Piece 2 Ranexa patient guide final Feb 26_2020

Up to ~30% of angina patients experience recurrent angina pectoris and require multi-drug regimens1 What can RanexaTM do?

RanexaTM could help provide further symptom relief and Uncontrolled on improve daily activities for the patient.2,3 first-line treatment Observational studies of ‘real-world’ symptomatic patients taking Ranolazine >3 fewer angina attacks per A clear declining trend in angina symptoms after both 3 week vs. baseline3 and 6 months of therapy (p<0.001)2 Reduction in mean number of Reduction in % patients experiencing 1–3 angina attacks weekly angina attacks3 in the indicated time intervals2 4.4 Baseline 88.4% Baseline 1.1 3 months (p<0.0001) 26.5% 6 months (p<0.001) Adapted from Diedrichs H et al. 20153 Adapted from Alexopoulus D et al. 20162 ARETHA: Application of ranolazine in stable angina pectoris therapy. Patients (n=1,537, full analysis set) with stable OSCAR-GR: Prospective, multicentre, observational, study in 189 patients with chronic stable angina. Ranolazine angina pectoris receiving ranolazine were enrolled and monitored at baseline and after 3 months. Only patients was prescribed, and 6 months’ follow-up was performed, with study visits at baseline, 3 and 6 months.2 receiving ranolazine for the first time were monitored (provided that therapy did not start earlier than 2 to a maximum of 4 weeks previously and the dosage still equalled the recommended starting dose).3 In OSCAR-GR there was a significant improvement in patients’ daily activity scores (p<0.001), with the greatest improvement seen in employment activities:2 37% improvement in mean scores over 6 months (3.81 to 2.39 measured on a visual analogue scale where 0=no limitation and 10=severe limitation). RanexaTM recommended initial dose 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.4

The patient still experiences angina despite maximum doses of his CCB and beta blocker, and he may be experiencing some adverse effects5 What can RanexaTM do?

RanexaTM could help reduce the frequency of the patient’s angina with no substantial haemodynamic effects6 In a meta-analysis, Ranolazine was shown to be substantially haemodynamically neutral in patients with chronic stable angina6 Supine Supine SBP Supine DBP Supine HR Intolerant to first-line treatment NEUTRAL NEUTRAL NEUTRAL Standing (MD: −0.647; 95% CI: −1.431 to 0.0136; (MD: 0.016; 95% CI:−0.425 to 0.280; (MD: −0.051; 95% CI: −0.549 to 0.447; comparison p = 0.105; heterogeneity comparison p = 0.944; heterogeneity comparison p = 0.841; heterogeneity p = 0.734; i2 =0.0%) p = 0.932; i2 = 0.0%) p = 0.374; i2 = 3.7%) Standing SBP Standing DBP Standing HR MODESTLY NEUTRAL NEUTRAL REDUCED (-1.55 mmHg) (MD: −1.553; 95% CI: −2.363 to −0.743; (MD: −0.404; 95% CI: −0.862 to −0.055; (MD:−0.162; 95% CI:−0.697 to 0.374; comparison p=0.0001; heterogeneity comparison p = 0.084; heterogeneity comparison p = 0.555; heterogeneity p=0.672; i2 =0.0%) p = 0.287; i2 = 20.4%) p = 0.143; i2 = 44.7%) Data from Savarese G et al. 20136 Meta-analysis of six clinical trials assessing the effects of Ranolazine on angina, nitroglycerin consumption, functional capacity, electrocardio-graphic signs of ischaemia and haemodynamic parameters in patients with chronic stable CAD (coronary artery disease). Three clinical trials involving 8,216 patients were included in the blood pressure and heart rate analysis. CI, confidence interval; DBP, diastolic blood pressure; HR, heart rate; MD, mean difference; SBP, systolic blood pressure. Ranexa 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 (such as betablockers and/or calcium antagonists)4 RanexaTM recommended initial dose 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.4

Older traditional beta-blockers have the potential to facilitate or accelerate new-onset diabetes in predisposed patients, or aggravate the glycaemic profile in patients with pre-existing diabetes1 What can RanexaTM do?

RanexaTM could help reduce the patient’s angina symptoms and medication use7 Ranolazine significantly reduced the frequency of angina symptoms (p=0.008) and sublingual nitroglycerin use (p=0.003) vs placebo in patients with type 2 diabetes, CAD, and chronic stable angina, who were being treated with 1 to 2 anti-anginal agents.7 Efficacy endpoints in CAD/CSA patients with diabetes treated with Ranolazine for 8 weeks7 p=0.54 7 6.6 6.8 p=0.008 p=0.27 Ranolazine 6 4.1 4.5 Placebo Number reported 5 4.3 p=0.003 TERISA (Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable 4 3.8 2.1 Angina): a randomised, double-blind, international multicentre trial of ranolazine versus placebo in 949 patients with diabetes, coronary artery disease and stable 3 1.7 angina treated with 1−2 antianginals. After a 4-week placebo run-in, patients were randomised to 8 weeks of double-blind ranolazine (target dose 1000 mg 2 bd) or placebo. Anginal episodes and nitroglycerin use were recorded daily. CAD & Diabetes Primary outcome was the average weekly number of anginal episodes over the 1 last 6 weeks of the study. 0 Baseline On treatment Baseline On treatment Adapted from Kosiborod M et al. 20137 Mean number of angina attacks/week Mean weekly sublingual nitroglycerin consumption (doses) The combined anti-ischaemic and HbA1c lowering effects of Ranolazine indicate that this agent may become the preferred anti-anginal agent for the management of diabetic patients with stable coronary artery disease1,7,8 RanexaTM recommended initial dose 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.4 CAD, coronary artery disease; CCB, calcium channel blocker; CSA, chronic stable angina.

Women are more likely than men to present with chest pain uncomplicated by myocardial infarction and unstable angina9 (86% of women vs 66% of men in the Framingham heart study)9 What can RanexaTM do?

RanexaTM is an effective add-on antianginal therapy Stable angina for women10–11 in female patients Ranolazine and ivabradine both significantly improved angina symptoms and QoL vs baseline in patients (80% women) with effort-induced angina without obstructive coronary artery disease10 Ivabradine Ranolazine Adapted from Villano et al. 2013.10 n=46 patients with stable microvascular angina (effort angina, positive exercise stress test, normal coronary angiography, coronary flow reserve <2.5), who had symptoms inadequately controlled by standard anti-ischaemic therapy, were randomised to ivabradine (5 mg bd), ranolazine (375 mg bd), or placebo for 4 weeks. Primary endpoints were anginal status assessed by the Seattle Angina Questionnaire, items (physical limitation, angina frequency, angina stability, treatment satisfaction, disease perception) scored on a 0 to 100 scale (higher scores indicate better functional status); and quality of life (QoL) assessed by the validated EuroQoL visual analogue scale, from 0 (worst condition) to 100 (best condition). Women with angina, evidence of ischaemia, and no obstructive coronary artery disease have significant benefit from ranolazine vs. placebo in objective SAQ scores, including anginal stability, physical functioning and quality of life11 RanexaTM recommended initial dose 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.4

• Improve quality of life and increase exercise duration2,12-14 • Decrease frequency of angina attacks3,14,15 • Reduce severity of angina12 • Reduce recurrent ischaemia and worsening angina16 Reduce angina, keep them active2,3,12-16

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).4

RanexaTM posology and method of administration4 Initiate and titrate4 Titrate4 RanexaTM Abbreviated prescribing information 1. NAME OF THE MEDICINAL PRODUCT. RanexaTM 375mg prolonged-release tablets. RanexaTM 500mg The recommended initial dose of Ranexa is 375 mg twice daily. After 2–4 weeks, According to the patient’s response, prolonged-release tablets. RanexaTM 750mg prolonged-release tablets. 2. QUALITATIVE AND QUANTITATIVE the dose should be titrated to 500 mg twice daily. further titrated to a recommended COMPOSITION. Each RanexaTM 375mg prolonged-release tablets contain 375mg of ranolazine. Each RanexaTM maximum dose of 750 mg twice daily. 500mg prolonged-release tablets contain 500mg of ranolazine. Each RanexaTM 750mg prolonged-release tablets contain 750mg of ranolazine. 3. THERAPEUTIC INDICATIONS. In adult as add-on therapy for the symptomatic INITIAL DOSE AFTER 2-4 WEEKS MAXIMUM DOSE 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 antagonist. 4. DOSAGE. Adults: The recommended 375 mg 2-4 500 mg 750 mg initial dose of RanexaTM is 375mg twice daily. After 2-4 weeks, the dose should be titrated to 500mg twice daily and, + weeks + + according to the patient’s response, further titrated to a recommended maximum dose of 750mg twice daily. 5. CONTRAINDICATIONS. Hypersensitivity to the active substance or to any of the excipients, severe renal 375 mg 500 mg 750 mg impairment (creatinine clearance < 30m/min), moderate or severe hepatic impairment, concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, 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. 6. 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 (≤ 60kg), patients with moderate to severe CHF (NYHA Class III-IV) 7. UNDESIRABLE EFFECTS. Undesirable effects in patients receiving RanexaTM are generally mild to moderate in severity and often develop within the first 2 weeks of treatment. 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 general population. Of the most commonly reported, the following events occurred more often with RanexaTM (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%) References: 1. Manolis AJ, Poulimenos LE, Ambrosio G, Kallistratos MS, Lopez-Sendon J, Dechend R, Mancia G, et al. Medical treatment of stable angina: a tailored therapeutic approach. Int J Cardiol 2016;220:445-53. doi: 10.1016/j.ijcard.2016.06.150 2. Alexopoulos D, Kochiadakis G, Afthonidis D, Barbetseas J, Kelembekoglou P, Limberi S, et al. Ranolazine reduces angina frequency and severity and improves quality of life: observational study in patients with chronic angina under ranolazine treatment in Greece (OSCAR-GR). Int J Cardiol 2016;205:111-6. doi: 10.1016/j.ijcard.2015.10.180. 3. Diedrichs H, Wollenberg U, Schmerbach K, Limberg R, Schiffhorst G, Zeiher AM. Application of Ranolazine in Stable Angina Pectoris Therapy (ARETHA): Real-World Data from an Observational Study. J Clin Exp Cardiolog 2015;6:12. doi:10.4172/2155-9880.1000412. 4. Ranexa Summary of Product Characteristics. 5. Mobeirek A, Albackr H, Shamiri M, Albacker T. Review of medical treatment of stable ischemic heart disease. Int J Clin Med 2014;5:249-59. doi:10.4236/ijcm.2014.55039. 6. Savarese G, Rosano G, D’Amore C, Musella F, Della Ratta GL, Pellegrino AM, et al. Effects of ranolazine in symptomatic patients with stable coronary artery disease. A systematic review and meta-analysis. Int J Cardiol 2013;169:262-70. doi: 10.1016/j.ijcard.2013.08.131. 7. Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 diabetes evaluation of ranolazine in subjects with chronic stable angina). J Am Coll Cardiol 2013;61:2038-45. doi: 10.1016/j.jacc.2013.02.011. 8. Ambrosio G, Tamargo J, Grant PJ. Non-haemodynamic anti-anginal agents in the management of patients with stable coronary artery disease and diabetes: a review of the evidence. Diab Vasc Dis Res 2016;13:98-112. doi: 10.1177/1479164115609028. 9. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population. Am Heart J 1986;111:383-90. 10. Villano A, Di Franco A, Nerla R, Sestito A, Tarzia P, Lamendola P, et al. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am J Cardiol 2013;112:8-13. doi: 10.1016/j.amjcard.2013.02.045. 11. Mehta PK, Goykhman P, Thomson LE, Shufelt C, Wei J, Yang Y, et al. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imaging 2011;4:514-22. doi: 10.1016/j. jcmg.2011.03.007. 12. Muhlestein JB, Grehan S. Ranolazine reduces patient-reported angina severity and frequency and improves quality of life in selected patients with chronic angina. Drugs R D 2013;13:207-13. doi: 10.1007/s40268-013-0026-4. 13. Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004;43:1375-82. 14. Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 2004;291:309-16. 15. Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol 2006;48:566-75. 16. Wilson SR, Scirica BM, Braunwald E, Murphy SA, Karwatowska-Prokopczuk E, Buros JL, et al. Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial. J Am Coll Cardiol 2009;53:1510-6. doi: 10.1016/j.jacc.2009.01.037. ใบอนุญาตโฆษณาเลขท่ี ฆศ. 0118/2563 A. Menarini (Thailand) Limited, TH/RAN/102019/003 63 Athenee Tower, 33rd Floor, Wireless Road, Lumpini, Pathumwan, Bangkok 10330, Thailand Tel: 0 2696 8500 Fax: 0 2168 8759 www.menariniapac.com