Regulatory Decision Summary for Corzyna

Patients with coronary artery disease (CAD) commonly develop chronic stable angina, a clinical syndrome that results in incapacitating chest pain and related symptoms upon physical and/or emotional exertion. Current pharmacological therapies are used to help control the frequency and intensity of these anginal episodes, and include various combinations of beta-blockers, calcium-channel blockers and/or long-acting nitrates. However, many patients may have inadequate control of their symptoms, despite these treatments, resulting in limited mobility and activity levels, diminished quality of life, and consequent adverse effects on mental status. Although coronary revascularisation may abrogate anginal symptoms following successful intervention, many patients are not candidates for these procedures or wait for extended periods of time for these interventions. Furthermore, some patients who undergo these procedures are left with incomplete revascularisation and ongoing anginal symptoms.

This New Drug Submission (NDS) consisted of a Submission Relying on Third-Party Data (SRTD), comprising two pivotal trials (the CARISA and ERICA trials) and four supportive clinical trials and/or analyses (the MARISA, TERISA, MERLIN TIMI-36, RIVER-PCI trials). There were 1,388 patients evaluated in the pivotal trials and 10,351 in the supportive trials, resulting in a total of 11,739 patients in these studies, of which a little more than half were exposed to extended-release ranolazine.

The clinical evidence from the identified pivotal studies provided from the medical literature demonstrated a dose-related effect of extended-release ranolazine on a variety of relevant exercise treadmill testing (ETT) endpoints for anginal symptom control, such as total exercise duration, time-to-onset of angina, and time-to-onset of 1 millimetre (mm) ST segment depression. When extended-release ranolazine was used as add-on therapy to various guideline-directed treatments for anginal symptom control, including beta-blockers, calcium channel blockers, and/or long-acting nitrates, consistent beneficial effects at doses of ranolazine up to 1,000 milligrams (mg) twice daily were observed on ETT parameters, and on weekly frequency of anginal attacks and need for rescue short-acting nitroglycerin use. More robust results on ETT parameters were observed at peak, compared to trough. The CARISA trial was carried out in 823 patients with chronic stable angina using a three-group, double-blind, randomised, placebo-controlled trial design that evaluated the effect of extended-release ranolazine on ETT, following 2, 6 and 12 weeks of treatment of either ranolazine 750 mg or 1,000 mg twice daily. Ranolazine was evaluated for anginal symptom control as an add-on to a background fixed-dose treatment of either atenolol 50 mg once daily, diltiazem 180 mg once daily or amlodipine 5 mg once daily. The ERICA trial evaluated 565 patients with chronic stable angina treated with extended-release ranolazine 1,000 mg twice daily in a double-blind, randomised, placebo-controlled manner over 6 weeks, following an initial one-week titration phase with ranolazine 500 mg twice daily. All patients received amlodipine 10 mg per day as background anti-anginal therapy, while 45% also received long-acting nitrates daily.

The most common adverse reactions observed with ranolazine treatment in the studies identified as pivotal included dizziness, headache, constipation and nausea, which resulted in a limitation of the maximum recommended dose of 1,000 mg twice daily. These appear to be more common in elderly patients above 75 years old, especially at higher doses. Ranolazine was also seen to prolong QTc interval in a dose-related manner in pharmacodynamic studies. While the magnitude to cause torsade-de-pointes and life-threatening ventricular arrhythmias is not entirely clear, the Corzyna Product Monograph includes a black box warning, contraindications, additional warnings and precautions and other cautionary language with regards to the QTc interval prolongation. Safety data from two large randomised and double-blinded clinical trials were conducted in 9,211 patients with CAD. These data gave no overall indication of an increase in adverse cardiovascular events with ranolazine use, including for sudden cardiac death, cardiovascular death, myocardial infarction and symptomatic ventricular arrhythmias when compared to placebo. There are evolving published data suggesting that a subset of patients with congenital long QT syndrome (patients with type III) may benefit from treatment of their condition with ranolazine, rather than be harmed by such treatment. This may be due to the action of ranolazine on the late inward sodium current in cardiac tissues. Accordingly, it was determined that an absolute contraindication in all patients with congenital long QT syndrome of this type was not warranted, as there is already information about the risk for these patients in warnings and precautions. The use of ranolazine has been contraindicated in patients with advanced hepatic impairment, due to its propensity to result in substantially increased plasma levels of ranolazine, leading to an unacceptable safety profile in these patients. The use in patients with severe renal impairment has also been contraindicated due to the occurrence of acute renal failure events in some of these patients exposed to ranolazine.

Ranolazine can be of benefit, as an add-on treatment, in patients with inadequate control of symptoms of chronic stable angina, in combination with beta-blockers, calcium-channel blockers and/or long-acting nitrate therapies. Drug product labelling and post-marketing measures have been instituted, including a general patient education program upon initiation of ranolazine therapy. The benefit-harm-uncertainty profile of ranolazine as an add-on treatment in the management of symptoms of chronic stable angina in patients inadequately responsive to or intolerant to first-line agents in this condition has been determined to be acceptable.