Summary Basis of Decision for Rasilez
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:
Rasilez
Aliskiren fumarate, 150 mg and 300 mg, Tablet, Oral
Novartis Pharmaceuticals Canada Inc.
Submission control no: 105388
Date issued: 2008-05-01
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),PrRASILEZ*, fumarate d'aliskirène, 150 mg et 300 mg comprimés, Novartis Pharmaceuticals Canada Inc. No de contrôle de la présentation 105388
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):
- 02302063 - 150 mg
- 02302071 - 300 mg
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
* Registered trademark
2 Notice of decision
On November 14, 2007, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product Rasilez*.
Rasilez* contains the medicinal ingredient aliskiren (as aliskiren fumarate) which is a renin inhibitor.
Rasilez* is indicated for the treatment of mild to moderate essential hypertension. It may be used alone or concomitantly with thiazide diuretics, angiotensin converting enzyme inhibitors or dihydropyridine calcium channel blockers. Rasilez* inhibits renin, the enzyme catalyzing the formation of angiotensin I from the decapeptide angiotensinogen. This means that angiotensin II cannot be generated. Angiotensin II is a powerful vasoconstrictor which also promotes aldosterone secretion and the consequent sodium reabsorption by the renal tubules. Both of these effects lead to an increase in blood pressure. By inhibiting renin, Rasilez* prevents these effects.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Rasilez* were demonstrated in five randomised, double-blind, placebo-controlled 8-week studies and one 12-month randomised open-label study in patients with mild-to-moderate essential hypertension. A substantial proportion of the blood pressure lowering effect was observed within two weeks of treatment.
Rasilez* (150 mg and 300 mg, aliskiren fumarate) is presented as tablets. The usual recommended starting dose of Rasilez* is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg.
Rasilez* is contraindicated for patients who are hypersensitive to any component of this product. Similar to other inhibitors of the renin-angiotensin system, Rasilez* should not be used during any state of pregnancy. Rasilez* 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 Rasilez* are described in the Product Monograph.
Health Canada considers that the benefit/risk profile of Rasilez* is favourable for the treatment of mild to moderate essential hypertension.
3 Scientific and Regulatory Basis for Decision
A New Drug Submission (NDS) for Rasilez* (aliskiren fumarate) with an indication for the treatment of mild to moderate hypertension was filed with Health Canada in April 2004. Due to a number of deficiencies and concerns regarding gastrointestinal safety, the submission received a Notice-of-Non-compliance (NON) in March 2007. In response to the NON, additional clinical studies and long-term safety data were provided. The safety concerns that led to the NON were satisfactorily addressed and the NDS was granted a Notice of Compliance in November 2007. The timeline of these events are reported in section 4 Submission Milestones. Discussions regarding the safety of Rasilez* appear in section 3.3.4 Clinical Safety.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Aliskiren fumarate, the medicinal ingredient of Rasilez*, is a renin inhibitor which was developed for the treatment of mild to moderate essential hypertension. Rasilez* prevents the body from producing angiotensin II which is a powerful vasoconstrictor which promotes aldosterone secretion and sodium reabsorption by the renal tubules. These effects lead to an increase in blood pressure.
Manufacturing Process and Process Controls
The drug substance is synthetically derived. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of aliskiren fumarate is considered to be 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/or were qualified from toxicological studies and therefore, are considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of aliskiren fumarate.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on accelerated and long-term testing show that aliskiren fumarate 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
Rasilez* (aliskiren fumarate) is presented as film-coated tablets containing 150 mg or 300 mg of aliskiren fumarate:
- The 150 mg strength tablets are light-pink, biconvex, and round. Imprints consist of NVR on one side and IL on the other side.
- The 300 mg strength tablets are light-red, biconvex, and oval. Imprints consist of NVR on one side and IU on the other side.
All strengths are packaged in blister packages (4 strips of 7 tablets).
The non-medicinal ingredients in the tablets are colloidal silicon dioxide, crospovidone, hypromellose, iron oxide colorants, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.
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 aliskiren fumarate 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 method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Rasilez* is tested to verify that the identity, appearance, mass, dissolution, content uniformity and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are considered satisfactory.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
The proposed shelf-life of two years is considered acceptable for Rasilez* blister packages when stored below 30°C protected from moisture.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
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 activities and products manufactured.
All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Rasilez* 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
In in vitro studies, aliskiren fumarate was shown to be a specific inhibitor of human renin, inactive against other aspartic proteinases. The blood pressure (BP) lowering effect of aliskiren fumarate was assessed in several hypertensive animal models, including double transgenic rats (dTGR). These animals were well suited to test for organ protective effects. Untreated dTGR died earlier compared to those that were treated with aliskiren fumarate.
The BP lowering effect of aliskiren fumarate measured in various conditions was impressive, and it was accompanied with a renal protective effect. However, the findings also included transient tachycardia consecutive to administration of the drug, enterohepatic recirculation with high doses, and a single observation of a greater effect in lowering diastolic blood pressure than in lowering systolic blood pressure.
3.2.2 Pharmacokinetics
Absorption
After oral administration of radiolabelled aliskiren, absorption was low to moderate (and variable) in rats and marmosets, and ranged from 2-25% of the dose (3 mg/kg in marmosets and 100 mg/kg in rats).
Aliskiren was rapidly absorbed in rats, dogs, and marmosets. Peak concentrations of aliskiren were observed in approximately 1-2 hours after single oral administration.
Distribution
Aliskiren distributed well into the blood cells although the largest fraction was found in plasma. The fraction in plasma was species-dependent; in rats 54% of the dose was found in plasma while marmosets had 84%. Aliskiren was moderately bound to plasma protein. The protein binding was also species-dependent.
In rats, aliskiren was distributed into all of the investigated organs and tissues. The highest levels were observed in the liver and kidney, and the lowest level was in the brain.
Fetuses of pregnant rabbits were exposed to aliskiren/and or its metabolites 24-hours post-dose. Aliskiren was also detected in the milk of lactating rats.
Metabolism
In rats, metabolism of aliskiren was minimal. The parent compound was the main compound in plasma, urine, and feces.
In vitro studies suggested that CYP3A4 contributes predominantly to the human liver microsomal biotransformation of aliskiren.
Excretion
Elimination of aliskiren was predominantly via the feces. Urinary excretion was a minor route of elimination. In rats, most of the drug-related material was eliminated within 48 hours after oral administration, 95.25% in the feces and 0.58% in the urine.
3.2.3 Toxicology
Single-Dose Toxicity
No deaths were reported following a single oral gavage dose of 2000 mg/kg in rats.
Repeat-Dose Toxicity
The systemic exposure to aliskiren was relatively limited in the oral repeat-dose toxicity studies. In rats and mice, dose levels were limited by deaths and severe clinical signs that were attributed to pathological lesions in the respiratory tract caused by local respiratory irritation. Other findings included soft feces/diarrhea and inflammation, erosion / ulceration and mucosal hyperplastic pathologic changes in the stomach, small and/or large intestines.
Evidence of exaggerated pharmacology, i.e. altered kidney function, occurred in marmosets following repeat-dosing. In the marmosets that survived to study termination, there was no clear evidence of treatment-related renal histopathologic lesions indicative of nephrotoxicity.
Genotoxicity/Mutagenicity
Aliskiren was not mutagenic or clastogenic in the in vitro and in vivo mutagenicity studies, including the Ames and chromosomal aberration assays.
Carcinogenicity
Aliskiren was non-carcinogenic in rats and mice at daily oral dose levels <1500 mg/kg. At 1500 mg/kg, a single occurrence of colonic adenoma was reported in one male rat and cecal adenocarcinoma was reported in another male rat. Hemangioma and/or hemangiosarcoma occurred in treated female rats but not in treated males. In treated female mice, the incidence of hemangioma/hemagiosarcoma was low with no statistically significant difference from controls.
Reproductive and Developmental Toxicity
The toxicity studies included fertility and early embryonic development studies in rats, embryo-fetal development studies in rats and rabbits, and a pre- and post-natal development study in rats. These studies showed no evidence of reproductive toxicity. Fertility and pre- and post-natal development were unaffected.
3.2.4 Conclusion
The results of the pharmacological and pharmacokinetic non-clinical studies did not raise any safety or efficacy issues. In the carcinogenicity studies in rats and mice, two neoplasms were observed: one colonic adenoma in one rat and one cecal adenocarcinoma in another rat, both at the highest dose. These findings were not unexpected. In all the toxicology studies, signs of gastrointestinal irritation, but no neoplasms, were observed in mice and rats at relatively high doses, and in marmosets at doses 2 mg/kg and higher. Neoplasms were not observed during the other toxicological studies.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Aliskiren is a potent and selective inhibitor of human renin. Treatment with Rasilez* (aliskiren fumarate) decreased plasma renin activity and increased plasma renin concentrations in hypertensive patients. There was a weak correlation between the magnitudes of elevated plasma renin concentrations and reductions in blood pressure.
3.3.2 Pharmacokinetics
Absorption
Aliskiren was absorbed quickly after oral dosing. Peak plasma concentrations occurred at 1-3 hours post-dose. The bioavailability of aliskiren was approximately 2.6%. Steady state plasma concentrations were reached within 5-7 days after starting once-daily administration, and steady-state levels were approximately 2-fold greater than that achieved with the initial dose.
Distribution
Aliskiren is evenly distributed systemically after oral administration. Following intravenous administration, mean volume of distribution at steady state was approximately 135 L indicating that aliskiren distributes extensively into extravascular space.
Aliskiren was moderately (47-51%) bound to human plasma protein, independent of drug concentration.
Metabolism
Approximately 1.4% of the total oral dose was metabolized. The enzyme responsible for this metabolism was CYP3A4.
Elimination
Following oral administration of radiolabelled aliskiren, 91.5% of the radioactivity was recovered within 7 days. The majority of the radioactive dose (91%) was eliminated in the feces as unchanged drug (mostly unabsorbed) with 0.6% of the radiolabelled dose eliminated in the urine.
3.3.3 Clinical Efficacy
Five major studies were submitted to confirm the efficacy of Rasilez* in patients with mild to moderate essential hypertension. The studies were randomized, double-blind, placebo-controlled, and 8-weeks in duration. Oral doses of 75 mg to 600 mg were evaluated. The primary efficacy variable was the change from baseline in the sitting blood pressure (BP) measurements, mean sitting systolic blood pressure (msSBP), and mean sitting diastolic blood pressure (msDSP) measured 22-26 hours (trough) after the study drug was administered. Compared to placebo, the BP-lowering effects of the 150 mg, 300 mg, and 600 mg doses were more effective, however, the 600 mg dose proved to be no more effective in lowering BP than the 300 mg dose.
In a 12-month, Phase III, open-label, long-term safety study, test results demonstrated consistent BP lowering throughout the recommended 24-hour dosing interval. It was also shown that after 11-months of treatment, the BP lowering effect was maintained and there was no rebound effect when therapy was discontinued abruptly.
Treatment of hypertensive patients with Rasilez* in combination with hydrochlorothiazide, amlodipine or ramipril had greater BP-lowering effects than those seen with monotherapy using the individual components.
Patients on long-term monotherapy and combination therapy exhibited similar geometric mean decreases from baseline in plasma renin activity. Renin concentration (active renin) increased to a greater extent with combination treatment than with monotherapy suggesting an additive effect of aliskiren and hydrochlorothiazide on blockade of the renin angiotensin system.
3.3.4 Clinical Safety
Rasilez* was evaluated for safety in more than 7,440 patients, including at least 2,580 treated for over six months, and at least 1,730 for over one year. Short-term and long-term (one year) safety data were derived from the major efficacy studies. Additional safety data were derived from additional efficacy studies and ongoing studies. Particular focus was aimed at a number of events of significance to renin-angiotensin system (RAS) inhibition, hypotension, or potential adverse events (AEs) specific to Rasilez*. The following events were of particular interest: renal dysfunction and/or decreases in hemoglobin (Hb) or hematocrit [seen with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)], angioedema or cough (seen with ACEIs), cerebrovascular accidents (strokes were reported in 3 patients <50 years of age in the earlier studies with Rasilez*), and potential gastrointestinal (GI) issues (based on intestinal irritation/hyperplasia in rodents, and diarrhea at high doses of Rasilez* in the earlier studies).
Renal Function
In the pooled controlled studies, Rasilez* monotherapy was associated with a somewhat smaller proportion of patients with hypokalemia (K+ <3.5 mmol/L) compared to those that received placebo, but when Rasilez* was adminstered with hydrochlorothiazide (HCTZ) or a calcium channel blocker (CCB), this difference disappeared. Hyperkalemia (K+ >5.5 mmol/L) occurred more often in Rasilez* monotherapy groups than in the placebo groups. The incidence of hyperkalemia appeared somewhat facilitated in combination with an ARB but considerably more so with an ACEI. The levels of blood urea nitrogen (BUN) or creatinine were not clinically significantly higher in patients with hyperkalemia. In fact, increases in BUN (>14.28 mm/L) and creatinine (>176.8 μmol/l) were infrequent in the controlled studies. Rasilez* in combination with an ACEI in diabetics was associated with a 5.5% incidence of hyperkalemia and a 2.2% incidence of K+ >6.0 mmol/L. No patient was discontinued from the study due to elevated potassium levels.
Erythropoiesis
As with other agents acting on the RAS system, small decreases in Hb and hematocrit were seen with Rasilez* treatment. No patients were discontinued due to anemia.
Angioedema
Angioedema is a well-known side effect of other RAS inhibitors, and may have fatal consequences. Angioedema occurred in three patients in the placebo-controlled studies, and in one patient in the open-label, long term study.
The sponsor estimated that, up to the reporting cut-off date of June 25, 2007, 44,573 new patients were exposed to prescribed Rasilez* post-launch, and that another 29,005 patients were exposed via free sample use, for a total exposure of 73,578 patients. During this period, 21 cases of an angioedema-type reaction were reported. The incidence rate of angioedema-type reactions can therefore be calculated as 0.029%. This percentage is regarded as a relatively rare AE.
Cough
The available information suggests that Rasilez*, like the other RAS blockers, is associated with a higher incidence of cough compared to placebo.
Cerebrovascular Accidents
The incidence of strokes and transient ischemic attacks (TIAs) was within the range to be expected in this patient population.
Gastrointestinal Adverse Events
Concern with regard to the GI system was based on the incidence of intestinal irritation/hyperplasia seen in rodents, as well as reported cases of diarrhea at high Rasilez* doses in the clinical trials. Diarrhea occurred dose-dependently in the safety population of the pooled placebo-controlled studies. Diarrhea began to be symptomatic at the 300 mg dose, but was clearly established as an AE at 600 mg. Diarrhea was in most cases considered mild, and usually did not lead to discontinuation of the patient. The etiology of diarrhea caused by Rasilez* is unknown.
A concern which arose during review was the report of 7 cases of colorectal hyperplasia/neoplasm in Rasilez*-treated patients: 2 colonic polyps and 5 colorectal cancers were reported (1 at 75 mg, 1 at 150 mg, 4 at 300 mg, and 1 at 600 mg). Although a causal relationship cannot be ruled out with certainty, it appears unlikely that Rasilez* is carcinogenic for the following reasons. The incidence rate in Rasilez* patients (0.05%, 7/13,430) was similar to that in control patients on active comparator drugs (0.02%, 1/5,387) and 5 of the 7 events were observed within 3 months after the initial treatment which is too early to implicate Rasilez* (the other 2 events occurred 7 and 11 months after the start of therapy). In addition, these incidences are well within the prevalence for hyperplastic colorectal polyps (8-15%) or colon cancer (0.1-0.3%) in the USA and Europe.
In an effort to explain the small decreases in hemoglobin and hematocrit associated with Rasilez* treatment, the AEs of GI bleeding or fecal blood were reviewed from all of the controlled studies. The incidence of GI bleeding/blood in stools was not higher in patients treated with Rasilez* compared to placebo.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/risk assessment
Rasilez* has demonstrated consistent blood pressure lowering effects throughout the recommended 24-hour dosing interval. It was also shown that after 11 months of treatment, the blood pressure lowering effect was maintained and there was no rebound effect when therapy was discontinued abruptly. Treatment of hypertensive patients with aliskiren in combination with hydrochlorothiazide, amlodipine, or ramipril had greater BP-lowering effects than those seen with monotherapy using the individual components.
The safety profile of Rasilez* was for the most part consistent with that to be expected from a powerful blood pressure lowering and renin-angiotensin system blocking agent, with the exception of a dose-related increase in the incidence of diarrhea. Cough occurred at a higher incidence than in placebo-treated patients. Concomitant use of aliskiren and other agents blocking the renin-angiotensin system was not associated with unexpected adverse events, with the exception of a higher incidence of hyperkalemia in diabetic patients.
In conclusion, the benefits of Rasilez* therapy for the treatment of mild to moderate essential hypertension seem to outweigh the risks. Restrictions to manage risks associated with this drug have been incorporated into the indication, labelling, and Product Monograph.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Rasilez* 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: Rasilez
| Submission Milestone | Date |
|---|---|
| Submission filed | 2006-04-20 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2006-05-24 |
| Review 1 | |
| Biopharmaceutics Evaluation complete | 2007-03-15 |
| Quality Evaluation complete | 2007-03-17 |
| Clinical Evaluation complete | 2007-03-19 |
| NON issued by Director General (safety issues) | 2007-03-20 |
| Response filed | 2007-05-24 |
| Screening 2 | |
| Screening Acceptance Letter issued | 2007-06-18 |
| Review 2 | |
| Quality Evaluation complete | 2007-11-07 |
| Clinical Evaluation complete | 2007-11-07 |
| Labelling Review complete | 2007-11-09 |
| NOC issued by Director General | 2007-11-14 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| RASILEZ | 02302063 | NODEN PHARMA DAC | ALISKIREN (ALISKIREN FUMARATE) 150 MG |
| RASILEZ | 02302071 | NODEN PHARMA DAC | ALISKIREN (ALISKIREN FUMARATE) 300 MG |