Ranolazine MR Tablets for Treatment of Stable Angina

New Medicines Committee Briefing September 2016 Ranolazine MR tablets for treatment of stable angina

Ranolazine MR tablets are to be reviewed for use within: Primary Care  Secondary Care  Summary:

 It is estimated by NICE that 8% of men and 3% of women aged between 55 and 64 years currently have or have had angina.1

 Ranolazine 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.

 NICE recommends ranolazine as an alternative to beta-blockers and calcium channel blockers if one or both are not tolerated or are contraindicated.2

 The Scottish Medicines Compendium has concluded that ranolazine is not recommended for use within NHS Scotland.3

 All Wales Medicines Strategy Group recommends that ranolazine as an add-on therapy is recommended as an option for restricted use within NHS Wales for the symptomatic treatment of patients with stable angina pectoris.4

 In 2009 the RTDC stated that “the limited data available means that its place in therapy remains uncertain, and as QT-prolongation and drug interactions are important potential hazards, prescribing of ranolazine should be initiated by cardiologists only”.5

 In 2009 MTRAC recommended that ranolazine “cannot be recommended for prescribing as the current evidence for its efficacy and safety is inadequate to support its use”. 6

 Ranolazine has been shown to reduce the frequency of angina attacks7, and clinically significant arrhythmias but does not appear to improve mortality rates. 8

 There has been little reported difference in the incidence of adverse events when ranolazine is compared to placebo with the most common side effects reported being dizziness, nausea and constipation.9

Formulary application

Consultant submitting application: Dr Adrian Large (Consultant Cardiologist)

Clinical Director supporting application: Dr Grant Heatley (Clinical Director for Cardiology)

Dr Large requested for ranolazine MR tablets to be considered for inclusion in the North Staffordshire Joint Formulary. In his application form he noted that Ranolazine is contraindicated in patients with preexisting QT interval prolongation or hepatic disease, and in patients taking other drugs that prolong the QT interval or that are potent or moderately potent inhibitors of CYP3A4, such as diltiazem and verapamil. Ranolazine also inhibits pathways involved in the metabolism of digoxin and simvastatin, and dose reduction may be required.

Like other drugs that prolong the QT interval, ranolazine inhibits the KCNH2 channel (formerly called HERG channel). However, the effect is generally less than with other drugs (mean QTc prolongation 2.4 ms in a review of 746 patients treated for almost three years) and torsade de pointes has not yet been described.

Dr Large stated in the form that the efficacy of ranolazine in patients with chronic stable angina has been demonstrated in several randomized trials (see evidence summary section).

Background

Angina pectoris is a symptom of an underlying cardiac condition, in most cases coronary heart disease. Coronary heart disease occurs when there is a build-up of plaque on the artery wall which causes reduced blood flow. 10

Angina is characterised as a pain in the chest which may radiate down the arms and up to the jaw. It is categorised as stable or unstable and less commonly variant or microvascular.

In unstable angina pain is unpredictable and is commonly a precursor to a myocardial infarction. Stable angina is related to exercise and can occurs due to increased myocardial oxygen demand. Figure A shows the location of the heart in the body. Figure B shows a normal coronary artery with normal blood flow. The Stable angina usually responds well to pharmacotherapy. Drugs inset image shows a cross-section of a normal coronary artery. such as GTN spray and other nitrates encourage cardiovascular Figure C shows a coronary artery narrowed by plaque. The vasodilation to increase perfusion. They also act to reduce build-up of plaque limits the flow of oxygen-rich blood through the artery. The inset image shows a cross-section of the plaque- cardiac preload and afterload by causing peripheral vasodilation narrowed artery.10 which reduces cardiac oxygen requirements.11

It is estimated by NICE that 8% of men and 3% of women aged between 55 and 64 years currently have or have had angina. For those between 65 and 74 years this figure rises to 14% of men and 8% of women.1

Current formulary status

Therapeutic class and mode of action12 Pharmacotherapeutic group: Other cardiac preparations, ATC code: C01EB18

Mechanism of action: The mechanism of action of ranolazine is largely unknown. Ranolazine may have some antianginal effects by inhibition of the late sodium current in cardiac cells. This reduces intracellular sodium accumulation and consequently decreases intracellular calcium overload. Ranolazine, via its action to decrease the late sodium current, is considered to reduce these intracellular ionic imbalances during ischaemia. This reduction in cellular calcium overload is expected to improve myocardial relaxation and thereby decrease left ventricular diastolic stiffness. Clinical evidence of inhibition of the late sodium current by ranolazine is provided by a significant shortening of the QTc interval and an improvement in diastolic relaxation in an open- label study of 5 patients with a long QT syndrome (LQT3 having the SCN5A ∆KPQ gene mutation).

These effects do not depend upon changes in heart rate, blood pressure, or vasodilation.

Licensed indications12

Ranexa 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).

Dosage and administration12

Patients should be given the Ranexa package leaflet and the Patient Alert Card and instructed to present their Patient Alert Card and medication list to their health care professional at each visit.

Posology Ranexa is available as 375 mg, 500 mg, and 750 mg prolonged-release tablets.

Adults: The recommended initial dose of Ranexa is 375 mg twice daily. After 2–4 weeks, the dose should be titrated to 500 mg twice daily and, according to the patient's response, further titrated to a recommended maximum dose of 750 mg twice daily. If a patient experiences treatment-related adverse events (e.g. dizziness, nausea, or vomiting), down-titration of Ranexa to 500 mg or 375 mg twice daily may be required. If symptoms do not resolve after dose reduction, treatment should be discontinued.

Concomitant treatment with CYP3A4 and P-glycoprotein (P-gp) inhibitors: Careful dose titration is recommended in patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole, erythromycin) or P-gp inhibitors (e.g. verapamil, ciclosporin). Concomitant administration of potent CYP3A4 inhibitors is contraindicated.

Renal impairment: Careful dose titration is recommended in patients with mild to moderate renal impairment (creatinine clearance 30–80 ml/min). Ranexa is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min).

Hepatic impairment: Careful dose titration is recommended in patients with mild hepatic impairment. Ranexa is contraindicated in patients with moderate or severe hepatic impairment.

Elderly: Dose titration in elderly patients should be exercised with caution. Elderly may have increased ranolazine exposure due to age-related decrease in renal function. The incidence of adverse events was higher in the elderly.

Low weight: The incidence of adverse events was higher in patients with low weight (≤ 60 kg). Dose titration in patients with low weight should be exercised with caution.

Congestive heart failure (CHF): Dose titration in patients with moderate to severe CHF (NYHA Class III–IV) should be exercised with caution.

Paediatric population The safety and efficacy of Ranexa in children below the age of 18 years have not been established. No data are available

Method of administration Ranexa tablets should be swallowed whole and not crushed, broken, or chewed. They may be taken with or without food.

Safety and adverse effects12 Contraindications Hypersensitivity to the active substance or to any of the excipients. Severe renal impairment (creatinine clearance < 30 ml/min) Moderate or severe hepatic impairment Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazol, posaconazol, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone Concomitant administration of Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol) antiarrhythmics other than amiodarone.

Special warnings and precautions for use Caution should be exercised when prescribing or uptitrating ranolazine to patients in whom an increased exposure is expected: • Concomitant administration of moderate CYP3A4 inhibitors • Concomitant administration of P-gp inhibitors • Mild hepatic impairment • Mild to moderate renal impairment (creatinine clearance 30–80 ml/min) • Elderly • Patients with low weight (≤ 60 kg) • Patients with moderate to severe CHF (NYHA Class III–IV) In patients with a combination of these factors, additional exposure increases are expected. Dose- dependent side effects are likely to occur. If Ranexa is used in patients with a combination of several of these factors, monitoring of adverse events should be frequent, the dose reduced, and treatment discontinued, if needed. The risk for increased exposure leading to adverse events in these different subgroups is higher in patients lacking CYP2D6 activity (poor metabolisers, PM) than subjects with CYP2D6 metabolising capacity (extensive metabolisers, EM). The above precautions are based on the risk in a CYP2D6 PM patient, and are needed when the CYP2D6 status is unknown. There is a lower need for precautions in patients with CYP2D6 EM status. If the CYP2D6 status of the patient has been determined (e.g. by genotyping) or is previously known to be EM, Ranexa can be used with caution in these patients when they have a combination of several of the above risk factors.

QT prolongation: A population-based analysis of combined data from patients and healthy volunteers demonstrated that the slope of the plasma concentration-QTc relationship was estimated to be 2.4 msec per 1000 ng/ml, which is approximately equal to a 2- to 7-msec increase over the plasma concentration range for ranolazine 500 to 1000 mg twice daily. Therefore, caution should be observed when treating patients with a history of congenital or a family history of long QT syndrome, in patients with known acquired QT interval prolongation, and in patients treated with drugs affecting the QTc interval.

Drug-drug interactions: Co-administration with CYP3A4 inducers is expected to lead to lack of efficacy. Ranexa should not be used in patients treated with CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort).

Renal impairment: Renal function decreases with age and it is therefore important to check renal function at regular intervals during treatment with ranolazine. <750 mg tablet> Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. Azo colouring agent E102: This medicinal product contains the azo colouring agent E102 which may cause allergic reactions.

Fertility, pregnancy and lactation

Pregnancy: There are no adequate data from the use of ranolazine in pregnant women. Animal studies are insufficient with respect to effects on pregnancy and embryofoetal development. The potential risk for humans is unknown. Ranexa should not be used during pregnancy unless clearly necessary.

Breast-feeding: It is unknown whether ranolazine is excreted in human breast milk. The excretion of ranolazine in milk has not been studied in animals. Ranexa should not be used during breast-feeding.

Fertility: In animals, reproduction studies indicated no adverse effects on fertility. The effect of ranolazine on human fertility is unknown.

Effects on ability to drive and use machines

No studies on the effects of Ranexa on the ability to drive and use machines have been performed. Ranexa may cause dizziness, blurred vision, diplopia, confusional state, coordination abnormal, hallucination, which may affect the ability to drive and use machines.

Undesirable effects

Undesirable effects in patients receiving Ranexa are generally mild to moderate in severity and often develop within the first 2 weeks of treatment. These were reported during the Phase 3 clinical development programme, which included a total of 1,030 chronic angina patients treated with Ranexa. The adverse events, considered to be at least possibly related to treatment, are listed below by body system, organ class, and absolute frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000).

Metabolism and nutrition disorders Uncommon: anorexia, decreased appetite, dehydration. Rare: hyponatremia

Psychiatric disorders Uncommon: anxiety, insomnia, confusional state, hallucination. Rare: disorientation.

Nervous system disorders

Common: dizziness, headache. Uncommon: lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness, paresthesia. Rare: amnesia, depressed level of consciousness, loss of consciousness, coordination abnormal, gait disturbance, parosmia.

Eye disorders Uncommon: blurred vision, visual disturbance, diplopia.

Ear and labyrinth disorders Uncommon: vertigo, tinnitus. Rare: impaired hearing.

Vascular disorders Uncommon: hot flush, hypotension. Rare: peripheral coldness, orthostatic hypotension.

Respiratory, thoracic, and mediastinal disorders Uncommon: dyspnoea, cough, epistaxis. Rare: throat tightness.

Gastrointestinal disorders Common: constipation, vomiting, nausea. Uncommon: abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort. Rare: pancreatitis, erosive duodenitis, oral hypoaesthesia.

Skin and subcutaneous tissue disorders Uncommon: pruritus, hyperhydrosis. Rare: angioedema, allergic dermatitis, urticaria, cold sweat, rash.

Musculoskeletal and connective tissue disorders Uncommon: pain in extremity, muscle cramp, joint swelling, muscular weakness.

Renal and urinary disorders Uncommon: dysuria, haematuria, chromaturia. Rare: acute renal failure, urinary retention.

Reproductive system and breast disorders Rare: erectile dysfunction.

General disorders and administration site conditions Common: asthenia. Uncommon: fatigue, peripheral oedema.

Investigations Uncommon: increased blood creatinine, increased blood urea, prolonged QT corrected interval, increased platelet or white blood cell count, decreased weight. Rare: elevated levels of hepatic enzyme. The adverse event profile was generally similar in the MERLIN-TIMI 36 study. In this long term study, acute renal failure was also reported with an incidence less than 1% in placebo and ranolazine patients. Evaluations in patients who may be considered at higher risk of adverse events when treated with other antianginal medicinal products, e.g. patients with diabetes, Class I and II heart failure, or obstructive airway disease, confirmed that these conditions were not associated with clinically meaningful increases in the incidence of adverse events.

Elderly, renal impairment, and low weight: In general, adverse events occurred more frequently among elderly patients and patients with renal impairment; however, the types of events in these subgroups were similar to those observed in the general population. Of the most commonly reported, the following events occurred

more often with Ranexa (placebo-corrected frequencies) in elderly (≥ 75 years of age) than younger patients (< 75 years of age): constipation (8% versus 5%), nausea (6% versus 3%), hypotension (5% versus 1%), and vomiting (4% versus 1%).

In patients with mild or moderate renal impairment (creatinine clearance ≥ 30–80 ml/min) compared to those with normal renal function (creatinine clearance > 80 ml/min), the most commonly reported events and their placebo-corrected frequencies included: constipation (8% versus 4%), dizziness (7% versus 5%), and nausea (4% versus 2%).

In general, the type and frequency of adverse events reported in patients with low body weight (≤ 60 kg) were similar to those of patients with higher weight (> 60 kg); however, the placebo-corrected frequencies of the following common adverse events were higher in low body weight than heavier patients: nausea (14% versus 2%), vomiting (6% versus 1%), and hypotension (4% versus 2%).

Laboratory findings: Small, clinically insignificant, reversible elevations in serum creatinine levels have been observed in healthy subjects and patients treated with Ranexa. There was no renal toxicity related to these findings. A renal function study in healthy volunteers demonstrated a reduction in creatinine clearance with no change in glomerular filtration rate consistent with inhibition of renal tubular secretion of creatinine.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Overdose In an oral high-dose tolerability study in angina patients, the incidence of dizziness, nausea, and vomiting increased in a dose-dependent manner. In addition to these adverse events, diplopia, lethargy, and syncope were observed in an intravenous overdose study in healthy volunteers. In the event of overdose, the patient should be closely monitored and the treatment should be symptomatic and supportive.

Approximately 62% of ranolazine is bound to plasma proteins, and therefore, complete clearance by haemodialysis is unlikely.

Drug Interactions12 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on ranolazine

CYP3A4 or P-gp inhibitors: Ranolazine is a substrate of cytochrome CYP3A4. Inhibitors of CYP3A4 increase plasma concentrations of ranolazine. The potential for dose-related adverse events (e.g. nausea, dizziness) may also increase with increased plasma concentrations. Concomitant treatment with ketoconazole 200 mg twice daily increased the AUC of ranolazine by 3.0- to 3.9-fold during ranolazine treatment. Combining ranolazine with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated. Grapefruit juice is also a potent CYP3A4 inhibitor.

Diltiazem (180 to 360 mg once daily), a moderately potent CYP3A4 inhibitor, causes dose-dependent increases in average ranolazine steady-state concentrations of 1.5- to 2.4-fold. Careful dose titration of Ranexa is recommended in patients treated with diltiazem and other moderately potent CYP3A4 inhibitors (e.g. erythromycin, fluconazole). Down-titration of Ranexa may be required. Ranolazine is a substrate for P-gp. Inhibitors of P-gp (e.g. ciclosporin, verapamil) increase plasma levels of ranolazine. Verapamil (120 mg three times daily) increases ranolazine steady-state concentrations 2.2-fold. Careful dose titration of Ranexa is recommended in patients treated with P-gp inhibitors. Down-titration of Ranexa may be required.

CYP3A4 inducers: Rifampicin (600 mg once daily) decreases ranolazine steady-state concentrations by approximately 95%. Initiation of treatment with Ranexa should be avoided during administration of inducers of CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort) (see section 4.4).

CYP2D6 inhibitors: Ranolazine is partially metabolised by CYP2D6; therefore, inhibitors of this enzyme may increase plasma concentrations of ranolazine. The potent CYP2D6 inhibitor paroxetine, at a dose of 20 mg once daily, increased steady-state plasma concentrations of ranolazine 1000 mg twice daily by an average of 1.2-fold. No dose adjustment is required. At the dose level 500 mg twice daily, co-administration of a potent inhibitor of CYP2D6 could result in an increase in ranolazine AUC of about 62%.

Effects of ranolazine on other medicinal products Ranolazine is a moderate to potent inhibitor of P-gp and a mild inhibitor of CYP3A4, and may increase plasma concentrations of P-gp or CYP3A4 substrates. Tissue distribution of drugs which are transported by P-gp may be increased. Dose adjustment of sensitive CYP3A4 substrates (e.g., simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic range (e.g., ciclosporin, tacrolimus, sirolimus, everolimus) may be required as RANEXA may increase plasma concentrations of these drugs. Available data suggest that ranolazine is a mild inhibitor of CYP2D6. Ranexa 750 mg twice daily increased plasma concentrations of metoprolol by 1.8-fold. Therefore the exposure to metoprolol or other CYP2D6 substrates (e.g. propafenone and flecainide or, to a lesser extent, tricyclic antidepressants and antipsychotics) may be increased during co-administration with Ranexa, and lower doses of these medicinal products may be required. The potential for inhibition of CYP2B6 has not been evaluated. Caution is advised during co-administration with CYP2B6 substrates (e.g. bupropion, efavirenz, cyclophosphamide).

Digoxin: An increase in plasma digoxin concentrations by an average of 1.5-fold has been reported when Ranexa and digoxin are co-administered. Therefore, digoxin levels should be monitored following initiation and termination of Ranexa therapy.

Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranexa 1000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid by about 2 fold. Rhabdomyolysis has been associated with high doses of simvastatin and cases of rhabdomyolysis have been observed in patients receiving Ranexa and simvastatin, in postmarketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking any dose of Ranexa.

Atorvastatin: Ranexa 1000 mg twice daily increased Cmax and AUC of atorvastatin 80 mg once daily by 1.4- and 1.3 -fold, respectively and changed the Cmax and AUC of atorvastatin metabolites less than 35%. Dose limitation of atorvastatin and appropriate clinical monitoring may be considered when taking Ranexa. Dose limitation of other statins, metabolised by CYP3A4 (e.g. lovastatin), may be considered when taking Ranexa.

Tacrolimus, ciclosporin, sirolimus, everolimus: Increased plasma concentrations of tacrolimus, a CYP3A4 substrate, have been observed in patients after ranolazine administration. It is recommended that tacrolimus blood levels are monitored when co-administering Ranexa and tacrolimus and that tacrolimus dosage is adjusted accordingly. This is also recommended for other CYP3A4 substrates with a narrow therapeutic range (e.g., ciclosporin, sirolimus, everolimus).

Drugs transported by the Organic Cation Transporter-2 (OCT2): Plasma exposure of metformin (1000 mg twice daily) increased 1.4- and 1.8-fold in subjects with type 2 diabetes mellitus when co-administered with RANEXA 500 mg and 1000 mg twice daily respectively. The exposure of other OCT2 substrates, including but not limited to pindolol and varenicline, may be affected to a similar degree. There is a theoretical risk that concomitant treatment of ranolazine with other drugs known to prolong the QTc interval may give rise to a pharmacodynamic interaction and increase the possible risk of ventricular arrhythmias. Examples of such drugs include certain antihistamines (e.g. terfenadine, astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide), erythromycin, and tricyclic antidepressants (e.g. imipramine, doxepin, amitriptyline).

Presentation12

 Ranexa 375 mg prolonged-release tablets

 Ranexa 500 mg prolonged-release tablets

 Ranexa 750 mg prolonged-release tablets

Guidance and Evidence Summary

NICE guidance2 YES

The NICE Guideline, Stable angina: management (CG126) states:

 If the person cannot tolerate beta blockers and calcium channel blockers or both are contraindicated, consider monotherapy with one of the following drugs: o a long-acting nitrate o or ivabradine o or nicorandil o or ranolazine.

Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs.

 For people on beta blocker or calcium channel blocker monotherapy whose symptoms are not controlled and the other option (calcium channel blocker or beta blocker) is contraindicated or not tolerated, consider one of the following as an additional drug: o a long-acting nitrate o or ivabradine o or nicorandil o or ranolazine.

Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs.

Do not offer a third anti-anginal drug to people whose stable angina is controlled with two anti-anginal drugs.

 Consider adding a third anti-anginal drug only when: the person’s symptoms are not satisfactorily controlled with two anti-anginal drugs and the person is waiting for revascularisation or revascularisation is not considered appropriate or acceptable.

Decide which drug to use based on comorbidities, contraindications, the person's preference and drug costs.

Trade off between clinical benefits and harms We found no evidence on the effects of ranolazine monotherapy or ranolazine in combination with other antianginal drugs on long-term outcome in people with stable angina.

Quality of Evidence The available evidence for ranolazine was of moderate or high quality but were not designed to assess the long-term effects of ranolazine on mortality or other major adverse cardiac events. The improvements in exercise time and symptom severity associated with short-term ranolazine treatment are modest and of uncertain clinical significance. No economic evidence was available on this question.

SMC recommended use within NHS Scotland3 YES

The Scottish Medicines Consortium (SMC) has completed its review of ranolazine and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows:

ADVICE: following an Independent Review Panel Assessment: ranolazine (Ranexa®) is not recommended for use within NHS Scotland. Indication under review: 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).

When added to standard doses of antianginal drugs, ranolazine increased exercise duration at trough drug levels compared with placebo after 12 weeks treatment. Although significant, the effect size was modest, but not uncommon in studies of patients with stable angina pectoris.

The submitting company did not present a sufficiently robust clinical and economic case to gain acceptance by the Independent Review Panel (IRP).

All Wales Medicines Strategy Group (AWSG)4 YES

Recommendation of AWMSG:

Ranolazine (Ranexa®▼) as an add-on therapy is recommended as an option for restricted use within NHS Wales for the symptomatic treatment of patients with stable angina pectoris. Treatment should be initiated by a Cardiologist.

Ranolazine (Ranexa®▼) should be restricted for use in patients who remain symptomatic despite treatment with all other pharmacological anti-anginal therapies and where revascularisation has been considered and undertaken or is not considered appropriate.

Regional Drug and Therapeutic Centre (RDTC)5 YES

Ranolazine is an adjunctive therapy licensed for use in patients with stable angina that remains inadequately controlled despite treatment with first-line anti-anginal agents such as beta-blockers, calcium-channel blockers and nitrates. Placebo-controlled studies have demonstrated modest improvements in exercise time and in the frequency of angina attacks, although these studies did not use optimised / maximal background anti-anginal therapy. The limited data available means that its place in therapy remains uncertain, and as QT-prolongation and drug interactions are important potential hazards, prescribing of ranolazine should be initiated by cardiologists only.

MTRAC6 YES

Cochrane Review NO

Not reviewed

Anti-Ischemic Effects and Long-Term Survival During Ranolazine Monotherapy in Patients With Chronic Severe Angina (MARISA)13

In 2003 Chaitman et al. undertook a multinational, randomised, double-blind, placebo controlled study which involved 191 patients with chronic angina.

Patients were 21 years of age or over, had well documented coronary artery disease and at least a three month history of effort angina which responded to beta-blockers, calcium channel blockers, and/or long acting nitrates. All patients stopped taking other antianginals during this study, except for the use of sublingual nitroglycerin as needed.

Exclusion criteria were as follows: conditions which may compromise ECG or ETT interpretation; New York Heart Association functional class III or IV congestive heart failure; unstable angina, myocardial infarction, or and coronary revascularisation procedure within two months of enrolment; corrected QT interval >500ms or any medication known to prolong the QT interval; requirement of any medication or food known to affect metabolism by cytochrome P450 3A4.

The primary efficacy end point was total exercise duration at trough ranolazine concentrations. Other endpoints included time to onset of angina and time to 1mm ST- segment depression at trough and the same three EET end points at peak.

All participants entered a single blind placebo- treatment qualifying phase and undertook two ETTs one week apart. If during these tests they developed exercise limiting angina and ≥1mm horizontal or down sloping ST-segment depression between 3 and 9 minutes during each ETT and the difference between the two tests did not exceed 20% of the longer test or 1 minute then they went on to be randomised in the double-blind phase.

Participants received ranolazine 500mg, ranolazine 1000mg, ranolazine 1500mg, or placebo twice daily for one week, according to a four-period, balanced Latin Square crossover design. At the end of each treatment period ETTs were performed at trough and peak ranolazine concentrations, along with HR and BP measurements at rest and at maximal exercise during the ETTs and ECG monitoring throughout.

The primary efficacy endpoint, exercise duration at trough, was analysed for all patients who completed at least three crossover periods. All patients who received at least one dose of study drug were included in the safety evaluation.

In terms of the study population 73.3% were men and 91.1% were Caucasian, 52.3% had had a previous myocardial infarction, 64.4% had hypertension and 24.1% had diabetes.

Of the 191 participants 88% completed all four crossover periods and 85.1% agreed to participate in an open- label study looking at titration of ranolazine dose from 750mg to 1000mg twice daily as necessary.

Three of the four crossover periods were completed by 91.6% of the participants. Of the patients who discontinued before completing all four periods (12%) there were 15 patients who discontinued due to adverse events (7.9%), four who withdrew electively (2.1%), one patient who died (<1%) and one patient who was inappropriately enrolled (<1%), and two patients who withdrew for other reasons (1%).

Treatment with ranolazine at all doses significantly improved exercise duration, time to angina and time to 1mm ST-segment depression at both the trough and peak time points when compared to placebo, see Figure 2A.

As shown in figure 2B there was an increase in exercise duration with increases in ranolazine plasma concentration, this effect plateaued at higher ranolazine concentrations.

The percentage of patients who stopped exercise due to angina showed a dose-response relationship and was highest for those receiving placebo and lowest for those receiving 1500mg twice daily. The differences in proportions versus placebo were significant for the 1000mg and 1500mg ranolazine groups at both trough and peak (p<0.04). No clinically significant changes were observed for HR and BP at rest or during exercise.

The overall adverse event rate was similar for the placebo group and 500mg ranolazine group at 15.6% and 16%, respectively. Adverse events were more common at higher doses with the most common being dizziness, nausea, asthenia and constipation. Early withdrawal from the study due to adverse events occurred mainly in the 1500mg group, with 11 patients withdrawing out of a total of 15. Ranolazine was found to have a minimal impact on QTc prolongation. Clinically significant increases in eosinophil counts were seen in 3.6% of patients but they all returned to normal during the open-label study which followed.

There was no significant difference in exercise tolerance between the diabetic and non-diabetic groups (p=0.77). This was also the case when comparing side effect profile between diabetic patients and non-diabetic patients. When looking at age, gender and heart failure there was no statistical significant in the treatment effects between the groups.

Of the 143 participants who went on to participate in the open-label study 80.4% were still receiving ranolazine at one year and 69.9% of patients were receiving ranolazine at two years, with over 70% receiving 1000mg twice daily. The survival rates for those taking ranolazine were 96.3% (95% CI, 93.0%-99.5%) at year 1 and 93.6% (95% CI, 89.3%-98.0%) at year 2.

The authors concluded that ranolazine at doses of 1000mg and 1500mg twice daily significantly improves exercise performance and delays or prevents the symptoms and ECG evidence of myocardial ischemia during exercise testing in patients with chronic angina.

A limitation of this study is that for the double blind period there was only one week’s duration of treatment for each regime, this makes it difficult to determine the long term efficacy. The open label study was not blinded meaning that data from this period may be subject to bias.

Effects of Ranolazine With Atenolol, Amlodipine, or Diltiazem on Exercise Tolerance and Angina Frequency in Patients With Severe Chronic Angina (CARISA)9

In 2004 Chaitman et al. undertook a randomised 3-group parallel, double-blind, placebo controlled trial which involved 823 patients with symptomatic chronic angina.

Inclusion criteria were as follows: coronary artery disease, minimum 3-month history of exertional angina, reproducible angina, ischemic ST-segment depression of at least 1mm and limited exercise capacity on treadmill testing.

Exclusion criteria were: factors which precluded satisfactory interpretation of the ECG, class III or IV heart failure, or an acute coronary syndrome or chronic revascularisation procedure within the prior 2 months.

The primary aim was to compare the effects of ranolazine vs. placebo on treadmill exercise duration at trough ranolazine levels (12 hours post dose). The secondary efficacy end points were exercise duration at peak drug levels (4 hours post dose), time to angina, time to 1mm ST-segment depression at peak and trough, and anginal attacks and sublingual nitroglycerin uses reported in the patients daily diaries.

At enrolment 43% of patients were taking atenolol, 31.1% amlodipine and 25.9% diltiazem, baseline characteristics were similar between the three groups. Patients were randomised to receive placebo BD (n=269), ranolazine 750mg BD (n=279) or ranolazine 1000mg BD (n=275) for 12 weeks.

Exercise treadmill tests were performed at trough levels at weeks 2, 6 and 12, and at peak levels at weeks 2 and 12.

Exercise duration was increased for all patients taking ranolazine when compared to placebo (p=0.01).

Table 2 shows the treadmill exercise data; each ranolazine dose increased treadmill exercise duration at both trough (P=0.03) and peak (p<0.02) compared to placebo.

Ranolazine was also shown to reduce the number of angina attacks per week from 3.3 for placebo to 2.5 for the 750mg ranolazine (p=0.006) and 2.1 for 1000mg ranolazine (p<0.001). A similar reduction in nitroglycerin use was observed, as shown in figure 4.

Adverse events were reported in 26.4% of patients in the placebo group, 31.2% of patients on the 750mg ranolazine group and 32.7% of patients in the 1000mg ranolazine group. The most common adverse events were constipation, dizziness, nausea and asthenia. Five patients taking 100mg twice daily ranolazine experienced Figure 4. Angina Frequency and Nitroglycerin Consumption in the Intent-to-Treat Population syncope but all recovered spontaneously.

Mortality during the 12-week randomisation trial was 1.1% in the placebo group and 0.7% and 0.4% in the 750mg and 1000mg ranolazine groups, respectively.

Long term follow up was undertaken one and two years after the end of the study. After 2 years 128 patients were still taking ranolazine at a dose of less than 1000mg twice daily. The survival rates for those taking ranolazine were 98.4% (95% CI, 97.4%-99.5%) at year 1 and 95.9% (95% CI, 94.0%-97.7%) at year 2.

The authors concluded that ranolazine may benefit patients with severe chronic angina who are symptomatic whilst receiving amlodipine, atenolol or diltiazem.

Antianginal Efficacy of Ranolazine When Added to Treatment With Amlodipine (ERICA)7

In 2006 Stone et al., undertook a randomised, double-blind, placebo-controlled trial with 565 patients with a history of coronary artery disease.

Patients were 18 years or over, had a documented history of coronary artery disease, chronic stable angina for at least 3 months. They had to have three or more episodes of angina per week during a 2 week or more qualification period where they were receiving 10mg/day of amlodipine. Patients were required to have started amlodipine two weeks or more before entering the qualification period.

Exclusion criteria were as follows: New York Hear Association functional class IV congestive heart failure, a history of myocardial infarction or unstable angina within the previous 2 months, active acute myocarditis, pericarditis, hypertrophic cardiomyopathy, or uncontrolled hypertension, history of torsades de pointes, those receiving agents known to prolong the QTc interval, those with a QTc interval >500ms, use of medications which are cytochrome P450-3A4 inhibitors, clinically significant hepatic disease, creatinine clearance <30ml/min, chronic illness likely to interfere with the study protocol, patients taking digitalis preparations, perhexiline, trimetazidine, beta-blockers or calcium channel blockers other than amlodipine, participation in an investigative trial within 30 days of start date.

The primary efficacy variable was weekly average frequency of self-reported angina episodes during the 6-week double-blind full-dose treatment phase. The secondary efficacy variables were average weekly nitroglycerin consumption rate during the 6-week double-blind full-dose treatment phase and the change from baseline of the 5 dimensions of the Seattle Angina Questionnaire (SAQ).

There were 627 patients who undertook the qualifying phase and were administered placebo twice daily. Five-hundred and sixty five patients then underwent randomisation. During a one week initial phase everyone received amlodipine 10mg daily and 281 received ranolazine 500mg twice daily and 284 received placebo twice daily. After the initial phase those in the ranolazine group had their dose of ranolazine increased to 1000mg twice daily, this phase continued for six weeks. In terms of the baseline characteristics and concomitant medication use both the placebo and ranolazine groups were similar.

There were several data points which were identified as outliers when looking at the weekly rates of angina attacks and nitroglycerin consumption. All observations were averaged except for the bottom 2% and top 2% to reduced influence of the outliers.

The primary efficacy results are shown in figure 3A. The number of weekly angina attacks per week was significantly reduced in the group who were taking ranolazine vs. placebo (p=0.028). In the 25th percentile the difference in the number of attacks and nitroglycerin use was smaller between placebo and ranolazine compared to the 75th percentile, indicating a greater treatment effect in those with worse disease states. It is unclear as to whether this is a significant difference. This was supported in the subgroup analysis where it was shown that those who experienced ≤4.5 angina attacks per week experienced significantly reduced angina

frequency (p=0.036) but the reduction in nitroglycerin use was not significant (p=0.28). Whereas those who experience >4.5 angina attacks per week experienced statistically significant reductions in angina frequency (p=0.029) and nitroglycerin use (p=0.001).

The secondary efficacy results are shown in figure 3B. The number of nitroglycerin uses per week were also significantly reduced in the ranolazine group (p=0.014). When these figures were adjusted based on the differences in the baseline values the p value was 0.033. The scores on the SAQ relating to angina frequency were significantly improved in patients in the ranolazine group (p=0.008). Scores for the other dimensions: physical limitation, angina stability, disease perception, and treatment satisfaction, were not significantly different between groups.

Vital signs did not fluctuate throughout the study and there was no significant difference between groups. There was also no clinical effect on postural changes and blood pressure in the ranolazine group. Adverse events occurred in 35.3% of placebo and 39.9% of ranolazine patients, most were mild to moderate, with constipation being the most common. Three patients in the ranolazine group and four in the placebo group terminated the study due to adverse events. One patient from the ranolazine group died during the study but it was determined to be unrelated to the treatment. One patient in the placebo group died due to an acute myocardial infarction during the study.

The authors concluded that the addition of ranolazine in patients who take the maximum recommended dose of 10mg/day of amlodipine have a significant reduction in the frequency of angina episodes incidence of nitroglycerin use.

They also recognise that this study is limited by the short duration and the fact that amlodipine is the only other antianginal being used.

Long-Term Safety of a Novel Antianginal Agent in Patients With Severe Chronic Stable Angina (ROLE)14

In 2007 Koren et al., undertook an open label trial with 746 chronic angina patients who had previously been enrolled in the MARISA and CARISA trials. Of the 168 eligible participants from the MARISA trial 143 went on to participate and of the 731 eligible participants from the CARISA trial 603 went on to participate. Twenty-three per cent of the population was diabetic, and 58% had a previous MI.

Throughout the trial investigators could titrate the doses of ranolazine between 500mg twice daily and 1000mg twice daily depending on clinical response or adverse events. Background antianginal therapy was continued or adjusted, and new agents were initiated at the discretion of the investigators.

Safety and tolerability assessments were undertaken and this included measurement of vital signs, ECGs and adverse event evaluations. Adverse events, study drug discontinuation and ECG intervals were summarised from first exposure to 1st April 2005.

The summary of reported averse events is shown in Table 3. It should be noted that “Myocardial Infarction” and “Acute MI” are presented separately. If these incidents were reported together this would account for 8.3% of adverse events, making it the fourth most common AE alongside peripheral oedema.

The risk of study cessation due compared to different demographic and clinical categories was also reported. This showed that those who had a history of congestive heart failure had a relatively reduced risk (RR 0.55 (0.320–0.943); P=0.030) compared to those without. Those who were over 64 years had a relatively increased risk (RR 2.32 (1.49–

3.61) P=0.001) compared to those who were under 64 years.

There were no patients withdrawn from the study due to QTc prolongation and no reported incidence of Torsades de Pointes. In total 2233 patient years of ranolazine treatment were observed, in this time there were 68 deaths in those patients who were taking ranolazine; this gives a yearly mortality rate of 3%. The Duke Treadmill Score was used to predict a baseline yearly mortality rate of 5% for patients partaking in this study. The authors concluded that this means that survival rates appear to be improved in patients taking ranolazine.

Effects of Ranolazine on Recurrent Cardiovascular Events in Patients With Non-ST-Elevation Acute Coronary Syndromes (MERLIN-TIMI 36)8

In 2007 Morrow et al., undertook a randomised, double blind, placebo-controlled multinational clinical trial. It involved 6560 patients who were selected within 48 hours of ischemic symptoms which were treated with intravenous ranolazine.

All participants were 18 years and over, had symptoms consistent with myocardial ischemia at rest, at least one indicator for moderate to high risk of death or recurrent ischemic events. Exclusion criteria were as follows: cardiogenic shock, persistent ST-segment elevation, successful revascularisation of the culprit stenosis before randomisation, clinically significant hepatic disease, end stage renal disease requiring dialysis, treatment with agents known to prolong the QT interval, abnormalities of the electrocardiogram that would interfere with interpretation of Holter monitoring of ischemia, or a life expectancy of less than 12 months.

The study protocol specified that patients were to receive standard treatment for non-ST-elevation ACS and secondary presentation. Patients were randomised to receive either ranolazine or placebo in a 1:1 ratio. Initially patients received 200mg of IV ranolazine or placebo over 1 hour, followed by an 80mg/hour IV infusion, this was reduced to 40mg/hour for patients with and eGFR <30ml/min, for 12-96 hours. After the infusion patients continued dosing and received either ranolazine MR 1000mg twice daily or placebo twice daily. Doses were adjusted at any point to 750 mg, 500mg or 375mg twice daily depending on renal function and adverse effects.

Patients were examined and their quality of life and experience of adverse events was assessed at 14 days, 4 months and then on a 4 monthly basis. A continuous ECG monitor was used from randomisation for 7 days, including after discharge. There was also an exercise tolerance test performed at month 8 or at the last study visit. The trial went on until there were 310 recorded deaths and 730 major cardiovascular incidents reported.

The primary efficacy end point was the first occurrence of any element of the composite of cardiovascular death, MI, or recurrent ischemia. The major secondary end point was the occurrence of a major cardiovascular event defined by the composite of cardiovascular death, MI or severe recurrent ischemia. Other secondary end points were failure of therapy, defined as the composite of cardiovascular death, MI, recurrent ischemia, a positive Holter ECG for ischemia, hospitalisation for new or worsening heart failure or an early positive exercise tolerance test. Quality of life was assessed as a secondary end point using the angina frequency and physical limitation scales of the Seattle Angina Questionnaire at four months of follow-up. Safety end-points included death from any cause, the composite of death from any cause of any cardiovascular hospitalisation, the incidence of symptomatic documented arrhythmias or clinically significant arrhythmias.

The baseline characteristics were similar for both the placebo and the ranolazine groups. The proportion of people treated with aspirin was 96.1%, 90.3% were treated with heparin or a LMWH, and 14.6% with a glycoprotein IIb/IIIa receptor antagonist. Sixty point five per cent of patients were medically managed, 31.6% patients were underwent PCI and 7.9% of patients had a CABG. People were administered concomitant

medications with beta blockers (89.2%), statins (82.4%), ACE inhibitors and ARBs (78.2%) being the most common.

The primary efficacy end point (first occurrence of any element of the composite of cardiovascular death, MI, or recurrent ischemia) occurred in 696 patients (21.8%) in the ranolazine group and 753 patients (23.5%) in the placebo group (HR 0.92; 95% CI 0.83-1.02; P=0.11) as shown in figure 2.

The major secondary end point (occurrence of a major cardiovascular event defined by the composite of cardiovascular death, MI or severe recurrent ischemia) occurred in 1173 patients (36.8%) in the ranolazine group and 1233 (38.3%) patients in the placebo group. (HR 0.94; 95% CI 0.87-1.02; P=0.16).

The only statistically significant result was that ranolazine reduced the cumulative reported incidence of recurrent ischemia was reduced in the ranolazine group (HR 0.87; 95% CI 0.76-0.99; P=0.03). Within this composite group of data the only statistically significant result related to the incidence of worsening angina (HR 0.77; 95% CI 0.62-0.97; P=0.02) and ranolazine had no effect on recurrent ischemia: with ECG changes, leading to hospitalisation or leading to revascularisation.

There was no difference in death from any cause between the placebo and ranolazine groups (HR, 0.99; 95% CI, 0.80-1.22; P=0.91). The rates of death or hospitalisation due to cardiac events and the rate of documented arrhythmias were also similar between both groups. There was a significant reduction in clinically significant arrhythmias (P<0.001) and ventricular tachycardia (P<0.001) in patients who were taking ranolazine. More patients taking ranolazine discontinued therapy due to adverse events in the ranolazine group compared to the placebo group (P<0.001). The most commonly reported adverse events were dizziness, nausea and constipation and all three were more commonly reported in the ranolazine group. Syncope was significantly more frequent in patients receiving ranolazine (P=0.01).

The results of the primary efficacy end point for this trial were non-significant. The trial does however show a reduction in clinically significant arrhythmias in patients treated with ranolazine and a similar incidence of death from cardiac events.

Cost analysis:

Primary care excl VAT Ranolazine (Ranexa®) dose Pack size (DT Prices) Cost per pack / 30 day course cost 4 week induction: 375mg twice daily 60 x 375mg £48.98

Treatment dose: 500mg twice daily 60 x 500mg £48.98

Treatment dose: 750mg twice daily 60 x 750mg £48.98

Ranolazine (Ranexa®) NMC Review September 2016: Usage and Expenditure for July15-June16

NORTH STOKE ON TRENT UHNM ROYAL STAFFORDSHIRE CCG Drug STOKE CCG Based on Total Based on Total Act (VAT included) Act Cost (VAT not Cost (VAT not included) included) RANOLAZINE 375MG MODIFIED-RELEASE £5,777.79 £14,148.82 £16,489.24 TABLET RANOLAZINE 500MG MODIFIED-RELEASE £1,898.64 £11,317.25 £16,480.60 TABLET RANOLAZINE 750MG MODIFIED-RELEASE £0.00 £4,938.63 £4,366.21 TABLET TOTAL COST £7,676.42 £30,404.70 £37,336.05

References

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11 Torfgård KE, Ahlner J. Mechanisms of action of nitrates. Cardiovascular Drugs and Therapy. 1994;8(5):701-17. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7873467 [Accessed 01/09/16] 12 A. Menarini Farmaceutica Internazionale SRL. Ranexa prolonged-release tablets. Electronic Medicines Compendium. 2015. Available from: https://www.medicines.org.uk/emc/medicine/21402 [Accessed 01/09/16] 13 Chaitman B, et al. Anti-Ischemic Effects and Long-Term Survival During Ranolazine Monotherapy in Patients With Chronic Severe Angina. Journal of the American College of Cardiology. 2004;43(8)1375-1382. 14 Koren M, et al. Long-Term Safety of a Novel Antianginal Agent in Patients With Severe Chronic Stable Angina. Journal of the American College of Cardiology. 2007;49(10):1027-1034.

Produced by Annie Sellers Specialist Rotational Clinical Pharmacist University Hospital of North Midlands e-mail: [email protected]

Produced for use within the NHS. Not to be reproduced for commercial purposes.