Ritmonorm, 150 mg 50 pcs.

Propafenone has membrane stabilizing properties, properties of a sodium channel blocker (class 1C) and weakly expressed beta-adrenoblocking activity (class II).

It slows down the rise of action potential, due to which the pulse conduction velocity decreases (negative dromotropic effect). The refractory period in the atrium, atrioventricular (AV) node and ventricles is prolonged. Propafenone also lengthens the refractory period in additional conduction pathways in patients with Wolff-Parkinson-White syndrome (WPW).

Pharmacokinetics

Propafenone is a racemic mixture consisting of R-propafenone and S-propafenone.

Introduction

The maximum plasma concentration (Cmax) of the drug is generated between 2 and 3 hours after oral administration. Propafenone undergoes significant and saturable presystemic biotransformation via CYP2D6 isoenzyme (effect of “primary passage” through the liver), in connection with this the absolute bioavailability of the drug depends on the dose and dosage form. Although food intake caused an increase in bioavailability and plasma Cmax in a single-dose study, long-term use of propafenone with food in healthy volunteers did not result in a significant change in bioavailability.

Distribution

Propafenone is rapidly distributed in the body. The volume of distribution in the equilibrium state is from 1.9 to 3.0 L/kg. The degree of binding of propafenone to plasma proteins is concentration-dependent and decreases from 97.3% when a dose of 0.25 ng/ml is administered to 91.3% when a dose of 100 ng/ml is administered.

Metabolism and excretion

There are two genetically determined pathways of propafenone metabolism. In more than 90% of patients, the drug is rapidly and significantly metabolized, with a half-life (Tsh) of 2 to 10 hours (so-called “fast metabolizers”), In these patients propafenone is metabolized to form 2 active metabolites – 5-hydroxypropafenone via CYP2D6 isoenzyme and N -depropylpropafenone (norpropafenone) via CYP3A4 and CYP1A2 isoenzymes. In less than 10% of patients, propafenone is metabolized more slowly because 5-hydroxypropafenone is not formed or is formed in small amounts (so-called “slow metabolizers”). In this type of metabolism, Tsh ranges from 10 to 32 hours. The clearance of propafenone is 0.67 to 0.81 L/h/kg. Since the equilibrium state of pharmacokinetic parameters or parameters is reached 3-4 days after drug administration in all patients, the dosing regimens of propafenone are the same for all patients regardless of metabolic rate (“fast” or “slow” metabolizers).

In significant metabolism with a saturable hydroxylation cycle via the CYP2D6 isoenzyme, the pharmacokinetics of propafenone is nonlinear; in slow metabolism, it is linear.

The pharmacokinetics of propafenone have considerable individual variability, which is mainly due to the effect of “primary passage” through the liver, as well as nonlinearity of pharmacokinetics with significant metabolism. The variability of propafenone blood concentrations requires cautious dose titration and monitoring of clinical and electrocardiographic signs of the drug.

Elderly Patients

In elderly patients with normal renal function, propafenone levels varied widely and were not significantly different from those in healthy young patients. The 5-hydroxypropafenone content was approximately similar, but the propafenone glucuronide content was twice as high.

Renal dysfunction

In patients with impaired renal function, propafenone and 5-hydroxypropafenone levels were similar compared with healthy volunteers, but there was cumulation of glucuronide metabolites. Propafenone should be used with caution if renal function is impaired.

Hepatic impairment

Bioavailability and T½ with oral administration are increased in patients with hepatic impairment. Dose adjustment of propafenone in patients with hepatic impairment is necessary.

Indications

Supraventricular and ventricular extrasystoles; supraventricular tachycardia, ventricular tachycardia.

Pharmacological effect

Propafenone has membrane-stabilizing properties, sodium channel blocker properties (class 1C) and weak beta-blocking activity (class II).

It slows down the rise of the action potential, as a result of which the speed of impulse conduction decreases (negative dromotropic effect). The refractory period in the atrium, atrioventricular (AV) node and ventricles is prolonged. Propafenone also prolongs the refractory period in accessory pathways in patients with Wolff-Parkinson-White (WPW) syndrome.

Pharmacokinetics

Propafenone is a racemic mixture consisting of R-propafenone and S-propafenone.

Suction

The maximum concentration (Cmax) of the drug in the blood plasma is created in the interval from 2 to 3 hours after oral administration. Propafenone undergoes significant and saturable presystemic biotransformation using the CYP2D6 isoenzyme (first pass effect through the liver), and therefore the absolute bioavailability of the drug depends on the dose and dosage form. Although food intake caused an increase in bioavailability and plasma Cmax in a single dose study, chronic administration of propafenone with food in healthy volunteers did not result in a significant change in bioavailability.

Distribution

Propafenone is rapidly distributed in the body. The volume of distribution at steady state ranges from 1.9 to 3.0 l/kg. The degree of binding of propafenone to plasma proteins depends on the concentration and decreases from 97.3% when a dose of 0.25 ng/ml is administered to 91.3% when a dose of 100 ng/ml is administered.

Metabolism and excretion

There are two genetically determined pathways for the metabolism of propafenone. In more than 90% of patients, the drug is rapidly and significantly metabolized, the half-life (Tw) ranges from 2 to 10 hours (so-called “rapid metabolizers”). In such patients, propafenone is metabolized to form 2 active metabolites – 5-hydroxypropafenone via the CYP2D6 isoenzyme and N-depropylpropafenone (norpropafenone) via the CYP3A4 isoenzyme and CYP1A2. In less than 10% of patients, propafenone is metabolized more slowly because 5-hydroxypropafenone is not formed or is formed in small quantities (so-called “poor metabolizers”). With this type of metabolism, Tsh ranges from 10 to 32 hours. The clearance of propafenone ranges from 0.67 to 0.81 l/h/kg. Since the equilibrium state of pharmacokinetic parameters or indicators is achieved 3-4 days after taking the drug in all patients, the dosage regimens of propafenone are the same for all patients, regardless of metabolic rate (“fast” or “slow” metabolizers).

With significant metabolism with a cycle of saturable hydroxylation using the CYP2D6 isoenzyme, the pharmacokinetics of propafenone are nonlinear, and with slow metabolism – linear.

The pharmacokinetics of propafenone has significant individual variability, which is mainly due to the effect of “first pass” through the liver, as well as the nonlinearity of pharmacokinetics with significant metabolism. The variability of propafenone blood concentrations requires careful titration of the dose and monitoring of clinical and electrocardiographic signs of drug action.

Elderly patients

In elderly patients with normal renal function, the content of propafenone varied greatly and did not differ significantly from that in healthy young patients. The content of 5-hydroxypropafenone was approximately similar, but the content of propafenone glucuronides was twice as high.

Renal dysfunction

In patients with impaired renal function, the content of propafenone and 5-hydroxypropafenone was similar compared to healthy volunteers, but accumulation of glucuronide metabolites was observed. If renal function is impaired, propafenone should be used with caution.

Liver dysfunction

Bioavailability and T½ when taken orally are increased in patients with impaired liver function. It is necessary to adjust the dose of propafenone in case of liver dysfunction.

Active ingredient

Propaphenone

Composition

Each tablet contains:

Active ingredient:
propafenone hydrochloride 150 mg.
Excipients:
microcrystalline cellulose -25.40 mg;
croscarmellose sodium -10.00 mg;
corn starch – 20.00 mg;
hypromellose-2910 8.00 mg;
magnesium stearate – 0.50 mg;
water – 6.10 mg.
Film coating:
macrogol 400 -0.52 mg; macrogol 6000 – 4.176 mg; hypromellose-2910 – 6.264 mg, titanium dioxide (E 171) – 1.04 mg.

Contraindications

severe forms of chronic heart failure
electrolyte imbalance
myasthenia gravis
bronchial asthma
hypersensitivity to the drug Ritmonorm.

Side Effects

Possible proarrhythmogenic effect, increased heart failure, orthostatic hypotension, dyspeptic disorders, headache, visual and taste disturbances, fatigue.

Interaction

When propafenone is used together with local anesthetics (for example, during implantation of a pacemaker, during surgery, in dentistry) or other drugs that reduce heart rate and/or reduce myocardial contractility (for example, beta-blockers, tricyclic antidepressants), side effects may increase.

The simultaneous use of propafenone with drugs metabolized by the CYP2D6 isoenzyme (for example, venlafaxine) may cause an increase in the concentration of these drugs in the blood plasma. Increased plasma concentrations of propranolol, metoprolol, desipramine, cyclosporine, theophylline and digoxin may also be observed when taken concomitantly with propafenone. If necessary, if symptoms of overdose are detected, the doses of these drugs should be reduced.

Drugs that inhibit the isoenzymes CYP2D6, CYP1A2, CYP3A4, for example, ketoconazole, cimetidine, quinidine, erythromycin and grapefruit juice, may cause an increase in the concentration of propafenone in the blood plasma. When using propafenone concomitantly with inhibitors of these isoenzymes, patients should be closely monitored and, if necessary, the dose of the drug should be adjusted.

Combination therapy with amiodarone and propafenone can cause conduction and repolarization disturbances, as well as be accompanied by a proarrhythmogenic effect. In this case, the dose of both drugs may need to be adjusted.

Although no changes in the pharmacokinetics of propafenone and lidocaine were observed when they were used together, an increased risk of lidocaine-related CNS side effects was reported.

Because phenobarbital is an inducer of the CYP3A4 isoenzyme; the response to therapy should be monitored if propafenone is added to long-term therapy with phenobarbital.

The simultaneous use of propafenone and rifampicin may reduce the concentration of propafenone in the blood plasma and, as a result, reduce its antiarrhythmic activity.

It is necessary to monitor the state of the blood coagulation system in patients simultaneously receiving indirect anticoagulants (phenprocoumon, warfarin), since propafenone can enhance the pharmacological effect of these drugs and cause an increase in prothrombin time. If necessary, if symptoms of overdose are detected, the doses of these drugs should be reduced.

When propafenone is co-administered with selective serotonin reuptake inhibitors (such as fluoxetine or paroxetine), increased plasma concentrations of propafenone may occur. The combined use of propafenone and fluoxetine in “rapid metabolizers” increases the Cmax and AUC of propafenone S by 39% and 50%, and propafenone R by 71% and 50%, respectively. Thus, the desired therapeutic effect can be achieved by using propafenone in lower doses.

Overdose

Symptoms

From the myocardium: the consequences of an overdose of propafenone for the myocardium are manifested by such disorders as prolongation of the PQ interval, widening of the QRS complex, suppression of the automaticity of the sinus node, AV block, ventricular tachycardia, ventricular fibrillation, ventricular flutter. Decreased contractility (negative inotropic effect) can lead to a pronounced decrease in blood pressure, which in severe cases can cause collapse.

Extracardiac symptoms: Headache, dizziness, blurred vision, paresthesia, tremor, nausea, constipation and dry oral mucosa may often occur. In very rare cases, seizures have been reported as a result of overdose. A case of death was also reported. In cases of severe poisoning, clonic-tonic convulsions, paresthesia, drowsiness, coma and respiratory arrest are possible.

Treatment

Attempts to remove Ritmonorm from the body through hemoperfusion are ineffective.

Since propafenone has a large Vd and a high degree of binding to plasma proteins (>95%), hemodialysis is ineffective.

In addition to general emergency measures, it is necessary to monitor vital signs in the intensive care unit and adjust them if necessary.

Defibrillation and dopamine and isoproterenol infusions are effective measures to control heart rate and blood pressure. Convulsions are controlled with intravenous diazepam.

General supportive measures such as ventilator support and chest compressions may be required.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 25 °C.

Shelf life

5 years

Manufacturer

Famar Lyon, France