Chemical formula: C₂₄H₃₃N₃O₄ Molecular mass: 427.537 g/mol PubChem compound: 56959
Ranolazine interacts in the following cases:
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).
Ranolazine blocks IKr and prolongs the QTc interval in a dose-related 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.
Available data suggest that ranolazine is a mild inhibitor of CYP2D6. Ranolazine 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, and lower doses of these medicinal products may be required.
The potential for inhibition of CYP2B6 by ranolazine has not been evaluated. Caution is advised during co-administration with CYP2B6 substrates (e.g. bupropion, efavirenz, cyclophosphamide).
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 RANEXA may increase plasma concentrations of these drugs.
Careful dose titration of ranolazine is recommended in patients treated with moderate CYP3A4 inhibitors (e.g. diltiazem, fluconazole, erythromycin) or P-gp inhibitors (e.g. verapamil, ciclosporin).
Careful dose titration is recommended in patients with mild to moderate renal impairment (creatinine clearance 30–80 ml/min).
Dose titration of ranolazine in patients with moderate to severe CHF (NYHA Class III–IV) should be exercised with caution.
Careful dose titration of ranolazine is recommended in patients with mild hepatic impairment.
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%.
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. John’s Wort).
Ranolazine 1,000 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.
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 ranolazine therapy.
Plasma exposure of metformin (1,000 mg twice daily) increased 1.4- and 1.8-fold in subjects with type 2 diabetes mellitus when coadministered with ranolazine 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.
Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranolazine 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 ranolazine and simvastatin, in postmarketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking any dose of ranolazine.
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.
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 breast-feeding.
In animals, reproduction studies indicated no adverse effects on fertility. The effect of ranolazine on human fertility is unknown.
No studies on the effects of ranolazine on the ability to drive and use machines have been performed. Ranolazine may cause dizziness, blurred vision, diplopia, confusional state, coordination abnormal, hallucination, which may affect the ability to drive and use machines.
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.
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 (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000).
Uncommon: anorexia, decreased appetite, dehydration.
Rare: hyponatremia
Uncommon: anxiety, insomnia, confusional state, hallucination.
Rare: disorientation.
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.
Uncommon: blurred vision, visual disturbance, diplopia.
Uncommon: vertigo, tinnitus.
Rare: impaired hearing.
Uncommon: hot flush, hypotension.
Rare: peripheral coldness, orthostatic hypotension.
Uncommon: dyspnoea, cough, epistaxis.
Rare: throat tightness.
Common: constipation, vomiting, nausea.
Uncommon: abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort.
Rare: pancreatitis, erosive duodenitis, oral hypoaesthesia.
Uncommon: pruritus, hyperhydrosis.
Rare: angioedema, allergic dermatitis, urticaria, cold sweat, rash.
Uncommon: pain in extremity, muscle cramp, joint swelling, muscular weakness.
Uncommon: dysuria, haematuria, chromaturia.
Rare: acute renal failure, urinary retention.
Rare: erectile dysfunction.
Common: asthenia.
Uncommon: fatigue, peripheral oedema.
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 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 where patients with incomplete revascularization 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 ischemic 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%).
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%).
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.
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