Ranolazine

Registered South African indications:

• As add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists)

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Severe renal impairment (CrCl<30ml/min)
• Moderate or severe hepatic impairment
• Concomitant administration of potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone)
• Concomitant administration of Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol) antidysrhythmics other than amiodarone
• Pregnancy
• Lactation

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Severe renal impairment (CrCl<30ml/min)
• Moderate or severe hepatic impairment
• Concomitant administration of potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone)
• Concomitant administration of Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol) antiarrhythmics other than amiodarone

Recommendations below are applicable to South Africa and other jurisdictions

Caution in the follo wing patient groups (caution should be exercised when prescribing or uptitrating ranolazine to patients in whom an increased exposure is expected)

• Mild to moderate renal impairment (CrCl 30-80ml/min)
• Mild hepatic impairment
• Elderly
• Concomitant administration of moderate CYP3A4 inhibitors
• Concomitant administration of P-gp inhibitors
• Patients with low weight (≤60kg)
• Patients with moderate to severe CHF (NYHA Class III–IV)

Patients with a combination of above factors

• In patients with a combination of these factors, additional exposure increases are expected. Dose-dependent side effects are likely to occur. If ranolazine is used in patients with a combination of several of these factors, monitoring of adverse events should be frequent, the dose reduced, and treatment discontinued, if needed
• The risk for increased exposure leading to adverse events in these different subgroups is higher in patients lacking CYP2D6 activity (poor metabolisers, PM) than subjects with CYP2D6 metabolising capacity (extensive metabolisers, EM)
• The above precautions are based on the risk in a CYP2D6 PM patient, and are needed when the CYP2D6 status is unknown
• There is a lower need for precautions in patients with CYP2D6 EM status. If the CYP2D6 status of the patient has been determined (e.g. by genotyping) or is previously known to be EM, ranolazine can be used with caution in these patients when they have a combination of several of the above risk factors

QT prolongation

• A population-based analysis of combined data from patients and healthy volunteers demonstrated that the slope of the plasma concentration-QTc relationship was estimated to be 2.4msec per 1000ng/ml
• This is approximately equal to a 2- to 7-msec increase over the plasma concentration range for ranolazine 500-1000mg twice daily
• Caution should be observed when treating patients with a history of congenital or a family history of long QT syndrome, in patients with known acquired QT interval prolongation, and in patients treated with medicines affecting the QTc interval

Medicine-medicine interactions

• Co-administration with CYP3A4 inducers is expected to lead to a lack of efficacy
• Ranolazine should not be used in patients treated with CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St John’s wort)

Renal impairment

• Renal function decreases with age, and it is therefore important to check renal function at regular intervals during treatment with ranolazine

Lactose

• Ranolazine 750mg tablets contain lactose monohydrate
• Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take ranolazine 750mg 

Ability to drive and use machines

• No studies on the effects of ranolazine on the ability to drive a vehicle and use machines have been performed. Ranolazine may cause dizziness, blurred vision, diplopia, confusional state, abnormal coordination, hallucination, which may affect the ability to drive a vehicle and use machines

Additional precautions applicable to South Africa

Tartrazine

• Ranolazine 750mg tablets contains tartrazine (FD&C Yellow No. 5 lake) which may cause allergic reactions

Additional precautions applicable for other jurisdictions

Caution in the follo wing patient groups

• Pregnancy
• Breastfeeding

Sodium content

• This medicine contains less than 1mmol sodium (23mg) per prolonged release tablet, that is to say essentially 'sodium-free'

Forms avail. in SA and covered in this monograph: prt

South African registered indications and dosages

Patients should be given the ranolazine patient information leaflet and patient alert card and be instructed to present their patient alert card and list of medicines used to their health care providers at each visit

As add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists)

• Oral (prt): Initial: 375mg, twice daily; Titrate to 500mg, twice daily after 2-4 weeks, according to patient response; Further titrated to a recommended max. dose of 750mg, twice daily; Downtitration recommended to 500mg, twice daily OR 375mg, twice daily if patient experiences treatment-related side effects, such as dizziness, nausea or vomiting; Discontinue if symptoms do not resolve after dose reduction

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Ranolazine tablets should be swallowed whole and not crushed, broken or chewed. Ranolazine tablets may be taken with or without food

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Concomitant treatment with CYP3A4 and P-glycoprotein (P-gp) inhibitors:
Careful dose titration is recommended in patients treated with moderate CYP3A4 inhibitors, such as diltiazem, fluconazole and erythromycin or P-glycoprotein (P-gp) inhibitors, such as verapamil and ciclosporin. Concomitant administration of ranolazine with potent CYP3A4 inhibitors is contraindicated, see Contraindications

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• There are no adequate data from the use of ranolazine in pregnant women
• Animal studies are insufficient with respect to effects on pregnancy and embryofoetal development
• The potential risk for humans is unknown. Ranolazine should not be used during pregnancy

Recommendations in other jurisdictions

• Caution; not recommended
• There are limited amount of data from the use of ranolazine in pregnant women
• Studies in animals showed embryo toxicity. The potential risk for humans is unknown
• Ranolazine should not be used during pregnancy unless clearly necessary

Breastfeeding

South African recommendations

• Contraindicated
• It is unknown whether ranolazine is excreted in human breast milk
• The excretion of ranolazine in milk has not been studied in animals. Ranolazine should not be used during breastfeeding

Recommendations in other jurisdictions

• Caution; not recommended
• It is unknown whether ranolazine is excreted in human breast milk
• Available pharmacodynamic/toxicological data in rats have shown excretion of ranolazine in milk
• A risk to the suckling child cannot be excluded. Ranolazine should not be used during breastfeeding

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• In animals, reproduction studies indicated no adverse effects on fertility. The effect of ranolazine on human fertility is unknown

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate (CrCl 30-80ml/min): Caution; no dose adjustment recommended
  Careful dose titration is recommended in these patients
• Severe (CrCl<30ml/min): Contraindicated

Recommendations below are applicable to South Africa and other jurisdictions

• Mild: Caution; no dose adjustment recommended
  Careful dose titration is recommended in these patients
• Moderate or severe: Contraindicated

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended
  Dose titration in elderly patients should be exercised with caution
  The elderly may have increased ranolazine exposure due to age-related decrease in renal function. The incidence of adverse events was higher in the elderly

Metabolism and Nutrition Disorders

Uncommon

• Anorexia
• Decreased appetite
• Dehydration

Rare

• Hyponatremia

Psychiatric Disorders

Uncommon

• Anxiety
• Insomnia
• Confusional state
• Hallucination

Rare

• Disorientation

Nervous System Disorders

Common

• Dizziness
• Headache

Uncommon

• Lethargy
• Syncope
• Hypoaesthesia
• Somnolence
• Tremor
• Postural dizziness
• Paresthesia

Rare

• Amnesia
• Depressed level of consciousness
• Loss of consciousness
• Coordination abnormal
• Gait disturbance
• Parosmia

Not known

• Myoclonus

Eye Disorders

Uncommon

• Blurred vision
• Visual disturbance
• Diplopia

Ear and Labyrinth Disorders

Uncommon

• Vertigo
• Tinnitus

Rare

• Impaired hearing

Vascular Disorders

Uncommon

• Hot flush
• Hypotension

Rare

• Peripheral coldness
• Orthostatic hypotension

Respiratory, Thoracic, and Mediastinal Disorders

Uncommon

• Dyspnoea
• Cough
• Epistaxis

Rare

• Throat tightness

Gastrointestinal Disorders

Common

• Constipation
• Vomiting
• Nausea

Uncommon

• Abdominal pain
• Dry mouth
• Dyspepsia
• Flatulence
• Stomach discomfort

Rare

• Pancreatitis
• Erosive duodenitis
• Oral hypoaesthesia

Skin and Subcutaneous Tissue Disorders

Uncommon

• Pruritus
• Hyperhidrosis

Rare

• Angioedema
• Allergic dermatitis
• Urticaria
• Cold sweat
• Rash

Musculoskeletal and Connective Tissue Disorders

Uncommon

• Pain in extremity
• Muscle cramp
• Joint swelling
• Muscular weakness

Renal and Urinary Disorders

Uncommon

• Dysuria
• Haematuria
• Chromaturia

Rare

• Acute renal failure
• Urinary retention

Reproductive System and Breast Disorders

Rare

• Erectile dysfunction

General Disorders and Administration Site Conditions

Common

• Asthenia

Uncommon

• Fatigue
• Peripheral oedema

Investigations

Uncommon

• Increased blood creatinine
• Increased blood urea
• Prolonged QT corrected interval
• Increased platelet or white blood cell count
• Decreased weight

Rare

• Elevated levels of hepatic enzyme

• Potent CYP3A4 inhibitors
• Itraconazole
• Ketoconazole
• Voriconazole
• Posaconazole
• HIV protease inhibitors
• Clarithromycin
• Telithromycin
• Nefazodone
• Moderate CYP3A4 inhibitors
• Diltiazem
• Erythromycin
• Fluconazole
• P-gp inhibitors
• Verapamil
• CYP3A4 inducers
• Rifampicin
• Phenytoin
• Phenobarbital
• Carbamazepine
• CYP2D6 inhibitors
• Paroxetine
• P-gp substrates
• CYP3A4 substrates
• Simvastatin
• Lovastatin
• Atorvastatin
• Tacrolimus
• Ciclosporin
• Sirolimus
• Everolimus
• CYP2D6 substrates
• Metoprolol
• Propafenone
• Flecainide
• Tricyclic antidepressants
• Imipramine
• Doxepin
• Amitriptyline
• Antipsychotics
• CYP2B6 substrates
• Bupropion
• Efavirenz
• Cyclophosphamide
• Digoxin
• Drugs transported by Organic Cation Transporter-2 (OCT2)
• Metformin
• Pindolol
• Varenicline
• Drugs that may prolong the QTc interval
• Certain antihistamines
• Terfenadine
• Astemizole
• Mizolastine
• Certain antiarrhythmics
• Class Ia antidysrhythmics
• Quinidine
• Class III antidysrhythmics (other than amiodarone)
• Dofetilide
• Sotalol
• Disopyramide
• Procainamide

Other interactions

• Grapefruit juice (potent CYP3A4 inhibitor)
• St. John's Wort

• Electrocardiogram (ECG)
  - Baseline and follow up ECG to evaluate QT interval
• Serum potassium
  - Correct and maintain serum potassium in normal limits

Specific cases may require

• Renal function
  - Periodically monitor renal function in patients with moderate to severe renal impairment, with particular attention to increases in serum creatinine accompanied by elevated BUN
• Blood pressure
  - Consider monitoring blood pressure in patients with renal dysfunction

Low weight

• The incidence of adverse events was higher in patients with low weight (≤60kg)
• Dose titration in patients with low weight should be exercised with caution

Congestive heart failure (CHF)

• Dose titration in patients with moderate to severe congestive heart failure (New York Heart Association (NYHA) Class III-IV) should be exercised with caution

The mechanism of action of ranolazine is largely unknown. Ranolazine may have some antianginal effects by inhibition of the late sodium current in cardiac cells. This reduces intracellular sodium accumulation and consequently decreases intracellular calcium overload. Ranolazine, via its action to decrease the late sodium current, is considered to reduce these intracellular ionic imbalances during ischaemia. This reduction in cellular calcium overload is expected to improve myocardial relaxation and thereby decrease left ventricular diastolic stiffness. Clinical evidence of inhibition of the late sodium current by ranolazine is provided by a significant shortening of the QTc interval and an improvement in diastolic relaxation in an open-label study of 5 patients with a long QT syndrome (LQT3 having the SCN5A ΔKPQ gene mutation). These effects do not depend upon changes in heart rate, blood pressure, or vasodilation.