Ranexa

Ranolazine is used alone or with other medications to treat chronic angina (ongoing chest pain or pressure that is felt when the heart does not get enough oxygen). Ranolazine is in a class of medications called anti-anginals. The exact way that ranolazine works is not known at this time.

Ranolazine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• constipation
• headache
• dizziness

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

• fast, pounding, or irregular heartbeat
• difficulty breathing
• fainting

Ranolazine may cause other side effects. Call your doctor if you have any unusual problems while you are taking this medication.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• nausea
• vomiting
• dizziness
• confusion
• double vision
• pain, burning, numbness, or tingling in any part of the body
• fainting
• uncontrollable shaking of a part of the body
• difficulty speaking
• seeing things or hearing voices that do not exist

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.

Pharmacodynamics

Patients with chronic angina treated with RANEXA in controlled clinical studies had minimal changes in mean heart rate ( < 2 bpm) and systolic blood pressure ( < 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.

Dose and plasma concentration-related increases in the QTc interval [see WARNINGS AND PRECAUTIONS], reductions in T wave amplitude, and, in some cases, notched T 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 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].

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 a 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 ≥ 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.

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 RANEXA. 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.

After oral administration of RANEXA, 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 RANEXA 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, RANEXA 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.

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.

Drug Interactions

In vitro data indicate that ranolazine is a substrate of CYP3A and, to a lesser degree, of CYP2D6. Ranolazine is also a substrate of P-glycoprotein.

Plasma levels of ranolazine with RANEXA 1000 mg twice daily are increased by 220% when co-administered with ketoconazole 200 mg twice daily [see CONTRAINDICATIONS].

Plasma 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].

The 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.

Rifampin 600 mg once daily decreases the plasma concentrations of ranolazine (1000 mg twice daily) by approximately 95% [see CONTRAINDICATIONS].

Paroxetine 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.

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.

The plasma levels of simvastatin, a 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]. 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.

The pharmacokinetics of diltiazem is not affected by ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and RANEXA 1000 mg twice daily.

Ranolazine increases digoxin concentrations by 50% in healthy volunteers receiving RANEXA 1000 mg twice daily and digoxin 0.125 mg once daily [see DRUG INTERACTIONS].

RANEXA 750 mg twice daily increases the plasma concentrations of a single dose of immediate release metoprolol (100 mg), a CYP2D6 substrate, by 80% in extensive CYP2D6 metabolizers with no need for dose adjustment of metoprolol. In extensive metabolizers of dextromethorphan, a substrate of CYP2D6, ranolazine inhibits partially the formation of the main metabolite dextrorphan.

In subjects with type 2 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].

Clinical Studies

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 RANEXA 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 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 1 : Exercise Treadmill Results (CARISA)

The effects of RANEXA on angina frequency and nitroglycerin use are shown in Table 2.

Table 2 : Angina Frequency and Nitroglycerin Use (CARISA)

Tolerance 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 1 week, followed by 6 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 3 : Angina Frequency and Nitroglycerin Use (ERICA)

Effects 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.

There were insufficient numbers of non-Caucasian patients to allow for analyses of efficacy or safety by racial subgroup.

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 Pharmacodynamics], 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).

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.

Ranexa is a prescription medication used to treat chronic angina (ongoing chest pain).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Gilead Sciences, Inc.

Antianginal agent; a piperazine derivative.1 2 3 4 6 9 10 11 12 13 14 15 16 18 19 20

Metabolized by CYP isoenzymes, principally CYP3A and, to a lesser extent, CYP2D6.1 6 9 10 11 15 16 19 20 Weak inhibitor of CYP isoenzyme 3A and moderate inhibitor of CYP isoenzyme 2D6.1 11 16 Does not inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, or 2E1.1 24

Substrate and moderate inhibitor of the p-glycoprotein transport system.1 11 16

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A and 2D6 inhibitors: Potential pharmacokinetic interaction (increased plasma ranolazine concentrations).1 Avoid concomitant use with potent CYP3A inhibitors.1 Maximum ranolazine dosage of 500 mg twice daily in patients receiving moderate CYP3A inhibitors (see Specific Drugs and Foods under Interactions).1

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A and 2D6 substrates: Potential pharmacokinetic interaction (increased plasma concentration of substrate).1

Drugs that Inhibit the p-Glycoprotein Transport System

Potential pharmacokinetic interaction (increased absorption of ranolazine) with p-glycoprotein inhibitors.1 11 16 19 Reduce dosage of ranolazine as needed based on clinical response in patients receiving p-glycoprotein inhibitors (see Specific Drugs and Foods under Interactions).1

Drugs That Prolong QT Interval

Potential pharmacologic effect (additive effect on QT interval prolongation).11 Experience with concomitant use of ranolazine with drugs that prolong the QT interval is limited.1

Specific Drugs and Foods

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

If you will be taking this medicine for a long time, it is very important that your doctor check you at regular visits for any problems or unwanted effects that may be caused by this medicine. Blood tests may be needed to check for unwanted effects.

Do not use ranolazine together with carbamazepine (Tegretol®), clarithromycin (Biaxin®), nefazodone (Serzone®), phenobarbital, phenytoin (Dilantin®), rifabutin (Mycobutin®), rifampin (Rifadin®, Rimactane®), rifapentine (Priftin®), medicine to treat fungus infections (eg, itraconazole, ketoconazole, Nizoral®, Sporanox®), medicine to treat HIV or AIDS (eg, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, Crixivan®, Fortovase®, Invirase®, Norvir®, Viracept®), or St. John's wort.

Do not use this medicine to treat a sudden onset of chest pain.

This medicine can cause a change in the heart rhythm called prolongation of the QT interval. This condition may change the way your heart beats and can cause palpitations or fainting spells. Check with your doctor right away if you start having any of these symptoms.

This medicine may cause acute kidney failure in some patients with severe kidney disease. Check with your doctor right away if you have the following symptoms: agitation, confusion, decreased urine output, depression, dizziness, headache, hostility, irritability, lethargy, muscle twitching, nausea, rapid weight gain, seizures, stupor, swelling of the face, ankles, or hands, or unusual tiredness or weakness.

This medicine may cause some people to become dizzy, lightheaded, drowsy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Grapefruit and grapefruit juice may increase the effects of ranolazine by increasing the amount of medicine in the body. You should not eat grapefruit or drink grapefruit juice while you are taking this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Dizziness

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• continuous ringing or buzzing or other unexplained noise in the ears
• difficult or labored breathing
• fast, irregular, pounding, or racing heartbeat or pulse
• feeling of constant movement of self or surroundings
• hearing loss
• lightheadedness
• rapid weight gain
• sensation of spinning
• tightness in the chest
• tingling of the hands or feet
• unusual weight gain or loss

• Abnormal or decreased touch sensation
• agitation
• blood in the urine
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain or discomfort
• chills
• cold sweats
• coma
• confusion
• decreased urine output
• depression
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• headache
• hostility
• irritability
• lethargy
• muscle twitching
• nausea
• seizures
• shakiness in the legs, arms, hands, or feet
• slow or irregular heartbeat
• stupor
• sweating
• trembling or shaking of the hands or feet
• unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Difficulty having a bowel movement (stool)

• Dry mouth
• stomach pain

• Lack or loss of strength

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Ranexa may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Grapefruit and grapefruit juice may interact with ranolazine and lead to unwanted side effects. Discuss the use of grapefruit products with your doctor.