Of the patients treated with Ranexa, 1,026 were enrolled in three double-blind, placebo-controlled, randomized studies of up to 12 weeks duration. In addition, upon study completion, 746 patients received continued treatment with Ranexa in open-label, long-term studies; 639 patients were exposed to Ranexa for more than 1 year, 578 patients for more than 2 years, and 372 for more than 3 years. Subgroup evaluations in patients with reactive airway disease, CHF, and diabetes were also conducted. These conditions did not alter the general nature or frequency of treatment- emergent adverse events observed in the broader ranolazine-treated population.

In controlled clinical trials of angina patients, the most frequently reported treatment-emergent adverse events ( > 4%), occurring more often with ranolazine than placebo, were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). In open-label, long-term treatment studies, a similar adverse event profile was observed in patients treated with ranolazine.

About 6% of patients discontinued treatment with Ranexa due to 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%), and nausea (1% versus 0%), asthenia, constipation and headache (each about 0.5% versus 0%).

Small, reversible elevations in serum creatinine and BUN levels have been observed in clinical studies with ranolazine. These elevations were observed without evidence of renal toxicity (see PRECAUTIONS and Laboratory Tests).

Adverse Events Occurring at an Incidence of ≥ 2% Among Ranexa-treated Angina Patients in the CARISA and ERICA Trials

The most commonly observed treatment-emergent adverse events for chronic angina patients from CARISA and ERICA that occurred more frequently with ranolazine than placebo are shown in Table 4.

Table 4: Treatment-Emergent Adverse Events in CARISA and ERICA ( ≥ 2% in Ranexa-treated Patients)

The dose-related adverse events of dizziness and syncope are shown in Table 5.

Table 5: Incidence of Dizziness and Syncope in CARISA and ERICA

Adverse Events Occurring Among All Ranolazine-treated Patients with Chronic Angina

A total of 2,018 patients with chronic angina were treated with ranolazine in controlled clinical trials.

The following additional adverse events occurred at an incidence of > 0.5 to < 2.0% in patients treated with ranolazine and were more frequent than the incidence observed in placebo-treated patients.

Cardiac Disorders – palpitations

Ear and Labyrinth Disorders – tinnitus, vertigo

Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting

General Disorders and Administrative Site Adverse Events – peripheral edema

Respiratory, Thoracic and Mediastinal Disorders – dyspnea

Other more rare ( ≤ 0.5%) but potentially medically important adverse events observed more frequently with ranolazine than placebo treatment in controlled studies included: bradycardia, hematuria, hypoesthesia, hypotension, orthostatic hypotension, paresthesia, tremor, and blurred vision.

Drug Abuse And Dependence

Ranolazine does not have any potential for abuse or dependence.

(also see CLINICAL PHARMACOLOGY, Drug-Drug Interactions, and DOSAGE AND ADMINISTRATION)

Pharmacokinetic Interactions: Effects of Other Drugs on Ranolazine

Ketoconazole

As a potent inhibitor of CYP3A, ketoconazole (200 mg b.i.d.) increases average steady-state plasma concentrations of ranolazine 3.2-fold. Ranexa should not be used during treatment with ketoconazole (see CONTRAINDICATIONS).

Diltiazem

As a moderate inhibitor of CYP3A, diltiazem (180 to 360 mg daily) causes dose-dependent mean increases in average ranolazine steady-state concentrations of about 1.8- to 2.3-fold.

Verapamil

Verapamil 120 mg t.i.d. increases ranolazine steady-state plasma concentrations about 2-fold.

Cimetidine

Co-administration of cimetidine does not increase the plasma concentrations of ranolazine. No dose adjustment of Ranexa is required in patients treated with cimetidine.

Rifampin

Rifampin 600 mg q.d. decreases the plasma concentration of ranolazine by approximately 95%. Co-administration of Ranexa and rifampin should be avoided.

Digoxin

Co-administration of digoxin does not increase the plasma concentration of ranolazine. No dose adjustment of Ranexa is required in patients treated with digoxin.

Paroxetine

Paroxetine, a potent inhibitor of CYP2D6, increased average steady-state plasma concentrations of ranolazine 1.2-fold. No dose adjustment of Ranexa is required in patients treated with paroxetine or other CYP2D6 inhibitors.

Pharmacokinetic Interactions: Effects of Ranolazine on Other Drugs

Digoxin

As a result of an interaction at the P-gp level, co-administration of ranolazine and digoxin results in a 1.5-fold elevation of digoxin plasma concentrations. The dose of digoxin may have to be adjusted when ranolazine is co-administered with digoxin.

Simvastatin

Co-administration of ranolazine and simvastatin results in about a 2-fold increase in plasma concentrations of simvastatin, and its active metabolite.

Warfarin

Ranolazine has no significant effect on the pharmacokinetics of (+) R- and (-) S-warfarin.

Drug/Laboratory Test Interactions

Ranolazine is not known to interfere with any laboratory test.

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