RANEXA 750mg prolonged tablets medication leaflet

Ranexa 750 mg prolonged-release tablets

Each tablet contains 750 mg of ranolazine.

Excipients: Each tablet contains 0.04 mg azo colouring agent E102 and 12.0 mg lactose monohydrate.

For the full list of excipients see section 6.1.

Prolonged-release tablet

Pale green oval-shaped tablet engraved with 750 on one side.

Ranexa is indicated in adults as add-on therapy for the symptomatic treatment of patients with stableangina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such asbeta-blockers and/or calcium antagonists).

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 doseshould be titrated to 500 mg twice daily and, according to the patient’s response, further titrated to arecommended maximum dose of 750 mg twice daily (see section 5.1).

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 afterdose reduction, treatment should be discontinued.

Concomitant treatment with CYP3A4 and P-glycoprotein (P-gp) inhibitors: Careful dose titration isrecommended in patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole,erythromycin) or P-gp inhibitors (e.g. verapamil, ciclosporin) (see sections 4.4 and 4.5).

Concomitant administration of potent CYP3A4 inhibitors is contraindicated (see sections 4.3 and 4.5).

Renal impairment: Careful dose titration is recommended in patients with mild to moderate renalimpairment (creatinine clearance 30-80 ml/min) (see sections 4.4, pct. 4.8, and 5.2). Ranexa iscontraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min) (seesections 4.3 and 5.2).

Hepatic impairment: Careful dose titration is recommended in patients with mild hepatic impairment(see sections 4.4 and 5.2). Ranexa is contraindicated in patients with moderate or severe hepaticimpairment (see sections 4.3 and 5.2).

Elderly: Dose titration in elderly patients should be exercised with caution (see section 4.4). Elderlymay have increased ranolazine exposure due to age-related decrease in renal function (see section 5.2).

The incidence of adverse events was higher in the elderly (see section 4.8).

Low weight: The incidence of adverse events was higher in patients with low weight (≤ 60 kg). Dosetitration in patients with low weight should be exercised with caution (see sections 4.4, pct. 4.8, and 5.2).

Congestive heart failure (CHF): Dose titration in patients with moderate to severe CHF (NYHA

Class III-IV) should be exercised with caution (see sections 4.4 and 5.2).

The safety and efficacy of Ranexa in children below the age of 18 years have not been established.

No data are available

Ranexa tablets should be swallowed whole and not crushed, broken, or chewed. They may be takenwith or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe renal impairment (creatinine clearance < 30 ml/min) (see sections 4.2 and 5.2).

Moderate or severe hepatic impairment (see sections 4.2 and 5.2).

Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole,voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) (seesections 4.2 and 4.5).

Concomitant administration of Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol)antiarrhythmics other than amiodarone.

Caution should be exercised when prescribing or uptitrating ranolazine to patients in whom anincreased exposure is expected:

* Concomitant administration of moderate CYP3A4 inhibitors (see sections 4.2 and 4.5).

* Concomitant administration of P-gp inhibitors (see sections 4.2 and 4.5).

* Mild hepatic impairment (see sections 4.2 and 5.2).

* Mild to moderate renal impairment (creatinine clearance 30-80 ml/min) (see sections 4.2, pct. 4.8,and 5.2).

* Elderly (see sections 4.2, pct. 4.8, and 5.2).

* Patients with low weight (≤ 60 kg) (see sections 4.2, pct. 4.8, and 5.2).

* Patients with moderate to severe CHF (NYHA Class III-IV) (see sections 4.2 and 5.2).

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 severalof these factors, monitoring of adverse events should be frequent, the dose reduced, and treatmentdiscontinued, if needed.

The risk for increased exposure leading to adverse events in these different subgroups is higher inpatients lacking CYP2D6 activity (poor metabolisers, PM) than subjects with CYP2D6 metabolisingcapacity (extensive metabolisers, EM) (see section 5.2). The above precautions are based on the risk ina CYP2D6 PM patient, and are needed when the CYP2D6 status is unknown. There is a lower needfor precautions in patients with CYP2D6 EM status. If the CYP2D6 status of the patient has beendetermined (e.g. by genotyping) or is previously known to be EM, Ranexa can be used with caution inthese patients when they have a combination of several of the above risk factors.

QT prolongation: Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner. Apopulation-based analysis of combined data from patients and healthy volunteers demonstrated thatthe 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 forranolazine 500 to 1000 mg twice daily. Therefore, caution should be observed when treating patientswith 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 (see section 4.5also).

Drug-drug interactions: Co-administration with CYP3A4 inducers is expected to lead to lack ofefficacy. Ranexa should not be used in patients treated with CYP3A4 inducers (e.g. rifampicin,phenytoin, phenobarbital, carbamazepine, St. John’s Wort) (see section 4.5).

Renal impairment: Renal function decreases with age and it is therefore important to check renalfunction at regular intervals during treatment with ranolazine (see sections 4.2, pct. 4.3, pct. 4.8, and 5.2).

Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take thismedicinal product.

Azo colouring agent E102: This medicinal product contains the azo colouring agent E102 which maycause allergic reactions.

Sodium: This medicine contains less than 1 mmol sodium (23 mg) per prolonged-release tablet, that isto say essentially ‘sodium-free’.

Effects of other medicinal products on ranolazine

CYP3A4 or P-gp inhibitors: Ranolazine is a substrate of cytochrome CYP3A4. Inhibitors of CYP3A4increase plasma concentrations of ranolazine. The potential for dose-related adverse events (e.g.nausea, dizziness) may also increase with increased plasma concentrations. Concomitant treatmentwith ketoconazole 200 mg twice daily increased the AUC of ranolazine by 3.0- to 3.9-fold duringranolazine treatment. Combining ranolazine with potent CYP3A4 inhibitors (e.g. itraconazole,ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin,nefazodone) is contraindicated (see section 4.3). Grapefruit juice is also a potent CYP3A4 inhibitor.

Diltiazem (180 to 360 mg once daily), a moderately potent CYP3A4 inhibitor, causes dose-dependentincreases 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 CYP3A4inhibitors (e.g. erythromycin, fluconazole). Down-titration of Ranexa may be required (see sections4.2 and 4.4).

Ranolazine is a substrate for P-gp. Inhibitors of P-gp (e.g. ciclosporin, verapamil) increase plasmalevels of ranolazine. Verapamil (120 mg three times daily) increases ranolazine steady-stateconcentrations 2.2-fold. Careful dose titration of Ranexa is recommended in patients treated with P-gpinhibitors. Down-titration of Ranexa may be required (see sections 4.2 and 4.4).

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

CYP2D6 inhibitors: Ranolazine is partially metabolised by CYP2D6; therefore, inhibitors of thisenzyme 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 mgtwice daily by an average of 1.2-fold. No dose adjustment is required. At the dose level 500 mg twicedaily, 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 mayincrease plasma concentrations of P-gp or CYP3A4 substrates. Tissue distribution of drugs which aretransported by P-gp may be increased.

Dose adjustment of sensitive CYP3A4 substrates (e.g. simvastatin, lovastatin) and CYP3A4 substrateswith a narrow therapeutic range (e.g. ciclosporin, tacrolimus, sirolimus, everolimus) may be requiredas RANEXA may increase plasma concentrations of these drugs.

Available data suggest that ranolazine is a mild inhibitor of CYP2D6. Ranexa 750 mg twice dailyincreased plasma concentrations of metoprolol by 1.8-fold. Therefore the exposure to metoprolol orother CYP2D6 substrates (e.g. propafenone and flecainide or, to a lesser extent,. tricyclicantidepressants and antipsychotics) may be increased during co-administration with Ranexa, and lowerdoses of these medicinal products may be required.

The potential for inhibition of CYP2B6 has not been evaluated. Caution is advised duringco-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 reportedwhen Ranexa and digoxin are co-administered. Therefore, digoxin levels should be monitoredfollowing initiation and termination of Ranexa therapy.

Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranexa1000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid, byabout 2-fold. Rhabdomyolysis has been associated with high doses of simvastatin and cases ofrhabdomyolysis have been observed in patients receiving Ranexa and simvastatin, in postmarketingexperience. 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 dailyby 1.4- and 1.3 -fold, respectively and changed the Cmax and AUC of atorvastatin metabolites lessthan 35%. Dose limitation of atorvastatin and appropriate clinical monitoring may be considered whentaking Ranexa.

Dose limitation of other statins, metabolised by CYP3A4 (e.g lovastatin), may be considered whentaking Ranexa.

Tacrolimus, ciclosporin, sirolimus, everolimus: Increased plasma concentrations of tacrolimus, a

CYP3A4 substrate, have been observed in patients after ranolazine administration. It is recommendedthat tacrolimus blood levels are monitored when co-administering Ranexa and tacrolimus and thattacrolimus dosage is adjusted accordingly. This is also recommended for other CYP3A4 substrateswith 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 similardegree.

There is a theoretical risk that concomitant treatment of ranolazine with other drugs known to prolongthe QTc interval may give rise to a pharmacodynamic interaction and increase the possible risk ofventricular 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).

Pregnancy: There are limited amount of data from the use of ranolazine in pregnant women. Studies inanimals showed embryo toxicity (see Section 5.3). The potential risk for humans is unknown. Ranexashould not be used during pregnancy unless clearly necessary.

Breast-feeding: It is unknown whether ranolazine is excreted in human breast milk. Availablepharmacodynamic/toxicological data in rats have shown excretion of ranolazine in milk (for detailssee Section 5.3). A risk to the suckling child cannot be excluded. Ranexa should not be used duringbreast-feeding.

Fertility: In animals, reproduction studies indicated no adverse effects on fertility (see section 5.3).

The effect of ranolazine on human fertility is unknown.

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, andhallucination (see section 4.8), which may affect the ability to drive and use machines.

Undesirable effects in patients receiving Ranexa are generally mild to moderate in severity and oftendevelop within the first 2 weeks of treatment. These were reported during the Phase 3 clinicaldevelopment 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 bodysystem, 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), andvery rare (< 1/10,000).

Uncommon: anorexia, decreased appetite, dehydration.

Rare: hyponatremia

Uncommon: anxiety, insomnia, confusional state, hallucination.

Rare: disorientation.

Common: dizziness, headache.

Uncommon: lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness, paresthesia.

Rare: amnesia, depressed level of consciousness, loss of consciousness, coordination abnormal, gaitdisturbance, parosmia.

Not known: myoclonus.

Uncommon: blurred vision, visual disturbance, diplopia.

Ear and labyrinth disorders

Uncommon: vertigo, tinnitus.

Rare: impaired hearing.

Uncommon: hot flush, hypotension.

Rare: peripheral coldness, orthostatic hypotension.

Respiratory, thoracic, and mediastinal disorders

Uncommon: dyspnoea, cough, epistaxis.

Rare: throat tightness.

Common: constipation, vomiting, nausea.

Uncommon: abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort.

Rare: pancreatitis, erosive duodenitis, oral hypoaesthesia.

Uncommon: pruritus, hyperhydrosis.

Rare: angioedema, allergic dermatitis, urticaria, cold sweat, rash.

Uncommon: pain in extremity, muscle cramp, joint swelling, muscular weakness.

Uncommon: dysuria, haematuria, chromaturia.

Rare: acute renal failure, urinary retention.

Rare: erectile dysfunction.

Common: asthenia.

Uncommon: fatigue, peripheral oedema.

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 termstudy, acute renal failure was also reported with an incidence less than 1% in placebo and ranolazinepatients. Evaluations in patients who may be considered at higher risk of adverse events when treatedwith other antianginal medicinal products, e.g. patients with diabetes, Class I and II heart failure, orobstructive airway disease, confirmed that these conditions were not associated with clinicallymeaningful increases in the incidence of adverse events.

An increased incidence of adverse events was seen among ranolazine treated patients in the RIVER-

PCI trial (see section 5.1) where patients with incomplete revascularization post-PCI were givenranolazine up to 1000 mg twice daily or placebo for approximately 70 weeks. In this study, there was ahigher reporting rate for congestive heart failure in the ranolazine group (2.2% vs 1.0% in placebo).

Also, transient ischemic attack occurred more frequently in patients treated with ranolazine 1000 mgtwice daily compared with placebo (1.0% vs 0.2%, respectively); however, the incidence of stroke wassimilar between treatment groups (ranolazine 1.7% vs placebo 1.5%).

Elderly, renal impairment, and low weight: In general, adverse events occurred more frequentlyamong elderly patients and patients with renal impairment; however, the types of events in thesesubgroups 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) comparedto those with normal renal function (creatinine clearance > 80 ml/min), the most commonly reportedevents 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 thanheavier patients: nausea (14% versus 2%), vomiting (6% versus 1%), and hypotension (4% versus2%).

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In an oral high-dose tolerability study in angina patients, the incidence of dizziness, nausea, andvomiting 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 theevent of overdose, the patient should be closely monitored and the treatment should be symptomaticand supportive.

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

In postmarketing experience, there have been reports of intentional overdose of Ranexa alone or incombination with other drugs with a fatal outcome.

Pharmacotherapeutic group: Other cardiac preparations, ATC code: C01EB18

Mechanism of action: The mechanism of action of ranolazine is largely unknown. Ranolazine mayhave some antianginal effects by inhibition of the late sodium current in cardiac cells. This reducesintracellular sodium accumulation and consequently decreases intracellular calcium overload.

Ranolazine, via its action to decrease the late sodium current, is considered to reduce theseintracellular ionic imbalances during ischaemia. This reduction in cellular calcium overload isexpected 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 significantshortening of the QTc interval and an improvement in diastolic relaxation in an open-label study of5 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.

Haemodynamic effects: Minimal decreases in mean heart rate (< 2 beats per minute) and meansystolic blood pressure (< 3 mm Hg) were observed in patients treated with ranolazine either alone orin combination with other antianginal medicinal products in controlled studies.

Electrocardiographic effects: Dose and plasma concentration-related increases in the QTc interval(about 6 msec at 1000 mg twice daily), reductions in T wave amplitude, and in some cases notched

T waves, have been observed in patients treated with Ranexa. These effects of ranolazine on thesurface electrocardiogram are believed to result from inhibition of the fast-rectifying potassiumcurrent, which prolongs the ventricular action potential, and from inhibition of the late sodium current,which shortens the ventricular action potential. A population analysis of combined data from1,308 patients and healthy volunteers demonstrated a mean increase in QTc from baseline of 2.4 msecper 1000 ng/ml ranolazine plasma concentration. This value is consistent with data from pivotalclinical studies, where mean changes from baseline in QTcF (Fridericia’s correction) after doses of500 and 750 mg twice daily were 1.9 and 4.9 msec, respectively. The slope is higher in patients withclinically significant hepatic impairment.

In a large outcome study (MERLIN-TIMI 36) in 6,560 patients with UA/NSTEMI ACS, there was nodifference between Ranexa and placebo in the risk of all-cause mortality (relative riskranolazine:placebo 0.99), sudden cardiac death (relative risk ranolazine:placebo 0.87), or thefrequency of symptomatic documented arrhythmias (3.0% versus 3.1%).

No proarrhythmic effects were observed in 3,162 patients treated with Ranexa based on 7-day Holtermonitoring in the MERLIN-TIMI 36 study. There was a significantly lower incidence of arrhythmiasin patients treated with Ranexa (80%) versus placebo (87%), including ventricular tachycardia≥ 8 beats (5% versus 8%).

Clinical efficacy and safety: Clinical studies have demonstrated the efficacy and safety of Ranexa inthe treatment of patients with chronic angina, either alone or when the benefit from other antianginalmedicinal products was sub-optimal.

In the pivotal study, CARISA, Ranexa was added to treatment with atenolol 50 mg once daily,amlodipine 5 mg once daily, or diltiazem 180 mg once daily. Eight-hundred and twenty-three patients(23% women) were randomised to receive 12 weeks of treatment with Ranexa 750 mg twice daily,1000 mg twice daily, or placebo. Ranexa demonstrated greater efficacy than placebo in prolongingexercise time at trough at 12 weeks for both doses studied when used as an add-on therapy. However,there was no difference in exercise duration between the two doses (24 seconds compared to placebo;p ≤ 0.03).

Ranexa resulted in significant decreases in the number of angina attacks per week and consumption ofshort-acting nitroglycerin compared to placebo. Tolerance to ranolazine did not develop duringtreatment and a rebound increase in angina attacks was not observed following abrupt discontinuation.

The improvement in exercise duration in women was about 33% of the improvement in men at the1000 mg twice-daily dose level. However, men and women had similar reductions in frequency ofangina attacks and nitroglycerin consumption. Given the dose-dependent side effects and similarefficacy at 750 and 1000 mg twice daily, a maximum dose of 750 mg twice daily is recommended.

In a second study, ERICA, Ranexa was added to treatment with amlodipine 10 mg once daily (themaximum labelled dose). Five-hundred and sixty-five patients were randomised to receive an initialdose of Ranexa 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with

Ranexa 1000 mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mgonce daily. Additionally, 45% of the study population also received long-acting nitrates. Ranexaresulted in significant decreases in the number of angina attacks per week (p = 0.028) andconsumption of short-acting nitroglycerin (p = 0.014) compared to placebo. Both the average numberof angina attacks and nitroglycerin tablets consumed decreased by approximately one per week.

In the main dose-finding study, MARISA, ranolazine was used as monotherapy. One-hundred andninety-one patients were randomised to treatment with Ranexa 500 mg twice daily, 1000 mg twicedaily, 1500 mg twice daily, and matching placebo, each for 1 week in a crossover design. Ranexa wassignificantly superior to placebo in prolonging exercise time, time to angina, and time to 1 mm STsegment depression at all doses studied with an observed dose-response relationship. Improvement ofexercise duration was statistically significant compared to placebo for all three doses of ranolazinefrom 24 seconds at 500 mg twice daily to 46 seconds at 1500 mg twice daily, showing a dose-relatedresponse. In this study, exercise duration was longest in the 1500 mg group; however, there was adisproportional increase in side effects, and the 1500 mg dose was not studied further.

In a large outcome study (MERLIN-TIMI 36) in 6,560 patients with UA/NSTEMI ACS, there was nodifference in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99), sudden cardiacdeath (relative risk ranolazine:placebo 0.87), or the frequency of symptomatic documentedarrhythmias (3.0% versus 3.1%) between Ranexa and placebo when added to standard medical therapy(including beta-blockers, calcium channel blockers, nitrates, anti-platelet agents, lipid-loweringmedicinal products, and ACE inhibitors). Approximately one-half of the patients in MERLIN-TIMI 36had a history of angina. The results showed that exercise duration was 31 seconds longer in ranolazinepatients versus placebo patients (p = 0.002). The Seattle Angina Questionnaire showed significanteffects on several dimensions, including angina frequency (p < 0.001), compared to placebo-treatedpatients.

A small proportion of non-Caucasians was included in the controlled clinical studies; therefore, noconclusions can be drawn regarding the effect and safety in non-Caucasians.

In a phase 3, double-blind, placebo-controlled, event-driven trial (RIVER-PCI) in 2604 patients aged≥18 years with a history of chronic angina and incomplete revascularisation after percutaneouscoronary intervention (PCI) patients were up-titrated to 1000 mg twice daily (dosage not approved inthe current SmPC). No significant difference occurred in the composite primary endpoint (time to firstoccurrence of ischaemia-driven revascularisation or ischaemia-driven hospitalisation withoutrevascularisation) in the ranolazine group (26.2%) versus the placebo group (28.3%), hazard ratio0.95, 95% CI 0.82-1.10 p= 0.48. The risk of all cause mortality, CV death or major adversecardiovascular events (MACE) and heart failure hospitalisation was similar between treatment groupsin the overall population; however, MACE were reported more frequently in patients ≥ 75 yearstreated with ranolazine compared with placebo (17.0% vs 11.3%, respectively); in addition there was anumerical increase in all cause mortality in patients ≥ 75 years (9.2% vs. 5.1%, p = 0.074).

After oral administration of Ranexa, peak plasma concentrations (Cmax) are typically observed between2 and 6 hours. Steady state is generally achieved within 3 days of twice-daily dosing.

Absorption: The mean absolute bioavailability of ranolazine after oral administration of immediate-release ranolazine tablets ranged from 35−50%, with large inter-individual variability. Ranexaexposure increases more than in proportion to dose. There was a 2.5- to 3-fold increase in steady-state

AUC as the dose was increased from 500 mg to 1000 mg twice daily. In a pharmacokinetic study inhealthy volunteers, steady-state Cmax was, on average, approximately 1770 (SD 1040) ng/ml, andsteady-state AUC0-12 was, on average, 13,700 (SD 8290) ng x h/ml following a dose of 500 mg twicedaily. Food does not affect the rate and extent of absorption of ranolazine.

Distribution: Approximately 62% of ranolazine is bound to plasma proteins, mainly alpha-1 acidglycoprotein and weakly to albumin. The mean steady-state volume of distribution (Vss) is about 180 l.

Elimination: Ranolazine is eliminated primarily by metabolism. Less than 5% of the dose is excretedunchanged in the urine and faeces. Following oral administration of a single 500 mg dose of[14C]-ranolazine to healthy subjects, 73% of the radioactivity was recovered in urine and 25% infaeces.

Clearance of ranolazine is dose-dependent, decreasing with increased dose. The elimination half-life isabout 2−3 hours after intravenous administration. The terminal half-life at steady state after oraladministration of ranolazine is about 7 hours, due to the absorption rate-limited elimination.

Biotransformation: Ranolazine undergoes rapid and extensive metabolism. In healthy young adults,ranolazine accounts for approximately 13% of the radioactivity in plasma following a single oral500 mg dose of [14C]-ranolazine. A large number of metabolites has been identified in human plasma(47 metabolites), urine (> 100 metabolites), and faeces (25 metabolites). Fourteen primary pathwayshave been identified of which O-demethylation and N-dealkylation are the most important. In vitrostudies using human liver microsomes indicate that ranolazine is metabolised primarily by CYP3A4,but also by CYP2D6. At 500 mg twice daily, subjects lacking CYP2D6 activity (poor metabolisers,

PM) had 62% higher AUC than subjects with CYP2D6 metabolising capacity (extensive metabolisers,

EM). The corresponding difference at the 1000 mg twice-daily dose was 25%.

The influence of various factors on the pharmacokinetics of ranolazine was assessed in a populationpharmacokinetic evaluation in 928 angina patients and healthy subjects.

Gender effects: Gender had no clinically relevant effect on pharmacokinetic parameters.

Elderly patients: Age alone had no clinically relevant effect on pharmacokinetic parameters.

However, the elderly may have increased ranolazine exposure due to age-related decrease in renalfunction.

Body weight: Compared to subjects weighing 70 kg, exposure was estimated to be about 1.4-foldhigher in subjects weighing 40 kg.

CHF: CHF NYHA Class III and IV were estimated to have about 1.3-fold higher plasmaconcentrations.

Renal impairment: In a study evaluating the influence of renal function on ranolazinepharmacokinetics, ranolazine AUC was on average 1.7- to 2-fold higher in subjects with mild,moderate, and severe renal impairment compared with subjects with normal renal function. There wasa large inter-individual variability in AUC in subjects with renal impairment. The AUC of metabolitesincreased with decreased renal function. The AUC of one pharmacologically active ranolazinemetabolite was 5-fold increased in patients with severe renal impairment.

In the population pharmacokinetic analysis, a 1.2-fold increase in ranolazine exposure was estimatedin subjects with moderate impairment (creatinine clearance 40 ml/min). In subjects with severe renalimpairment (creatinine clearance 10-30 ml/min), a 1.3- to 1.8-fold increase in ranolazine exposurewas estimated.

The influence of dialysis on the pharmacokinetics of ranolazine has not been evaluated.

Hepatic impairment: The pharmacokinetics of ranolazine have been evaluated in patients with mild ormoderate hepatic impairment. There are no data in patients with severe hepatic impairment.

Ranolazine AUC was unaffected in patients with mild hepatic impairment but increased 1.8-fold inpatients with moderate impairment. QT prolongation was more pronounced in these patients.

Paediatric population: The pharmacokinetic parameters of ranolazine have not been studied in thepaediatric population (< 18 years).

Adverse reactions not observed in clinical studies, but seen in animals at levels similar to clinicalexposure, were as follows: Ranolazine was associated with convulsions and increased mortality in ratsand dogs at plasma concentrations approximately 3-fold higher than at the proposed maximum clinicaldose.

Chronic toxicity studies in rats indicated that treatment was associated with adrenal changes atexposures slightly greater than those seen in clinical patients. This effect is associated with increasedplasma cholesterol concentrations. No similar changes have been identified in humans. No effect onthe adreno-cortical axis was noted in humans.

In long-term carcinogenicity studies at doses of ranolazine up to 50 mg/kg/day (150 mg/m2/day) inmice and 150 mg/kg/day (900 mg/m2/day) in rats, no relevant increases in the incidence of any tumourtypes were seen. These doses are equivalent to 0.1 and 0.8 times, respectively, the maximumrecommended human dose of 2 grams on a mg/m2 basis, and represent the maximum tolerated doses inthese species.

In male and female rats, oral administration of ranolazine that produced exposures (AUC) 3.6-fold or6.6-fold higher than expected in humans, respectively, had no effect on fertility.

Embryofetal toxicity studies were conducted in rats and rabbits: no effect were noted in rabbit fetuseswhen mothers were exposed at levels (AUC) of plasma ranolazine similar to expected human levels.

In rats, no effects in fetuses was noted when mothers were exposed to 2-fold greater levels (AUC) thanexpected in humans, whereas decreased fetal weight and reduced ossification were observed when theexposure of mothers was 7.5-fold than those obtained in humans. Post-natal mortality of pups was notrecorded when the exposure of nursing mothers was 1.3 fold higher than in expected humans, whereasat 3-fold higher exposure post-natal mortality was recorded, concomitant with evidence of milkexcretion of ranolazine in rats. No adverse effects on newborn rats were observed at levels ofexposures similar to those observed in humans.

Excipients for all ranolazine prolonged-release tablets:

Carnauba wax

Hypromellose

Magnesium stearate

Methacrylic acid-ethyl acrylate copolymer (1:1)

Microcrystalline cellulose

Sodium hydroxide

Titanium dioxide

Additional excipients for 750 mg tablet:

Glycerol triacetate

Lactose monohydrate

Blue #1/Brilliant Blue FCF Aluminium Lake (E133) and Yellow #5/Tartrazine Aluminium Lake(E102)

Not applicable

Blister pack: 5 years

Bottle pack: 4 years

This medicinal product does not require any special storage conditions.

PVC/PVDC/Aluminium blisters of 15 or 20 tablets per blister card. Each carton contains 2, 3, or5 blister cards (30, 60, or 100 tablets) or one HDPE bottle containing 60 tablets.

Not all pack-sizes may be marketed.

No special requirements

Menarini International Operations Luxembourg S.A.1, Avenue de la Gare, L-1611 Luxembourg

Luxembourg

EU/1/08/462/005 60 tablets in blister pack

EU/1/08/462/006 60 tablets in bottle

EU/1/08/462/011 30 tablets in blister pack

EU/1/08/462/012 100 tablets in blister pack

Date of first authorisation: 09 July 2008

Date of last renewal: 06 March 2013

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.