those observed with other statins in controlled trials. No new and unexpected adverse events were reported for this class of medication.
An overall summary is provided in Table 4.
CATEGORY |
Rosuva. (1, 2.5, 5, 10, 20, 40, 80 mg) n= 5319 |
Other Statins | Placebo n = 369 |
|||
|---|---|---|---|---|---|---|
| Atorva. (10, 20, 40, 80 mg) n = 2945 |
Simva. (20, 40, 80 mg) n =1457 |
Prava. (20, 40 mg) n = 1281 |
TOTAL n = 5682 |
|||
| All Adverse Events | 49.8 | 45.9 | 44.3 | 43.2 | 44.9 | 56.4 |
| AE leading to death | 0.2 | 0.2 | 0.2 | 0.1 | 0.2 | 0.3 |
| AE leading to withdrawal | 3.2 | 3.5 | 2.7 | 2.7 | 3.1 | 4.9 |
| Non-fatal Serious AE | 2.4 | 2.1 | 2.3 | 1.6 | 2 | 1.4 |
| AE causally related | 14.6 | 13.5 | 10 | 9.1 | 11.6 | 17.6 |
The non-fatal serious adverse events were similar across the statins used. However, in all controlled trials, there were 4 renal failures presumed related to rosuvastatin 80 mg (withdrawn by the sponsor at the time of review) and none in the patients treated with the other statins or placebo. None of the deaths occurring were related to treatment with any one of the statins. Most of the deaths reported were related to cardiovascular conditions as one would expect in this group of patients. Similarly, no patterns emerged regarding co-treatment with other lipid metabolic regulating drugs nor with drugs commonly used to treat co-morbidities in these patients.
Eighty mg doses of rosuvastatin resulted in elevations of transaminases12 as a marker of liver toxicity, muscle effects (myopathy) and protein in urine. As a result, a summary of clinically relevant results from the higher 80 mg dose (withdrawn by the sponsor at the time of review) is presented below to draw comparisons with 10, 20, and 40 mg strengths.
12 Elevations of transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), commonly referred to as liver enzymes, are taken as signs of impaired liver function. ALT is found predominantly in the liver while AST is also found in muscle.
Summary of Clinical Results Comparing Rosuvastatin 80 mg (withdrawn) to 10 - 40 mg (approved) doses
Liver concern:
The numbers and frequency of isolated elevations of transaminases from 3 to 9 times the upper limit of normal (ULN) were 3 to 5 times higher with the dose of 80 mg rosuvastatin than with the lower doses.
The number and percent of multiple elevations during a given observation period were also similarly higher. There were no significant differences between the 4 lower doses (5 to 40 mg), i.e., a dose-relationship if it exists was not evident.
Transaminase elevations are commonly used to screen drugs, including statins, for liver toxicity. The Product Monographs of currently marketed statins include a warning and precaution stating that statins have been seen to be associated with persistent increases in serum transaminases, and that liver function should be assessed prior to commencement of treatment as well as periodically thereafter.
Multiple elevations, as with higher elevations of transaminases, are suggestive of liver damage but isolated elevations can occur at any time in an individual and do not indicate liver toxicity. Consecutive elevations qualify as persistent elevations only when done within a given time frame, usually 4 to 10 days which is not always done in clinical trials. The liver concern was resolved in considering the incidence of single and multiple elevations reported for rosuvastatin and the other statins. There was a clear increase in elevation of single and multiple transaminases at the highest rosuvastatin dose of 80 mg.
There were no significant differences in the incidences of single and multiple elevations (3 to 9 x ULN) with the rosuvastatin doses of 5 ,10, 20 and 40 mg. With the 40 mg dose, incidences of multiple elevations were 0.4% for 3 x ULN and 0.03% for 9 x ULN. In addition, half of the patients with multiple elevations continued on the same dose or at a lower dose of rosuvastatin without any other sign of liver function impairment or worsening. There were no cases of liver failure or unexplained hepatitis with rosuvastatin.
Therefore, there are no more liver-related safety concerns with rosuvastatin than with any other statin presently on the Canadian market.
Muscle concern:
The Product Monographs of all current statins include a warning of myopathy and possible rhabdomyolysis. Myopathy is defined as muscle pain or weakness accompanied by elevation of creatinine kinase (CK) 10 x ULN (upper limit of normal). Rhabdomyolosis is defined as the destruction of skeletal muscle cells.
All cases of rosuvastatin-related myopathy (12) were seen in patients
on
80 mg. Of the12 cases, 5 were classified as rhabdomyolysis (1 went
to renal failure). Three of the 5 patients with rhabdomyolysis were also
on concomitant treatments which are also known to potentially cause this
condition. No rhabdomyolysis was seen with rosuvastatin doses of 40 mg
or lower. Some cases with a CK > 10x ULN were observed with the doses
of 5 and 10 mg but none could be demonstrated to be causally related to
rosuvastatin treatment.
Myopathy and rhabdomyolysis, which can cause renal failure13 and death, have been reported post-marketing for all available statins in Canada. The occurrence of these events in clinical trials with rosuvastatin is reported for the first time for a statin. CK has been taken as a marker for potential skeletal muscle toxicity. Transient unexplained CK elevations do not predict future myopathy or rhabdomyolysis, however it remains useful for comparison of drugs during a given trial. The incidence of CK greater than 10xULN with the dose of 40 mg was not higher than the incidence observed in the clinical trials submitted for the approval of other statins currently on the Canadian market or than the incidence observed in published clinical trials14 and the USA package insert15. It can be concluded, therefore, that rosuvastatin at doses of 10 to 40 mg are no more likely to induce rhabdomyolysis than any one of the other statins currently on the Canadian market.
13 Following skeletal damage (rhabdomyolysis), excessive release of myoglobin which is normally filtered out by the kidney, overcome the filtering capacity and can cause renal failure.
14 Simvastatin 0.1% in the HPS study (Lancet 2002;360;7); lovastatin 40 and 80 mg respectively 0.03 and 0.2% in EXCEL study (Arch Int Med 1991;151: 43).
15 Pravastatin <0.1%; simvastatin 0.02 to 0.3%; fluvastatin and atorvastatin 0%; lovastatin 0.02 to 0.2%.
Renal concern:
It was noted in controlled trials that the incidence of patients with any grade of proteinuria (protein in urine) at baseline increased from 21% to 30% at the end of the treatment period. In contrast, there were decreases in frequency from 21% to 17% in patients on other statins and from 28% to 23% for placebo patients. Calculations include trace results which may not be clinically relevant (i.e. related to administration of the statin) in all cases but nevertheless, are not considered "normal" and would require follow up with a physician.
The data appeared to indicate a dose-dependant proteinuria at the doses of 40 and 80 mg. These observations came from routine measurements at baseline and at the last trial visit using a commercially available dipstick16 and they raised a concern. The proteinuria was studied further by the sponsor using timed overnight collections and protein/creatinine ratio in spot urine samples. It was demonstrated that a protein/creatinine ratio greater than 0.15 provided a good estimate of a timed overnight collection.
16 The dipstick use is said to provide the
following information: if the test is negative or trace = < 300 mg
protein/litre of urine; + = >300 and <1000 mg/L;
++ = between 1 and 3 g/L; +++ = 3 g/L; ++++ = > 3 g/L.
| Dose | N | % | 95% C.I. |
|---|---|---|---|
| Placebo | 157 | 7 | 3.0 and 11.0 |
| Rosuvastatin 5 mg 10 mg 20 mg 40 mg 80 mg |
430 481 117 188 654 |
10.9 10.4 10.3 15.4 38.8 |
8.0, 13.9 7.7, 13.1 4.8, 15.8 10.3, 20.6 35.1, 42.6 |
| Pravastatin 20mg 40 mg |
137 52 |
8.8 3.8 |
4.0, 13.5 -1.4, 9.1 |
| Simvastatin 20 mg 40 mg 80 mg |
163 13 19 |
9.8 0 15.8 |
5.2, 14.4 -0;6, 32.2 |
| Atorvastatin 10 mg 20 mg 40 mg 80 mg |
224 53 56 270 |
9.8 9.4 7.1 13.0 |
5.9, 13.7 1.6, 17.3 0.4, 13.9 9.0, 17.0 |
The shift in urine dipstick protein category in feeder trials in relation to the dose is summarized in the next table.
| Dose of rosuvastatin (mg) | Total # of patients with no or trace proteinuria at baseline | % of patients who shifted to ≥ + | % of patients who shifted to ≥ ++ |
|---|---|---|---|
| Placebo | 261 | 4.6 | 0.4 |
| 5 | 568 | 3.5 | 0.2 |
| 10 | 677 | 2 | 0.3 |
| 20 | 138 | 5.1 | 0.7 |
| 40 | 265 | 9.1 | 2.3 |
| 80 | 798 | 24.8 | 10 |
Table 6 appears to show a dose-related increase in the frequency of dipstick protein shifts from none/trace to + starting at the dose of 20 mg and from none/trace to ++ from the dose of 40 mg. However, further analyses revealed that more patients had a decrease in urinary protein dipstick with the dose of 20 mg. In contrast, the opposite was seen with the doses of 40 and particularly 80 mg.
Follow-up data from extension trials showed that with continued treatment there was no increase or even a decrease in proteinuria as summarized in Table 7. In addition, it was observed that there was no association between rosuvastatin treatment and the development of hematuria except at the dose of 80 mg. Rosuvastatin in the range of 10-40 mg, did not lead to an increase in serum creatine.
Rosuvastatin Dose |
Number and (%) of patients | ||
|---|---|---|---|
| Further increase in proteinuria | No change in proteinuria | Decrease in Proteinuria | |
| 5 | 0 | 6 (28.6) | 15 (71.4) |
| 10 | 3 (3.2) | 20 (21.5) | 70 (75.3) |
| 20 | 1 (3.0) | 3 (9.1) | 29 (87.9) |
| 40 | 1 (2.3) | 3 (7.0) | 39 (90.7) |
| 80 | 27 (13.6) | 54 (27.3) | 117 (59.1) |
The sponsor measured other protein components to differentiate the origin of the protein, i.e., from the renal tubules or the glomeruli. It appeared that for most patients who had detectable protein, proteinuria was tubular in origin.
Renal failure was observed in 11 patients, with causality presumed to be linked to rosuvastatin 80 mg in 5 of these cases. Four of the 5 had rhabdomyolysis and a non-steroidal anti-inflammatory drug was also suspected as the possible cause in the fifth patient. In addition, 8 patients had other renal abnormalities, mainly albuminuria, which led to discontinuation of treatment; 7 were on 80 mg and 1 on 5 mg rosuvastatin but no causality could be established.
Upon initial review, it appeared that rosuvastatin may have induced kidney damage and thereby, proteinuria. This hypothesis however, was not confirmed by further investigation. Indeed if one was to assume that rosuvastatin did in fact cause renal damage and, thereby proteinuria, this condition would not be improved or remain stationary in most patients when treatment with rosuvastatin continued at the same dose levels. If rosuvastatin caused significant renal damage, the existing proteinuria should have increased and should certainly not have decreased as seen in the majority of the patients.
The evaluator believes that the proteinuria observed, not only with rosuvastatin, but with all statins used in the controlled trials could well be due to causes other than treatment with a statin. Although proteinuria observed with all statins was the subject of postmarketing reports, no causal relationship has ever been established. What came as a surprise was that proteinuria was observed in pre-approval clinical trials with rosuvastatin in contrast to other statins. The converse is equally surprising however, particularly since proteinuria was in fact seen with pravastatin, simvastatin and atorvastatin, when used in controlled trials for comparison with rosuvastatin.
Many of the observations can be explained by a transient effect of rosuvastatin
on renal tubules without a significant decrease in the glomerular filtration
rate. Even if one still argued that there was a higher risk, albeit small,
for proteinuria with rosuvastatin 40 mg, we believe that the risk/benefit
ratio would favour its use in some patients. The patients likely to be
prescribed
40 mg should be those in whom it is difficult to bring LDL-C
to target levels. As seen earlier (see table "Percent of patients
reaching NCEP targets considering risks and plasma LDL-C levels"
page 13)17, rosuvastatin was very effective
even with a dose as low as 10 mg. Therefore, we believe that rosuvastatin
40 mg will fill a gap in patients difficult to treat. In addition, patients
on 40 mg will be or at least should be monitored more closely than others
if only because they are inherently at higher risk of cardiovascular events.
The more stringent monitoring should help prevent some drug-induced adverse
events, including clinically significant proteinuria. It should be noted
also that the dose of 40 mg is only recommended in patients who do not
achieve treatment goals with rosuvastatin 20 mg. In the majority of patients
10 and 20 mg should be sufficient to reach target LDL-C levels.
17 It is immaterial for the purpose of this discussion that new guidelines NCEP III (2002) have replaced the guidelines of 1993 (NCEP II).
2.4.7 Additional Considerations
Pharmacokinetic studies established that formulation(s) used in pivotal clinical studies were bioequivalent to the formulation intended for the Canadian market.
The submission sponsor filed a request for priority review status of
the Crestor® NDS, which was subsequently reviewed by an
informal adjudicating committee. It was found that the submission did
not meet criteria as outlined in Health Canada's Priority Review
policy for the following reasons: (1) clinical trials for Crestor® were not designed to demonstrate superiority i.e. to establish whether
or not there was a significant difference between Crestor® and other statins, and
(2) surrogate endpoints were used to establish
efficacy, which although acceptable for approval of a lipid metabolism
regulator, does not demonstrate that Crestor® would provide
an effective treatment for patients at risk of CAD or stroke i.e. decreases
morbidity or mortality to a significant degree over existing therapy.
As a result of the above, Crestor® did not fulfil the criteria
for priority review status.
2.5 Benefit/risk Assessment and Recommendation
2.5.1 Benefit/risk assessment
Risks/benefits have been discussed in the foregoing sections which can be summarized as follows. No single statin or any other lipid metabolism regulating drugs included trials with clinical outcomes such as morbidity or mortality when they were first approved. Crestor® is no exception. In any event, it has been demonstrated that Crestor® is very effective in reducing LDL-C.
LDL-C is a surrogate endpoint which is accepted by Regulatory Agencies worldwide and by the medical profession in general. There is a strong, independent and consistent association between a lowering in LDL-C and reduction in morbidity and mortality in patients low as well as high risk of a cardiovascular event.
The most troublesome adverse event in this submission was the apparent effect of rosuvastatin 80 mg (withdrawn by the sponsor) on proteinuria. The magnitude of proteinuria with doses of 5,10 and 20 mg was the same and in the range of that seen with the other statins used in comparison trials. There was a trend for a larger incidence of proteinuria with the dose of 40 mg. However further investigation demonstrated that when patients with proteinuria remained on rosuvastatin, the renal condition improved with time in the majority of patients. In our opinion, this, goes against the hypothesis that rosuvastatin causes renal damage and it has been concluded that risk/benefit considerations favour even the use of doses as high as 40 mg in difficult to treat patients.
2.5.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of CRESTOR® is favourable in the treatment of lipid metabolism regulation. 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.
3 SUBMISSION MILESTONES
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2001.05.10 |
| Request for priority status | |
| Filed | 2001.06.04 |
| Rejection issued | 2001.07.10 |
| Submission filed | 2001.07.04 |
| Screening 1 | 2001.07.05 |
| Screening Acceptance Letter issued | 2001.07.24 |
| Review 1 Completed | 2003.02.07 |
| NOC issued by Director General | 2003.02.18 |
