USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on RANEXA use in pregnant women to inform any drug-associated risks. Studies in rats and rabbits showed no evidence of fetal harm at exposures times the maximum recommended human dose (MRHD) (see Data).In the U.S. general population, the estimated background risk of major birth defects and of miscarriage of clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal DataEmbryofetal toxicity studies were conducted in rats and rabbits orally administered ranolazine during organogenesis. In rats, decreased fetal weight and reduced ossification were observed at doses (corresponding to 4-fold the AUC for the MRHD) that caused maternal weight loss. No adverse fetal effects were observed in either species exposed (AUC) to ranolazine at exposures (AUC) equal to the MRHD.. 8.2Lactation Risk SummaryThere are no data on the presence of ranolazine in human milk, the effects on the breastfed infant, or the effects on milk production. However, ranolazine is present in rat milk [see Use in Specific Populations (8.1)]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for RANEXA and any potential adverse effects on the breastfed infant from RANEXA or from the underlying maternal condition.Adult female rats were administered ranolazine orally from gestation day through postnatal day 20. No adverse effects on pup development, behavior, or reproduction parameters were observed at maternal dosage level of 60 mg/kg/day (equal to the MHRD based on AUC). At maternally toxic doses, male and female pups exhibited increased mortality and decreased body weight, and female pups showed increased motor activity. The pups were potentially exposed to low amounts of ranolazine via the maternal milk.. 8.4 Pediatric Use. Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use. Of the chronic angina patients treated with RANEXA in controlled studies, 496 (48%) were >= 65 years of age, and 114 (11%) were >= 75 years of age. No overall differences in efficacy were observed between older and younger patients. There were no differences in safety for patients >= 65 years compared to younger patients, but patients >= 75 years of age on RANEXA, compared to placebo, had higher incidence of adverse events, serious adverse events, and drug discontinuations due to adverse events. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease, or other drug therapy.. 8.6Use in Patients with Hepatic Impairment RANEXA is contraindicated in patients with liver cirrhosis. In study of cirrhotic patients, the Cmax of ranolazine was increased 30% in cirrhotic patients with mild (Child-Pugh Class A) hepatic impairment, but increased 80% in cirrhotic patients with moderate (Child-Pugh Class B) hepatic impairment compared to patients without hepatic impairment. This increase was not enough to account for the 3-fold increase in QT prolongation seen in cirrhotic patients with mild to moderate hepatic impairment [see Clinical Pharmacology (12.2)].. 8.7Use in Patients with Renal Impairment A pharmacokinetic study of RANEXA in subjects with severe renal impairment (CrCL 30 mL/min) was stopped when of subjects developed acute renal failure after receiving RANEXA 500 mg twice daily for days (lead-in phase) followed by 1000 mg twice day (1 dose in one subject and 11 doses in the other). Increases in creatinine, BUN, and potassium were observed in subjects during the 500 mg lead-in phase. One subject required hemodialysis, while the other subjects improved upon drug discontinuation [see Warnings and Precautions (5.2)]. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue RANEXA if acute renal failure develops.In separate study, Cmax was increased between 40% and 50% in patients with mild, moderate, or severe renal impairment compared to patients with no renal impairment, suggesting similar increase in exposure in patients with renal failure independent of the degree of impairment. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis.. 8.8Use in Patients with Heart Failure Heart failure (NYHA Class to IV) had no significant effect on ranolazine pharmacokinetics. RANEXA had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class to IV. No dose adjustment of RANEXA is required in patients with heart failure.. 8.9Use in Patients with Diabetes Mellitus A population pharmacokinetic evaluation of data from angina patients and healthy subjects showed no effect of diabetes on ranolazine pharmacokinetics. No dose adjustment is required in patients with diabetes. RANEXA produces small reductions in HbA1c in patients with diabetes, the clinical significance of which is unknown. RANEXA should not be considered treatment for diabetes.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (> 4% and more common than with placebo) are dizziness, headache, constipation, nausea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc., at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. total of 2018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with RANEXA, 1026 were enrolled in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks duration. In addition, upon study completion, 1251 patients received treatment with RANEXA in open-label, long-term studies; 1227 patients were exposed to RANEXA for more than year, 613 patients for more than years, 531 patients for more than years, and 326 patients for more than years. At recommended doses, about 6% of patients discontinued treatment with RANEXA because of an adverse event in controlled studies in angina patients compared to about 3% on placebo. The most common adverse events that led to discontinuation more frequently on RANEXA than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated.In controlled clinical trials of angina patients, the most frequently reported treatment-emergent adverse reactions (> 4% and more common on RANEXA than on placebo) were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Dizziness may be dose-related. In open-label, long-term treatment studies, similar adverse reaction profile was observed. The following additional adverse reactions occurred at an incidence of 0.5 to 4.0% in patients treated with RANEXA and were more frequent than the incidence observed in placebo-treated patients:Cardiac Disorders bradycardia, palpitationsEar and Labyrinth Disorders tinnitus, vertigo Eye Disorders blurred visionGastrointestinal Disorders abdominal pain, dry mouth, vomiting, dyspepsiaGeneral Disorders and Administrative Site Adverse Events asthenia, peripheral edemaMetabolism and Nutrition Disorders anorexiaNervous System Disorders syncope (vasovagal)Psychiatric Disorders confusional stateRenal and Urinary Disorders hematuriaRespiratory, Thoracic, and Mediastinal Disorders dyspneaSkin and Subcutaneous Tissue Disorders hyperhidrosisVascular Disorders hypotension, orthostatic hypotensionOther (< 0.5%) but potentially medically important adverse reactions observed more frequently with RANEXA than placebo treatment in all controlled studies included: angioedema, renal failure, eosinophilia, chromaturia, blood urea increased, hypoesthesia, paresthesia, tremor, pulmonary fibrosis, thrombocytopenia, leukopenia, and pancytopenia.A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating benefit for RANEXA, but there was no apparent proarrhythmic effect in these high-risk patients [see Clinical Studies (14.2)]. Laboratory Abnormalities:RANEXA produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal function, likely because of inhibition of creatinines tubular secretion. In general, the elevation has rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of RANEXA, and is not accompanied by changes in BUN. In healthy volunteers, RANEXA 1000 mg twice daily had no effect upon the glomerular filtration rate. More marked and progressive increases in serum creatinine, associated with increases in BUN or potassium, indicating acute renal failure, have been reported after initiation of RANEXA in patients with severe renal impairment [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)]. 6.2Postmarketing Experience. The following adverse reactions have been identified during postapproval use of RANEXA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure:Nervous System Disorders Tremor, paresthesia, abnormal coordination, and other serious neurologic adverse events have been reported to occur, sometimes concurrently, in patients taking ranolazine. The onset of events was often associated with an increase in ranolazine dose or exposure. Many patients reported symptom resolution following drug discontinuation or dose decrease.Metabolism and Nutrition Disorders Cases of hypoglycemia have been reported in diabetic patients on antidiabetic medication.Psychiatric Disorders hallucination Renal and Urinary Disorders dysuria, urinary retentionSkin and Subcutaneous Tissue Disorders angioedema, pruritus, rash.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of action of ranolazines antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (INa). However, the relationship of this inhibition to angina symptoms is uncertain. The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential. 12.2 Pharmacodynamics. Hemodynamic EffectsPatients with chronic angina treated with RANEXA in controlled clinical studies had minimal changes in mean heart rate (< bpm) and systolic blood pressure (< mm Hg). Similar results were observed in subgroups of patients with CHF NYHA Class or II, diabetes, or reactive airway disease, and in elderly patients. Electrocardiographic Effects Dose and plasma concentration-related increases in the QTc interval [see Warnings and Precautions (5.1)], reductions in wave amplitude, and, in some cases, notched waves, have been observed in patients treated with RANEXA. These effects are believed to be caused by ranolazine and not by its metabolites. The relationship between the change in QTc and ranolazine plasma concentrations is linear, with slope of about 2.6 msec/1000 ng/mL, through exposures corresponding to doses several-fold higher than the maximum recommended dose of 1000 mg twice daily. The variable blood levels attained after given dose of ranolazine give wide range of effects on QTc. At Tmax following repeat dosing at 1000 mg twice daily, the mean change in QTc is about msec, but in the 5% of the population with the highest plasma concentrations, the prolongation of QTc is at least 15 msec. In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc is much steeper [see Contraindications (4)]. Age, weight, gender, race, heart rate, congestive heart failure, diabetes, and renal impairment did not alter the slope of the QTc-concentration relationship of ranolazine. No proarrhythmic effects were observed on 7-day Holter recordings in 3162 acute coronary syndrome patients treated with RANEXA. There was significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with RANEXA (80%) versus placebo (87%), including ventricular tachycardia >= beats (52% versus 61%). However, this difference in arrhythmias did not lead to reduction in mortality, reduction in arrhythmia hospitalization, or reduction in arrhythmia symptoms.. 12.3 Pharmacokinetics. Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at dose of 1000 mg twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. The apparent terminal half-life of ranolazine is hours. Steady state is generally achieved within days of twice-daily dosing with RANEXA. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0- increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine is unaffected by age, gender, or food. Absorption and DistributionAfter oral administration of RANEXA, peak plasma concentrations of ranolazine are reached between and hours. After oral administration of 14C-ranolazine as solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine from RANEXA tablets relative to that from solution of ranolazine is 76%. Because ranolazine is substrate of P-gp, inhibitors of P-gp may increase the absorption of ranolazine.Food (high-fat breakfast) has no important effect on the Cmax and AUC of ranolazine. Therefore, RANEXA may be taken without regard to meals. Over the concentration range of 0.25 to 10 ug/mL, ranolazine is approximately 62% bound to human plasma proteins. Metabolism and ExcretionRanolazine is metabolized mainly by CYP3A and, to lesser extent, by CYP2D6. Following single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about to 33% that of ranolazine, and display apparent half-lives ranging from to 22 hours. Drug Interactions. Effect of Other Drugs on RanolazineIn vitro data indicate that ranolazine is substrate of CYP3A and, to lesser degree, of CYP2D6. Ranolazine is also substrate of P-glycoprotein.. Strong CYP3A InhibitorsPlasma levels of ranolazine with RANEXA 1000 mg twice daily are increased by 220% when co-administered with ketoconazole 200 mg twice daily [see Contraindications (4)]. Moderate CYP3A InhibitorsPlasma levels of ranolazine with RANEXA 1000 mg twice daily are increased by 50 to 130% by diltiazem 180 to 360 mg, respectively. Plasma levels of ranolazine with RANEXA 750 mg twice daily are increased by 100% by verapamil 120 mg three times daily [see Drug Interactions (7.1)]. Weak CYP3A InhibitorsThe weak CYP3A inhibitors simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to ranolazine in healthy volunteers.. CYP3A InducersRifampin 600 mg once daily decreases the plasma concentrations of ranolazine (1000 mg twice daily) by approximately 95% [see Contraindications (4)]. CYP2D6 InhibitorsParoxetine 20 mg once daily increased ranolazine concentrations by 20% in healthy volunteers receiving RANEXA 1000 mg twice daily. No dose adjustment of RANEXA is required in patients treated with CYP2D6 inhibitors.. Digoxin Plasma concentrations of ranolazine are not significantly altered by concomitant digoxin at 0.125 mg once daily.. Effect of Ranolazine on Other Drugs In vitro ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A and moderate inhibitors of CYP2D6 and P-gp. In vitro ranolazine is an inhibitor of OCT2.. CYP3A SubstratesThe plasma levels of simvastatin, CYP3A substrate, and its active metabolite are increased by 100% in healthy volunteers receiving 80 mg once daily and RANEXA 1000 mg twice daily [see Drug Interactions (7.2)]. Mean exposure to atorvastatin (80 mg daily) is increased by 40% following co-administration with RANEXA (1000 mg twice daily) in healthy volunteers. However, in one subject the exposure to atorvastatin and metabolites was increased by ~400% in the presence of RANEXA. DiltiazemThe pharmacokinetics of diltiazem is not affected by ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and RANEXA 1000 mg twice daily.. P-gp SubstratesRanolazine increases digoxin concentrations by 50% in healthy volunteers receiving RANEXA 1000 mg twice daily and digoxin 0.125 mg once daily [see Drug Interactions (7.2)]. CYP2D6 SubstratesRANEXA 750 mg twice daily increases the plasma concentrations of single dose of immediate release metoprolol (100 mg), CYP2D6 substrate, by 80% in extensive CYP2D6 metabolizers with no need for dose adjustment of metoprolol. In extensive metabolizers of dextromethorphan, substrate of CYP2D6, ranolazine inhibits partially the formation of the main metabolite dextrorphan.. OCT2 SubstratesIn subjects with type diabetes mellitus, the exposure to metformin is increased by 40% and 80% following administration of ranolazine 500 mg twice daily and 1000 mg twice daily, respectively. If co-administered with RANEXA 1000 mg twice daily, do not exceed metformin doses of 1700 mg/day [see Drug Interactions (7.2)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Chronic Stable Angina. CARISA (Combination Assessment of Ranolazine In Stable Angina) was study in 823 chronic angina patients randomized to receive 12 weeks of treatment with twice-daily RANEXA 750 mg, 1000 mg, or placebo, who also continued on daily doses of atenolol 50 mg, amlodipine mg, or diltiazem CD 180 mg. Sublingual nitrates were used in this study as needed.In this trial, statistically significant (p 0.05) increases in modified Bruce treadmill exercise duration and time to angina were observed for each RANEXA dose versus placebo, at both trough (12 hours after dosing) and peak (4 hours after dosing) plasma levels, with minimal effects on blood pressure and heart rate. The changes versus placebo in exercise parameters are presented in Table 1. Exercise treadmill results showed no increase in effect on exercise at the 1000 mg dose compared to the 750 mg dose. Table Exercise Treadmill Results (CARISA)Mean Difference from Placebo (sec)Study CARISA (N=791) RANEXA Twice-daily Dose 750 mg 1000 mg Exercise Duration Trough24p-value <= 0.05 24 Peak34p-value <= 0.005 26 Time to Angina Trough30 26 Peak38 38 Time to mm ST-Segment Depression Trough2021 Peak41 35 The effects of RANEXA on angina frequency and nitroglycerin use are shown in Table 2.Table Angina Frequency and Nitroglycerin Use (CARISA)PlaceboRANEXA750 mgTwice daily RANEXA1000 mg Angina Frequency (attacks/week)N258272261Mean 3.32.52.1P-value vs placebo--0.006< 0.001Nitroglycerin Use (doses/week)N252262244Mean 3.12.11.8P-value vs placebo--0.016< 0.001Tolerance to RANEXA did not develop after 12 weeks of therapy. Rebound increases in angina, as measured by exercise duration, have not been observed following abrupt discontinuation of RANEXA.RANEXA has been evaluated in patients with chronic angina who remained symptomatic despite treatment with the maximum dose of an antianginal agent. In the ERICA (Efficacy of Ranolazine In Chronic Angina) trial, 565 patients were randomized to receive an initial dose of RANEXA 500 mg twice daily or placebo for week, followed by weeks of treatment with RANEXA 1000 mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mg once daily. In addition, 45% of the study population also received long-acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. Results are shown in Table 3. Statistically significant decreases in angina attack frequency (p=0.028) and nitroglycerin use (p=0.014) were observed with RANEXA compared to placebo. These treatment effects appeared consistent across age and use of long-acting nitrates.Table Angina Frequency and Nitroglycerin Use (ERICA)PlaceboRANEXA1000 mg twice daily Angina Frequency (attacks/week)N281277Mean4.33.3Median2.42.2Nitroglycerin Use (doses/week)N281277Mean3.62.7Median1.71.3. GenderEffects on angina frequency and exercise tolerance were considerably smaller in women than in men. In CARISA, the improvement in Exercise Tolerance Test (ETT) in females was about 33% of that in males at the 1000 mg twice-daily dose level. In ERICA, where the primary endpoint was angina attack frequency, the mean reduction in weekly angina attacks was 0.3 for females and 1.3 for males. RaceThere were insufficient numbers of non-Caucasian patients to allow for analyses of efficacy or safety by racial subgroup. 14.2Lack of Benefit in Acute Coronary Syndrome In large (n=6560) placebo-controlled trial (MERLIN-TIMI 36) in patients with acute coronary syndrome, there was no benefit shown on outcome measures. However, the study is somewhat reassuring regarding proarrhythmic risks, as ventricular arrhythmias were less common on ranolazine [see Clinical Pharmacology (12.2)], and there was no difference between RANEXA and placebo in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99 with an upper 95% confidence limit of 1.22).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit RANEXA to 500 mg twice daily. (7.1)P-gp inhibitors (e.g., cyclosporine): Ranolazine exposure increased. Titrate RANEXA based on clinical response. (7.1)CYP3A substrates: Limit simvastatin to 20 mg when used with RANEXA. Doses of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may need to be reduced with RANEXA. (7.2)OCT2 substrates: Limit the dose of metformin to 1700 mg daily when used with RANEXA 1000 mg twice daily. Doses of other OCT2 substrates may require adjusted doses. (7.2)Drugs transported by P-gp (e.g., digoxin), or drugs metabolized by CYP2D6 (e.g., tricyclic antidepressants) may need reduced doses when used with RANEXA. (7.2). Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit RANEXA to 500 mg twice daily. (7.1). P-gp inhibitors (e.g., cyclosporine): Ranolazine exposure increased. Titrate RANEXA based on clinical response. (7.1). CYP3A substrates: Limit simvastatin to 20 mg when used with RANEXA. Doses of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may need to be reduced with RANEXA. (7.2). OCT2 substrates: Limit the dose of metformin to 1700 mg daily when used with RANEXA 1000 mg twice daily. Doses of other OCT2 substrates may require adjusted doses. (7.2). Drugs transported by P-gp (e.g., digoxin), or drugs metabolized by CYP2D6 (e.g., tricyclic antidepressants) may need reduced doses when used with RANEXA. (7.2). 7.1Effects of Other Drugs on Ranolazine. Strong CYP3A InhibitorsDo not use RANEXA with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir [see Contraindications (4), Clinical Pharmacology (12.3)].. Moderate CYP3A InhibitorsLimit the dose of RANEXA to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. P-gp InhibitorsConcomitant use of RANEXA and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate RANEXA based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine [see Dosage and Administration (2.2)]. CYP3A InducersDo not use RANEXA with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. Johns wort [see Contraindications (4), Clinical Pharmacology (12.3)].. 7.2 Effects of Ranolazine on Other Drugs. Drugs Metabolized by CYP3ALimit the dose of simvastatin in patients on any dose of RANEXA to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may be required as RANEXA may increase plasma concentrations of these drugs [see Clinical Pharmacology (12.3)].. Drugs Transported by P-gpConcomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted [see Clinical Pharmacology (12.3)]. Drugs Metabolized by CYP2D6The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with RANEXA, and lower doses of these drugs may be required. Drugs Transported by OCT2In subjects with type diabetes mellitus, concomitant use of RANEXA 1000 mg twice daily and metformin results in increased plasma levels of metformin. When RANEXA 1000 mg twice daily is co-administered with metformin, metformin dose should not exceed 1700 mg/day. Monitor blood glucose levels and risks associated with high exposures of metformin. Metformin exposure was not significantly increased when given with RANEXA 500 mg twice daily [see Clinical Pharmacology (12.3)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Inform patients that RANEXA will not abate an acute angina episode.. Strong CY3PA Inhibitors, CYP3A Inducers, Liver CirrhosisInform patients that RANEXA should not be used with drugs that are strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir) [(see Contraindications (4), Drug Interactions (7.1)]. Inform patients that RANEXA should not be used with drugs that are inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, barbiturates, carbamazepine, phenytoin, St. Johns wort) [(see Contraindications (4), Drug Interactions (7.1)]. Inform patients that RANEXA should not be used in patients with liver cirrhosis [(see Contraindications (4), Use in Specific Populations (8.6)]. Inform patients that RANEXA should not be used with drugs that are strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir) [(see Contraindications (4), Drug Interactions (7.1)]. Inform patients that RANEXA should not be used with drugs that are inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, barbiturates, carbamazepine, phenytoin, St. Johns wort) [(see Contraindications (4), Drug Interactions (7.1)]. Inform patients that RANEXA should not be used in patients with liver cirrhosis [(see Contraindications (4), Use in Specific Populations (8.6)]. Moderate CYP3A Inhibitors, P-gp Inhibitors, Grapefruit ProductsAdvise patients to inform their physician if they are receiving drugs that are moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin) [see Drug Interactions (7)]. Advise patients to inform their physician if they are receiving drugs that are P-gp inhibitors (e.g., cyclosporine) [see Drug Interactions (7)]. Advise patients to limit grapefruit juice or grapefruit products when taking RANEXA [see Drug Interactions (7)]. Advise patients to inform their physician if they are receiving drugs that are moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin) [see Drug Interactions (7)]. Advise patients to inform their physician if they are receiving drugs that are P-gp inhibitors (e.g., cyclosporine) [see Drug Interactions (7)]. Advise patients to limit grapefruit juice or grapefruit products when taking RANEXA [see Drug Interactions (7)]. QT Interval ProlongationInform patients that RANEXA may produce changes in the electrocardiogram (QTc interval prolongation) [see Warnings and Precautions (5.1)]. Advise patients to inform their physician of any personal or family history of QTc prolongation, congenital long QT syndrome, or if they are receiving drugs that prolong the QTc interval such as Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol, amiodarone) antiarrhythmic agents, erythromycin, and certain antipsychotics (e.g., thioridazine, ziprasidone) [see Warnings and Precautions (5.1)]. Inform patients that RANEXA may produce changes in the electrocardiogram (QTc interval prolongation) [see Warnings and Precautions (5.1)]. Advise patients to inform their physician of any personal or family history of QTc prolongation, congenital long QT syndrome, or if they are receiving drugs that prolong the QTc interval such as Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol, amiodarone) antiarrhythmic agents, erythromycin, and certain antipsychotics (e.g., thioridazine, ziprasidone) [see Warnings and Precautions (5.1)]. Use in Patients with Renal ImpairmentPatients with severe renal impairment may be at risk of renal failure while on RANEXA. Advise patients to inform their physician if they have impaired renal function before or while taking RANEXA [see Warnings and Precautions (5.2)]. Dizziness, FaintingInform patients that RANEXA may cause dizziness and lightheadedness. Patients should know how they react to RANEXA before they operate an automobile or machinery, or engage in activities requiring mental alertness or coordination [see Adverse Reactions (6.1)]. Advise patients to contact their physician if they experience fainting spells while taking RANEXA.. Inform patients that RANEXA may cause dizziness and lightheadedness. Patients should know how they react to RANEXA before they operate an automobile or machinery, or engage in activities requiring mental alertness or coordination [see Adverse Reactions (6.1)]. Advise patients to contact their physician if they experience fainting spells while taking RANEXA.. AdministrationInstruct patients to swallow RANEXA tablets whole, with or without meals, and not to crush, break, or chew tablets. Inform patients that if dose is missed, to take the usual dose at the next scheduled time. The next dose should not be doubled. Inform patients that doses of RANEXA higher than 1000 mg twice daily should not be used [see Dosage and Administration (2)]. Advise patients to inform their physician of any other medications taken concurrently with RANEXA, including over-the-counter medications.. Instruct patients to swallow RANEXA tablets whole, with or without meals, and not to crush, break, or chew tablets. Inform patients that if dose is missed, to take the usual dose at the next scheduled time. The next dose should not be doubled. Inform patients that doses of RANEXA higher than 1000 mg twice daily should not be used [see Dosage and Administration (2)]. Advise patients to inform their physician of any other medications taken concurrently with RANEXA, including over-the-counter medications.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Hemodynamic EffectsPatients with chronic angina treated with RANEXA in controlled clinical studies had minimal changes in mean heart rate (< bpm) and systolic blood pressure (< mm Hg). Similar results were observed in subgroups of patients with CHF NYHA Class or II, diabetes, or reactive airway disease, and in elderly patients. Electrocardiographic Effects Dose and plasma concentration-related increases in the QTc interval [see Warnings and Precautions (5.1)], reductions in wave amplitude, and, in some cases, notched waves, have been observed in patients treated with RANEXA. These effects are believed to be caused by ranolazine and not by its metabolites. The relationship between the change in QTc and ranolazine plasma concentrations is linear, with slope of about 2.6 msec/1000 ng/mL, through exposures corresponding to doses several-fold higher than the maximum recommended dose of 1000 mg twice daily. The variable blood levels attained after given dose of ranolazine give wide range of effects on QTc. At Tmax following repeat dosing at 1000 mg twice daily, the mean change in QTc is about msec, but in the 5% of the population with the highest plasma concentrations, the prolongation of QTc is at least 15 msec. In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc is much steeper [see Contraindications (4)]. Age, weight, gender, race, heart rate, congestive heart failure, diabetes, and renal impairment did not alter the slope of the QTc-concentration relationship of ranolazine. No proarrhythmic effects were observed on 7-day Holter recordings in 3162 acute coronary syndrome patients treated with RANEXA. There was significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with RANEXA (80%) versus placebo (87%), including ventricular tachycardia >= beats (52% versus 61%). However, this difference in arrhythmias did not lead to reduction in mortality, reduction in arrhythmia hospitalization, or reduction in arrhythmia symptoms.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at dose of 1000 mg twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. The apparent terminal half-life of ranolazine is hours. Steady state is generally achieved within days of twice-daily dosing with RANEXA. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0- increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine is unaffected by age, gender, or food. Absorption and DistributionAfter oral administration of RANEXA, peak plasma concentrations of ranolazine are reached between and hours. After oral administration of 14C-ranolazine as solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine from RANEXA tablets relative to that from solution of ranolazine is 76%. Because ranolazine is substrate of P-gp, inhibitors of P-gp may increase the absorption of ranolazine.Food (high-fat breakfast) has no important effect on the Cmax and AUC of ranolazine. Therefore, RANEXA may be taken without regard to meals. Over the concentration range of 0.25 to 10 ug/mL, ranolazine is approximately 62% bound to human plasma proteins. Metabolism and ExcretionRanolazine is metabolized mainly by CYP3A and, to lesser extent, by CYP2D6. Following single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about to 33% that of ranolazine, and display apparent half-lives ranging from to 22 hours. Drug Interactions. Effect of Other Drugs on RanolazineIn vitro data indicate that ranolazine is substrate of CYP3A and, to lesser degree, of CYP2D6. Ranolazine is also substrate of P-glycoprotein.. Strong CYP3A InhibitorsPlasma levels of ranolazine with RANEXA 1000 mg twice daily are increased by 220% when co-administered with ketoconazole 200 mg twice daily [see Contraindications (4)]. Moderate CYP3A InhibitorsPlasma levels of ranolazine with RANEXA 1000 mg twice daily are increased by 50 to 130% by diltiazem 180 to 360 mg, respectively. Plasma levels of ranolazine with RANEXA 750 mg twice daily are increased by 100% by verapamil 120 mg three times daily [see Drug Interactions (7.1)]. Weak CYP3A InhibitorsThe weak CYP3A inhibitors simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to ranolazine in healthy volunteers.. CYP3A InducersRifampin 600 mg once daily decreases the plasma concentrations of ranolazine (1000 mg twice daily) by approximately 95% [see Contraindications (4)]. CYP2D6 InhibitorsParoxetine 20 mg once daily increased ranolazine concentrations by 20% in healthy volunteers receiving RANEXA 1000 mg twice daily. No dose adjustment of RANEXA is required in patients treated with CYP2D6 inhibitors.. Digoxin Plasma concentrations of ranolazine are not significantly altered by concomitant digoxin at 0.125 mg once daily.. Effect of Ranolazine on Other Drugs In vitro ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A and moderate inhibitors of CYP2D6 and P-gp. In vitro ranolazine is an inhibitor of OCT2.. CYP3A SubstratesThe plasma levels of simvastatin, CYP3A substrate, and its active metabolite are increased by 100% in healthy volunteers receiving 80 mg once daily and RANEXA 1000 mg twice daily [see Drug Interactions (7.2)]. Mean exposure to atorvastatin (80 mg daily) is increased by 40% following co-administration with RANEXA (1000 mg twice daily) in healthy volunteers. However, in one subject the exposure to atorvastatin and metabolites was increased by ~400% in the presence of RANEXA. DiltiazemThe pharmacokinetics of diltiazem is not affected by ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and RANEXA 1000 mg twice daily.. P-gp SubstratesRanolazine increases digoxin concentrations by 50% in healthy volunteers receiving RANEXA 1000 mg twice daily and digoxin 0.125 mg once daily [see Drug Interactions (7.2)]. CYP2D6 SubstratesRANEXA 750 mg twice daily increases the plasma concentrations of single dose of immediate release metoprolol (100 mg), CYP2D6 substrate, by 80% in extensive CYP2D6 metabolizers with no need for dose adjustment of metoprolol. In extensive metabolizers of dextromethorphan, substrate of CYP2D6, ranolazine inhibits partially the formation of the main metabolite dextrorphan.. OCT2 SubstratesIn subjects with type diabetes mellitus, the exposure to metformin is increased by 40% and 80% following administration of ranolazine 500 mg twice daily and 1000 mg twice daily, respectively. If co-administered with RANEXA 1000 mg twice daily, do not exceed metformin doses of 1700 mg/day [see Drug Interactions (7.2)].

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information RANEXA(R) (rah NEX ah)(ranolazine) extended-release tablets Dosing Strengths: 500 mg tablets 1000 mg tabletsRead this Patient Information before you start taking RANEXA and each time you get refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. What is RANEXARANEXA is prescription medicine used to treat angina that keeps coming back (chronic angina).RANEXA may be used with other medicines that are used for heart problems and blood pressure control.It is not known if RANEXA is safe and effective in children.Who should not take RANEXADo not take RANEXA if:you take any of the following medicines:for fungus infection: ketoconazole (Nizoral(R)), itraconazole (Sporanox(R), Onmel(TM))for infection: clarithromycin (Biaxin(R))for depression: nefazodonefor HIV: nelfinavir (Viracept(R)), ritonavir (Norvir(R)), lopinavir and ritonavir (Kaletra(R)), indinavir (Crixivan(R)), saquinavir (Invirase(R))for tuberculosis (TB): rifampin (Rifadin(R)), rifabutin (Mycobutin(R)), rifapentine (Priftin(R))for seizures: phenobarbital, phenytoin (Phenytek(R), Dilantin(R), Dilantin-125(R)), carbamazepine (Tegretol(R))St. Johns wort (Hypericum perforatum) you have scarring (cirrhosis) of your liverWhat should tell my doctor before taking RANEXABefore you take RANEXA, tell your doctor if you:have or have family history of heart problem, called QT prolongation or long QT syndrome.have liver problems.have kidney problems.are pregnant or plan to become pregnant. It is not known if RANEXA will harm your unborn baby.are breast-feeding or plan to breast-feed. It is not known if RANEXA passes into your breast milk. You and your doctor should decide if you will breast-feed.Tell your doctor about all the medicines you take, including all prescription and nonprescription medicines, vitamins, and herbal supplements. RANEXA may affect the way other medicines work and other medicines may affect how RANEXA works.Tell your doctor if you take medicines:for your heart for cholesterolfor diabetesfor infectionfor fungusfor transplantfor nausea and vomiting because of cancer treatmentsfor mental problemsKnow the medicines you take. Keep list of them to show your doctor or pharmacist when you get new medicine.How should take RANEXATake RANEXA exactly as your doctor tells you.Your doctor will tell you how much RANEXA to take and when to take it.Do not change your dose unless your doctor tells you to.Tell your doctor if you still have symptoms of angina after starting RANEXA.Take RANEXA by mouth, with or without food.Swallow the RANEXA tablets whole. Do not crush, break, or chew RANEXA tablets before swallowing.If you miss dose of RANEXA, wait to take the next dose of RANEXA at your regular time. Do not make up for the missed dose. Do not take more than dose at time.If you take too much RANEXA, call your doctor, or go to the nearest emergency room right away.What should avoid while taking RANEXAGrapefruit and grapefruit juice. Limit products that have grapefruit in them. They can cause your blood levels of RANEXA to increase.RANEXA can cause dizziness, lightheadedness, or fainting. If you have these symptoms, do not drive car, use machinery, or do anything that needs you to be alert.What are the possible side effects of RANEXARANEXA may cause serious side effects, including:changes in the electrical activity of your heart called QT prolongation. Your doctor may check the electrical activity of your heart with an ECG. Tell your doctor right away if you feel faint, lightheaded, or feel your heart beating irregularly or fast while taking RANEXA. These may be symptoms related to QT prolongation.kidney failure in people who already have severe kidney problems. Your doctor may need to do tests to check how your kidneys are working.The most common side effects of RANEXA include:dizzinessheadacheconstipationnauseaTell your doctor if you have any side effect that bothers you or does not go away.These are not all the possible side effects of RANEXA. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store RANEXAStore RANEXA tablets at room temperature between 59 to 86F (15 to 30C).Keep RANEXA and all medicines out of the reach of children.General information about RANEXA.Medicines are sometimes prescribed for purposes other than those listed in the Patient Information. Do not use RANEXA for condition for which it was not prescribed. Do not give RANEXA to other people, even if they have the same condition you have. It may harm them.The Patient Information summarizes the most important information about RANEXA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about RANEXA that is written for health professionals.For more information, go to www.ranexa.com or call Gilead Sciences, Inc. at 1-800-445-3235.What is chronic anginaChronic angina means pain or discomfort in the chest, jaw, shoulder, back, or arm that keeps coming back. There are other possible signs and symptoms of angina including shortness of breath. Angina usually comes on when you are active or under stress. Chronic angina is symptom of heart problem called coronary heart disease (CHD), also known as coronary artery disease (CAD). When you have CHD, the blood vessels in your heart become stiff and narrow. Oxygen-rich blood cannot reach your heart muscle easily. Angina comes on when too little oxygen reaches your heart muscle.What are the ingredients in RANEXAActive ingredient: ranolazineInactive ingredients: 500 mg tablet: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, titanium dioxide, polyvinyl alcohol, talc, Iron Oxide Yellow, and Iron Oxide Red.1000 mg tablet: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, titanium dioxide, lactose monohydrate, triacetin, and Iron Oxide Yellow.This Patient Information has been approved by the U.S. Food and Drug Administration.Manufactured for: Gilead Sciences, Inc. Foster City, CA 94404Revised: January 2016 RANEXA is trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.(C) 2016 Gilead Sciences, Inc.21-526-GS-015. you take any of the following medicines:for fungus infection: ketoconazole (Nizoral(R)), itraconazole (Sporanox(R), Onmel(TM))for infection: clarithromycin (Biaxin(R))for depression: nefazodonefor HIV: nelfinavir (Viracept(R)), ritonavir (Norvir(R)), lopinavir and ritonavir (Kaletra(R)), indinavir (Crixivan(R)), saquinavir (Invirase(R))for tuberculosis (TB): rifampin (Rifadin(R)), rifabutin (Mycobutin(R)), rifapentine (Priftin(R))for seizures: phenobarbital, phenytoin (Phenytek(R), Dilantin(R), Dilantin-125(R)), carbamazepine (Tegretol(R))St. Johns wort (Hypericum perforatum) for fungus infection: ketoconazole (Nizoral(R)), itraconazole (Sporanox(R), Onmel(TM)). for infection: clarithromycin (Biaxin(R)). for depression: nefazodone. for HIV: nelfinavir (Viracept(R)), ritonavir (Norvir(R)), lopinavir and ritonavir (Kaletra(R)), indinavir (Crixivan(R)), saquinavir (Invirase(R)). for tuberculosis (TB): rifampin (Rifadin(R)), rifabutin (Mycobutin(R)), rifapentine (Priftin(R)). for seizures: phenobarbital, phenytoin (Phenytek(R), Dilantin(R), Dilantin-125(R)), carbamazepine (Tegretol(R)). St. Johns wort (Hypericum perforatum). you have scarring (cirrhosis) of your liver. have or have family history of heart problem, called QT prolongation or long QT syndrome.. have liver problems.. have kidney problems.. are pregnant or plan to become pregnant. It is not known if RANEXA will harm your unborn baby.. are breast-feeding or plan to breast-feed. It is not known if RANEXA passes into your breast milk. You and your doctor should decide if you will breast-feed.. for your heart for cholesterol. for diabetes. for infection. for fungus. for transplant. for nausea and vomiting because of cancer treatments. for mental problems. Take RANEXA exactly as your doctor tells you.. Your doctor will tell you how much RANEXA to take and when to take it.. Do not change your dose unless your doctor tells you to.. Tell your doctor if you still have symptoms of angina after starting RANEXA.. Take RANEXA by mouth, with or without food.. Swallow the RANEXA tablets whole. Do not crush, break, or chew RANEXA tablets before swallowing.. If you miss dose of RANEXA, wait to take the next dose of RANEXA at your regular time. Do not make up for the missed dose. Do not take more than dose at time.. If you take too much RANEXA, call your doctor, or go to the nearest emergency room right away.. Grapefruit and grapefruit juice. Limit products that have grapefruit in them. They can cause your blood levels of RANEXA to increase.. RANEXA can cause dizziness, lightheadedness, or fainting. If you have these symptoms, do not drive car, use machinery, or do anything that needs you to be alert.. changes in the electrical activity of your heart called QT prolongation. Your doctor may check the electrical activity of your heart with an ECG. Tell your doctor right away if you feel faint, lightheaded, or feel your heart beating irregularly or fast while taking RANEXA. These may be symptoms related to QT prolongation.. kidney failure in people who already have severe kidney problems. Your doctor may need to do tests to check how your kidneys are working.. dizziness. headache. constipation. nausea.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. QT interval prolongation: Can occur with ranolazine. Little data available on high doses, long exposure, use with QT interval-prolonging drugs, potassium channel variants causing prolonged QT interval, in patients with family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. (5.1)Renal failure: Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL<60 mL/min). If acute renal failure develops, discontinue RANEXA. (5.2) QT interval prolongation: Can occur with ranolazine. Little data available on high doses, long exposure, use with QT interval-prolonging drugs, potassium channel variants causing prolonged QT interval, in patients with family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. (5.1). Renal failure: Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL<60 mL/min). If acute renal failure develops, discontinue RANEXA. (5.2) 5.1QT Interval Prolongation. Ranolazine blocks IKr and prolongs the QTc interval in dose-related manner. Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death [see Clinical Studies (14.2)]. However, there is little experience with high doses (> 1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in long QT interval, in patients with family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.. 5.2Renal Failure. Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] 30 mL/min) while taking RANEXA. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue RANEXA and treat appropriately [see Use in Specific Populations (8.7)].Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL 60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.