RANOLAZINE tablet, film coated, extended release

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

RANOLAZINE (UNII: A6IEZ5M406) (RANOLAZINE - UNII:A6IEZ5M406)

Available from:

Amneal Pharmaceuticals 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 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. 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. Safety and effectiveness have not been established in pediatric patients. 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. 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)] . A pharmacokinetic study of ranolazine in subjects with severe renal impairment (CrCL <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. 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. 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.

Product summary:

Ranolazine extended-release tablets, 500 mg , are supplied as light orange, oblong shaped, film-coated, unscored tablets, debossed with “AN376” on one side and plain on the other side. They are available as follows: Bottles of 60:                          NDC: 65162-376-06 Bottles of 180:                        NDC: 65162-376-18 Bottles of 500:                        NDC: 65162-376-50 Ranolazine extended-release tablets, 1000 mg , are supplied as pale yellow, oblong shaped, film-coated, unscored tablets, debossed with “AN379” on one side and plain on the other side. They are available as follows: Bottles of 60:                          NDC: 65162-379-06 Bottles of 180:                        NDC: 65162-379-18 Bottles of 500:                        NDC: 65162-379-50 Store ranolazine extended-release tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP controlled Room Temperature].

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

RANOLAZINE- RANOLAZINE TABLET, FILM COATED, EXTENDED RELEASE
AMNEAL PHARMACEUTICALS 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)
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)
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 <60 mL/min). If acute renal failure develops,
discontinue ranolazine. (5.2)
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 AMNEAL PHARMACEUTICALS,
AT 1-877-835-
5472 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)
CYP3