Summary Basis of Decision for Olmetec ®
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:
Olmetec®
Olmesartan medoxomil, 5mg, 20mg, and 40 mg, Tablets, Oral
Schering-Plough Canada Inc.
Submission control no: 115991
Date issued: 2009-02-11
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):
- 02318652 - 5 mg
- 02318660 - 20 mg
- 02318679 - 40 mg
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
® Trademark of Daiichi Sankyo Company, Limited, used under license by Schering-Plough Canada Inc.
2 Notice of decision
On October 28, 2008, Health Canada issued a Notice of Compliance to Schering-Plough Canada Inc. for the drug product Olmetec.
Olmetec contains the medicinal ingredient olmesartan medoxomil which is an angiotensin II AT1 receptor blocker.
Olmetec is indicated for the treatment of mild to moderate essential hypertension. Olmesartan medoxomil is a prodrug whose active metabolite, olmesartan, blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle.
The market authorization was based on quality, non-clinical, and clinical information submitted.
The antihypertensive effects of Olmetec were demonstrated in seven double-blind, placebo-controlled, parallel-group studies at doses ranging from 2.5 to 80 mg for 6 to 12 weeks. A total of 548 patients received placebo and 2145 patients received Olmetec. Olmetec once daily was shown to lower systolic and diastolic blood pressure. The response was dose-related, however doses >40 mg had little additional effect.
Olmetec (5, 20, and 40 mg olmesartan medoxomil) is presented as film-coated tablets. The dosage must be individualized. The usual recommended starting dose is 20 mg once daily when used as monotherapy in patients who are not volume-depleted. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of Olmetec may be increased to 40 mg. Dosing recommendations are available in the Product Monograph.
Olmetec is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Olmetec should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Olmetec 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 Olmetec is favourable for the treatment of mild to moderate essential hypertension.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Olmesartan medoxomil , the medicinal ingredient of Olmetec, is classed as an angiotensin II AT1 receptor blocker and is intended for the treatment of mild to moderate essential hypertension. Olmesartan medoxomil is a prodrug. Olmesartan, the active metabolite of Olmesartan medoxomil, blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle.
Manufacturing Process and Process Controls
Olmesartan medoxomil is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of Olmesartan medoxomil has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and are therefore considered acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of Olmesartan medoxomil.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on long-term and stress testing show that Olmesartan medoxomil 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
Olmetec (Olmesartan medoxomil) tablets are presented in three strengths of Olmesartan medoxomil and have the following physical appearance.
- 5 mg: yellow circular film-coated tablets with C12 debossed on one side.
- 20 mg: white circular film-coated tablets with C14 debossed on one side.
- 40 mg: white oval film-coated tablets with C15 debossed on one side.
The 5 mg tablets are packaged as 30 tablets per bottle. The 20 and 40 mg tablets are packaged in blister cards of 7 tablets per card, 4 cards per carton.
The non-medicinal ingredients in Olmetec are: hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, and yellow iron oxide (5 mg tablets only).
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of Olmesartan medoxomil with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The manufacturing process uses conventional manufacturing techniques, namely: milling, mixing, wet granulation, wet sizing, drying, sieving, blending, tableting, and film-coating.
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Olmetec is tested to verify that its identity, appearance, content uniformity, assay, dissolution, water content, levels of drug-related impurities and microbiological impurities are within acceptance criteria.
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of Olmetec.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed shelf-life of 36 months is considered acceptable when the Olmetec tablets are packaged in the proposed packaging and stored at 15-30°C.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Olmetec are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
There are two excipients that may potentially be derived from human or animal origin: magnesium stearate and lactose monohydrate. The manufacturer of magnesium stearate has confirmed that this excipient is from vegetable origin. The manufacturer of lactose monohydrate has provided a written assurance that the lactose is produced from milk sourced from healthy animals under the same conditions as milk collected for human consumption.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Olmetec 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.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Olmesartan medoxomil was studied in vitro and in vivo to elucidate the pharmacological effects in animals. The non-clinical pharmacology studies demonstrated that olmesartan, the active metabolite of olmesartan medoxomil, blocked the vasoconstrictor effects of angiotensin II by selectively binding to the AT1 receptor found in many tissues. Binding to the AT2 receptor was negligible. Blood pressure was lowered in a dose-dependent manner, with a slow onset and long duration of action. The antihypertensive effects of olmesartan were observed more potently in renal hypertensive rats compared to the other hypertensive animal models tested. The results of the animal pharmacology studies demonstrated that olmesartan medoxomil exhibits specific antihypertensive activity at pharmacologically effective doses without inducing significant toxicity.
3.2.2 Pharmacokinetics
Absorption
In rats, the absolute bioavailability of olmesartan medoxomil, administered as a suspension, was 27.8% with the 5 mg/kg dose and 31.3% with the 10 mg/kg dose. In dogs, the absolute bioavailability was 14.1% and 11.7% after administration of 25 mg/kg olmesartan medoxomil as a solution and as a capsule, respectively.
In rats and dogs, the maximum plasma concentration (Cmax) and drug exposure (AUC) values for the active metabolite olmesartan increased in proportion to the dose of olmesartan medoxomil administered. In rats, the terminal elimination half-life of the active metabolite was 0.97-2.34 hours and the time of maximal concentration (Tmax) was 0.44-3.05 hours. In dogs, the half-life of the active metabolite was 0.88-1.52 hours, and the Tmax was 0.33-1.50 hours.
Distribution
Rats that received radiolabelled olmesartan medoxomil had the highest levels of radioactivity in the gastrointestinal tract, followed by the liver, kidney, blood, lung, skin, heart, and other tissues and organs. The placental penetration in pregnant rats was low, and a small amount of radioactivity was transferred into the milk of lactating rats.
The plasma protein binding of the active metabolite olmesartan was high in mice, rats, and dogs.
Metabolism
Olmesartan medoxomil, after oral or intravenous administration, was rapidly and completely hydrolyzed to olmesartan. The hydrolytic decomposition was compared both in vivo and in vitro in a number of studies. The hydrolytic activity in human plasma was 20 times higher than that measured in microsomes of human liver and small intestine, the latter which were comparable. The half-life of Olmesartan medoxomil extrapolated to undiluted plasma was 2 seconds. These results are consistent with Olmesartan medoxomil first being hydrolyzed during passage from the intestinal mucosa to the serosal site, second in the portal blood, and finally in the liver. The continuous exposure of the prodrug to high hydrolyzing activities after absorption is believed to completely convert the prodrug to the active metabolite in first-pass metabolism.
The effect of Olmesartan medoxomil on drug-metabolizing enzymes in the liver was studied both in vitro and after repeat-dose oral administration to rats for 7 days. The results indicate that Olmesartan medoxomil would have only minor effects on drug metabolizing enzymes at clinically relevant plasma levels.
Excretion
The main route of excretion in rats and dogs was the feces via biliary excretion. Almost all of the radioactivity found in the urine and feces was accounted for by the active metabolite olmesartan. In rats, urinary excretion was 0.3-1.52% and fecal excretion was 95.98-100.9% of the radiolabelled dose of Olmesartan medoxomil.
3.2.3 Toxicology
Single-Dose Toxicity
Olmesartan medoxomil demonstrated low oral acute toxicity in rodents and non-rodents.
Repeat-Dose Toxicity
In the repeat-dose toxicity studies, treatment-related effects in rodents and non-rodents were predictable and essentially reflected exaggerated pharmacologic effects associated with the angiotensin II AT1 receptor blockade. Principal effects consisted of mild to moderate decreases in red blood cell parameters, increases in blood urea nitrogen and creatinine, renal changes, and gastric changes in some studies. The renal changes included the expected juxtaglomerular apparatus hyperplasia and tubular regeneration in rodents and dogs. Advancement of the spontaneously occurring chronic progressive nephropathy also occurred in rats. At high-dose levels, pathologies associated with uremia were identified and the severity of the uremic changes resulted in the death of one dog that received 500 mg/kg/day. Pharmacologic effects were manifest at relatively low-dose levels in the toxicity studies and at systemic exposure levels that approximated anticipated human exposure at the maximum intended human therapeutic dose of 40 mg/day. However, these effects can be readily monitored for in patients.
Mutagenicity
Olmesartan medoxomil and the active metabolite olmesartan tested negative in the bacterial mutagenicity tests, and Olmesartan medoxomil was negative in the in vivo micronucleus test. Positive results for Olmesartan medoxomil and olmesartan in vitro in mammalian cultured cells and/or the mouse lymphoma assay were considered to reflect cytotoxicity or other non-genotoxic mechanisms rather than mutagenicity.
Carcinogenicity
Olmesartan medoxomil was non-carcinogenic when administered orally in transgenic mice at dose levels up to 1000 mg/kg/day for 26 weeks or in rats at dose levels up to 2000 mg/kg/day for 2 years.
Reproductive and Developmental Toxicity
Olmesartan medoxomil had no effect on fertility in rats, and was non-teratogenic in rats and mice. However, maternal toxicity and secondary embryo-fetal developmental and post-natal effects were observed following administration of Olmesartan medoxomil in rats. Potential teratogenicity and embryo-fetal development effects could not be assessed in rabbits due to marked maternal toxicity observed following Olmesartan medoxomil administration in pregnant rabbits. Discontinuation of Olmetec (Olmesartan medoxomil) or any drug that acts on the renin-angiotensin-aldosterone system (RAAS) is recommended if and when pregnancy occurs during treatment.
3.2.4 Conclusion
The non-clinical pharmacology and toxicology studies support the use of Olmetec (olmesartan medoxomil) for the proposed indication.
The non-clinical pharmacology studies demonstrated that olmesartan, the active form of olmesartan medoxomil, is a potent and a long-lasting AII antagonist that produced antihypertensive effects in different animal models of hypertension. Olmesartan had little effect on a variety of physiological systems, except for those that would be expected based on its pharmacological activity.
In the non-clinical toxicity program there was no evidence of findings to preclude the proposed therapeutic administration of Olmetec in patients. Findings indicative of exaggerated pharmacology that occurred at relatively low-dose levels and systemic exposures in animals were predictable, are well known, and can be monitored for clinically.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Olmesartan medoxomil is a potent and orally active angiotensin II receptor blocker with an antihypertensive effect resulting from its inhibitory activity on blood vessels.
The pharmacodynamic effects of olmesartan medoxomil on the RAAS system were demonstrated in a multitude of clinical pharmacology studies. The results of several studies consistently demonstrated that plasma concentrations of angiotensin I, angiotensin II, and plasma renin activity increased after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients. Conversely, repeated administration of olmesartan medoxomil up to 80 mg had minimal influence on aldosterone levels.
Olmesartan medoxomil was significantly more effective than placebo, and similarly as effective as enalapril 20 mg in inhibiting the rise of systolic blood pressure induced by intravenous administration of exogenous angiotensin I. The peak reduction in blood pressure was roughly similar across the range of doses tested (i.e., 2.5, 5, 10, 20, and 40 mg olmesartan medoxomil); however, higher doses of olmesartan medoxomil were effective for a much longer period of time.
3.3.2 Pharmacokinetics
Absorption
Olmesartan medoxomil was rapidly hydrolyzed during absorption to the active form olmesartan. This conversion was essentially complete and occurred pre-systemically such that only olmesartan was detected in the plasma. After oral administration of olmesartan medoxomil, the maximum plasma concentration of olmesartan occurred within approximately 1-2 hours. Absolute bioavailabilty was approximately 26%. Steady-state conditions were achieved after the third day of dosing and there was no evidence of drug accumulation with repeated doses.
Distribution
The volume of distribution was moderate and ranged from 16.1-29.0 L. These values are consistent with limited extravascular tissue distribution. Olmesartan was highly bound to serum albumin (>99%).
Metabolism
Olmesartan medoxomil was rapidly hydrolyzed (converted by esterase activity during intestinal absorption) to its only active metabolite, olmesartan. The major enzyme responsible for the conversion was arylesterase which is often encountered in tissues including intestinal mucosa and plasma. No trace of involvement of the cytochrome P450 enzyme system was found. There was no evidence of further metabolism of olmesartan and this was the only compound detected in urine and feces.
Excretion
In healthy subjects, approximately 35-50% of the systemically available olmesartan was excreted in urine while the remainder of the dose was excreted in feces, probably via secretion in the bile.
Drug-Drug Interaction Studies
Olmesartan medoxomil produced no significant drug interactions with each of the following drugs: warfarin, digoxin, pravastatin, hydrochlorothiazide, and antacids.
Drug-Food Interaction Studies
There was no significant difference in the rate and extent of absorption of olmesartan when 20 mg olmesartan medoxomil tablets were administered under standard fed or fasting conditions.
Special Populations
Liver Impairment
Exposure to olmesartan increased with the severity of liver impairment in 12 patients with mild to moderate hepatic impairment, after the oral administration of 10 mg olmesartan medoxomil. Study results are limited and data is lacking with respect to the use of 20 mg and 40 mg olmesartan medoxomil; therefore a lower starting dose is recommended in patients with moderate liver disease and the maximum dose of 20 mg olmesartan medoxomil daily should not be exceeded. Furthermore, it is known that a fair amount of the absorbed dose is eliminated through biliary elimination; therefore Olmetec should not be prescribed to patients with biliary obstruction. No information is available in patients with severe liver disease; therefore, use of Olmetec in this group of patients is not recommended.
Renal Impairment
Serum concentrations of olmesartan increased with the severity of renal impairment in a study with 10 mg olmesartan medoxomil. Limited data is available regarding the use of higher doses in patients with renal impairment, therefore the maximum dose in patients with mild to moderate renal impairment is 20 mg once daily. The use of olmesartan medoxomil in patients with severe renal impairment is not recommended as there was limited experience in this patient group.
Elderly Patients
Increased drug exposure was observed in patients 65-76 years of age; a consequence of the slower rate of elimination in older patients. Generally, no dose adjustment is required in elderly patients.
Biopharmaceutics
The clinical formulation tablets that were employed in the pivotal studies required bridging to the commercial formulation proposed for the Canadian market. Test results met the standards for comparative bioavailability, successfully bridging the 20 mg clinical tablet and the 20 mg production tablet.
The 5 and 40 mg production tablets are proportionally formulated to the proposed 20 mg production tablets according to Bioequivalence of Proportional Formulations: Solid Oral Dosage Forms (1996) as confirmed by the New Drugs Quality Division, and waivers from conducting bridging studies with these two strengths have been granted.
3.3.3 Clinical Efficacy
The clinical efficacy of Olmetec (olmesartan medoxomil) for the treatment of mild to moderate essential hypertension was evaluated in seven double-blind, placebo-controlled, parallel-group, Phase II and Phase III studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks. A total of 548 patients received placebo and 2145 patients received Olmetec. The primary efficacy parameter was the change from baseline in trough sitting diastolic blood pressure at the primary time points (Week 6, Week 8, or Week 12).
In an 8-week Phase III study (n=526, randomized), all Olmetec doses (i.e., 2.5, 5, 10, 20, and 40 mg) were statistically more effective in decreasing sitting diastolic and systolic blood pressure at Week 8 compared to placebo. All doses were more effective than placebo after two weeks of treatment (the higher doses were more effective after Week 1 in lowering sitting systolic blood pressure and standing systolic blood pressure), and the percentage of responders at Week 8 was statistically significantly higher in the 10 mg, 20 mg, and 40 mg dose groups compared to the placebo group.
In a 12-week Phase III study (n=780, randomized), Olmetec doses of 10, 20, 40, and 80 mg showed statistically significant differences in blood pressure lowering compared to placebo, and the 80 mg dose did not show a higher efficiency in reducing diastolic and systolic blood pressure compared to the 40 mg dose. The diastolic and systolic blood pressure lowering effect was observed after two weeks of treatment, and after eight weeks the effect was close to its maximum. After 12 weeks of treatment, more than 65% (10 mg dose group), and up to 79% (20 mg dose group) were categorized as responders to the treatment. The trough to peak ratio for all doses indicated that the blood pressure lowering effect was maintained throughout the 24-hour interval between two consecutive doses.
In the seven placebo-controlled studies, the blood pressure lowering effect was statistically significantly greater than that for placebo for all doses of Olmetec. A dose response relationship with the degree of blood pressure lowering effect achieved was present for doses between 10 mg and 40 mg. This dose response was also observed for responder rates. No tachyphylaxis and no rebound phenomenon were observed, and giving the drug twice a day had no advantage over a once a day regimen.
3.3.4 Clinical Safety
The clinical safety database included data from the Phase II and Phase III studies, the safety update reports, as well as the post-marketing safety update report. In the Phase II and Phase III studies, the majority of the 3275 hypertensive patients treated with Olmetec received doses of 5, 10, or 20 mg; 900 patients were treated for at least 6 months, and more than 525 patients were treated for at least one year.
A total of 10 patients died during the course of the study period. Three deaths (two myocardial infarctions, one presumed cerebrovascular accident) were assessed as possibly related to Olmetec.
Serious adverse events (SAEs) were uncommon (<1%) and occurred with similar incidence in the Olmetec group and placebo group. In the long-term open-label studies, the most commonly reported SAEs were chest pain (4 patients) and angina (3 patients).
More patients discontinued as a result of AEs in the Olmetec group compared to the placebo group, 1.6% vs. 0.7%, respectively.
The following AEs were the most commonly reported in the placebo-controlled studies with a frequency in the Olmetec group superior by at least 1% compared to the placebo group: flu-like symptoms, dizziness, bronchitis, hematuria, back pain, increased creatine kinase (CK), injury, hypertriglyceridemia, and diarrhea. Dizziness and influenza-like symptoms showed a slight dose relationship. No effects on heart rate and ECG were reported.
A slightly higher frequency of increased liver enzyme levels (>2x the upper limit of normal) was observed in the Olmetec treatment groups, although the percentage was low. The incidence of alanine transaminase (ALT) or aspartate aminotransferase (AST) elevations >3x the upper limit of normal was higher in the placebo group. However, gamma glutamyl transferase (γGT) seemed to be a more sensitive target for olmesartan medoxomil. Approximately half of the liver enzyme level related AEs corresponded to an increase in γGT. However, the overall incidence of increase in γGT was similar to placebo.
QTc interval prolongation studies were not performed for Olmetec. This is considered acceptable because other members of the same pharmacological class have not been associated with QT/QTc interval prolongation, there was no indication from the non-clinical studies that olmesartan affected QT interval, and the ECG data from the clinical studies as well as the post-market safety data did not show evidence of QT prolongation. The possibility that Olmetec causes QT prolongation was concluded to be very remote.
Overall, Olmetec was well tolerated and demonstrated a safety profile that had no major issues. Most of the AEs that occurred during the studies were expected and typical of an angiotensin II antagonist. Furthermore, the frequency and occurrence of most of the AEs in the Olmetec treatment groups were similar to the placebo/control groups.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The efficacy of Olmetec was established in clinical trials of over 2600 patients with mild to moderate essential hypertension treated with the monotherapy or with the concomitant use of hydrochlorothiazide.
The drug showed an acceptable safety profile with no unusual or unexpected adverse events. However, due to limited experience with high doses in patients with mild to moderate renal impairment as well as patients with moderate hepatic impairment, the use of Olmetec in these patients is limited to a maximal daily dose of 20 mg, and is not recommended in patients with severe renal or hepatic impairment.
The animal toxicity studies demonstrated maternal toxicity and secondary embryo-fetal developmental and postnatal effects in rats. Drugs that act directly on the renin-angiotensin-aldosterone-system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, Olmetec should be discontinued as soon as possible.
Based on the safety and efficacy profile, the benefits of Olmetec therapy seem to outweigh the risks. The clinical studies demonstrated that Olmetec was well-tolerated and associated with a manageable safety profile. Restrictions to manage risks associated with the identified safety concerns have been incorporated into the Olmetec Product Monograph.
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 Olmetec is favourable in the treatment of mild to moderate essential hypertension. 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: Olmetec®
| Submission Milestone | Date |
|---|---|
| Submission filed | 2007-08-03 |
| Screening | |
| Screening Deficiency Notice issued | 2007-09-26 |
| Response filed | 2007-11-09 |
| Screening Acceptance Letter issued | 2008-01-02 |
| Review | |
| Biopharmaceutics Evaluation complete | 2008-10-16 |
| Quality Evaluation complete | 2008-10-27 |
| Clinical Evaluation complete | 2008-10-14 |
| Labelling Review complete | 2008-10-27 |
| Notice of Compliance issued by Director General | 2008-10-28 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| OLMETEC | 02318679 | ORGANON CANADA INC. | OLMESARTAN MEDOXOMIL 40 MG |
| OLMETEC | 02318660 | ORGANON CANADA INC. | OLMESARTAN MEDOXOMIL 20 MG |
| OLMETEC | 02318652 | ORGANON CANADA INC. | OLMESARTAN MEDOXOMIL 5 MG |