Ranolazine is a medication primarily used to treat chronic angina (chest pain) in individuals who haven't adequately responded to other medications. It belongs to a class of drugs called anti-anginals. Ranolazine works by improving blood flow to the heart to relieve chest pain. It does this by blocking certain sodium channels in heart muscle cells, which helps to stabilize the heart's electrical activity and improve its function.

Ranolazine is used for the management of stable ischemic heart disease patients with chronic angina, particularly those who fall into the following categories:

• Patients intolerant to Beta Blockers,
• When Beta Blockers are less effective
• Contraindication to a Beta Blocker as in asthma
• when the response to beta-blockers is insufficient, in conjunction with a beta blocker for symptomatic relief.
• in ventricular arrhythmia patients (off-label use)

Ranolazine Dose in Adults

Ranolazine is a medicine that helps people with chest pain called angina. It works by improving blood flow to the heart, making chest pain less likely. You usually take it twice a day, with or without food. It can be used together with other medicines like beta-blockers, nitrates, calcium channel blockers, and others that help the heart or blood vessels work better.

Ranolazine Dose in patients with chronic angina:

• The typical starting dose is 500 mg taken twice a day by mouth.
• If needed and based on symptoms, the dose can be increased to 1,000 mg twice daily.
• The maximum recommended dose is 1,000 mg twice daily.

Missed Dose:

• If you forget to take a dose, take it when you remember unless it's close to the time for your next dose.
• In that case, just take your next scheduled dose; don't take double the amount to make up for the missed dose.

Ranolazine Dose in ventricular arrhythmias:

• Ranolazine is typically taken orally at a dose ranging from 500 to 1,000 mg every 12 hours.

Dose adjustment with concomitant medications:

• It's crucial to adjust the dosage based on other medications being taken simultaneously.
• If you're using medications like diltiazem, erythromycin, fluconazole, verapamil, or other moderate CYP3A inhibitors, the maximum dose of ranolazine should not exceed 500 mg twice daily.
• Avoid using strong CYP3A inhibitors or inducers with ranolazine, as it's contraindicated. When taking P-glycoprotein inhibitors like cyclosporine, adjust the ranolazine dose according to how your body responds to it.

Ranolazine Dose in Children

Not recommended for use in children (Not studied)

Pregnancy Category D

• Adverse events have been observed in animal reproduction studies of ranolazine, indicating potential risks to pregnant individuals and their unborn babies.

Ranolazine during breastfeeding:

• The excretion of ranolazine into breast milk has not been established.
• Therefore, it's uncertain whether it passes into breast milk and if it can affect nursing infants.
• According to the manufacturer's guidelines, the decision to breastfeed while undergoing ranolazine therapy should be made by considering the potential risk of exposure to the infant and weighing it against the benefits of treatment for the mother.

Ranolazine Dose in Renal Disease:

• The manufacturer's instructions don't include specific dosage adjustments.
• However, in people with different levels of kidney problems, the amount of ranolazine in the blood increases by about 40% to 50%.
• If someone develops sudden kidney failure while taking ranolazine, they should stop using it.
• Ranolazine hasn't been studied in people who need dialysis, but it's unlikely that dialysis would remove much of it from the blood because it's tightly bound to proteins in the blood.

Ranolazine Dose in Liver Disease:

• The manufacturer's instructions don't mention any changes to the dosage.
• However, ranolazine shouldn't be used by people with hepatic cirrhosis; it's not safe for them.

Common side effects of Ranolazine include:

• Cardiovascular:
  • Bradycardia, palpitation, hypotension, edema, and prolonged QT interval.
• Central nervous system:
  • Dizziness, headache, confusion, vertigo, and syncope.
• Skin-related adverse effects:
  • hyperhidrosis
• Gastrointestinal effects:
  • Constipation, anorexia, abdominal pain, xerostomia, nausea, and dyspepsia.
• Genitourinary:
  • Hematuria
• Neuromuscular:
  • Weakness
• Respiratory:
  • Shortness of breath
• Ophthalmic:
  • blurred vision
• ENT-related effects:
  • Tinnitus

Contraindications to Ranolazine:

• For individuals with hepatic cirrhosis, as well as those using strong CYP3A inhibitors or inducers, the use of ranolazine is not recommended due to potential risks or interactions.

Warnings & Precautions:

Altered cardiac conduction:

• Ranolazine can affect the way your heart beats by prolonging the QTc interval, especially when the dosage or plasma concentration is high.
• When taken at a dose of 1000 mg twice daily, the average increase in QTc is around 6 milliseconds.
• However, in about 5% of people with the highest levels of the drug in their blood, the increase can be at least 15 milliseconds.
• Patients with mild to moderate liver cirrhosis may experience a threefold increase in QT prolongation, which is why ranolazine is not recommended for them.
• Although one trial showed that the incidence of symptomatic arrhythmias was similar to placebo, it's essential to weigh the risks and benefits, especially in patients on higher doses, those taking other medications that prolong the QT interval, those with certain genetic factors, or those with a history of QT prolongation.

Acute coronary syndrome:

• Ranolazine is not effective for relieving acute angina episodes, and it has not shown any benefit in treating acute coronary syndrome.

Hepatic impairment:

• In individuals with mild hepatic impairment (Child-Pugh class A), the levels of ranolazine in the blood increase by about 30%.
• For those with moderate hepatic impairment (Child-Pugh class B), the increase is even higher, around 80%.
• Due to these significant increases, the use of ranolazine is not recommended for patients with cirrhosis.

Renal impairment:

• In individuals with severe renal impairment (with a creatinine clearance of less than 30 mL/minute), there have been cases of acute renal failure observed.
• If acute renal failure occurs, characterized by a significant increase in serum creatinine along with elevated blood urea nitrogen (BUN), ranolazine should be stopped, and appropriate management should be initiated.
• Patients with moderate to severe renal impairment should have their renal function monitored regularly, especially for changes in serum creatinine and BUN levels.
• In a study involving renal impairment, patients with severe impairment initially experienced a rise in diastolic blood pressure, although this effect lessened over time.
• Therefore, blood pressure should be monitored in patients with renal dysfunction.
• Ranolazine hasn't been studied in patients requiring dialysis.

Monitoring Parameters:

ECG Monitoring for QT Interval:

• Before starting ranolazine and periodically afterward, doctors may perform an ECG (electrocardiogram) to check the QT interval, which measures heart rhythm.
• This helps ensure that ranolazine isn't causing dangerous heart rhythm changes.

Renal Function Monitoring:

• Patients with moderate to severe kidney problems should have their kidney function checked regularly.
• Doctors will look for increases in serum creatinine (a marker of kidney function) along with higher levels of blood urea nitrogen (BUN).

Blood Pressure Monitoring:

• People with kidney issues should also have their blood pressure monitored regularly.
• This helps track any changes in blood pressure that may occur while taking ranolazine.

Potassium Levels:

• It's important to keep potassium levels in the blood within normal limits.
• Doctors may recommend correcting and maintaining normal potassium levels while using ranolazine, especially in patients with renal impairment.

How to Administer Ranolazine?

• You can take ranolazine with or without food.
• It's important to swallow the tablet whole.

Do's:

• Swallow the tablet as a whole, without crushing, breaking, or chewing it.

Don'ts:

• Avoid crushing, breaking, or chewing the tablet.

Remember:

• Follow these instructions carefully to ensure you're taking ranolazine correctly for best results.

Mechanism of action of Ranolazine:

• Ranolazine works to alleviate chest pain and improve blood flow to the heart without affecting heart rate or blood pressure.
• It does this by targeting specific channels in heart muscle cells.
• At therapeutic levels, ranolazine targets the late phase of the inward sodium channel, which helps stabilize the heart's electrical activity during repolarization, leading to reduced calcium influx and decreased tension in the heart muscle.
• This ultimately reduces the heart's need for oxygen.
• However, the exact way ranolazine relieves chest pain isn't fully understood.
• At higher concentrations, ranolazine also affects another channel, prolonging the time it takes for the heart to reset between beats, which can lead to a longer QT interval on an ECG.

Absorption:

• Ranolazine absorption varies widely among individuals.

Protein Binding:

• Approximately 62% of ranolazine binds to proteins in the blood.

Metabolism:

• Ranolazine undergoes extensive metabolism, mainly in the liver through CYP3A enzymes (major) and to a lesser extent, CYP2D6 enzymes. Some metabolism also occurs in the intestines.

Bioavailability:

• When taken as a tablet, about 76% of the drug is absorbed into the bloodstream compared to a solution form.

Half-life Elimination:

• Ranolazine has a terminal elimination half-life of around 7 hours.
• Metabolites, which are not fully understood in their activity, have half-lives ranging from 6 to 22 hours.

Time to Peak Plasma Concentration:

• It takes about 2 to 5 hours for ranolazine to reach its peak concentration in the blood after administration.

Excretion:

• The primary route of excretion for ranolazine is through the urine, with approximately 75% eliminated, mostly as metabolites.
• A smaller portion is excreted in feces, with about 25% eliminated, also mostly as metabolites. Less than 5% of the drug is excreted unchanged in both urine and feces.

International Brands of Ranolazine:

• Cartinex
• Cartinex-OD
• Ralozine
• Ranasafe
• Ranev
• Ranexa
• Ranola ER
• Ranolin XR
• Ranosin
• Ranx
• Razine

Ranolazine Brands in Pakistan:

• Rancard XR (searle pharma)
• Ranola (Highnoon pharma)
• Razin Er (Getz Pharma)
• Ranzol SR (Maple Pharma)