FDA Label for Ranolazine

1 Indications And Usage

Ranolazine extended-release tablets are indicated for the treatment of chronic angina.

Ranolazine extended-release tablets may be used with beta-blockers, nitrates, calcium channel blockers, anti- platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers.

2.1 Dosing Information

Initiate ranolazine extended-release tablets dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take ranolazine extended-release tablets with or without meals. Swallow ranolazine extended-release tablets whole; do not crush, break, or chew.

The maximum recommended daily dose of ranolazine extended-release tablets is 1000 mg twice daily.

If a dose of ranolazine extended-release tablets is missed, take the prescribed dose at the next scheduled time; do not double the next dose.

2.2 Dose Modification

Dose adjustments may be needed when ranolazine extended-release tablets are taken in combination with certain other drugs [see Drug Interactions (7.1)]. Limit the maximum dose of ranolazine extended-release tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of ranolazine extended-release tablets with strong CYP3A inhibitors is contraindicated [see Contraindications (4), Drug Interactions (7.1)]. Use of P-gp inhibitors, such as cyclosporine, may increase exposure to ranolazine extended-release tablets. Titrate ranolazine extended-release tablets based on clinical response [see Drug Interactions (7.1)].

3 Dosage Forms And Strengths

Ranolazine extended-release tablets are supplied as oblong-shaped, biconvex, film-coated extended-release tablets in the following strengths:

•   500 mg tablets are white to off white, debossed with "LS703" on one side and plain on other side
•   1000 mg tablets are pale yellow, debossed with "LS704" on one side and plain on other side

4 Contraindications

Ranolazine extended-release tablets are contraindicated in patients:

• Taking strong inhibitors of CYP3A [see Drug Interactions (7.1)]
• Taking inducers of CYP3A [see Drug Interactions (7.1)]
• With liver cirrhosis [see Use in Specific Population (8.6)]

5.1 Qt Interval Prolongation

Ranolazine blocks I_Kr and prolongs the QTc interval in a 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, or potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.

5.2 Renal Failure

Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] <30 mL/min) while taking ranolazine extended-release tablets. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue ranolazine extended-release tablets 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.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 2018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with ranolazine extended-release tablets, 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 ranolazine extended-release tablets in open-label, long-term studies; 1227 patients were exposed to ranolazine extended-release tablets for more than 1 year, 613 patients for more than 2 years, 531 patients for more than 3 years, and 326 patients for more than 4 years.

At recommended doses, about 6% of patients discontinued treatment with ranolazine extended-release tablets 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 ranolazine extended-release tablets 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 ranolazine extended-release tablets 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, a 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 ranolazine extended-release tablets and were more frequent than the incidence observed in placebo-treated patients:

Cardiac Disorders – bradycardia, palpitations

Ear and Labyrinth Disorders – tinnitus, vertigo

Eye Disorders – blurred vision

Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting, dyspepsia

General Disorders and Administrative Site Adverse Events – asthenia, peripheral edema

Metabolism and Nutrition Disorders – anorexia

Nervous System Disorders – syncope (vasovagal)

Psychiatric Disorders – confusional state

Renal and Urinary Disorders – hematuria

Respiratory, Thoracic, and Mediastinal Disorders – dyspnea

Skin and Subcutaneous Tissue Disorders – hyperhidrosis

Vascular Disorders – hypotension, orthostatic hypotension

Other (<0.5%) but potentially medically important adverse reactions observed more frequently with ranolazine extended-release tablets 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 a benefit for ranolazine extended-release tablets, but there was no apparent proarrhythmic effect in these high-risk patients [see Clinical Studies (14.2)].

Laboratory Abnormalities

Ranolazine extended-release tablets produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal function, likely because of inhibition of creatinine's tubular secretion. In general, the elevation has a rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of ranolazine extended-release tablets, and is not accompanied by changes in BUN. In healthy volunteers, ranolazine extended-release tablets 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 ranolazine extended-release tablets in patients with severe renal impairment [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ranolazine extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Nervous System Disorders – Abnormal coordination, myoclonus, paresthesia, tremor, 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 retention

Skin and Subcutaneous Tissue Disorders – angioedema, pruritus, rash

Risk Summary

There are no available data on ranolazine extended-release tablets use in pregnant women to inform any drug- associated risks. Studies in rats and rabbits showed no evidence of fetal harm at exposures 4 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 Data

Embryofetal 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.

8.2 Lactation

Risk Summary

There 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 mother's clinical need for ranolazine extended-release tablets and any potential adverse effects on the breastfed infant from ranolazine extended-release tablets or from the underlying maternal condition.

Adult female rats were administered ranolazine orally from gestation day 6 through postnatal day 20. No adverse effects on pup development, behavior, or reproduction parameters were observed at a 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 ranolazine extended-release tablets 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 ranolazine extended-release tablets, compared to placebo, had a 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.

8.6 Use In Patients With Hepatic Impairment

Ranolazine extended-release tablets are contraindicated in patients with liver cirrhosis. In a study of cirrhotic patients, the C_max 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)].

8.7 Use In Patients With Renal Impairment

A pharmacokinetic study of ranolazine extended-release tablets in subjects with severe renal impairment (CrCL <30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving ranolazine extended-release tablets 500 mg twice daily for 5 days (lead-in phase) followed by 1000 mg twice a day (1 dose in one subject and 11 doses in the other). Increases in creatinine, BUN, and potassium were observed in 3 subjects during the 500 mg lead-in phase. One subject required hemodialysis, while the other 2 subjects improved upon drug discontinuation [see Warnings and Precautions (5.2)]. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue ranolazine extended-release tablets if acute renal failure develops.

In a separate study, C_max was increased between 40% and 50% in patients with mild, moderate, or severe renal impairment compared to patients with no renal impairment, suggesting a 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.

8.8 Use In Patients With Heart Failure

Heart failure (NYHA Class I to IV) had no significant effect on ranolazine pharmacokinetics. Ranolazine extended-release tablets had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class I to IV. No dose adjustment of ranolazine extended-release tablets are required in patients with heart failure.

8.9 Use 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.

Ranolazine extended-release tablets produces small reductions in HbA1c in patients with diabetes, the clinical significance of which is unknown. Ranolazine extended-release tablets should not be considered a treatment for diabetes.

10 Overdosage

Hypotension, QT prolongation, bradycardia, myoclonic activity, severe tremor, unsteady gait/incoordination, dizziness, nausea, vomiting, dysphasia, and hallucinations have been seen in cases of oral overdose of ranolazine extended-release tablets. In cases of extreme overdose of ranolazine extended-release tablets fatal outcomes have been reported. In clinical studies, high intravenous exposure resulted in diplopia, paresthesia, confusion, and syncope.

In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose

Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing ranolazine

11 Description

Ranolazine extended-release tablets are available as a film-coated, non-scored, extended-release tablet for oral administration.

Ranolazine is a racemic mixture, chemically described as 1-piperazineacetamide, N  (2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-. It has an empirical formula of C₂₄H₃₃N₃O₄, a molecular weight of 427.54 g/mole, and the following structural formula:

Chemical Structure - ranolazine er tabs 8569 1

Ranolazine is a white to off-white crystalline powder. Ranolazine is soluble in dichloromethane and methanol; sparingly soluble in tetrahydrofuran and acetonitrile slightly soluble in toluene.

Ranolazine extended-release tablets contain 500 mg or 1000 mg of ranolazine and the following inactive ingredients: hypromellose, magnesium stearate, methacrylic acid and ethyl acrylate copolymer (1:1) Type A, microcrystalline cellulose, polysorbate 80, sodium hydroxide and sodium lauryl sulphate. Additional inactive ingredients for the 500 mg tablet include macrogol/PEG 4000, polyvinyl alcohol, talc and titanium dioxide. Additional inactive ingredients for the 1000 mg tablet include iron oxide yellow, macrogol/PEG 4000, polyvinyl alcohol, talc and titanium dioxide.

12.1 Mechanism Of Action

The mechanism of action of ranolazine's 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, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (I_Na). 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 I_Kr, which prolongs the ventricular action potential.

12.3 Pharmacokinetics

Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg twice daily, the mean steady-state C_max 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 7 hours. Steady state is generally achieved within 3 days of twice-daily dosing with ranolazine extended-release tablets. At steady state over the dose range of 500 to 1000 mg twice daily, C_max and AUC_0-T 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.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Ranolazine tested negative for genotoxic potential in the following assays: Ames bacterial mutation assay, Saccharomyces assay for mitotic gene conversion, chromosomal aberrations assay in Chinese hamster ovary (CHO) cells, mammalian CHO/HGPRT gene mutation assay, and mouse and rat bone marrow micronucleus assays.

There was no evidence of carcinogenic potential in mice or rats. The highest oral doses used in the carcinogenicity studies were 150 mg/kg/day for 21 months in rats (900 mg/m²/day) and 50 mg/kg/day for 24 months in mice (150 mg/m²/day). These maximally tolerated doses are 0.8 and 0.1 times, respectively, the daily maximum recommended human dose (MRHD) of 2000 mg on a surface area basis. A published study reported that ranolazine promoted tumor formation and progression to malignancy when given to transgenic APC (min/+) mice at a dose of 30 mg/kg twice daily [see References (15)].

The clinical significance of this finding is unclear.

In male and female rats, oral administration of ranolazine that produced exposures (AUC) approximatelty 3-fold or 5-fold higher, respectively, than the MRHD had no effect on fertility.

14.1 Chronic Stable Angina

CARISA (Combination Assessment of Ranolazine In Stable Angina) was a study in 823 chronic angina patients randomized to receive 12 weeks of treatment with twice-daily ranolazine extended-release tablets 750 mg, 1000 mg, or placebo, who also continued on daily doses of atenolol 50 mg, amlodipine 5 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 ranolazine extended-release tablets 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.

The effects of ranolazine extended-release tablets on angina frequency and nitroglycerin use are shown in Table 2.

Tolerance to ranolazine extended-release tablets 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 ranolazine extended-release tablets.

Ranolazine extended-release tablets 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 ranolazine extended-release tablets 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with ranolazine extended-release tablets 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 ranolazine extended-release tablets compared to placebo. These treatment effects appeared consistent across age and use of long-acting nitrates.

14.2 Lack Of Benefit In Acute Coronary Syndrome

In a 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 ranolazine extended-release tablets and placebo in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99 with an upper 95% confidence limit of 1.22).

15 References

M.A. Suckow et al. The anti-ischemia agent ranolazine promotes the development of intestinal tumors in APC (min/+) mice. Cancer Letters 209(2004):165−9.

16 How Supplied/Storage And Handling

Ranolazine extended-release tablets are supplied as oblong-shaped, biconvex, film-coated extended-release tablets in the following strengths:

•   500 mg tablets are white to off white, debossed with "LS703" on one side and plain on other side
•   1000 mg tablets are pale yellow, debossed with "LS704" on one side and plain on other side

Ranolazine extended-release tablets are available in:

	Strength	NDC
Blistercards of 30 tablets	500 mg	0615-8569-39

Store Ranolazine extended-release tablets at 20°C - 25°C (68°F to 77°F). [See USP Controlled Room Temperature].

Dispense in a well-closed, child-resistant container as defined in the USP.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information). Inform patients that ranolazine extended-release tablets will not abate an acute angina episode.

Strong CY3PA Inhibitors, CYP3A Inducers, Liver Cirrhosis

• Inform patients that ranolazine extended-release tablets 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 ranolazine extended-release tablets should not be used with drugs that are inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, barbiturates, carbamazepine, phenytoin, St. John's wort) [(see Contraindications (4),Drug Interactions (7.1) ].
• Inform patients that ranolazine extended-release tablets 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 Products

• 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 ranolazine extended-release tablets [seeDrug Interactions (7) ].

QT Interval Prolongation

• Inform patients that ranolazine extended-release tablets 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) [seeWarnings and Precautions (5.1) ].

Use in Patients with Renal Impairment

Patients with severe renal impairment may be at risk of renal failure while on ranolazine extended-release tablets.

Advise patients to inform their physician if they have impaired renal function before or while taking ranolazine extended-release tablets [see Warnings and Precautions (5.2)].

Dizziness, Fainting

• Inform patients that ranolazine extended-release tablets may cause dizziness and lightheadedness. Patients should know how they react to ranolazine extended-release tablets 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 ranolazine extended-release tablets.

Administration

• Instruct patients to swallow ranolazine extended-release tablets whole, with or without meals, and not to crush, break, or chew tablets. Inform patients that if a 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 ranolazine extended-release tablets 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 ranolazine extended-release tablets, including over-the-counter medications.