Ranolazine

Ranolazine Uses, Dosage, Side Effects, Food Interaction and all others data.

Ranolazine has anti-ischemlc and antlanginal effects that do not depend upon reductions in heart rate or blood pressure.The exact mechanism of action of ranolazine is unknown. 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.

Ranolazine exerts both antianginal and ischemic effects independent from lowering heart rate or blood pressure. It blocks IKr, the rapid portion of the delayed rectifier potassium current, and prolongs the QTc interval in a dose-dependent fashion. The Ikr is important for cardiac repolarization. Ranolazine exerts its therapeutic effects without negative chronotropic, dromotropic, or inotropic actions neither at rest, nor during exercise.

Trade Name Ranolazine
Availability Prescription only
Generic Ranolazine
Ranolazine Other Names Ranolazina, Ranolazine
Related Drugs amlodipine, aspirin, metoprolol, carvedilol, propranolol, atenolol
Weight 1000mg, 500mg
Type Oral tablet, extended release
Formula C24H33N3O4
Weight Average: 427.5365
Monoisotopic: 427.247106559
Protein binding

Approximately 62% of the administered dose of ranolazine is bound to plasma proteins. Ranolazine appears to have a higher binding affinity for alpha-1 acid glycoprotein.

Groups Approved, Investigational
Therapeutic Class Other Anti-anginal & Anti-ischaemic drugs
Manufacturer
Available Country United States
Last Updated: September 19, 2023 at 7:00 am
Ranolazine
Ranolazine

Uses

Ranolazine is used for the treatment of chronic angina. Ranolazine 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 Ranolazine 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.

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

How Ranolazine 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.

Ranolazine 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. Ranolazine exerts antagonistic activity towards the alpha 1 and beta 1 adrenergic receptors and inhibition of fatty acid oxidation.

Dosage

Ranolazine dosage

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

Ranolazine 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 Ranolazine 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 Ranolazine with inducers.

P-gp Inhibitors (e.g., Cyclosporin): May need to lower the Ranolazine 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.

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. Ranolazine 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 Ranolazine, taking into account the importance of the drug to the mother.

Contraindication

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

Innovators Monograph

You find simplified version here Ranolazine

Ranolazine contains Ranolazine see full prescribing information from innovator Ranolazine Monograph, Ranolazine MSDS, Ranolazine FDA label

FAQ

What is Ranolazine used for?

Ranolazine used to treat heart related chest pain. Typically it is used together with other medications when those are insufficient.

How safe is Ranolazine?

Ranolazine is a safe drug with minimal side effects. It is metabolized mainly in the liver and cleared by the kidney.

How does Ranolazine work?

Ranolazine by reducing the flow of calcium into the cells, Ranolazine is thought to help the heart to relax, improving blood flow to the heart muscle and relieving the symptoms of angina pectoris.

What are the common side effects of Ranolazine?

Common side effects of Ranolazine include:

  • dizziness,
  • spinning sensation,
  • nausea,
  • vomiting,
  • stomach pain,
  • constipation,
  • headache,
  • dry mouth,
  • weakness,
  • ringing in your ears,
  • swelling in hands/ankles/feet,
  • slow/fast/irregular heartbeats,
  • tremors,
  • blood in the urine, and
  • shortness of breath.

Is Ranolazine safe during pregnancy?

This drug should not be used during pregnancy unless clearly needed. The manufacturer makes no recommendation regarding use during pregnancy. Animal studies failed to reveal evidence of fetal harm at exposures 4 times the maximum recommended human dose.


Is Ranolazine safe during breastfeeding?

Use should be avoided.Benefit should outweigh risk.The effects in the nursing infant are unknown.

Can I drink alcohol with Ranolazine?

Intake of alcohol with Ranolazine will make you feel dizzy and sleepy. It is better to avoid alcohol when you are on this drug especially when you have to be alert.

When is the best time to take Ranolazine?

Try to take your doses at the same times of day each day, as this will help you to remember to take them regularly. You can take Ranolazine either before or after a meal.

How long does it take for Ranolazine to start working?

Ranolazine doesn't work very fast, and usually takes about 4 hours for peak effect.

What does Ranolazine do for the heart?

By reducing the flow of calcium into the cells, Ranolazine is thought to help the heart to relax, improving blood flow to the heart muscle and relieving the symptoms of angina pectoris.

Does Ranolazine lower blood pressure?

Ranolazine has beneficial metabolic properties and does not affect heart rate or blood pressure.

What happens if I stop taking Ranolazine?

Do not suddenly stop taking this medication without consulting your doctor. Your condition may become worse when the drug is suddenly stopped. Your dose may need to be gradually decreased.

Can Ranolazine cause shortness of breath?

Ranolazine can causes slow/fast/irregular heartbeats, tremors, blood in the urine, and. shortness of breath.

Who should not take Ranolazine?

You should not take Ranolazine if you have cirrhosis of the liver.
Tell your doctor about all your current medicines and any you start or stop using. Many drugs can interact, and some drugs should not be used together.

What happens if I miss a dose?

Skip the missed dose and use your next dose at the regular time. Do not use two doses at one time.

What happens if I overdose?

Seek emergency medical attention.Overdose can cause nausea, vomiting, numbness or tingling, dizziness, double vision, confusion, or fainting.

What does Ranolazine do for the heart?

By reducing the flow of calcium into the cells, Ranolazine is thought to help the heart to relax, improving blood flow to the heart muscle and relieving the symptoms of angina pectoris.

Is Ranolazine bad for kidneys?

Ranolazine does not commonly cause kidney problems.

*** Taking medicines without doctor's advice can cause long-term problems.
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