Ranolazine Extended Release Tablets - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

Ranolazine extended-release tablets are used for the treatment of chronic angina, a condition in which the heart's blood supply is reduced and causes chest pain. As a metabolic modulator (a drug that modulates heart metabolism without affecting hemodynamics), it is frequently prescribed to individuals with chronic angina who do not exhibit sufficient antianginal responses in conjunction with other drugs such as Amlodipine, beta-blockers, or nitrates. The Food and Drug Administration (FDA) first approved Ranolazine extended-release tablets on January 27, 2006.

Drug Group

Extended-release Ranolazine tablets are antianginal medications used to treat chronic angina, a kind of chest pain brought on by a decrease in heart blood flow.

Indications

Ranolazine extended-release tabletshave been recommended to treat chronic angina.

Contraindications

Ranolazine extended-release tablets should not be used in the following situations:

• Potent CYP3A inhibitors, such as Nelfinavir, Clarithromycin, and Ketoconazole.

• CYP3A inducers such as St. John's wort, Phenobarbital, and Rifampin.

• Cirrhosis (liver scarring) of the liver.

Dosage Forms and Available Strengths

Ranolazine is an extended-release tablet in dosages of 500 mg (milligrams) and 1000 mg.

For Patients

What Is the Chronic Angina?

Chest pain or discomfort brought on by constricted or clogged cardiac arteries, sometimes referred to as ischemia, is known as chronic angina, or angina pectoris. It can extend to other upper body areas and typically starts beneath the breastbone. Angina can be classified into three types: unstable angina, which is unpredictable and lasts typically longer than stable angina; variant angina, which is caused by a transient spasm in the heart's arteries; and stable angina, which is the most common type and usually goes away with rest or angina medication.

How Do Ranolazine Extended-Release Tablets Work?

Ranolazine extended-release tablets work by preventing ischemic cardiac myocytes' late-phase inward sodium current (intercellular junction molecules) during cardiac repolarization (a process that allows the ventricular muscle to regain its ability to depolarize again). As a result of this inhibition, intracellular sodium concentrations are lowered, which decreases calcium influx through the sodium-calcium exchange. As the heart wall is less tense due to the reduced calcium levels, the muscles need less oxygen. Because Ranolazine enhances the heart's oxygen-using capacity, it is a valuable treatment for conditions such as chronic angina.

What Are the Benefits of Ranolazine Extended-Release Tablets?

For those with chronic angina, Ranolazine extended-release tablets offer the following advantages:

• Reduces the Frequency of Chest Pain: Ranolazine can reduce the frequency of chest pain episodes.

• Enhances Exercise Capacity: It might aid in improving exercise capacity.

• Functions Differently From Other Angina Treatments: Because Ranolazine functions differently from other angina treatments, patients can use it in combination with them, including nitrates, beta-blockers like Metoprolol, and calcium channel blockers like Amlodipine.

• Enhances the Heart's Oxygen Efficiency: It is believed to function by enhancing the heart's ability to use oxygen, allowing it to pump more blood while using less oxygen.

How Are Ranolazine Extended-Release Tablets Administered?

• Ranolazine extended-release (long-acting) tablets are available for oral use. Typically, Ranolazine tablets are taken twice a day, with or without food. Take Ranolazine daily at around the same time. Pay close attention to the instructions on the prescription label and ask the physician or pharmacist to explain anything the patient does not understand. Administer Ranolazine as prescribed. Never take more or less of it or more frequently than the physician has instructed.

• Do not break, chew, or crush the Ranolazine extended-release tablets; swallow them whole.

• Most likely, the physician will start patients on a low dosage of Ranolazine and increase it gradually.

• Never use Ranolazine to treat an angina attack that strikes suddenly. The doctor will advise patients on what to do in the event of an angina attack.

• Ranolazine will not cure the illness; it will only help manage it. Take Ranolazine as prescribed, even if patients feel well. Avoid stopping Ranolazine without consulting the doctor.

• Request a copy of the patient's manufacturer's information from the pharmacist or physician.

What Are the Side Effects of Ranolazine Extended-Release Tablets?

Ranolazine's adverse effects are likely to occur. If any of these symptoms are severe or persistent, let the physician know:

• Nausea.

• Constipation.

• Headache.

• Lightheadedness.

Certain adverse effects of Ranolazine may be dangerous. Give the physician a call right away if patients encounter any of the following symptoms:

• Erratic, rapid, or pounding heartbeat.

• Breathing difficulties.

• Fainting.

Sitting or lying down might cause dizziness and lightheadedness. To alleviate this, slowly get up. Allergic reactions such as hives (skin rash), breathing difficulties, or swelling of the face, lips, tongue, or neck are serious adverse effects. If patients encounter severe side effects, such as dizziness, get emergency medical attention.

What Are the Things to Inform the Doctor Before Taking Ranolazine Extended-Release Tablets?

1. If patients have a Ranolazine allergy or liver cirrhosis (liver scarring), then they should not use Ranolazine extended-release tablets.

2. Ranolazine extended-release tablets should not be taken with certain medications. If patients use it, then the treatment strategy might be modified.

• Clarithromycin.

• Nefazodone.

• St. John's Wort.

• Antifungal medication, such as Ketoconazole and Itraconazole.

• Medications for HIV (human immunodeficiency virus) or AIDS (acquired immunodeficiency syndrome) such as Indinavir, Lopinavir or Ritonavir, Nelfinavir, and Saquinavir.

• Medications for seizures (uncontrolled electrical activity in the brain) include Phenytoin, Phenobarbital, or Carbamazepine.

• Medications for tuberculosis (a bacterial infection) include Rifapentine, Rifampin, and Rifabutin.

3. Tell the doctor about any of the following to ensure that using this medication is safe for the patients:

• Long QT syndrome (in the patient or the family members).

• Liver illness.

• Renal illness.

4. Inform the doctor if a patient is pregnant or nursing a baby.

Dietary Considerations

When taking Ranolazine extended-release tablets, avoid consuming grapefruit juice or grapefruit-based products.

Missed Dose

Avoid taking a double dose of Ranolazine extended-release tablets to compensate for a missed dose and continue the regular dosing schedule.

Overdose

When taking extended-release Ranolazine tablets in excess, major adverse consequences may occur. One must seek emergency medical assistance as soon as one suspects an overdose. Over-dosage symptoms can include the following:

• Trouble speaking.

• Double vision.

• Hallucinations (false perception).

• Confusion.

• Uncontrolled shaking.

• Fainting.

• Numbness or tingling.

• Low blood pressure.

• Dizziness.

• Irregular heartbeats.

Contact the Poison Helpline if people have overdosed on Ranolazine.

Storage and Handling

Ranolazine extended-release tablets should be kept at room temperature (68 to 72 degrees Fahrenheit), securely closed, and out of children's reach.

Disposal

Dispose of unnecessary Ranolazine extended-release tablets in a way that keeps them out of the reach of kids, pets, and other people. Use the FDA's medication take-back program to get rid of them.

For Doctors

What Are the Pharmacological Actions of the Ranolazine Extended-Release Tablets?

Pharmacodynamics

Ranolazine has ischemia and antianginal effects without affecting blood pressure or heart rate. It prolongs the QTc interval and blocks IKr, a part of the delayed rectifier potassium current essential for cardiac repolarization. Neither during activity nor at rest does Ranolazine have any detrimental chronotropic, dromotropic, or inotropic effects when it comes to its therapeutic effects.

Mechanism of Action

Ranolazine inhibits the cardiac late sodium 205 current, which may help reduce the symptoms of angina. Its clinical value in the treatment of angina is still unknown, though. Ranolazine has little direct effect on atrioventricular nodal conduction and mild direct vasodilator properties due to its inhibiting sodium and potassium ion channel currents. In addition, it inhibits the oxidation of fatty acids and exhibits antagonistic activity towards alpha 1 and beta 1 adrenergic receptors. Additional modes of action have yet to receive confirmation.

Pharmacokinetics

• Absorption: The peak serum concentration of Ranolazine is typically two to six hours, with a steady state within three days. The FDA suggests a Tmax (time to peak drug concentration) of three to five hours with an average steady-state Cmax (maximum concentration) of 2600 ng/mL (nanograms per milliliter). Food consumption does not significantly affect Ranolazine absorption, and its bioavailability is 76 percent in tablet form compared to solution.

• Distribution: Ranolazine's average apparent volume of distribution is 53.2 L (liters), although its average steady-state volume of distribution is thought to vary between 85 and 180 L. A dose of 62 percent of Ranolazine has a greater binding affinity for alpha-1-acid glycoprotein.

• Metabolism: In the liver and gastrointestinal tract, Ranolazine is quickly and extensively metabolized by the CYP3A4 enzyme, with CYP2D6 playing a less significant role. More than 40 ranolazine metabolites have been found in plasma, while more than 100 metabolites have been found in urine. It is well known that Ranolazine and certain of its metabolites mildly inhibit CYP3A4. Nevertheless, the precise nature of Ranolazine's metabolites' function remains unclear.

• Excretion: When given twice daily at a dose of 500 mg, Ranolazine has a half-life of seven hours and a reported clearance rate of 45 L/h (liters per hour). Renal impairment can cause a 40 to 50 percent rise in the serum levels of Ranolazine, as its clearance rate is dose-dependent. One-fourth of the dose is eliminated through feces, approximately three-fourths is eliminated renally, and the remaining five percent is thought to remain unaltered.

Toxicity:

Oral Ranolazine LD50 (median lethal dose) in rats is 980 mg/kg (milligrams per kilogram); dose-related side effects include nausea, vomiting, and dizziness. High intravenous doses can result from syncope, paresthesia, diplopia, and disorientation. Supportive care and ongoing ECG (electrocardiogram) monitoring are necessary for overdoses to prevent QT interval prolongation.

What Are the Drug Interactions of the Ranolazine Extended-Release Tablets?

Effects of Other Drugs on Ranolazine

• Strong CYP3A Inhibitors (Ketoconazole, Itraconazole, Clarithromycin, Nefazodone, Nelfinavir, Ritonavir, Indinavir, and Saquinavir): It is not recommended to use Ranolazine extended-release tablets with potent CYP3A inhibitors.

• Moderate CYP3A Inhibitors (Diltiazem, Verapamil, Erythromycin, Fluconazole): The recommended dose of Ranolazine extended-release tablets for patients on moderate CYP3A inhibitors is 500 mg twice daily.

• P-gp Inhibitors (Cyclosporine): P-gp inhibitors and Ranolazine extended-release tablets can raise Ranolazine levels. For patients on primary P-gp inhibitor treatment, titrate Ranolazine extended-release tablets according to clinical response.

• CYP3A Inducers (Rifampin, Rifabutin, Rifapentine, Phenobarbital, Phenytoin, Carbamazepine, and St. John's Wort): When using CYP3A inducers, Ranolazine extended-release tablets should not be taken.

Effects of Ranolazine on Other Drugs

• Drugs Metabolized by CYP3A: Simvastatin should not be given to patients on Ranolazine extended-release tablets over 20 mg per day when Ranolazine is also being provided. For other sensitive CYP3A substrates and CYP3A substrates with a limited therapeutic range, dose modification might be required since Ranolazine extended-release tablets may raise the plasma concentrations of these medications.

• Drugs Transported by P-gp: Ranolazine and Digoxin concurrently increase exposure to Digoxin, potentially necessitating adjustments in the dose of Digoxin.

• Drugs Metabolized by CYP2D6: Lower dosages of CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be required when co-administered with Ranolazine extended-release tablets due to increased exposure to these medications.

• Drugs Transported by OCT2: Patients with type 2 diabetes (high blood sugar) who take Ranolazine extended-release tablets 1000 mg twice daily in addition to Metformin have higher plasma Metformin levels. It is advised that the daily dose should not exceed 1700 mg. Giving 500 mg of Ranolazine extended-release tablets twice a day did not significantly increase the exposure to Metformin.

Clinical Studies

In the CARISA (combination assessment of Ranolazine in stable angina) trial, 823 patients with chronic angina were randomly assigned to receive Ranolazine 750 mg, 1000 mg, or placebo for 12 weeks. Furthermore, daily dosages of Diltiazem CD 180 mg, Amlodipine 5 mg, or Atenolol 50 mg were given. With modest effects on blood pressure and heart rate, the study demonstrated significant increases in the duration of modified Bruce treadmill activity and the time to angina for each Ranolazine dose compared to placebo. After 12 weeks of treatment, tolerance to Ranolazine did not develop, and rebound increases in angina were not seen following an abrupt stop of Ranolazine. In patients with chronic angina who did not improve with treatment using the highest dose of an antianginal medication, Ranolazine was assessed as part of the ERICA (Efficacy of Ranolazine in chronic angina) study. The incidence of angina attacks and the use of nitroglycerin were significantly reduced when using Ranolazine as opposed to a placebo.

Warnings and Precautions

• QT Interval Prolongation: In a dose-related manner, Ranolazine prolongs the QTc interval and inhibits IKr. Clinical experience with patients with acute coronary syndrome did not reveal a higher risk of sudden death or proarrhythmia. On the other hand, little is known about large dosages, exposure, other medications extending the QT interval, potassium channel variations, long QT syndrome patients, or individuals with known acquired QT interval prolongation.

• Renal Failure: Patients with severe renal impairment have experienced acute renal failure when taking Ranolazine. If acute renal failure occurs, stop using Ranolazine and receive the proper care. After starting treatment, check for increased blood urea nitrogen and serum creatinine levels in patients with moderate to severe renal impairment, that is, creatinine clearance (CrCL) less than 60 mL/min (milliliters per minute).

Use in Specific Populations

• Pregnancy: Pregnant women have not been adequately investigated with Ranolazine extended-release tablets. It should be applied only in cases where the advantages outweigh the potential risks to the developing fetus. The manufacturer has not advised the use of Ranolazine extended-release tablets during pregnancy. Studies on animals exposed to four times the maximum human dose found no signs of prenatal damage. Controlled data on human pregnancy does not exist.

• Breastfeeding: Ranolazine extended-release tablets should not be used while lactating because of their unclear possible effects on lactation.

• Pediatric Use: The efficacy and safety of Ranolazine extended-release tablets for pediatric patients are unknown.

• Geriatric Use: Studies indicate that no age-specific issues restrict Ranolazine's effectiveness in the elderly. However, age-related liver, renal, or heart issues are more common in older people and may require dose modifications.

• Hepatic impairment: Ranolazine extended-release tablets are not recommended for use by patients with liver cirrhosis.

• Renal Impairment: The renal function of patients with moderate to severe renal impairment needs to be checked frequently. If acute renal failure occurs, Ranolazine extended-release tablets should be stopped.

• Use in Patients with Heart Failure: There was no need for a dose adjustment in patients with heart failure because Ranolazine pharmacokinetics did not significantly affect heart failure patients. It had minimal effect on heart rate and blood pressure.

• Use in Patients with Diabetes Mellitus: The study indicated that neither angina patients' nor healthy subjects' Ranolazine pharmacokinetics were affected by diabetes, and no dosage modification is required. Although Ranolazine lowers HbA1c in diabetic patients slightly, its therapeutic importance is unclear.