4.1. Therapeutic indications

Ranolazine Krka 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).

4.2. Posology and method of administration

Posology

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

Adults: The recommended initial dose of Ranolazine Krka is 375 mg twice daily.

After 2–4 weeks, the dose should be titrated to 500 mg twice daily and, according to the patient's response, further titrated to a recommended maximum dose of 750 mg twice daily (see section 5.1).

If a patient experiences treatment-related adverse events (e.g. dizziness, nausea, or vomiting), down-titration of Ranolazine Krka 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 (e.g. diltiazem, fluconazole, erythromycin) or P-gp inhibitors (e.g. verapamil, ciclosporin) (see sections 4.4 and 4.5).

Concomitant administration of 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 30–80 ml/min) (see sections 4.4, 4.8, and 5.2). Ranolazine Krka 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). Ranolazine Krka is contraindicated in patients with moderate or severe hepatic impairment (see sections 4.3 and 5.2).

Elderly: Dose titration in elderly patients should be exercised with caution (see section 4.4). 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 (≤ 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 CHF (NYHA Class III–IV) should be exercised with caution (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Ranolazine Krka in children below the age of 18 years has not been established.

No data is available

Method of administration

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

4.3. Contraindications

Hypersensitivity to the active substance 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) antiarrhythmics other than amiodarone.

4.4. Special warnings and precautions for use

Caution should be exercised when prescribing or up-titrating ranolazine 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 30–80 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 (≤ 60 kg) (see sections 4.2, 4.8, and 5.2).

- Patients with moderate to severe CHF (NYHA Class III–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 Ranolazine Krka 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, Ranolazine Krka can be used with caution in these patients when they have a combination of several of the above risk factors.

QT prolongation: Ranolazine blocks IKr and prolongs the QTc interval in a doserelated manner. 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 1000 ng/ml, which is approximately equal to a 2- to 7-msec increase over the plasma concentration range for ranolazine 500 to 1000 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 drugs affecting the QTc interval (see section 4.5 also).

Drug-drug interactions: Co-administration with CYP3A4 inducers is expected to lead to lack of efficacy. Ranolazine Krka should not be used in patients treated with CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's 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 ranolazine (see sections 4.2, 4.3, 4.8, and 5.2).

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially "sodium-free".

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on ranolazine

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 ranolazine 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 Ranolazine Krka is recommended in patients treated with diltiazem and other moderately potent CYP3A4 inhibitors (e.g. erythromycin, fluconazole). Down-titration of Ranolazine Krka 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 Ranolazine Krka is recommended in patients treated with P-gp inhibitors. Down-titration of Ranolazine Krka 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 Ranolazine Krka should be avoided during administration of inducers of CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's 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 steadystate plasma concentrations of ranolazine 1000 mg twice daily by an average of 1.2fold. No dose adjustment is required. At the dose level 500 mg twice daily, coadministration of a potent inhibitor of CYP2D6 could result in an increase in ranolazine AUC of about 62%.

Effects of ranolazine on other medicinal products

Ranolazine 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 drugs 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 Ranolazine Krka may increase plasma concentrations of these drugs.

Available data suggest that ranolazine is a mild inhibitor of CYP2D6. Ranolazine Krka 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 Ranolazine Krka, and lower doses of these medicinal products 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 Ranolazine Krka and digoxin are co-administered. Therefore, digoxin levels should be monitored following initiation and termination of Ranolazine Krka therapy.

Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranolazine Krka 1000 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 Ranolazine Krka and simvastatin, in postmarketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking any dose of Ranolazine Krka.

Atorvastatin: Ranolazine Krka 1000 mg twice daily increased Cmax and AUC of atorvastatin 80 mg once daily by 1.4- and 1.3 -fold, respectively and changed the Cmax and AUC of atorvastatin metabolites less than 35%. Dose limitation of atorvastatin and appropriate clinical monitoring may be considered when taking Ranolazine Krka.

Dose limitation of other statins, metabolised by CYP3A4 (e.g. lovastatin), may be considered when taking Ranolazine Krka.

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 Ranolazine Krka 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).

Drugs transported by the Organic Cation Transporter-2 (OCT2): Plasma exposure of metformin (1000 mg twice daily) increased 1.4- and 1.8-fold in subjects with type 2 diabetes mellitus when co-administered with Ranolazine Krka 500 mg and 1000 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 ranolazine with other drugs known to prolong the QTc interval may give rise to a pharmacodynamic interaction and increase the possible risk of ventricular arrhythmias. Examples of such drugs include certain antihistamines (e.g. terfenadine, astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide), erythromycin, and tricyclic antidepressants (e.g. imipramine, doxepin, amitriptyline).

4.6. Fertility, pregnancy and lactation

Pregnancy: There are limited amount of data from the use of ranolazine in pregnant women. Studies in animals showed embryo toxicity (see Section 5.3). The potential risk for humans is unknown. Ranolazine Krka should not be used during pregnancy unless clearly necessary.

Breast-feeding: It is unknown whether ranolazine is excreted in human breast milk. Available pharmacodynamic/toxicological data in rats have shown excretion of ranolazine in milk (for details see Section 5.3). A risk to the suckling child cannot be excluded. Ranolazine Krka should not be used during breast-feeding.

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Undesirable effects in patients receiving ranolazine 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 ranolazine.

- Very common (≥ 1/10)

- Common (≥ 1/100 to < 1/10)

- Uncommon (≥ 1/1 000 to < 1/100)

- Rare (≥ 1/10 000 to < 1/1 000)

- Very rare (< 1/10 000)

- Not known (cannot be estimated from the available data)

Very common

Common

Uncommon

Rare

Metabolism and nutrition disorders

anorexia, decreased appetite, dehydration

hyponatremia

Psychiatric disorders

anxiety, insomnia, confusional state, hallucination

disorientation

Nervous system disorders

dizziness, headache

lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness, paresthesia

amnesia, depressed level of consciousness, loss of consciousness, coordination abnormal, gait disturbance, parosmia

Eye disorders

blurred vision, visual disturbance , diplopia

Ear and labyrinth disorders

vertigo, tinnitus

impaired hearing

Vascular disorders

hot flush, hypotension

peripheral coldness, orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

dyspnoea, cough, epistaxis

throat tightness

Gastrointestinal disorders

constipation, vomiting, nausea

abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort

pancreatitis, erosive duodenitis, oral hypoaesthesia

Skin and subcutaneous tissue disorders

pruritus, hyperhidrosis

angioedema, allergic dermatitis, urticaria, cold sweat, rash

Musculoskeletal and connective tissue disorders

pain in extremity, muscle cramp, joint swelling, muscular weakness

Renal and urinary disorders

dysuria, haematuria, chromaturia

acute renal failure, urinary retention

Reproductive system and breast disorders

erectile dysfunction

General disorders and administration site conditions

asthenia

fatigue, peripheral oedema

Investigations

increased blood creatinine, increased blood urea, prolonged QT corrected interval, increased platelet or white blood cell count, decreased weight

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 medicinal products, 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 revascularization post-PCI were given ranolazine up to 1000 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 ischemic attack occurred more frequently in patients treated with ranolazine 1000 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 ranolazine (placebo-corrected frequencies) in elderly (≥ 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 ≥ 30– 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 (≤ 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 ranolazine. 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 the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.

In postmarketing experience, there have been reports of intentional overdose of ranolazine alone or in combination with other drugs with a fatal outcome.