Propanorm - instructions for use, dose, side effects, contraindications

core excipients: microcrystalline granular cellulose 21.00 mg / 41.50 mg; corn starch 14.70 mg / 28.90 mg; sodium croscarmellose 10.50 mg / 21.00 mg; Copovidone 10.00 mg / 20.00 mg; magnesium stearate 1.00 mg / 2.00 mg; sodium lauryl sulfate 0.80 mg / 1.60 mg;

excipients of the shell: Opaprai white 02F28310 7.46 mg / 14.92 mg (hypromellose-5 4.15 mg / 8.30 mg, titanium dioxide 2.06 mg / 4.12 mg, macrogol-6000 1.25 mg / 2.50 mg) , simethicone (dimethicone emulsion with silicon dioxide) 0.04 mg / 0.08 mg.

Description:

Round, biconvex tablets, film-coated, white or almost white.

Pharmacotherapeutic group:antiarrhythmic drug

ATX: & nbsp

C.01.B.C Antiarrhythmic drugs Ic class

C.01.B.C.03 Propafenone

Pharmacodynamics:

Propafenone is an antiarrhythmic drug with membrane-stabilizing properties, sodium channel blocker properties (class IC), and poorly expressed beta-adrenoblocking activity (class II).Antiarrhythmic effect is based on local anesthetic and direct membrane-stabilizing action on cardiomyocytes, as well as on blockade of beta adrenoreceptors and calcium channels.

Propaphenone, blocking the fast sodium channels, causes a dose-dependent decrease in the rate of depolarization and inhibits the phase 0 of the action potential and its amplitude in Purkinje fibers and contractile fibers of the ventricles, inhibits automatism. Slows the pulse on the Purkinje fibers. Lengthens the time spent on the sinoatrial (SA) node and atria. When propafenone is used, the PQ interval is extended and the QRS complex is expanded (from 15 to 25), as well as the AH and HV intervals. There are no significant changes in the QT interval.

Electrophysiological effects are more pronounced in ischemic than in normal myocardium. Propafenone reduces the rate of increase in the action potential, as a result of which the rate of conduction of the pulse decreases (negative dromotropic effect). The refractory period in the atrium, atrioventricular node and ventricles lengthens. Propafenone prolongs also the refractory period in additional conductive pathways in patients with Wolff-Parkinson-White syndrome (WPW).

The action of propafenone begins 1 hour after ingestion, reaches a maximum after 2-3 hours and persists for 8-12 hours.

Pharmacokinetics:

Absorption - more than 95%. Systemic bioavailability is 5-50%. Admission with food increases bioavailability in patients with intensive metabolism. Propafenone exhibits a dose-dependent bioavailability that increases non-linearly with increasing dose: it increases from 5% to 12% with an increase in the single dose from 150 mg to 300 mg, and at 450 mg to 40-50%.

Time to reach the maximum concentration in the blood plasma (TC_m_Oh) after oral administration is 1-3.5 h and its value varies from 500 to 1500 mcg / l. The equilibrium concentration (C_ss) in the blood plasma is achieved 3-4 days after the start of therapy. Permeability through the blood-brain and placental barrier is low. The concentration of propafenone in the umbilical cord is 30% of its concentration in the mother's blood.

The volume of distribution is 3-4 l / kg. Connection with proteins of blood plasma and internal organs (liver, lungs, etc.) - 85-97%.

Propaphenone undergoes significant and saturating presystemic biotransformation with the help of the CYP2D6 isoenzyme (the "first pass" effect through the liver), which leads to absolute bioavailability, dose-dependent and dosage form of the drug.

There are 2 models of genetically determined metabolism of propafenone. More than 90% of patients propafenone rapidly and significantly metabolized, half-life (T_1/2) is from 2.8 to 11 hours. 11 metabolites of propafenone are described, of which two are pharmacologically active: 5-hydroxypropaphenone is formed by the isoenzyme CYP2D6, and N-depropylpropapenone (norpropaphenone) by means of CYP3A4 and CYP1A2 isoenzymes. Less than 10% of patients propafenone is metabolized more slowly, since 5-hydroxypropaphenone is not formed or is formed in small amounts. In this type of metabolism, the elimination half-life is about 17h.

With extensive metabolism with a cycle of saturable hydroxylation with the help of the CYP2D6 isoenzyme, the pharmacokinetics of propafenone is nonlinear, and for slow metabolism it is linear.

Since the equilibrium state of pharmacokinetic parameters is achieved 3-4 days after oral administration of the drug in all patients, the dosage regimen of the drug is the same for all patients regardless of metabolic rate.

Pharmacokinetics has a significant individual variability, which is mainly due to the effect of "first passage" through the liver, as well as its non-linearity in extensive metabolism.The variability of the concentration of propafenone in the blood requires careful dose titration and monitoring of patients, including ECG monitoring.

Propafenone is excreted by the kidneys - 38% in the form of metabolites (less than 1% unchanged), through the intestines with bile - 53% (in the form of glucuronides and sulfates of metabolites and active substance). With hepatic failure, excretion decreases.

Indications:

Ventricular arrhythmias; paroxysmal supraventricular tachycardia, atrial fibrillation; paroxysmal tachycardia of the type of re-entry involving the atrioventricular (AV) node or additional ways of carrying out.

Contraindications:

- Hypersensitivity to propafenone and other components of the drug;

- syndrome of weakness of the sinus node;

- severe bradycardia and arterial hypotension;

- violations of intracirculatory conduction;

- atrioventricular blockade of II and III degree;

- blockade of the bundle of the bundle or distal blockade (in patients without an electrocardiostimulator);

- pronounced violations of the water-electrolyte balance (for example, disturbances in potassium metabolism);

- severe forms of chronic cardiac insufficiency (in the stage of decompensation), uncontrolled chronic heart failure;

- severe forms of chronic obstructive pulmonary disease (COPD);

- simultaneous application of ritonavir in a dose of 800-1200 mg / day;

- Myasthenia gravis;

- pronounced organic changes in the myocardium, such as refractory chronic heart failure with a left ventricular ejection fraction of less than 35% and cardiogenic shock, with the exception of arrhythmic shock;

- age under 18 years (efficiency and safety not established).

Carefully:

Myasthenia gravis, impaired renal and / or liver function, chronic obstructive pulmonary disease of mild and moderate degree (with extreme caution due to beta-adrenergic blocking action), advanced age, patients with an established pacemaker.

The simultaneous use of propafenone with digoxin leads to an increase in the concentration in the blood of digoxin, with the dose of the latter to be reduced by 25%.

Pregnancy and lactation:

The use of the drug Propanorm® during pregnancy, especially in the first trimester, is only possible if the expected benefit to the mother exceeds the potential risk to the fetus.

Propaphenone penetrates the placental barrier. The concentration of propafenone in the umbilical cord is 30% of its concentration in the mother's blood.

Propaphenone is excreted in breast milk. If necessary, the use of the drug Propanorm® during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside, after eating. Tablets should be swallowed whole, washed down with a small amount of water.

The dose of the drug should be selected individually, depending on the therapeutic effect and the tolerability of the patient's therapy.

It is recommended to begin therapy in a hospital, previously canceling all antiarrhythmic drugs (under the control of blood pressure, (BP), ECG, QRS latitude estimation).

If the QRS complex is enlarged or the QT interval is extended by more than 20% compared to the baseline values, or the PQ interval is extended by more than 50%, the QT interval is extended by more than 500 ms, the frequency and severity of the arrhythmia are increased dose or temporarily discontinue use of the drug.

In patients with a significantly expanded complex of QRS and AV blockades of II and III degree, it is recommended to reduce the dose.

With a body weight of 70 kg or more, the initial dose is 150 mg 3 times a day (in a hospital under the control of blood pressure, ECG).The dose can be increased gradually, at intervals of 3-4 days to 300 mg 2 times a day, and if necessary up to a maximum dose of 300 mg 3 times a day.

In elderly patients and patients with a body weight of less than 70 kg, the drug is started with lower doses, gradually increasing the dose. The same tactics should be followed when carrying out maintenance therapy.

Do not start increasing the dose if the duration of the drug is less than 5-8 days.

If the liver function is impaired, the drug is recommended to be used in doses of 20-30% of the usual dose, if the renal function is impaired (creatinine clearance less than 10 ml / min), the initial dose should be reduced.

Side effects:

From the side of the cardiovascular system: severe bradycardia, worsening of heart failure (in patients with reduced left ventricular function), SA blockade, AV blockade, intraventricular conduction disorders, arrhythmogenic effect, marked decrease in blood pressure, including postural and orthostatic hypotension (especially in elderly patients), chest pain .

From the digestive system: loss of taste, dryness of the oral mucosa, bitter taste in the mouth, nausea, vomiting, anorexia, abdominal pain, constipation, diarrhea, liver function abnormalities, including hepatocellular disorders, cholestatic jaundice, cholestasis, hepatitis.

From the central nervous system: headache, dizziness, fainting, seizures, diplopia, myoclonia, fatigue, confusion, ataxia, paresthesia, anxiety, weakness.

Laboratory indicators: leukopenia and / or granulocytopenia, agranulocytosis, thrombocytopenia, increased bleeding time, the appearance of antinuclear antibodies, increased activity of "liver" transaminases and alkaline phosphatase.

From the genitourinary system: oligospermia, decreased potency.

Allergic reactions: skin rash, itching, exanthema, reddening of the skin, urticaria, hemorrhagic rashes on the skin, lupus-like syndrome.

Other: blurred vision.

Overdose:

Intoxication may occur with a single-dose dose, 2 times the daily dose. Symptoms of intoxication appear after 1 hour, a maximum - in a few hours.

Symptoms: prolongation of the QT interval, expansion of the QRS complex, suppression of the automatism of the sinus node, AV blockade, ventricular tachycardia, ventricular fibrillation, ventricular flutter, asystole, marked decrease in blood pressure, drowsiness, convulsions, coma.

Treatment: symptomatic, gastric lavage, defibrillation, administration of dobutamine, diazepam; if necessary - artificial ventilation and indirect heart massage.

Because the propafenone has a large volume of distribution and a high degree of binding to plasma proteins (more than 95%), then hemodialysis and hemoperfusion are not effective.

Interaction:

An increase in the side effect of propafenone can be observed when it is used concomitantly with local anesthetics (for example, with pacemaker implantation, surgery, dental treatment) or other medications that reduce the frequency of heartbeat and / or myocardial contractility (eg, beta adrenoblockers, tricyclics antidepressants).

The simultaneous use of propafenone with drugs metabolized by the isoenzyme CYP2D6 (for example, venlafaxine), can cause an increase in the concentration of these drugs in blood plasma.

An increase in the concentration of propranolol, metoprolol, desipramine, cyclosporine, theophylline and digoxin can also be observed with simultaneous application with propafenone.

Preparations that inhibit the isoenzymes CYP2D6, CYP1A2, CYP3A4, for example, ketoconazole, cimetidine, quinidine, erythromycin and grapefruit juice can cause an increase in the concentration of propafenone in the blood plasma.

Taking ritonavir in a dose of 800-1200 mg / day simultaneously with propafenone is contraindicated because of the risk of increasing the concentration of propaphenone in the blood plasma. Simultaneous therapy with amiodarone and propafenone can cause disturbance of conduction and repolarization and is accompanied by arrhythmogenic effect. In this case, you may need to adjust the doses of both drugs.

Although no pharmacokinetics of propafenone and lidocaine have been observed with their combined use, there has been a reported increased risk of side-effects of lidocaine (intravenously) on the central nervous system. As phenobarbital is the inducer of the isoenzyme CYP3A4, it is necessary to monitor the patient's condition in the case of the addition of propafenone to long-term therapy with phenobarbital.

The combination of propafenone and rifampicin can reduce the concentration of propafenone in the blood plasma and, as a consequence, reduce its antiarrhythmic activity.

It is necessary to monitor the parameters of the blood coagulation system in patients who simultaneously receive indirect anticoagulants (fenprokumone, warfarin), because the propafenone can increase the effectiveness of these drugs and cause an increase in prothrombin time.

The combined use of propafenone and fluoxetine increases the maximum concentration in the blood plasma (C_m_Oh) and AUC (area under the concentration-time curve) of propafenone S by 39% and 50%, and propafenone R by 71% and 50%, respectively. With simultaneous use with paroxetine, the concentration of propafenone in the blood plasma can increase, so the desired therapeutic effect can be achieved with the use of the drug in smaller doses.

Special instructions:

Treatment should begin in a hospital, because the risk of arrhythmogenic action associated with the use of the drug Propanorm® is increased. It is recommended that the previous antiarrhythmic therapy be discontinued before the start of treatment at a time equal to 2-5 half-lives of these drugs.

Each patient who receives Propanorm® must undergo an electrocardiographic and clinical examination before and during therapy for the early detection of side effects, evaluation of the effectiveness of the drug and the need for continued therapy.

Propanorm® can worsen the course of myasthenia gravis.

Pacemakers should be checked and, if necessary, reprogrammed, as the drug may affect the sensitivity threshold and the frequency threshold of the artificial pacemaker.

There is a risk of conversion of paroxysmal atrial fibrillation to atrial flutter with AV blockade of 2: 1 or 1: 1.

As with other IC antiarrhythmic drugs, patients with organic myocardial changes with Propanorm® can be predisposed to serious side effects.

If the liver and / or kidney function is impaired because of the possible accumulation of propafenone, titration of the dose under the control of the ECG and its concentration in the blood plasma is necessary.

Effect on the ability to drive transp. cf. and fur:

During the treatment period it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities,requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Film-coated tablets, 150 mg and 300 mg.

Packaging:

For 10 tablets in a blister of PVC / aluminum foil.

5 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

In a dry, dark place at a temperature of 15-25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LS-001169

Date of registration:20.07.2010

The owner of the registration certificate:PRO.MED.CS Prague as.PRO.MED.CS Prague as. Czech Republic

Manufacturer: & nbsp

PRO.MED.CS Praha, a.s. Czech Republic

Representation: & nbspPRO.MED.CS Prague as. PRO.MED.CS Prague as. Czech Republic

Information update date: & nbsp04.09.2015

Illustrated instructions

Instructions

Propanorm® (Propanorm®)