Ranexa® [Ranolazine]

Pharmacological properties

the mechanism of action of ranolazine is still largely unknown. ranolazine may have some antianginal effect by suppressing the late flow of sodium ions into myocardial cells, reduces intracellular sodium accumulation and, accordingly, reduces the excess of intracellular calcium ions. it is believed that ranolazine by reducing the late current of sodium ions reduces intracellular ionic imbalance in ischemia. it can be expected that such a decrease in the excess of intracellular calcium will contribute to the relaxation of the myocardium and, thus, reduce ventricular diastolic stress. Clinical evidence of inhibition of late sodium current by ranolazine is a significant reduction in the q – tc interval and a positive effect on diastolic relaxation in patients with long q – t interval syndrome. these effects of the drug are not dependent on a decrease in heart rate, on hell or vasodilation.

Effect on hemodynamics. Clinical studies have shown that in patients receiving ranolazine alone or in combination with other drugs intended for the treatment of angina pectoris, there was a decrease in average heart rate (2 beats / min) and average systolic blood pressure (3 mmHg).

Effects manifested on the ECG. In patients receiving this drug, an extension of the Q – Tc interval was observed, which depended on the dose and concentration in the blood plasma (approximately 6 ms with 1000 mg 2 times a day), a decrease in the amplitude of the T wave and, in some cases, two-humped T waves. It is believed that this effect of ranolazine on ECG characteristics is the result of inhibition of the fast potassium current of the rectifier channel, which lengthens the ventricular action potential, and also inhibits late sodium current, which reduces the ventricular action potential. Studies have shown the dependence of the lengthening of the Q – Tc interval on a concentration of 2.4 ms per 1000 ng / ml ranolazine in blood plasma, which is approximately equal to an extension from 2 to 7 ms for a concentration range corresponding to a dose of 500 to 1000 mg 2 times a day . The rate of elongation was higher in patients with clinically significant liver failure.

Pharmacokinetics After oral administration of Ranex C_max ranolazine in blood plasma, as a rule, is observed after 2-6 hours. When applied 2 times a day, the equilibrium state is usually reached within 3 days.

Suction. The average bioavailability of ranolazine after oral administration of tablets with immediate release is 35-50%, with a high degree of individual variation. The effect of the Ranex drug is enhanced depending on the dose. With an increase in dose from 500 to 1000 mg 2 times a day, a 2.5–3-fold increase in AUC in equilibrium is observed. Meal time did not affect the rate and completeness of absorption.

Distribution. Approximately 62% of ranolazine binds to plasma proteins. The average volume of distribution in equilibrium (Vss) is approximately 180 liters.

Ranolazine is excreted mainly by the metabolic route. Less than 5% of the dose is excreted unchanged in urine and feces. After ingestion of a single dose of 500 mg labeled with radioactive carbon [¹⁴C] ranolazine by healthy individuals 73% of the radioactivity is determined in the urine and 25% in the feces. The clearance of ranolazine depends on the dose, decreasing with its increase. T_½ approximately 2–3 hours after iv administration. Terminal T_½ in equilibrium after oral administration of ranolazine is approximately 7 hours, which is due to the limitation of the rate of excretion by rapid absorption.

Biotransformation. Ranolazine undergoes a fast and large-scale metabolism. In healthy young volunteers, after a single oral administration of 500 mg of ranolazine labeled with radioactive carbon, 13% of the radioactivity is determined in blood plasma.A large number of metabolites were detected in human blood plasma (47 metabolites), urine (100 metabolites) and feces (25 metabolites). Fourteen major metabolic pathways were identified, among which O-demethylation and N-dealkylation are the most important. In vitro studies using human liver microsomes have shown that ranolazine is metabolized by CYP 3A4 as well as CYP 2D6. When using 500 mg of ranolazine 2 times a day in people with insufficient CYP 2D6 activity, the AUC indicator exceeds 62% in people with normal CYP 2D6 activity. The corresponding difference for a dose of 1000 mg 2 times a day was 25%.

The effect of gender. Gender has no clinical effect on pharmacokinetic parameters.

Elderly patients. Elderly age also has no clinical effect on pharmacokinetic parameters, however, in elderly people, an increased effect of ranolazine is possible due to an age-related decrease in renal function.

Body mass. In individuals with a body weight of 40 kg, the effect of ranolazine is approximately 1.4 times greater than in individuals with a body weight of 70 kg.

Congestive Heart Failure (CHF). CHF (NYHA classes III – IV) leads to an increase in plasma concentration of ranolazine by 1.3 times.

Renal failure. Studies have shown that in patients with mild, moderate or severe renal failure, the AUC was on average 1.7–2 times higher than in individuals with normal renal function. Significant individual variability of the AUC value in individuals with renal failure was also noted. AUC metabolites increase with decreased renal function. The studies revealed an increase in the effect of ranolazine by 1.2 times in patients with moderate renal failure (creatinine clearance - 40 ml / min) and 1.3-1.8 times in patients with severe renal failure (creatinine clearance - 10-30 ml / min).

Liver failure. Experience with the use of ranolazine in patients with severe hepatic insufficiency is absent. In persons with mild hepatic insufficiency, the AUC of ranolazine does not change, and in patients with moderate hepatic insufficiency, the AUC increases by 1.8 times. In such patients, a more pronounced increase in the Q – T interval.

Indications

Treatment of stable angina pectoris.

Application

Tablets should be swallowed whole (without crushing, without breaking, without chewing). the drug can be taken with food or regardless of food intake.

Adults The recommended initial dose of Ranex is 500 mg 2 times a day. After 2-4 weeks, the dose, if necessary, can be increased to 1000 mg 2 times a day. The maximum recommended dose is 1000 mg 2 times a day. If the patient has adverse reactions caused by the use of the drug (e.g. dizziness, nausea, vomiting), then the dose can be reduced to 500 mg. Treatment is stopped if adverse reactions do not go away.

Concomitant use with medium-potent CYP 3A4 inhibitors (e.g. diltiazem, fluconazole, erythromycin) and P-gp inhibitors (e.g. verapamil, cyclosporine). If patients receive these drugs, careful and careful dose selection is recommended.

Renal failure. Persons with renal insufficiency of mild to moderate severity (creatinine clearance ≥30–80 ml / min) are advised to carefully and carefully select the dose.

Liver failure. Patients with mild hepatic insufficiency are advised to carefully and carefully select the dose.

Elderly patients. The selection of the dose of this category of patients should be carried out with caution due to the fact that in the elderly an age-related decrease in renal function is possible, and the effect of ranolazine may increase. In elderly patients, an increased incidence of adverse reactions is noted.

Insufficient body weight.An increased incidence of adverse reactions is characteristic of patients with insufficient body weight (≤60 kg), therefore, dose selection for this category of patients should be carried out with caution.

CHF. Dose selection should be carried out with caution in patients with moderate or severe CHF (NYHA classes III – IV).

Contraindications

Hypersensitivity to the active substance or to any excipient of the drug. severe renal failure (creatinine clearance 30 ml / min). moderate or severe hepatic failure. the simultaneous use of potent cyp 3a4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone). the simultaneous use of class Ia antiarrhythmic drugs (quinidine) or class iii (e.g. dofetilide, sotalol), except for amiodarone.

Side effects

The following are adverse reactions associated with the use of the drug, classified by body systems, organ classes and absolute frequency. the frequency was determined as follows: very often (≥1 / 10), often (≥1 / 100 to 1/10), infrequently (≥1 / 1000 to 1/100), rarely (≥1 / 10,000 to 1/1000) very rarely (1/10 000).

From the side of metabolism and nutrition: infrequently - anorexia, decreased appetite, dehydration; rarely - hyponatremia.

From the psyche: infrequently - anxiety, insomnia, confusion, hallucinations; rarely - disorientation.

From the nervous system: often - dizziness, headache; infrequently - lethargy, loss of consciousness, hypesthesia, drowsiness, tremor, postural dizziness; rarely - amnesia, blurred consciousness, loss of consciousness, parosmia, impaired coordination, impaired gait.

From the side of the organ of vision: infrequently - blurred vision, visual disturbances, diplopia.

From the side of the organ of hearing and balance: infrequently - dizziness, tinnitus; rarely - hearing loss.

From the vessels: infrequently - hot flashes, arterial hypotension; rarely - cold extremities, orthostatic hypotension.

From the respiratory system: infrequently - shortness of breath, cough, nosebleeds; rarely, a sore throat.

From the digestive system: often - constipation, nausea, vomiting; infrequently - abdominal pain, dry mouth, dyspepsia, flatulence, discomfort in the stomach; rarely - pancreatitis, erosive duodenitis, oral hypesthesia.

On the part of the skin and subcutaneous fat: infrequently - itching, hyperhidrosis; rarely - angioedema, allergic dermatitis, urticaria, cold sweat, rash.

From the musculoskeletal system and connective tissue: infrequently - pain in the limbs, muscle cramps, swelling of the joints; rarely - myasthenia gravis.

From the kidneys and urinary tract: infrequently - dysuria, hematuria, chromaturia; rarely - acute renal failure, urinary retention.

From the reproductive system and mammary glands: rarely - erectile dysfunction.

Systemic disorders: often - asthenia; infrequently - fatigue, peripheral edema.

Data from additional research methods: infrequently - increased blood creatinine, increased blood urea, increased Q – T interval, increased platelet or white blood cell count, decreased body weight; rarely - increased levels of liver enzymes in the blood.

Elderly, renal failure and underweight: in general, adverse reactions occurred more often among elderly patients and people with renal insufficiency, however, the types of phenomena in these subgroups were similar to those observed in the general group of patients. In elderly patients (≥75 years), compared with younger patients (75 years), when using the drug, adverse reactions such as constipation, nausea, arterial hypotension, and vomiting more often occurred.

Patients with mild or moderate renal insufficiency (creatinine clearance ≥30–80 ml / min) compared with patients with normal renal function (creatinine clearance 80 ml / min) taking into account the placebo-corrected frequency when using the drug, constipation more often occurred. nausea, dizziness.

As a rule, the type and frequency of adverse reactions observed in patients with insufficient body weight (≤60 kg) were similar to similar reactions in patients with higher body weight (60 kg), however, in patients with insufficient body weight, a placebo-corrected frequency was higher for such common phenomena as nausea, vomiting, arterial hypotension.

Laboratory research methods. In healthy volunteers and in patients receiving Raneks®, a slight reversible increase in serum creatinine was noted, which is not of clinical significance. Renal failure was not associated with this phenomenon. A study of renal function in healthy volunteers showed a decrease in creatinine clearance in the absence of changes in glomerular filtration rate, which is consistent with inhibition of renal tubular secretion of creatinine.

Post-marketing experience. In the post-marketing experience, there were no reports of the occurrence of acute renal failure. The use of concomitant drugs (for example, other antianginal drugs), as well as the presence of diabetes mellitus, heart failure of I and II class or obstructive airway disease in patients did not significantly affect the frequency of adverse reactions.

special instructions

Caution should be exercised when applying or increasing the dose of ranolazine to patients for whom an increase in its action can be expected in such conditions:

• concomitant use of moderate strength CYP 3A4 inhibitors;
• concomitant use of P-gp inhibitors;
• mild liver failure;
• renal failure of mild or moderate severity (creatinine clearance - 30–80 ml / min);
• elderly age of the patient;
• insufficient body weight (≤60 kg);

CHF of moderate or severe severity (NYHA classes III – IV).

In patients with several of the above factors, an additional increase in action can be expected. Adverse reactions that are dose dependent may occur. When using ranolazine in patients with a combination of several of these factors, frequent monitoring of adverse reactions is required, and if necessary, reduce or stop the dose of ranolazine.

The risk of enhancing the effects of ranolazine, which leads to an increase in the frequency of adverse reactions in these groups, is increased in patients with inadequate CYP 2D6 activity (individuals with reduced metabolism) compared with patients with normal CYP 2D6 activity (patients with intensive metabolism). The above warnings are designed to take into account the potential risk for patients with a decreased CYP 2D6 metabolism and should be considered when the metabolic status of CYP 2D6 is unknown. For patients with an intensive metabolism of CYP 2D6, such reservations are less important. In patients for whom the normal metabolic status of CYP 2D6 has been determined (for example, by genotyping) or was previously known, ranolazine can be used with caution in the case when the patient has several of the above risk factors.

Extension of the Q – T interval. Caution is required in the treatment of patients with a history of congenital prolongation of the Q – T interval or with a hereditary extension of the Q – T interval in a family history, or with a known acquired extension of the Q – T interval, as well as patients receiving treatment with drugs that affect the duration of the Q interval –Tc (see INTERACTIONS AND PHARMACOLOGICAL PROPERTIES).

Renal failure. Renal function decreases with age, so it is important to check it regularly with ranolazine.

Lactose.The drug contains lactose, so it should not be used in patients with rare congenital galactose intolerance, lactase deficiency or impaired glucose and galactose absorption.

Use during pregnancy and lactation. There are no necessary data on the use of ranolazine in pregnant women, and the data obtained as a result of experiments on animals are insufficient to assess the effect on pregnancy and embryo development. The potential risk to humans is unknown. Ranex should not be used during pregnancy, unless absolutely necessary.

It is not known whether ranolazine passes into breast milk. The excretion of ranolazine in breast milk has not been studied in animals, so the Ranex drug should not be used by women during breastfeeding.

Children. It is not recommended to use the Ranex drug for children (up to 18 years old) due to insufficient data on safety and effectiveness.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Ranolazine can cause dizziness and blurred vision, double vision, confusion, impaired coordination and hallucinations, which can negatively affect the ability to drive vehicles or work with mechanisms.

Interactions

The effect of other drugs on ranolazine

Inhibitors of CYP 3A4 and P-gp. Ranolazine is a substrate of CYP 3A4, therefore, CYP 3A4 inhibitors increase the concentration of ranolazine in blood plasma. With an increase in its concentration in blood plasma, the manifestation of potential adverse reactions that depend on the dose (for example, nausea, dizziness) may intensify. The simultaneous use of ketoconazole at a dose of 200 mg 2 times a day increases the AUC of ranolazine by 3–3.9 times. Also a potent inhibitor of CYP 3A4 is grapefruit juice.

Diltiazem (180-360 mg once a day), an average power CYP 3A4 inhibitor, depending on the dose, increases the average equilibrium concentrations of ranolazine by 1.5–2.4 times. For patients receiving diltiazem and other moderate-potency CYP 3A4 inhibitors (eg, erythromycin, fluconazole), a careful and careful selection of the dose of Ranex is recommended. You may need a dose reduction.

Ranolazine is a substrate of P-gp. P-gp inhibitors (e.g. cyclosporine, verapamil) increase the concentration of ranolazine in blood plasma. Verapamil (120 mg 3 times a day) increases the equilibrium concentration of ranolazine in blood plasma by 2.2 times. For patients taking P-gp inhibitors, careful and careful selection of the dose of Ranex is recommended. You may need a dose reduction.

Inductors CYP 3A4. Rifampicin (600 mg once daily) reduces the equilibrium concentration of ranolazine by approximately 95%. Treatment with Ranex should not be started with CYP 3A4 inducers (rifampicin, phenytoin, phenobarbital, carbamazepine, St. Johns wort).

CYP 2D6 Inhibitors. Ranolazine is partially metabolized by CYP 2D6, therefore, CYP 2D6 inhibitors can increase the concentration of ranolazine in blood plasma. A powerful inhibitor of CYP 2D6 paroxetine (20 mg once a day) increases the average equilibrium concentration of ranolazine in blood plasma by 1.2 times (when using ranolazine 1000 mg 2 times a day). No dose adjustment is required. At a dose of ranolazine 500 mg 2 times a day, the simultaneous use of a potent inhibitor of CYP 2D6 can lead to an increase in AUC of ranolazine by about 62%.

The effect of ranolazine on other drugs. Ranolazine is a P-gp inhibitor (medium to strong exposure power) and a weak CYP 3A4 inhibitor, therefore, it can increase the concentration of substrate of these enzymes in blood plasma. The distribution of drugs transported by P-gp may also increase. Available evidence suggests that ranolazine is a weak inhibitor of CYP 2D6.The use of ranolazine 750 mg 2 times a day increases the concentration of metoprolol in blood plasma by 1.8 times, therefore, their simultaneous use may increase the effect of metoprolol or other CYP 2D6 substrates (for example, propafenone, flecainide; to a lesser extent this applies to tricyclic antidepressants and antipsychotics ), therefore, a dose reduction of these drugs may be required. The potential for inhibition of CYP 2B6 has not been established. When using ranolazine simultaneously with CYP 2B6 substrates (for example, bupropion, efavirenz, cyclophosphamide), caution is recommended.

Digoxin. There is evidence of an increase in plasma concentration of digoxin by an average of 1.5 times with simultaneous use with the Ranex drug, therefore it is necessary to monitor the level of digoxin at the beginning and at the end of the use of the Ranex drug.

Simvastatin. The metabolism and clearance of simvastatin are largely dependent on CYP 3A4. The use of Ranex at a dose of 1000 mg 2 times a day increases the concentration of simvastatin lactone, simvastatin acid by about 2 times. A connection between the use of simvastatin in high doses and the development of rhabdomyolysis was noted. Cases of rhabdomyolysis in patients taking ranolazine and simvastatin have also been reported as part of post-marketing surveillance. For patients taking ranolazine at any dose, the dose of simvastatin should not exceed 20 mg / day.

Atorvastatin. The use of ranolazine at a dose of 1000 mg 2 times a day increases C_max and AUC of atorvastatin, which is used in a dose of 80 mg once a day, 1.4 and 1.3 times, respectively, and changes C_max and AUC metabolites of atorvastatin by less than 35%. When using ranolazine, dose restriction of atorvastatin and appropriate clinical observation may be required. Also, when taking ranolazine, you may need to limit the dose of other statins metabolized by CYP 3A4 (for example, lovastatin).

Tacrolimus, cyclosporine, sirolimus, everolimus. The use of ranolazine in patients who received tacrolimus (CYP 3A4 substrate) led to an increase in the concentration of the latter in blood plasma. In case of prescribing the drug to patients receiving tacrolimus, it is recommended to control the concentration of tacrolimus in the blood plasma and, if necessary, adjust the dose of tacrolimus. Such control is also recommended when using other CYP 3A4 substrates with a narrow therapeutic range (e.g. cyclosporine, sirolimus, everolimus).

Medicines that are carried by the organic cation transporter 2 (OCT2). With the use of ranolazine at a dose of 500 and 1000 mg 2 times a day by patients with type II diabetes mellitus, the concentration of simultaneously used metformin (1000 mg 2 times a day) in blood plasma increased 1.4 and 1.8 times, respectively. The concentration of other OCT2 substrates, including pindolol and varenicline, can vary equally.

With the simultaneous use of ranolazine and other drugs that extend the Q – Tc interval, pharmacodynamic interaction may occur and the risk of ventricular arrhythmias may increase. Such drugs include some antihistamines (e.g. terfenadine, astemizole, misolastine), some antiarrhythmic drugs (e.g. quinidine, disopyramide, procainamide), erythromycin, and cyclic antidepressants (e.g. imipramine, doxepin, amitriptyline).

Overdose

When studying the tolerability of increasing the dose of the drug used orally in patients with angina pectoris, the incidence of dizziness, nausea, and vomiting increased in accordance with the dose. in case of an overdose, the patient requires careful monitoring; symptomatic and supportive therapy is recommended. since approximately 62% of ranolazine binds to plasma proteins, complete elimination during hemodialysis is unlikely.

Storage conditions

It does not require special storage conditions.