RANOLAZINE tablet, film coated, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
RANOLAZINE (UNII: A6IEZ5M406) (RANOLAZINE - UNII:A6IEZ5M406)
Available from:
Ascend Laboratories, LLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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. Ranolazine is 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 Populations (8.6)] Risk Summary   There are no available data on ranolazine 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 to 4% and 15 to 20%, respectively. Data   Animal Data   Embryofetal toxicity studies
Product summary:
Ranolazine is supplied as extended-release tablets in the following strengths: Ranolazine extended-release tablets are available in: Store ranolazine tablets at 25°C (77°F) with excursions permitted to 15° to 30°C (59° to 86°F).
Authorization status:
Abbreviated New Drug Application
Authorization number:
67877-525-10, 67877-525-38, 67877-525-60, 67877-526-05, 67877-526-38, 67877-526-60

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RANOLAZINE - ranolazine tablet, film coated, extended release

Ascend Laboratories, LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use RANOLAZINE EXTENDED-RELEASE

TABLETS safely and effectively. See full prescribing information for RANOLAZINE EXTENDED-RELEASE

TABLETS.

RANOLAZINE extended-release tablets for oral use

Initial U.S. Approval: 2006

INDICATIONS AND USAGE

Ranolazine extended-release tablets are an antianginal indicated for the treatment of chronic angina. (1) (1)

DOSAGE AND ADMINISTRATION

500 mg twice daily and increase to 1000 mg twice daily, based on clinical symptoms (2.1)

DOSAGE FORMS AND STRENGTHS

Extended-release tablets: 500 mg, 1000 mg (3) (3)

CONTRAINDICATIONS

· Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) (4, 7.1)

· CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) (4, 7.1)

· Liver cirrhosis (4,8.6)

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 a 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 less than 60 mL/min). If acute renal failure develops, discontinue ranolazine. (5.2)

ADVERSE REACTIONS

Most common adverse reactions (greater than 4% and more common than with placebo) are dizziness, headache,

constipation, nausea. (6.1)

To report SUSPECTED ADVERSE REACTIONS,contact Ascend Laboratories,LLC at 1-877-ASC-RX01 (877-272-7901) or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit ranolazine to 500 mg twice daily. (7.1)

P-gp inhibitors (e.g., cyclosporine): Ranolazine exposure increased.Titrate ranolazine based on clinical response. (7.1)

CYP3A substrates: Limit simvastatin to 20 mg when used with ranolazine. 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 ranolazine. (7.2)

OCT2 substrates: Limit the dose of metformin to 1700 mg daily when used with ranolazine 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 ranolazine. (7.2)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS & USAGE

2 DOSAGE & ADMINISTRATION

2.1 Dosing Information

2.2 Dose Modification

3 DOSAGE FORMS & STRENGTHS

4 CONTRAINDICATIONS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 QT Interval Prolongation

5.2 Renal Failure

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on Ranolazine

7.2 Effects of Ranolazine on Other Drugs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Use in Patients with Hepatic Impairment

8.7 Use in Patients with Renal Impairment

8.8 Use in Patients with Heart Failure

8.9 Use in Patients with Diabetes Mellitus

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

14 CLINICAL STUDIES

14.1 Chronic Stable Angina

14.2 Lack of Benefit in Acute Coronary Syndrome

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS & 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 DOSAGE & ADMINISTRATION

2.1 Dosing Information

Initiate ranolazine extended-release tablet dosing at 500 mg twice daily and increase to 1000 mg twice

daily, as needed, based on clinical symptoms. Take ranolazine extended-release tablet with or without

meals. Swallow ranolazine extended-release tablet whole; do not crush, break, or chew.

Sections or subsections omitted from the full prescribing information are not listed.

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

If a dose of ranolazine extended-release tablet 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 tablet is taken in combination with

certain other drugs [see Drug Interactions (7.1)]. Limit the maximum dose of ranolazine extended-release

tablet to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and

erythromycin. Use of ranolazine extended-release tablet 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 tablet. Titrate ranolazine extended-

release tablet based on clinical response [see Drug Interactions (7.1)].

3 DOSAGE FORMS & STRENGTHS

Ranolazine is supplied as extended-release tablets in the following strengths:

500 mg tablets are orange colored, oval shape, biconvex coated tablets, debossed with "500" on

one side and "A47" on other side.

1000 mg tablets are yellow colored, oval shape, biconvex coated tablets, debossed with "1000" on

one side and A48" on other side.

4 CONTRAINDICATIONS

Ranolazine is 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 Populations (8.6)]

5 WARNINGS AND PRECAUTIONS

5.1 QT Interval Prolongation

Ranolazine blocks I

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 (greater than 1000 mg

twice daily) or exposure, other QT-prolonging drugs, 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] less than 30 mL/min) while taking ranolazine. If acute renal failure develops (e.g.,

marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]),

discontinue ranolazine 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 less than 60 mL/min) for increases in serum creatinine accompanied by an increase in

BUN.

6 ADVERSE REACTIONS

6 ADVERSE REACTIONS

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, 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 in open-label, long-term studies; 1227

patients were exposed to ranolazine 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 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 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 (greater than 4% and more common on ranolazine 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 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 (less than 0.5%) but potentially medically important adverse reactions observed more frequently

with ranolazine 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, but there was no apparent proarrhythmic effect in these high-risk patients [see Clinical

Studies (14.2)].

Laboratory Abnormalities:

Ranolazine 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, and is not accompanied by changes in BUN. In healthy volunteers, ranolazine 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 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. 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

7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on Ranolazine

Strong CYP3A Inhibitors

Do not use ranolazine with strong CYP3A inhibitors, including ketoconazole, itraconazole,

clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir [see Contraindications

(4),Clinical Pharmacology (12.3)].

Moderate CYP3A Inhibitors

Limit the dose of ranolazine 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 Inhibitors

Concomitant use of ranolazine and P-gp inhibitors, such as cyclosporine, may result in increases in

ranolazine concentrations. Titrate ranolazine based on clinical response in patients concomitantly treated

with predominant P-gp inhibitors such as cyclosporine [see Dosage and Administration (2.2)].

CYP3A Inducers

Do not use ranolazine with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital,

phenytoin, carbamazepine, and St. John’s wort [see Contraindications (4), Clinical Pharmacology (12.3)].

7.2 Effects of Ranolazine on Other Drugs

Drugs Metabolized by CYP3A

Limit the dose of simvastatin in patients on any dose of ranolazine to 20 mg once daily, when ranolazine

is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A

substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may be required

as ranolazine may increase plasma concentrations of these drugs [see Clinical Pharmacology (12.3)].

Drugs Transported by P-gp

Concomitant 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 CYP2D6

The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be

increased during co-administration with ranolazine, and lower doses of these drugs may be required.

Drugs Transported by OCT2

In subjects with type 2 diabetes mellitus, concomitant use of ranolazine 1000 mg twice daily and

metformin results in increased plasma levels of metformin. When ranolazine 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 ranolazine 500 mg twice daily

[see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on ranolazine 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 to 4% and 15 to 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 and any potential adverse effects on the breastfed infant from

ranolazine 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 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, 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 is contraindicated in patients with liver cirrhosis. In a 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)].

8.7 Use in Patients with Renal Impairment

A pharmacokinetic study of ranolazine in subjects with severe renal impairment (CrCL less than 30

mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving ranolazine 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 if acute renal failure develops.

In a 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 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 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 is 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 produces small reductions in HbA1c in patients with diabetes, the clinical significance of

which is unknown. Ranolazine 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. In cases of extreme overdose of ranolazine 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 is 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

H N O , a molecular weight of 427.54 g/mole, and the following structural formula:

Ranolazine is a white to off-white solid. Ranolazine is soluble in dichloromethane and methanol;

sparingly soluble in tetrahydrofuran, ethanol, acetonitrile, and acetone; slightly soluble in ethyl acetate,

isopropanol, toluene, and ethyl ether; and very slightly soluble in water.

Ranolazine extended-release tablets contain 500 mg or 1000 mg of ranolazine and the following

inactive ingredients: colloidal silicon dioxide, hypromellose, iron oxide yellow, magnesium stearate,

methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol,

sodium hydroxide, talc, titanium dioxide and additional inactive ingredients for the 500 mg tablet include

iron oxide red.

12 CLINICAL PHARMACOLOGY

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 (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 Effects

Patients with chronic angina treated with ranolazine in controlled clinical studies had minimal changes in

mean heart rate (less than 2 bpm) and systolic blood pressure (less than 3 mm Hg). Similar results were

observed in subgroups of patients with CHF NYHA Class I 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 T wave amplitude, and, in some cases, notched T waves, have been observed in

patients treated with ranolazine. 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 a 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 a given dose of ranolazine give a wide range of effects on QTc. At Tmax following repeat dosing

at 1000 mg twice daily, the mean change in QTc is about 6 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 ranolazine. There was a significantly lower incidence of arrhythmias (ventricular

tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with

ranolazine (80%) versus placebo (87%), including ventricular tachycardia ≥3 beats (52% versus 61%).

However, this difference in arrhythmias did not lead to a reduction in mortality, a reduction in

arrhythmia hospitalization, or a 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 a 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 7 hours.

Steady state is generally achieved within 3 days of twice-daily dosing with ranolazine. At steady state

over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0-τ 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 Distribution

After oral administration of ranolazine, peak plasma concentrations of ranolazine are reached between 2

and 5 hours. After oral administration of 14C-ranolazine as a solution, 73% of the dose is systemically

available as ranolazine or metabolites. The bioavailability of ranolazine from ranolazine tablets relative

to that from a solution of ranolazine is 76%. Because ranolazine is a 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,

ranolazine may be taken without regard to meals. Over the concentration range of 0.25 to 10 µg/mL,

ranolazine is approximately 62% bound to human plasma proteins.

Metabolism and Excretion

Ranolazine is metabolized mainly by CYP3A and, to a lesser extent, by CYP2D6. Following a 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 5 to 33% that of ranolazine, and display

apparent half-lives ranging from 6 to 22 hours.

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