Ranoplan

Uses

Ranoplan is used for the treatment of chronic angina. Ranoplan may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. It has been shown to decrease angina episodes in patients with coronary artery disease on maximal doses of amlodipine. Because Ranoplan prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other antianginal drugs.The effect on angina rate or exercise tolerance appeared to be smaller in women than men.

Ranoplan is also used to associated treatment for these conditions: Chronic Angina, Arrhythmia of ventricular origin

How Ranoplan works

Myocardial ischemia exerts effects on adenosine triphosphate flux, leading to a decrease in the energy available for contraction and relaxation of the heart muscle. Electrolyte balance of sodium and potassium is necessary for maintaining normal cardiac contraction and relaxation. Disruption of adequate sodium and potassium electrolyte balance leads to excessively high concentrations of sodium and calcium, which likely interferes with oxygen supply to the heart muscle. This imbalance eventually leads to angina symptoms of chest pain or pressure, nausea, and dizziness, among others.

The mechanism of action for ranolazine is not fully understood. At therapeutic concentrations, it can inhibit the cardiac late sodium 205 current (INa), which may affect the electrolyte balance in the myocardium, relieving angina symptoms. The clinical significance this inhibition in the treatment of angina symptoms is not yet confirmed.

Ranoplan inhibits sodium and potassium ion channel currents. It has been shown to exert weak activity on L-type calcium channels making it a weak direct vasodilator and exerts minimal direct effects on atrioventricular nodal conduction. Some additional mechanisms have been elucidated. Ranoplan exerts antagonistic activity towards the alpha 1 and beta 1 adrenergic receptors and inhibition of fatty acid oxidation.

Dosage

Ranoplan dosage

Initiate Ranoplan dosing at 500 mg twice daily and increase to 1000 mg twice daily, if needed, based on clinical symptoms. Take Ranoplan with or without meals. Swallow Ranoplan tablets whole; do not crush, break or chew. The maximum recommended daily dose of Ranoplan is 1000 mg twice daily. If a dose of Ranoplan is missed, take the prescribed dose at the next scheduled time; do not double the next dose.

Side Effects

Cardiac Disorders: bradycardia, 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

Vascular Disorders: hypotension, orthostatic hypotension

Toxicity

The reported LD50 of oral ranolazine in the rat is 980 mg/kg. High oral doses of ranolazine have led to dizziness, nausea, and vomiting. These effects have been shown to be dose related. High intravenous doses can cause diplopia, confusion, paresthesia, in addition to syncope. In the case of an overdose, provide supportive therapy accompanied by continuous ECG monitoring for QT interval prolongation.

Precaution

Ranoplan blocks QTc 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.

Co-administration of ranolazine with digoxin increases the plasma concentrations of digoxin by approximately 1.5-fold and the dose of digoxin may have to be reduced accordingly. The dose of other P-gp substrates may have to be reduced as well when ranolazine Is co-admlnistered. Caution should be exercised when co-adminlstering ranolazine with P-gp inhibitors such as ritonavir or cydosporine.

Interaction

CYP 3A Inhibitors: Do not use Ranoplan with strong CYP 3A inhibitors. With moderate CYP 3A inhibitors (e.g., diltiazem, verapamil, erythromycin) limit maximum dose of ranolazine to 500 mg twice daily.

CYP 3A Inducers: Do not use Ranoplan with inducers.

P-gp Inhibitors (e.g., Cyclosporin): May need to lower the Ranoplan dose based on clinical dose.

Drugs transported by P-gp or metabolized by CYP2D6 (eg., digoxin, TCA): May need reduced doses of these drugs when used with ranolazine.

Food Interaction

• Avoid grapefruit products.
• Take with or without food. The absorption is unaffected by food.

[Major] GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of orally administered ranolazine.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Because ranolazine prolongs QT interval in a dose-dependent manner, high plasma levels of ranolazine may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes.

MANAGEMENT: Patients treated with ranolazine should avoid consumption of grapefruit juice and other grapefruit products if possible.

Otherwise, the dosage of ranolazine should be limited to 500 mg twice a day.

Ranoplan Drug Interaction

Major: atorvastatin, acetaminophen / hydrocodoneModerate: ticagrelor, apixaban, empagliflozin, metoprolol, metoprolol, rivaroxabanUnknown: aspirin, aspirin, ubiquinone, rosuvastatin, omega-3 polyunsaturated fatty acids, insulin glargine, furosemide, nitroglycerin, clopidogrel, cyanocobalamin, ascorbic acid, cholecalciferol

Ranoplan Disease Interaction

Major: severe hepatic impairmentModerate: QT prolongation, renal disease

Volume of Distribution

The mean apparent volume of distribution of ranolazine is reported to be 53.2 L and the average steady-state volume of distribution is estimated to range from 85 to 180 L.

Elimination Route

The time to reach peak serum concentration is quite variable but has been observed to be in the range of 2-6 hours, with steady-state within 3 days. The FDA indicates a Tmax of 3-5 hours. The average steady-state Cmax is about 2600 ng/mL. Absorption of ranolazine is not significantly affected by food consumption. The bioavailability of ranolazine taken in the tablet form compared to that from a solution of ranolazine is about 76%.

Half Life

The apparent terminal half-life of ranolazine is 7 hours.

Clearance

The reported clearance rate of orally administered ranolazine is of 45 L/h when administered at a dose of 500 mg twice daily. The clearance rate of ranolazine is dose-dependent and renal impairment can increase ranolazine serum concentration by 40-50%.

Elimination Route

From the administered dose, about 3/4 of the dose is excreted renally, while 1/4 of the dose is excreted in the feces. An estimated 5% of an ingested dose is excreted as unchanged drug.

Pregnancy & Breastfeeding use

Pregnancy Category C. There are no adequate studies assessing the effect of ranolazine on the developing fetus. There are no adequate well-controlled studies in pregnant women. Ranoplan should be used during pregnancy only when the potential benefit to the patient justifies the potential risk to the fetus.lt is not known whether ranolazine is excreted in human milk. Because of the potentiality for serious adverse reactions from ranolazine in nursing infants, a decision should be made whether to discontinue nursing or to discontinue Ranoplan, taking into account the importance of the drug to the mother.

Contraindication

Ranoplan is contraindicated in patients:

• With pre-existing QT prolongation
• With hepatic impairment
• Taking QT prolonging drugs
• Taking potent and moderately potent CYP3A inhibitors such as ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir, including diltiazem.

Special Warning

Pediatric use: Safety and effectiveness in pediatric patients have not been established.Renal Impairment:

• Mild to moderate (CrCl 30-80 mL/min): Dose titration needed
• Severe (CrCl <30 mL/min): Contraindicated

Hepatic Impairment:

• Mild: Dose titration needed
• Moderate to severe: Contraindicated

Acute Overdose

Symptoms: Dizziness, nausea, vomiting, diplopia, lethargy, syncope, severe tremor, incoordination, dysplasia, hallucination.

Management: Symptomatic and supportive treatment.

Storage Condition

Store Ranoplan tablets at 25°C with excursion permitted to 15° to 30°C. Protect from light and moisture.

Innovators Monograph

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