Ranexa 375 mg, 500 mg, 750 mg Prolonged-release tablets

RANEXA is indicated in adults 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).

Patients should be given the RANEXA 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.

Posology

RANEXA is available as 375 mg, 500 mg and 750 mg prolonged-release tablets.

Adults: The recommended initial dose of RANEXA is 375 mg twice daily. After 2 u2013 4 weeks, the dose should be titrated to 500 mg twice daily and according to the patientu2019s response, further titrated to a recommended maximum dose of 750 mg twice daily (see section 5.1). If a patient experiences treatment-related side effects, such as dizziness, nausea or vomiting, down-titration of RANEXA to 500 mg or 375 mg twice daily may be required. If symptoms do not resolve after dose reduction, treatment should be discontinued.

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 (see sections 4.4 and 4.5).

Concomitant administration of RANEXA with potent CYP3A4 inhibitors is contraindicated (see sections 4.3 and 4.5).

Renal impairment: Careful dose titration is recommended in patients with mild to moderate renal impairment (creatinine clearance 30 u2013 80 mL/min) (see sections 4.4, 4.8 and 5.2). RANEXA is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections 4.3 and 5.2).

Hepatic impairment: Careful dose titration is recommended in patients with mild hepatic impairment (see sections 4.4 and 5.2). RANEXA is contraindicated in patients with moderate or severe hepatic impairment (see sections 4.3 and 5.2).

Elderly patients: Dose titration in elderly patients should be exercised with caution (see section 4.4). The elderly may have increased ranolazine exposure due to age-related decrease in renal function (see section 5.2). The incidence of adverse events was higher in the elderly (see section 4.8).

Low weight: The incidence of adverse events was higher in patients with low weight (u2264 60 kg). Dose titration in patients with low weight should be exercised with caution (see sections 4.4, 4.8 and 5.2).

Congestive heart failure (CHF): Dose titration in patients with moderate to severe congestive heart failure (New York Heart Association (NYHA) Class III u2013 IV) should be exercised with caution (see sections 4.4 and 5.2).

Paediatric population: The safety and efficacy of RANEXA in children below the age of 18 years have not been established. No data are available.

Method of administration

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

• Hypersensitivity to ranolazine or to any of the excipients listed in section 6.1.
• Severe renal impairment (creatinine clearance < 30 mL/min) (see sections 4.2 and 5.2).
• Moderate or severe hepatic impairment (see sections 4.2 and 5.2).
• Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) (see sections 4.2 and 4.5).
• Concomitant administration of Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol) antidysrhythmics other than amiodarone.
• Pregnancy and lactation (see section 4.6).

Caution should be exercised when prescribing or uptitrating RANEX to patients in whom an increased exposure is expected:

• Concomitant administration of moderate CYP3A4 inhibitors (see sections 4.2 and 4.5).
• Concomitant administration of P-gp inhibitors (see sections 4.2 and 4.5).
• Mild hepatic impairment (see sections 4.2 and 5.2).
• Mild to moderate renal impairment (creatinine clearance 30 u2013 80 mL/min) (see sections 4.2, 4.8 and 5.2).
• Elderly (see sections 4.2, 4.8 and 5.2).
• Patients with low weight ( u2264 60 kg) (see sections 4.2, 4.8 and 5.2).
• Patients with moderate to severe CHF (NYHA Class III u2013 IV) (see sections 4.2 and 5.2).

In patients with a combination of these factors, additional exposure increases are expected. Dose-dependent side effects are likely to occur. If RANEXA 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) (see section 5.2). 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, RANEXA 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 2,4 msec per 1 000 ng/mL, which is approximately equal to a 2- to 7-msec increase over the plasma concentration range for ranolazine 500 to 1 000 mg twice daily. Therefore, 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 (see section 4.5).

Medicine-medicine interactions: Co-administration with CYP3A4 inducers is expected to lead to lack of efficacy. RANEXA should not be used in patients treated with CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St Johnu2019s wort) (see section 4.5).

Renal impairment: Renal function decreases with age and it is therefore important to check renal function at regular intervals during treatment with Ranexa (see sections 4.2, 4.3, 4.8 and 5.2).

Lactose: RANEXA 750 mg tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take RANEXA 750 mg tablets.

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

Effects of other medicines on RANEXA

CYP3A4 or P-gp inhibitors: Ranolazine is a substrate of cytochrome CYP3A4. Inhibitors of CYP3A4 increase plasma concentrations of ranolazine. The potential for dose-related adverse events (e.g. nausea, dizziness) may also increase with increased plasma concentrations. Concomitant treatment with ketoconazole 200 mg twice daily increased the AUC of ranolazine by 3,0- to 3,9-fold during RANEXA treatment. Combining ranolazine with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated (see section 4.3). Grapefruit juice is also a potent CYP3A4 inhibitor.

Diltiazem (180 to 360 mg once daily), a moderately potent CYP3A4 inhibitor, causes dose-dependent increases in average ranolazine steady-state concentrations of 1,5- to 2,4-fold. Careful dose titration of RANEXA is recommended in patients treated with diltiazem and other moderately potent CYP3A4 inhibitors (e.g. erythromycin, fluconazole). Down-titration of RANEXA may be required (see sections 4.2 and 4.4).

Ranolazine is a substrate for P-gp. Inhibitors of P-gp (e.g. ciclosporin, verapamil) increase plasma levels of ranolazine. Verapamil (120 mg three times daily) increases ranolazine steady-state concentrations 2,2-fold. Careful dose titration of RANEXA is recommended in patients treated with P gp inhibitors. Down-titration of RANEXA may be required (see sections 4.2 and 4.4).

CYP3A4 inducers: Rifampicin (600 mg once daily) decreases ranolazine steady-state concentrations by approximately 95 %. Initiation of treatment with RANEXA should be avoided during administration of inducers of CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St Johnu2019s wort) (see section 4.4).

CYP2D6 inhibitors: Ranolazine is partially metabolised by CYP2D6; therefore, inhibitors of this enzyme may increase plasma concentrations of ranolazine. The potent CYP2D6 inhibitor paroxetine, at a dose of 20 mg once daily, increased steady-state plasma concentrations of ranolazine 1 000 mg twice daily by an average of 1,2-fold. No dose adjustment is required. At the dose level 500 mg twice daily, co-administration of a potent inhibitor of CYP2D6 could result in an increase in ranolazine AUC of about 62 %.

Effects of RANEXA on other medicines

Ranolazine, as in RANEXA, is a moderate to potent inhibitor of P-gp and a mild inhibitor of CYP3A4, and may increase plasma concentrations of P-gp or CYP3A4 substrates. Tissue distribution of medicine which are transported by P-gp may be increased.

Dose adjustment of sensitive CYP3A4 substrates (e.g. simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic range (e.g. ciclosporin, tacrolimus, sirolimus, everolimus) may be required as RANEXA may increase plasma concentrations of these medicines.

Available data suggest that ranolazine is a mild inhibitor of CYP2D6. RANEXA 750 mg twice daily increased plasma concentrations of metoprolol by 1,8-fold. Therefore the exposure to metoprolol or other CYP2D6 substrates (e.g. propafenone and flecainide or, to a lesser extent, tricyclic antidepressants and antipsychotics) may be increased during co administration with RANEXA, and lower doses of these medicines may be required.

The potential for inhibition of CYP2B6 has not been evaluated. Caution is advised during co administration with CYP2B6 substrates (e.g. bupropion, efavirenz, cyclophosphamide).

Digoxin: An increase in plasma digoxin concentrations by an average of 1,5-fold has been reported when RANEXA and digoxin are co-administered. Therefore, digoxin levels should be monitored following initiation and termination of RANEXA therapy.

Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. RANEXA 1 000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid by about 2 fold. Rhabdomyolysis has been associated with high doses of simvastatin and cases of rhabdomyolysis have been observed in patients receiving RANEXA and simvastatin, in postmarketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking any dose of RANEXA.

Atorvastatin: Ranexa 1 000 mg twice daily increased C max and AUC of atorvastatin 80 mg once daily by 1,4- and 1,3-fold, respectively and changed the C max and AUC of atorvastatin metabolites less than 35 %. Dose limitation of atorvastatin and appropriate clinical monitoring may be considered when taking RANEXA. Dose limitation of other statins, metabolised by CYP3A4 (e.g. lovastatin), may be considered when taking RANEXA.

Tacrolimus, ciclosporin, sirolimus, everolimus: Increased plasma concentrations of tacrolimus, a CYP3A4 substrate, have been observed in patients after ranolazine administration. It is recommended that tacrolimus blood levels are monitored when co-administering RANEXA and tacrolimus and that tacrolimus dosage is adjusted accordingly. This is also recommended for other CYP3A4 substrates with a narrow therapeutic range (e.g. ciclosporin, sirolimus, everolimus).

Medicines transported by the organic cation transporter-2 (OCT2): Plasma exposure of metformin (1 000 mg twice daily) increased 1,4- and 1,8-fold in subjects with type 2 diabetes mellitus when co-administered with RANEXA 500 mg and 1 000 mg twice daily respectively. The exposure of other OCT2 substrates, including but not limited to pindolol and varenicline, may be affected to a similar degree. There is a theoretical risk that concomitant treatment of RANEXA with other medicines known to prolong the QTc interval may give rise to a pharmacodynamic interaction and increase the possible risk of ventricular dysrhythmias. Examples of such medicines include certain antihistamines (e.g. terfenadine, astemizole, mizolastine), certain antidysrhythmics (e.g. quinidine, disopyramide, procainamide), erythromycin and tricyclic antidepressants (e.g. imipramine, doxepin, amitriptyline).

Pregnancy: 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 (see section 5.3). The potential risk for humans is unknown. RANEXA should not be used during pregnancy.

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

Fertility: In animals, reproduction studies indicated no adverse effects on fertility (see section 5.3). The effect of ranolazine on human fertility is unknown.

No studies on the effects of RANEXA on the ability to drive a vehicle and use machines have been performed. RANEXA may cause dizziness, blurred vision, diplopia, confusional state, coordination abnormal, hallucination (see section 4.8), which may affect the ability to drive a vehicle and use machines.

Undesirable effects in patients receiving RANEXA are generally mild to moderate in severity and often develop within the first 2 weeks of treatment. These were reported during the Phase 3 clinical development programme, which included a total of 1 030 chronic angina patients treated with RANEXA.

The adverse events, considered to be at least possibly related to treatment, are listed below by body system, organ class and absolute frequency. Frequencies are defined as very common ( u2265 1/10), common ( u2265 1/100 to < 1/10), uncommon ( u2265 1/1 000 to < 1/100), rare ( u2265 1/10 000 to < 1/1 000) and very rare (< 1/10 000).

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, paraesthesia
• Rare: amnesia, depressed level of consciousness, loss of consciousness, abnormal coordination, gait disturbance, parosmia

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 hypaesthesia

Skin and subcutaneous tissue disorders

• Uncommon: pruritus, hyperhydrosis
• Rare: angioedema, allergic dermatitis, urticaria, cold sweat, rash

Musculoskeletal and connective tissue disorders

• Uncommon: pain in extremity, muscle cramps, 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

The adverse event profile was generally similar in the MERLIN-TIMI 36 study. In this long-term study, acute renal failure was also reported with an incidence less than 1 % in placebo and ranolazine patients. Evaluations in patients who may be considered at higher risk of adverse events when treated with other antianginal medicines, e.g. patients with diabetes, Class I and II heart failure, or obstructive airway disease, confirmed that these conditions were not associated with clinically meaningful increases in the incidence of adverse events.

An increased incidence of adverse events was seen among ranolazine treated patients in the RIVER-PCI trial (see section 5.1) where patients with incomplete revascularisation post-PCI were given ranolazine up to 1 000 mg twice daily or placebo for approximately 70 weeks. In this study, there was a higher reporting rate for congestive heart failure in the ranolazine group (2,2 % vs 1,0 % in placebo). Also, transient ischaemic attack occurred more frequently in patients treated with ranolazine 1 000 mg twice daily compared with placebo (1,0 % vs 0,2 %, respectively); however, the incidence of stroke was similar between treatment groups (ranolazine 1,7 % vs placebo 1,5 %).

Elderly, renal impairment and low weight: In general, adverse events occurred more frequently among elderly patients and patients with renal impairment; however, the types of events in these subgroups were similar to those observed in the general population. Of the most commonly reported, the following events occurred more often with RANEXA (placebo-corrected frequencies) in elderly ( u2265 75 years of age) than younger patients (< 75 years of age): constipation (8 % versus 5 %), nausea (6 % versus 3 %), hypotension (5 % versus 1 %) and vomiting (4 % versus 1 %).

In patients with mild or moderate renal impairment (creatinine clearance u2265 30 u2013 80 mL/min) compared to those with normal renal function (creatinine clearance > 80 mL/min), the most commonly reported events and their placebo-corrected frequencies included: constipation (8 % versus 4 %), dizziness (7 % versus 5 %) and nausea (4 % versus 2 %).

In general, the type and frequency of adverse events reported in patients with low body weight (u2264 60 kg) were similar to those of patients with higher weight (> 60 kg); however, the placebo-corrected frequencies of the following common adverse events were higher in low body weight than heavier patients: nausea (14 % versus 2 %), vomiting (6 % versus 1 %) and hypotension (4 % versus 2 %).

Laboratory findings: Small, clinically insignificant, reversible elevations in serum creatinine levels have been observed in healthy subjects and patients treated with RANEXA. There was no renal toxicity related to these findings. A renal function study in healthy volunteers demonstrated a reduction in creatinine clearance with no change in glomerular filtration rate consistent with inhibition of renal tubular secretion of creatinine.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of RANEXA is important. It allows continued monitoring of the benefit/risk balance of RANEXA. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

In an oral high-dose tolerability study in angina patients, the incidence of dizziness, nausea and vomiting increased in a dose-dependent manner. In addition to these adverse events, diplopia, lethargy and syncope were observed in an intravenous overdose study in healthy volunteers. In the event of overdose, the patient should be closely monitored and the treatment should be symptomatic and supportive. Approximately 62 % of ranolazine is bound to plasma proteins, and therefore, complete clearance by haemodialysis is unlikely.