Summary Basis of Decision for Corzyna

Review decision

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


Product type:

Drug

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

Recent Activity for Corzyna

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

The following table describes post-authorization activity for Corzyna, a product which contains the medicinal ingredient ranolazine. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

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

Updated: 2023-07-11

Drug Identification Number (DIN):

  • DIN 02510219 - 500 mg ranolazine, tablet (extended-release), oral administration
  • DIN 02510227 - 1,000 mg ranolazine, tablet (extended-release), oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02510227) market notification Not applicable Date of first sale: 2023-05-24 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations
Drug product (DIN 02510219) market notification Not applicable Date of first sale: 2021-05-03 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 239943 2020-05-27 Issued NOC 2020-12-31 NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Corzyna

Date SBD issued: 2021-03-31

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

Ranolazine

Drug Identification Number (DIN):

  • DIN 02510219 - 500 mg ranolazine, tablet (extended-release), oral administration
  • DIN 02510227 - 1,000 mg ranolazine, tablet (extended-release), oral administration

KYE Pharmaceuticals Inc.

New Drug Submission Control Number: 239943

On December 31, 2020, Health Canada issued a Notice of Compliance to KYE Pharmaceuticals Inc. for the drug product Corzyna.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit‑harm-uncertainty profile of Corzyna, as add-on therapy, is favourable for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies, including beta-blockers and calcium channel blockers.

1 What was approved?

Corzyna, an antianginal agent, was authorized as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies, including beta-blockers and calcium channel blockers.

No data are available to Health Canada regarding the use of Corzyna in patients younger than 18 years of age. Therefore, Health Canada has not authorized an indication for pediatric use.

Evidence from clinical studies suggests that the use of Corzyna in patients 75 years of age or older is associated with an increased incidence of adverse events, serious adverse events and drug discontinuations due to adverse events.

Corzyna is contraindicated in patients:

  • taking strong inhibitors of cytochrome P450 3A4 (CYP3A4), e.g., ketoconazole, clarithromycin, protease inhibitors such as nelfinavir, grapefruit juice;
  • taking class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide) or class III antiarrhythmics (e.g., sotalol, ibutilide, amiodarone, dronedarone);
  • taking inducers of CYP3A4, e.g., rifampicin, phenobarbital, carbamazepine, St. John's wort;
  • with severe renal impairment, i.e., estimated glomerular filtration rate ≤30 mL/min/1.73m2;
  • with moderate or severe hepatic impairment;
  • with a hypersensitivity to ranolazine or any of the excipients.

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

Corzyna (500 mg or 1,000 mg ranolazine) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains hypromellose, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, Opadry II 85F570040 beige, Opadry II 32K520117 yellow, purified water, and sodium hydroxide.

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

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

2 Why was Corzyna approved?

Health Canada considers that the benefit-harm-uncertainty profile of Corzyna, as add-on therapy, is favourable for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies, including beta-blockers and calcium channel blockers.

Angina pectoris (also referred to as angina) is the pain or discomfort associated with myocardial ischemia, i.e., inadequate blood supply to the myocardium, most commonly due to atherosclerotic obstruction of one or more coronary arteries. Typically, angina is described as a dull, constricting discomfort localized to the front of the chest, often with radiation to the neck, shoulders, jaw, or arms. Physical exertion, extreme cold, large meals, or emotional stress are the most common triggers of angina. Refractory angina is a debilitating condition defined as angina which is not adequately controlled by conventional treatments. In addition to the risks of mortality associated with the underlying coronary artery disease, patients with refractory angina suffer a markedly diminished quality of life, including impairment of functioning in activities of daily life, psychological distress, and increased dependency on others. Angina pectoris is therefore a serious and, in some cases, severely debilitating condition.

According to the Public Health Agency of Canada, over two million adults in Canada live with diagnosed ischemic heart disease. It has been estimated that as many as 500,000 of these Canadians may have unresolved symptoms of angina. The prevalence of this condition is expected to increase as the aging population grows.

In addition to standard medical and/or surgical treatment of underlying atherothrombotic coronary artery disease to improve prognosis, current management of angina requires treatment with beta-blockers, calcium channel blockers, and/or long-acting nitrates for angina symptom control. Unfortunately, many patients will have inadequate control of their angina despite these therapies, even when used in combination.

Ranolazine, the medicinal ingredient in Corzyna, is a piperazine derivative, which appears to exert antianginal effects independent of reductions in heart rate or blood pressure. The antianginal mechanism of action of ranolazine is not fully understood, but may be due to inhibition of the late inward sodium current (INa) in cardiac tissues, resulting in reductions in intracellular sodium accumulation, with limitation of intracellular calcium overload.

Ranolazine was authorized for marketing in the United States in 2006 and has a broad indication for treatment of chronic angina. In 2008, ranolazine received market authorization in Europe, with a narrower indication as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists). In Canada, ranolazine has been available through Health Canada's Special Access Programme.

As per the conditions and requirements set out in the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience), the sponsor provided evidence from the medical literature and market experience demonstrating the efficacy and safety of extended-release ranolazine for the intended patient population. Pivotal evidence was derived from two randomized, double-blind, placebo-controlled clinical trials, CARISA and ERICA. Published results of the randomized, double-blind, placebo-controlled clinical trials MARISA, TERISA, and MERLIN‑TIMI 36 provided additional evidence of efficacy and safety. Another supportive trial, RIVER‑PCI, contributed safety data to the overall assessment of the safety of extended-release ranolazine. In total, these trials involved 11,739 patients, over half of whom were exposed to extended-release ranolazine.

The sponsor also provided evidence that the product used in studies reported in the literature (i.e., the reference product) is representative of Corzyna, by submitting the results of comparative bioavailability studies, which compared Corzyna and Ranexa (extended-release ranolazine authorized in the United States) in healthy volunteers under fasting conditions and under high-fat, high-calorie fed conditions.

In the first pivotal trial, CARISA, 823 patients with chronic stable angina were randomized to receive extended-release ranolazine 750 mg, extended-release ranolazine 1,000 mg, or placebo, twice a day for 12 weeks, in addition to their background therapy of a fixed dose of a single antianginal agent. The background antianginal therapy consisted of a beta-blocker (atenolol 50 mg once a day) or a calcium channel blocker (diltiazem 180 mg once a day or amlodipine 5 mg once a day). At week 12, exercise duration at trough ranolazine concentration (hereafter also referred to as trough), i.e., 12 hours after dosing, increased by 115.6 seconds from baseline in the pooled ranolazine groups compared to 91.7 seconds in the placebo group (p = 0.01). Similarly, exercise duration at peak ranolazine concentration (hereafter also referred to as peak), i.e., 4 hours after dosing, the time to onset of angina at trough and peak, and the time to ischemic ST segment depression at peak significantly increased in both extended-release ranolazine groups compared to the placebo group, with minimal effects on blood pressure and heart rate. Results were consistently more robust at peak than at trough. Further, the frequency of angina episodes and short-acting nitroglycerin use were significantly reduced with both doses of extended-release ranolazine in an apparent dose-related manner.

In the second pivotal trial, ERICA, 565 patients with chronic stable angina were randomized to receive extended-release ranolazine 1,000 mg twice daily or placebo over 6 weeks, following an initial one-week run-in phase with extended-release ranolazine 500 mg twice daily or placebo. As background antianginal therapy, all patients received the maximum recommended dosage of the calcium channel blocker, amlodipine (10 mg daily). Forty-five percent of patients also received long-acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. The trial demonstrated a significant reduction in the number of weekly episodes of angina in patients treated with extended-release ranolazine compared to placebo-treated patients (2.9 versus 3.3; p = 0.03) and a significant reduction of the weekly consumption of rescue (short-acting) nitroglycerin (2.0 versus 2.7; p = 0.01).

The most common adverse reactions observed with ranolazine treatment in the studies identified as pivotal included dizziness, headache, constipation, and nausea. Ranolazine was also seen to prolong the corrected QT (QTc) interval in a dose-related manner in pharmacodynamic studies. A prolonged QTc interval creates an electrophysiological environment that predisposes the patient to torsade de pointes ventricular tachycardia. If sustained, torsade de pointes ventricular tachycardia can progress to ventricular fibrillation and sudden cardiac death. Strategies to mitigate the risk of proarrhythmia during treatment with a QTc-prolonging drug include (i) avoidance of use in patients with underlying risk factors, including, but not limited to, congenital long QT syndrome, bradycardia, and hypokalemia and (ii) avoidance of concomitant use with other QT-prolonging drugs or drugs that can lead to electrolyte depletion. Periodic monitoring of electrocardiograms and serum electrolytes is another component of the risk mitigation strategy. While the potential of ranolazine to lead to development of torsade de pointes and life-threatening ventricular arrhythmias is not entirely clear, a Serious Warnings and Precautions box is included in the Corzyna Product Monograph to highlight the QT prolongation effect of Corzyna and to warn that doses of 1,000 mg twice daily should not be exceeded. Moreover, Corzyna is contraindicated in patients who are treated with antiarrhythmic drugs that have prominent QT interval prolonging properties and in patients treated with strong CYP3A4 inhibitors. Warnings to avoid the use of Corzyna in patients with acquired long QT syndrome, in patients with most forms of congenital long QT syndrome, and with other drugs known to prolong the QT interval or induce torsade de pointes, have also been included in the Corzyna Product Monograph.

Substantially increased plasma concentrations of ranolazine were observed in patients with moderate hepatic impairment. Some patients with severe renal impairment developed acute renal failure after receiving ranolazine. Based on these findings, the use of Corzyna is contraindicated in patients with moderate to severe hepatic impairment as well as in patients with severe renal impairment.

A Risk Management Plan (RMP) for Corzyna was submitted by KYE Pharmaceuticals Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

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

A review of the submitted brand name assessment, including testing for look‑alike sound‑alike attributes, was conducted, and the proposed name Corzyna was accepted.

Based on the submitted information, the benefit-harm-uncertainty profile of Corzyna is considered favourable when used as an add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies, including beta-blockers and calcium channel blockers. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Corzyna Product Monograph to address the identified safety concerns.

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

3 What steps led to the approval of Corzyna?

The sponsor requested a priority review status for the New Drug Submission (NDS) for Corzyna. Upon review of the information in the submitted clinical assessment package, Health Canada determined that the sponsor's request fulfilled the criteria set out in the Priority Review Policy. Specifically, angina pectoris is listed as a serious or life-threatening condition in section 2.1 of the Health Canada's Guidance for Industry - Priority Review of Drug Submissions. In its request, the sponsor presented sufficient evidence of a potential favourable benefit-risk profile of ranolazine for the treatment of patients with angina pectoris who remained symptomatic despite treatment with currently available first-line antianginal therapy, including beta-blockers, calcium channel blockers, and long-acting nitrates.

Thereafter, the NDS for Corzyna was filed in accordance with the conditions and requirements set out in Health Canada's Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience). While a submission relying on third-party data may differ in the source of information used to support safety and effectiveness, it has to meet the same standards for approval as a conventional submission (that contains complete study reports of clinical safety and efficacy), i.e., to provide substantial evidence of safety and efficacy, as stipulated in the Food and Drug Regulations.

Submission Milestones: Corzyna

Submission Milestone Date
Request for priority status  
Filed 2020-03-18
Approval issued by Director, Medical Sciences Bureau 2020-04-16
Submission filed 2020-05-27
Screening  
Screening Deficiency Notice issued 2020-06-10
Response filed 2020-06-11
Screening Acceptance Letter issued 2020-07-06
Review  
Biopharmaceutics Evaluation complete 2020-11-16
Review of Risk Management Plan complete 2020-12-16
Quality Evaluation complete 2020-12-18
Non-Clinical Evaluation complete 2020-12-22
Labelling Review complete 2020-12-23
Clinical/Medical Evaluation complete 2020-12-29
Notice of Compliance issued by Director General, Therapeutic Products Directorate 2020-12-31

The Canadian regulatory decision on the review of Corzyna was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as a reference to confirm the linkage of the Canadian commercial formulation of Corzyna with the formulations of extended-release ranolazine used in the pivotal studies evaluated in this submission.

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

4 What follow-up measures will the company take?

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

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

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

The PAAT for Corzyna is found above.

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

6 What other information is available about drugs?

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

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

Clinical Pharmacology

The clinical pharmacology data support the use of Corzyna (ranolazine) for the recommended indication.

At therapeutic concentrations, ranolazine inhibits the cardiac late sodium current (INa). However, the relationship between this inhibition and the antianginal effects of ranolazine is not certain.

The absorption phase of Corzyna, an extended-release tablet, is prolonged, with maximum plasma concentrations (Cmax) of ranolazine observed 2 to 5 hours after dose intake. The apparent terminal half-life of ranolazine is 7 hours. Steady state is generally achieved within 3 days of twice-daily dosing.

Ranolazine is extensively metabolized by the enzyme cytochrome P450 (CYP) 3A4 (CYP3A4) and, to a lesser extent, by CYP2D6. The pharmacologic activity of the metabolites has not been well characterized. Less than 5% of a single oral dose is excreted as an unchanged drug in urine and feces.

Following a single oral administration, approximately 75% of the dose is excreted in urine and 25% in feces.

The pharmacokinetics of ranolazine is unaffected by sex, age, food, congestive heart failure, and diabetes mellitus.

The exposure of ranolazine (reflected by the area under the plasma concentration versus time curve, AUC) increases up to 2-fold with advancing degree of renal impairment. The Cmax of ranolazine was found to increase 80% in patients with moderate hepatic impairment relative to patients without hepatic impairment. Therefore, Corzyna is contraindicated in patients with severe renal impairment and patients with moderate to severe liver impairment.

In a double-blind, randomized, placebo-controlled, parallel-design electrocardiogram (ECG) assessment study, healthy subjects were treated with extended-release ranolazine 1,500 mg twice daily (number of subjects [n] = 10) or placebo (n = 10) for three days. On the basis of a pharmacokinetic-pharmacodynamic model, the predicted differences from placebo in the mean change from baseline Fridericia-corrected QT interval (QTcF = QT/RR0.33) at maximal plasma concentrations following the recommended therapeutic doses of 500 mg twice daily and 1,000 mg twice daily are 16.3 ms (90% confidence interval [CI]: 10.1, 22.6) and 33.4 ms (90% CI: 22.7, 44.6), respectively. These predicted differences from placebo were based on geometric mean steady-state Cmax values of 1,450 ng/mL for the 500 mg twice-daily dose and 3,590 ng/mL for the 1,000 mg twice-daily dose that were reported in a crossover trial of 14 healthy subjects. Ranolazine was not observed to have noteworthy effects on the PR interval, the QRS duration, or ventricular heart rate in this study.

As Corzyna is extensively metabolized by CYP3A4 and, to a lesser extent, by CYP2D6, concomitant exposure of Corzyna with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir, grapefruit juice) and CYP3A4 inducers (e.g., rifampicin, phenobarbital, carbamazepine, St. John's wort) is contraindicated. Use of Corzyna with class IA (e.g., procainamide, disopyramide) and class III antiarrhythmic medications (e.g., sotalol, amiodarone) is also contraindicated. The maximum dose of Corzyna must be limited to 500 mg twice daily when used concomitantly with moderate CYP3A4 inhibitors (e.g., diltiazem and verapamil). Dose adjustments of some other medications are also required when used in combination with Corzyna (e.g., simvastatin, metformin).

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

Clinical Efficacy

Evidence of the clinical efficacy of Corzyna as an add-on symptomatic treatment of patients with stable angina pectoris was obtained from published references. Pivotal efficacy data were derived from two published randomized, double-blind, placebo-controlled clinical trials, CARISA and ERICA. Published results of the randomized, double-blind, placebo-controlled clinical trials MARISA, TERISA, and MERLIN‑TIMI 36 provided additional evidence of efficacy.

In the CARISA trial, 823 patients with chronic stable angina were randomized to receive extended-release ranolazine 750 mg, extended-release ranolazine 1,000 mg, or placebo, twice a day for 12 weeks, in addition to their background therapy of a fixed dose of a single antianginal agent. The background antianginal therapy consisted of a beta-blocker (atenolol 50 mg once a day) or a calcium channel blocker (diltiazem 180 mg once a day or amlodipine 5 mg once a day).

The primary endpoint of the CARISA trial was exercise duration at trough ranolazine concentration, i.e., 12 hours after dosing, on an exercise treadmill test, conducted at week 12. Secondary endpoints included exercise duration at peak ranolazine concentration (i.e., 4 hours after dosing), time to onset of angina at trough and peak ranolazine concentrations, time to ischemic (≥1 mm) ST segment depression at trough and peak ranolazine concentrations, weekly angina frequency, and weekly nitroglycerin consumption. At week 12, exercise duration at trough concentration increased by 115.6 seconds from baseline in the pooled ranolazine groups compared to 91.7 seconds in the placebo group (p = 0.01). Similarly, exercise duration at peak concentration, the time to onset of angina at trough and peak concentrations, and the time to ischemic ST segment depression at peak concentration significantly increased in both extended-release ranolazine groups compared to the placebo group, with minimal effects on blood pressure and heart rate. However, the time to electrocardiographic ischemia at trough concentration did not significantly differ between the extended-release ranolazine groups and the placebo group. The frequency of weekly angina episodes and short-acting nitroglycerin use were also significantly reduced with both doses of extended-release ranolazine in an apparent dose-related manner.

In the ERICA trial, 565 patients with chronic stable angina were randomized to receive extended-release ranolazine 1,000 mg twice daily or placebo over 6 weeks, following an initial one-week run-in phase with extended-release ranolazine 500 mg twice daily or placebo. As background antianginal therapy, all patients received the maximum recommended dosage of the calcium channel blocker, amlodipine (10 mg daily). Forty-five percent of patients also received long-acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. Patients receiving ranolazine had a signi?cantly lower weekly frequency of angina episodes compared to patients receiving placebo (trimmed mean values of 2.9 versus 3.3; p = 0.03). Trimmed mean weekly consumption of rescue (short-acting) nitroglycerin use was also significantly reduced (2.0 for the ranolazine-treated patients versus 2.7 for the placebo-treated patients; p = 0.01). Trimmed mean values excluded individual patient values in the top and bottom 2% of values measured.

The key supportive trial, MARISA, was a double-blind, randomized, placebo-controlled, four-period crossover trial, conducted in 191 patients with chronic stable angina. It evaluated extended-release ranolazine as a monotherapy at doses of 500 mg, 750 mg, and 1,000 mg, each administered twice daily for one week as per the crossover design. Background antianginal therapy was not allowed in this study. The primary endpoint was total exercise duration assessed at trough ranolazine concentration using the exercise treadmill test. Other efficacy assessments during the exercise treadmill test included total exercise duration at peak ranolazine concentration, as well as time to onset to angina and time to 1 mm ST segment depression, that were both assessed at peak and trough ranolazine concentrations. Compared to placebo, treatment with ranolazine at all doses resulted in statistically significant and dose-related improvements in the exercise treadmill test parameters at both trough and peak concentrations. Ranolazine at a dose of 1,000 mg twice daily increased total exercise duration over placebo by 34 seconds at trough concentration (p<0.001) and by 50 seconds at peak concentration (p<0.001).

In the TERISA trial, the efficacy of extended-release ranolazine versus placebo was evaluated in patients who had type 2 diabetes mellitus, coronary artery disease with chronic stable angina, and who remained symptomatic despite treatment with one or two antianginal agents. In total, 462 patients received ranolazine 1,000 mg twice daily and 465 patients received placebo. Overall, 44% of patients were taking two background antianginal agents. Most patients (90%) received beta-blockers, 29% of patients were treated with calcium channel blockers, and 34% of patients were treated with long-acting nitrates. The primary efficacy endpoint was the weekly angina frequency determined over the last 6 weeks of the 8-week study treatment period. In ranolazine-treated patients, weekly angina frequency was significantly lower than in the placebo-treated patients (3.8 episodes per week versus 4.3 episodes per week, p = 0.008). Similarly, during weeks 2 to 8 after randomization, weekly sublingual nitroglycerin rescue use was significantly reduced with ranolazine compared to placebo (1.7 versus 2.1, p = 0.003).

The MERLIN‑TIMI 36 trial was a large, cardiovascular outcome trial in 6,560 patients randomized to receive ranolazine or placebo that was initiated intravenously within 48 hours of the onset of ischemic symptoms during an episode of non-ST-elevation acute coronary syndrome. Patients then received oral extended-release ranolazine 1,000 mg twice daily or placebo, and were followed up for a median of 348 days. Patients also received standard treatment following non-ST-elevation acute coronary syndrome. No effect of ranolazine was seen on the primary efficacy endpoint, which was defined as the first occurrence of any element of the composite of cardiovascular death, myocardial infarction, or recurrent ischemia. However, the recurrent ischemia component was reduced in the ranolazine group (13.9%) compared with the placebo group (16.1%; hazard ratio [HR], 0.87; 95% CI: 0.76, 0.99; p = 0.03). In addition, a subgroup analysis of 3,565 patients who had a history of chronic angina at study entry, showed that compared with placebo, ranolazine led to a significant decrease in recurrent ischemia (HR 0.78; 95% CI: 0.67, 0.91; p = 0.002).

Overall, the submitted information provided evidence of consistent beneficial effects when extended-release ranolazine at doses up to 1,000 mg twice daily was used across several clinical trials as add-on therapy to various guideline-recommended treatments for the symptomatic management of chronic stable angina, including beta-blockers, calcium channel blockers, and/or long-acting nitrates.

Indication

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

  • Corzyna is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists).
    Corzyna may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.

Following review of the material provided in the submission, Health Canada approved the following indication:

  • Corzyna (ranolazine extended-release tablets) is indicated as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies, including beta-blockers and calcium channel blockers.

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

Clinical Safety

The safety profile of ranolazine was evaluated from published references and post-marketing experience.

In controlled clinical trials, the most frequently reported adverse reactions to ranolazine treatment were dizziness, headache, constipation, and nausea. Occasional episodes of hypotension and syncope were also noted. In addition, QTc interval prolongation and rare events of torsade de pointes were reported in post-marketing experience.

In the large randomized, double-blind, placebo-controlled, clinical outcome trial (MERLIN‑TIMI 36, described in the Clinical Efficacy section) conducted in 6,560 patients with acute coronary syndrome, there was no increase in adverse cardiac outcomes with ranolazine use. Similarly, in another large clinical outcome trial (RIVER‑PCI) that assessed 2,651 patients with chronic stable angina and incomplete revascularization following percutaneous coronary intervention, the rates of major adverse cardiovascular events, all-cause mortality, stroke, and hospitalization due to heart failure did not differ between patients treated with ranolazine and those treated with placebo. However, among patients who were 75 years of age and older, the rate of major adverse cardiovascular events was increased over placebo (HR 1.79; 95% CI: 1.06, 3.06; p = 0.03). These findings and a relevant warning have been included in the Corzyna Product Monograph.

Ranolazine has been shown to prolong the QTc interval in a dose- and concentration-related manner. Rare events of torsade de pointes and ventricular fibrillation have been reported during post-market use. A Serious Warnings and Precautions box is included in the Corzyna Product Monograph to highlight the QT prolongation effect of Corzyna and to warn that doses of 1,000 mg twice daily should not be exceeded. Furthermore, Corzyna is contraindicated in patients who are treated with antiarrhythmic drugs that have prominent QT interval prolonging properties and in patients treated with strong CYP3A4 inhibitors. Warnings to avoid the use of Corzyna in patients with acquired long QT syndrome, in patients with most forms of congenital long QT syndrome, and with other drugs known to prolong the QT interval or induce torsade de pointes, have also been included in the Corzyna Product Monograph.

Substantially increased plasma concentrations of ranolazine were observed in patients with moderate hepatic impairment. Some patients with severe renal impairment developed acute renal failure after receiving ranolazine. Based on these data, the use of Corzyna is contraindicated in patients with moderate to severe hepatic impairment as well as in patients with severe renal impairment.

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

7.2 Non-Clinical Basis for Decision

The non-clinical data provided for Corzyna (ranolazine) rely on literature sources.

The publications reviewed identified the cardiac late sodium current (INa) as the main target of ranolazine. In ventricular muscle strips from end-stage failing human hearts and in cardiac myocytes of guinea pigs, rabbits, and dogs, ranolazine was shown to cause direct and indirect concentration-, voltage-, and frequency-dependent inhibition of late INa.

Anti-ischemic effects of ranolazine were demonstrated in rat and dog models of reversible ischemia. In dogs, the anti-ischemic effects occurred at doses of ranolazine similar to the human therapeutic doses. Ranolazine increased cardiac performance in dogs with heart failure induced by serial microembolizations, without affecting heart rate, arterial blood pressure, left ventricular contractility, or systemic vascular resistance.

Ranolazine is known to cause a concentration-dependent inhibition of the human ether-a-go-go-related gene (hERG) potassium channel in heterologous expression systems, with reported 20% inhibition concentration (IC20) and 50% inhibition concentration (IC50) values of 1.9 µM and 8.3 µM, respectively. The HERG gene encodes the pore-forming alpha subunit of the human rapid delayed rectifier K+ (IKr) channel. Suppression of the IKr current provides a mechanistic explanation for the corrected QT interval (QTc) prolongation observed with ranolazine in humans.

Based on the submitted publications, the relationship between the inhibition of late INa by ranolazine and its antianginal effects is not certain. Therefore, the mechanism of the antianginal effects of ranolazine has not been determined. However, it is recognized that the antianginal effects of ranolazine do not depend on reductions in heart rate or blood pressure.

Carcinogenicity studies in rats and mice did not show evidence of carcinogenic potential of ranolazine. A published study reported that ranolazine promoted tumour formation and progression to malignancy when given to transgenic APC(min/+) mice at a dose of 30 mg/kg twice daily. The clinical significance of this finding is unclear.

Ranolazine did not exhibit genotoxicity in the conducted assays.

In animal studies, ranolazine at exposures 1.5-times (in rabbits) to 2-times (in rats) the usual human exposure caused maternal toxicity, misshapen sternebra, and reduced ossification in offspring. These doses in rats and rabbits were associated with increased maternal mortality.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Corzyna Product Monograph. In view of the intended use of Corzyna, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

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

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Corzyna 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.

Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

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

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

All non-medicinal ingredients (i.e., excipients, described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. None of the excipients used in the formulation of Corzyna is of human or animal origin.

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