Ranexa, 1000 mg 60 pcs

Pharmacodynamics

Ranexa is an antianginal drug. Ranolazine is an inhibitor of late current of sodium ions in myocardial cells. Reduction of intracellular sodium accumulation leads to a decrease of excess intracellular calcium ions. This reduces intracellular ionic imbalance during ischemia.

The reduction of excess intracellular calcium promotes myocardial relaxation and thus reduces diastolic tension of the ventricular wall. Clinical evidence of the inhibition of late sodium current under the action of ranolazine is a significant shortening of the QTc interval (QTc is the corrected QT value with heart rate) and a positive effect on diastolic relaxation identified in an open study involving patients with prolonged QT syndrome (patients with LQT-3 syndrome, having SCN5A ΔKPQ gene mutations). These effects of the drug are independent of changes in HR, BP, or the degree of vasodilation.

The incidence of angina attacks per week and consumption of short-acting nitroglycerin are significantly reduced with ranolazine compared to placebo, regardless of patient gender. No development of tolerance to ranolazine occurs during treatment. The incidence of angina attacks does not increase after abrupt discontinuation of the drug.

Ranolazine has a significant advantage over placebo in increasing time to angina attack and to ST-segment depression by 1 mm when taken at a dose of 500-1000 mg 2 times/day. The drug significantly improves exercise tolerance. A dose-effect relationship has been reported for ranolazine: the antianginal effect was greater with a higher dose than with a lower dose.

. When adding ranelazine (1,500 mg or 2,000 mg daily, divided into 2 doses, compared with placebo for 12 weeks) to treatment with atenolol 50 mg/day or amlodipine 5 mg/day or diltiazem 180 mg/day, Ranex® was shown to be superior to placebo for duration of exercise for both study drug doses (24 sec longer compared with placebo). However, no differences were noted in the duration of tolerated exercise between the two doses of Ranex®.

Effects detected at ECG: in patients treated with Ranex® there were observed dose- and plasma concentration-dependent prolongation of QTc interval (approximately 6 ms when taking 1000 mg 2 times per day), decrease of T-wave amplitude and, in some cases, double-headed T-waves. The ECG findings in patients taking ranolazine are the result of both inhibition by the drug of the rate of the fast rectifying potassium current, which prolongs the ventricular action potential, and inhibition of the late sodium current, which shortens the ventricular action potential. Population analysis showed that the use of ranolazine in both patients with stable angina pectoris and healthy volunteers resulted in an average QTc prolongation relative to baseline of 2.4 ms at a plasma ranolazine concentration of 1000 ng/mL. The rate of QTc prolongation was higher in patients with clinically significant hepatic impairment.

Patients receiving ranolazine had a significantly lower incidence of arrhythmias compared with placebo, including pirouette-type ventricular tachycardia ≥8 contractions per episode.

Effects on hemodynamics In patients treated with ranolazine as monotherapy or in combination with other antianginal agents, a slight decrease in HR (< 2 bpm) and decrease in systolic BP (< 3 mm Hg) were noted.

Pharmacokinetics

Intake

After oral administration, the Cmax of ranolazine in plasma is usually reached after 2-6 h. The average absolute bioavailability of ranolazine after oral administration is 35-50%, with a high degree of individual variability. When the dose is increased from 500 to 1000 mg 2 times/day, a 2.5-3-fold increase in AUC at equilibrium is observed. When taking ranolazine 2 times/day, Css is usually reached within 3 days. In healthy volunteers, Cssmax is approximately 1770 ng/ml, AUC0-12 at equilibrium averages 13,700 ng×h/ml after taking the drug at 500 mg 2 times/day. Food intake has no effect on the rate and completeness of absorption of ranolazine.

Distribution

Approximately 62% of ranolazine binds to plasma proteins, mainly to alpha-1 acidic glycoproteins, and slightly to albumin. The average Vss is about 180L.

Metabolism

Ranolazine undergoes rapid and almost complete metabolism in the liver. The most important pathways of metabolism of ranolazine are O-demethylation and N-dealkylation. Ranolazine is metabolized mainly by CYP3A4 isoenzyme and also by CYP2D6 isoenzyme. When administered at 500 mg 2 times a day in people with insufficient CYP2D6 isoenzyme activity, the AUC exceeds that of people with normal metabolic rate by 62%.

The similar difference for a dose of 1000 mg 2 times/day was 25%.

Less than 5% of the administered dose of ranolazine is excreted unchanged in the urine and feces. Clearance of ranolazine is dose-dependent, decreasing with increasing dose. T1/2 of ranolazine in equilibrium after oral administration is about 7 hours.

Pharmacokinetics in special clinical cases

In chronic heart failure (NYHA functional classes III-IV), there is an increase of approximately 1.3-fold in plasma concentration of ranolazine.

In patients with mild, moderate and severe renal insufficiency, compared to volunteers with normal renal function, the AUC of ranolazine was on average 1.7-2 times higher. There was significant individual variability in the AUC in volunteers with renal impairment. AUC of pharmacologically active metabolites increased 5-fold in patients with severe renal failure. Duration of retention of ranolazine in blood plasma increased 1.2 times in patients with moderate renal insufficiency (CKR 30-60 ml/min). In patients with severe renal insufficiency (CC

AUC index of ranolazine does not change in patients with mild hepatic insufficiency, but it increases 1.8 times in case of moderate hepatic insufficiency (7-9 points by Child-Pugh classification); in such patients prolongation of QTc interval was more expressed. There is no experience of using ranolazine in patients with severe hepatic insufficiency (more than 9 points according to Child-Pugh classification).

Indications

Stable angina pectoris.

Active ingredient

Composition

Active ingredient:

ranylazine 1000 mg;

Associates:

Microcrystalline cellulose,

Methacrylic acid and ethyl acrylate copolymer (1:1),

Hypromellose,

Magnesium stearate,

Sodium hydroxide.

Composition of the film coating:

Opadray II orange 85F93265 (macrogol 3350, partially hydrolyzed polyvinyl alcohol, talc, titanium dioxide, iron oxide yellow dye (E172), iron oxide red dye (E172), carnauba wax (trace amounts).

How to take, the dosage

The recommended starting dose of Ranex® for adults is 500 mg twice daily. After 2-4 weeks, if necessary, the dose can be increased to 1000 mg 2 times a day. The maximum daily dose is 2000 mg.

In case of side effects caused by taking Ranex® (e.g., dizziness, nausea or vomiting), the single dose should be reduced to 500 mg.

If the symptoms do not disappear after this, the drug should be discontinued.

In patients with chronic heart failure (NYHA functional class III-IV), mild to moderate renal failure (CKR 30-80 ml/min), mild hepatic failure (Child-Pugh score 5-6), and in patients with body weight less than 60 kg and patients older than 75 years, titration of the drug dose is recommended.

Eating does not affect the bioavailability of the drug, so it can be taken regardless of meals. The tablets should be swallowed whole with plenty of fluid, without crushing, breaking or chewing.

Interaction

Simultaneous use is contraindicated

Powerful inhibitors of CYP3A4 isoenzyme

Ranolazine is a substrate of cytochrome CYP3A4. Concomitant use with inhibitors of CYP3A4 isoenzyme activity increases the plasma concentration of ranolazine. Potential dose-dependent side effects (e.g., nausea, dizziness) may also increase with increasing blood plasma concentrations of the drug. Concomitant treatment with ketoconazole 200 mg 2 times/day increases AUC of ranolazine by 3-3.9 times.

The concomitant use of ranolazine and potent CYP3A4 isoenzyme inhibitors (e.g., itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin. nefazodone) is contraindicated.

Grapefruit juice is also a potent inhibitor of CYP3A4 isoenzyme.

Simultaneous use with caution

Moderate CYP3A4 isoenzyme inhibitors

Diltiazem (180-360 mg once daily), a moderately potent CYP3A4 isoenzyme inhibitor, causes a 1.5-2.4-fold increase in mean plasma Css of ranolazine, depending on the dose. For patients receiving diltiazem and other medium-acting CYP3A4 isoenzyme inhibitors (e.g., erythromycin, fluconazole), dose titration of ranolazine is recommended. It may be necessary to reduce the dose of ranolazine.

Inductors of CYP3A4 isoenzyme activity

The simultaneous use of ranolazine with inducers of CYP3A4 isoenzyme activity (rifampicin, phenytoin, phenobarbital, carbamazepine, Hypericum perforatum) may lead to a decrease in the drug effectiveness. For example, rifampicin (600 mg once daily) reduces plasma Css of ranolazine by approximately 95%. Therefore, the use of ranolazine should not be started in patients treated with CYP3A4 isoenzyme inducers.

P-glycoprotein inhibitors

Ranolazine is a substrate of P-glycoprotein (P-gp). P-gp inhibitors (e.g., cyclosporine, verapamil) increase plasma concentrations of ranolazine. Verapamil (120 mg 3 times/day) increases Css of ranolazine by 2.2 times. Dose titration of ranolazine is recommended for patients treated with P-gp inhibitors. It may be necessary to reduce the dose of ranolazine. On the other hand, ranolazine is a moderately potent P-gp inhibitor and a weak CYP3A4 isoenzyme inhibitor and may increase plasma concentrations of P-gp substrates or CYP3A4 isoenzymes. Tissue distribution of drugs that are transported by P-gp may be increased.

CYP2D6 isoenzyme substrates

There is evidence that ranolazine is a weak inhibitor of the CYP2D6 isoenzyme. Administration of ranolazine 750 mg 2 times/day increases the plasma concentration of metoprolol by 1.8 times. Therefore, in concomitant use with ranolazine, the effect of metoprolol or other substrates of CYP2D6 isoenzyme (e.g., propafenone and flecainide, to a lesser extent, tricyclic antidepressants and neuroleptics) may be enhanced; therefore, the dose of these drugs may require reduction.

CYP2B6 isoenzyme substrates

The potential to inhibit CYP2B6 isoenzyme has not been established. Caution is recommended during administration together with CYP2B6 isoenzyme substrates (e.g., bupropion, efavirenz, cyclophosphamide).

Digoxin

There is evidence of an average 1.5-fold increase in plasma digoxin concentration with concomitant use of digoxin and ranolazine. Therefore, it is necessary to monitor digoxin levels at the beginning and after the end of therapy with ranolazine.

CYP3A4 isoenzyme substrates

. Ranolazine is a weak inhibitor of CYP3A4 isoenzyme, which may lead to increased plasma concentrations of CYP3A4 isoenzyme substrates and require dose adjustment of sensitive CYP3A4 isoenzyme substrates (e.g., simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus, everolimus).

The metabolism and clearance of simvastatin are highly dependent on the CYP3A4 isoenzyme. Taking ranolazine at 1000 mg 2 times a day increases the concentration of simvastatin lactone, simvastatin acid, which increases the inhibition of HMG-CoA reductase by 1.4-1.6 times. Administration of simvastatin in high doses is associated with the development of rhabdomyolysis, there have also been described cases of rhabdomyolysis with the simultaneous use of ranolazine and simvastatin. The maximum dose of simvastatin for patients concomitantly taking ranolazine should not exceed 20 mg/day. For other statins metabolized with participation of CYP3A4 isoenzyme (lovastatin), dose limitation is possible.

Tacrolimus, cyclosporine, sirolimus, everolimus

An increase in plasma concentrations of tacrolimus, a substrate of the CYP3A4 enzyme, has been observed in patients with ranylazine. When concomitant use of tacrolimus and ranolazine, it is recommended to monitor plasma concentrations of tacrolimus and, if necessary, to make dose adjustments. This approach is also recommended for other substrates of CYP3A4 isoenzyme with narrow therapeutic range (e.g., cyclosporine, sirolimus, everolimus).

Drugs that prolong the QT interval

There is a theoretical possibility that concomitant use of ranolazine and other drugs that prolong the QT interval may result in pharmacodynamic interaction and an increased risk of ventricular arrhythmias. These drugs include certain antihistamines (e.g., terfenadine, astemizole, misolastin), certain antiarrhythmic drugs (e.g., quinidine, disopyramide, procainamide), and erythromycin and tricyclic antidepressants (e.g., imipramine, doxepin, amitriptyline).

Special Instructions

The drug Ranexa® is intended for continuous therapy.

Dose titration is recommended for patients with mild to moderate renal impairment (CKR 30-80 ml/min). The drug Ranexa® is contraindicated in patients with renal failure of severe degree of severity (CK < 30 ml/min).

Dose titration is recommended for patients with mild hepatic impairment (Child-Pugh score 5-6). Ranexa® is contraindicated in patients with mild (7-9 Child-Pugh scores) or severe (greater than 9 Child-Pugh scores) hepatic impairment.

In elderly patients, an increase in the effect of Ranex® may be observed due to age-related reduction in renal function. There is an increased incidence of side effects.

The dose for patients weighing less than 60 kg must be adjusted with caution, because we have seen more side effects in these patients.

Chronic heart failure

Dose adjustment for patients with moderate to severe chronic heart failure (NYHA functional class III-IV) should be performed with caution. Frequent monitoring of side effects is necessary; if necessary the drug dose should be reduced or the treatment should be cancelled.

Long QT interval

Population analysis of pooled data from studies of patients and healthy volunteers showed that the dependence of QTc interval duration on plasma concentrations can be estimated as 2.4 ms per 1000 ng/ml, which is approximately equal to an increase from 2 to 7 ms for a range of plasma concentrations corresponding to a dose of 500 to 1000 mg of ranolazine taken 2 times/day. Therefore, caution should be exercised when treating patients with a history of congenital QT interval prolongation, a family history of QT interval prolongation, patients with known acquired QT interval prolongation, and patients treated with drugs that affect the QT interval.

Deficient CYP2D6 isoenzyme activity

The risk of increased incidence of side effects in the indicated groups is increased in patients with deficient CYP2D6 isoenzyme activity (patients with “slow” metabolism) compared to patients with normal CYP2D6 isoenzyme metabolism capacity (patients with “fast” metabolism). Precautions are tailored to the risk in patients with “slow” CYP2D6 isoenzyme metabolism and are necessary if the metabolism status of CYP2D6 isoenzyme is unknown. For patients with “fast” CYP2D6 isoenzyme metabolism, these precautions are not necessary. In patients with an identified (e.g., by genotyping) or previously known intensive CYP2D6 isoenzyme metabolism status, Ranex® should be used with caution if the patient has a combination of several risk factors listed above.

Influence on the ability to drive vehicles and other mechanisms requiring high concentration

There have been no studies on the effect of ranelazine on the ability to drive vehicles and operate mechanisms. Taking into account the possibility of developing such side effects as dizziness, blurred vision, mental confusion and hallucinations, caution should be exercised while driving vehicles and operating machinery as well as while performing potentially dangerous activities requiring high concentration and quick psychomotor reactions.

Contraindications

Side effects

Metabolism: infrequent – decreased appetite, anorexia, dehydration.

Psychiatric disorders: infrequent – anxiety, insomnia, confusion, hallucinations; rarely – disorientation.

Nervous system disorders: frequently – dizziness, headache; infrequent – lethargy, fainting, hypoesthesia, somnolence, tremor, postural dizziness; rarely – amnesia, confusion, loss of consciousness, parosmia.

VIight: infrequent – blurred vision and visual disturbances.

Hearing and labyrinth disorders: infrequent – vertigo, tinnitus; rarely – decreased hearing.

Cardiovascular system: infrequent – blood rush to the face, marked BP decrease; rarely – cold extremities, orthostatic hypotension.

Respiratory system: infrequent dyspnea, cough, nasal bleeding; rarely – feeling of tightness in the throat.

The digestive system: frequently – constipation, nausea, vomiting; infrequently – abdominal pain, dry mouth, dyspepsia, flatulence, discomfort in the stomach; rarely – pancreatitis, erosive duodenitis, oral hypoesthesia.

Skin and subcutaneous tissue disorders: infrequent – skin itching, hyperhidrosis; rarely – allergic dermatitis, urticaria, cold sweat, skin rash, angioedema.

Muscular system disorders: infrequent – pain in extremities, muscle cramps, joint swelling.

Urinary system disorders: infrequent dysuria, hematuria, chromaturia; rarely – acute renal failure.

Perior genital system disorders: rarely – erectile dysfunction.

Laboratory disorders: infrequent – increased plasma creatinine concentration, increased plasma urea concentration, prolongation of the corrected QTc interval, thrombocytosis and leukocytosis, weight loss; rarely – increased liver enzyme activity.

General disorders: frequent – asthenia; infrequent – fatigue, peripheral edema.

Overdose

Symptoms: Dizziness, nausea and vomiting, diplopia, lethargy, fainting. Symptoms may increase with increasing dose.

Treatment:conducting symptomatic therapy. Within 30 minutes after taking the drug, measures may be taken to prevent its absorption from the gastrointestinal tract (gastric lavage, use of activated charcoal). Hemodialysis is ineffective.

Pregnancy use

In the absence of data, the use of Ranex® during pregnancy and breastfeeding is contraindicated.

There are no data on the use of ranolazine in pregnant women.

The penetration of ranolazine into the breast milk has not been studied.