Ритмонорм®

General characteristics. Structure:

Active agent: propafenona hydrochloride of 150 mg.

Excipients: cellulose microcrystallic — 25,40 mg; starch corn — 20,00 mg; croscarmellose sodium — 10,00 mg; gipromelloza-2910 — 8,00 mg; magnesium stearate — 0,50 mg; water — 6,10 mg.

Film cover: macrogoal of 400 — 0,52 mg; macrogoal of 6000 — 4,176 mg; gipromelloza-2910 — 6, 264 mg, titanium dioxide — 1,04 mg.

Description

Round biconvex tablets, film coated white or almost white color, with an engraving "150" on one party.

Pharmacological properties:

Pharmacodynamics. Propafenon has membrane stabilizing properties, properties of a blocker of natrium channels (class 1C) and poorly expressed beta and adrenoceptor blocking activity (class II).

It slows down increase of action potential owing to what the speed of carrying out an impulse (negative dromotropic effect) decreases. The refractory period in an auricle, an atrioventricular (AV) node and ventricles is extended. Propafenon extends also refractory period in additional conduction paths at patients with a WPW-syndrome (WPW).

Pharmacokinetics. The maximum concentration (Cmax) of drug in a blood plasma is created in the range from 2 till 3 o'clock after intake. Propafenon is exposed to considerable and saturable presistemny biotransformation by means of CYP2D6 isoenzyme (effect of "primary passing" through a liver), in this regard absolute bioavailability of drug depends on a dose and a dosage form.

There are two genetically caused ways of metabolism of a propafenon. More

than at 90% of patients drug is quickly and considerably metabolized, the elimination half-life (T1/2) makes from 2 to 10 hours. 2 active metabolites — 5-gidroksipropafenon by means of an isoenzyme of CYP2D6 and N — депропилпропафенон (норпропафенон) by means of isoenzymes of CYP3A4 and CYP1A2 are formed. Less than at 10% of patients пропафенон it is metabolized more slowly therefore 5-gidroksipropafenon it is not formed or formed in insignificant quantities. At this type of metabolism T1/2 makes from 10 to 32 hours.

At considerable metabolism with a cycle of a saturable hydroxylation by means of CYP2D6 isoenzyme pharmacokinetics of a propafenon nonlinear, and at slow metabolism — linear.

As the equilibrium condition of pharmacokinetic parameters or indicators is reached in 3-4 days after administration of drug at all patients, the modes of dosing of a propafenon are identical to all patients irrespective of metabolism speed.

The pharmacokinetics of a propafenon has considerable individual variability that is caused, mainly, by effect of "primary passing" through a liver, and also nonlinearity of pharmacokinetics at considerable metabolism. Variability of concentration of a propafenon in blood demands careful titration of a dose and observation of clinical and elektorokardiografichesky signs of effect of drug.

Renal failure

Propafenon it is necessary to appoint with care at a renal failure.

Abnormal liver function

Correction of a dose of a propafenon at abnormal liver functions is necessary.

Indications to use:

Paroxysmal supraventricular tachyarrhythmias, including AV nodal tachycardia, supraventricular tachycardia at patients with a WPW-syndrome (WPW) and paroxysmal fibrillation of auricles.
Heavy paroxysmal ventricular tachyarrhythmia, life-threatening.

Route of administration and doses:

Inside.

Because of bitter taste and local anesthetic effect the drug Ritmonorm® should be accepted after food, to swallow entirely, without chewing and washing down with liquid.

The dose of the drug Ritmonorm® should be selected individually depending on response of the patient and the gained effect.

It is recommended to begin therapy in a hospital, previously having cancelled all antiarrhytmic means (under control of the arterial pressure (AP), an ECG, determination of width of the QRS complex).

At patients with considerably expanded QRS complexes and AV-blockade it is recommended to lower a dose.

Adults:

At the body weight of the patient of 70 kg and more initial dose of 150 mg 3 times a day (in a hospital under control of an ECG and arterial pressure). The dose can be increased bucketed, at least 3–4 days, to 300 mg (2 tablets) 2 times a day, and if necessary to the maximum dose of 300 mg 3 times a day.

At the body weight of the patient less than 70 kg treatment should be begun with lower doses of drug. It is not necessary to begin increase in a dose if duration of use of drug makes less than 3-4 days.

Distinctions in efficiency and safety of use of the drug Ritmonorm® for patients of advanced age and patients of younger age were not revealed. However it is impossible to exclude separate reactions of hypersensitivity to a propafenon or any of drug components therefore therapy by drug has to be carried out under careful control of the doctor. Arrive also at a maintenance therapy. It is not necessary to begin increase in a dose if duration of use of drug makes less than 5-8 days.

At patients with a renal failure and/or a liver because of possible cumulation of drug titration of a dose under careful clinical control and control of an ECG is necessary.

Features of use:

Treatment should be begun in the conditions of a hospital as the risk of the aritmogenny action connected using the drug Ritmonorm® is increased. It is recommended that the previous antiarrhytmic therapy was stopped prior to treatment in the terms equal to 2-5 elimination half-lives of these drugs.

Each patient who receives Ritmonorm® has to undergo electrocardiographic and clinical inspection prior to therapy and during its carrying out for early identification of side effect, assessment of efficiency of drug and need of continuation of therapy.

Reception of a propafenon can reveal an asymptomatic current of a syndrome of Brugad and cause brugadopodobny changes on an ECG. Therefore, after the beginning of therapy by the drug Ritmonorm® it is necessary to conduct electrocardiographic examination to exclude existence of a syndrome of Brugad and brugadopodobny changes on an ECG.

The drug Ritmonorm® can worsen a current of a myasthenia.

Electrocardiostimulators need to be checked and if necessary to reprogram as Ritmonorm® can affect a threshold of sensitivity and a frequency threshold of artificial pacemakers.

There is a risk of conversion of a paroxysmal ciliary arrhythmia in an atrial flutter with AV blockade 2:1 or 1:1.

As well as at use of other antiarrhytmic means of a class 1C, patients with considerable organic changes of a myocardium at administration of drug of Ritmonorm® can have serious side effects.

Influence on ability to driving of motor transport, to control of mechanisms

The sight illegibility, dizziness, weakness and postural hypotension can break the speed of reactions of the patient and ability to drive the car and mechanisms therefore during use of drug it is necessary to abstain from control of motor transport and occupations potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

In the table the side effects registered during clinical trials and at post-marketing use of the drug Ritmonorm® are included below. All reactions regarded as having at least possible communication using the drug Ritmonorm®, are presented on systems of bodies and frequency of occurrence: very often (≥ 1/10), it is frequent (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100) and it is unknown (are revealed during post-marketing use; it is not possible to estimate on the basis of the available data). In each group side effects are located as decrease in degree of gravity if that gave in to assessment.

System of bodies                                        Frequency            Undesirable effects
From blood and lymphatic
systems                                                      Infrequently           Thrombocytopenia   
                                                                  It is unknown        the Agranulocytosis
                                                                                             Leukopenia
                                                                                             Granulocytopenia
From immune system                     hypersensitivity Reaction Does not know (can
                                                                                             to be shown in the form of a cholestasia, a dyscrasia
                                                                                             blood, skin rash)
From a metabolism and food     Infrequently             Loss of appetite
Disturbances of mentality                                     Often             Alarm
                                                                  It is unknown       Confusion of consciousness
From a nervous system                     Dizziness Is very frequent (behind an exception вертиго)
                                                                      Often          Headache
                                                                    Infrequently         taste Disturbances
                                                                                           Syncope
                                                                                           Lack of coordination of movements
                                                                                            Paresthesias
From sense bodys                        Often           sight Illegibility
                                                                    Infrequently         Vertigo
From cardiovascular
systems                                                        conductivity Disturbance Is very frequent (including sinuatrial
                                                                                           blockade, AV blockade or intra ventricular blockade)
                                                                                 The Heart consciousness is frequent  
                                                                             Infrequently Sinus bradycardia
                                                                  It is unknown       Bradycardia
                                                                                            Tachycardia
                                                                                            Atrial flutter
                                                                                            Ventricular tachycardia
                                                                                            Arrhythmia
                                                                                            The expressed decrease in the ABP
                                                                                            Fibrillation of ventricles
                                                                                           Heart failure (including it is possible
                                                                                             deterioration in a course of heart failure)
                                                                                           Orthostatic hypotension
 
From a respiratory organs                     Often               Asthma
From digestive tract  Often            Abdominal pain
                                                                  It is unknown         Vomiting
                                                                                             Nausea
                                                                                             Lock
                                                                                          Dryness of a mucous membrane of an oral cavity
                                                                                          Gastrointestinal diseases
From a liver and bile-excreting
 ways                                                            Often         Dysfunctions pecheni1
                                                                   It is unknown   Hepatocellular disturbances
                                                                                          Cholestasia
                                                                                          Hepatitis
                                                                                          Jaundice
From skin and hypodermic fabrics      Infrequently       Small tortoiseshell
                                                                                          Skin itch
                                                                                          Skin rash
                                                                                          Erythema
From skeletal and muscular
the system and connecting fabric              Is unknown    the Volchanochnopodobny syndrome
 
From generative organs and
mammary glands                                                  Infrequently Erectile dysfunction
                                                                        Reversible decrease in quantity spermatozoidov2 is unknown
The general frustration                                       Often         Bol in a thorax
                                                                                            Weakness
                                                                                            Increased fatigue

1 Including changes of "hepatic tests": increase in activity of ALT (alaninaminotranspherase), nuclear heating plant (aspartate aminotransferase), gamma глутамилтрансферазы and alkaline phosphatase.

2 Is returned to norm after drug withdrawal.

Interaction with other medicines:

Strengthening of side effect of a propafenon can be observed at its combined use with local anesthetics (for example, at implantation of an electrocardiostimulator, at operative measures, at dental care) or other medicines which urezhat ChSS and/or contractility of a myocardium (for example, beta adrenoblockers, tricyclic antidepressants).

Simultaneous use of a propafenon with the drugs which are metabolized by means of CYP2D6 isoenzyme (for example, venlafaksiny), can cause increase in concentration of these drugs.

Increase in concentration of propranolol, metoprolol, desipramine, cyclosporine, theophylline and digoxin can be also observed at a concomitant use with propafenony.

Drugs which inhibit isoenzymes of CYP2D6, CYP1A2, CYP3A4, for example, кетоконазол Cimetidinum, quinidine, erythromycin and grapefruit juice can cause increase in concentration of a propafenon.

Reception of a ritonavir along with propafenony is contraindicated because of risk of increase in concentration of drugs in a blood plasma.

The combined therapy by Amiodaronum and propafenony can cause disturbance of conductivity and repolarization and to be followed by proaritmogenny effect. In this case correction of a dose of both drugs can be required.

Though changes of pharmacokinetics of a propafenon and lidocaine were not noted at their combined use, however, it was reported about the increased risk of development of side effects of intravenous lidocaine from the central nervous system.

As phenobarbital is CYP3A4 isoenzyme inductor, it is necessary to control the response to therapy in case of accession of a propafenon to long therapy by phenobarbital. The combination of a propafenon and rifampicin can reduce concentration of a propafenon in a blood plasma and, as a result, reduce its antiarrhytmic activity.

It is necessary to control a condition of coagulant system of blood at the patients who are at the same time receiving indirect anticoagulants (фенпрокурмон, warfarin) as пропафенон can strengthen pharmacological effect of these drugs and cause lengthening of a prothrombin time.

At combined use of a propafenon and selective serotonin reuptake inhibitors (such as fluoxetine or пароксетин) there can be an increase in concentration of a propafenon in a blood plasma. Combined use of a propafenon and fluoxetine at "bystry metabolizator" raises Cmax (the maximum concentration in a blood plasma) and the area under a pharmacokinetic curve "concentration time" (AUC) of a propafenon of S for 39% and 50%, and a propafenona of R for 71% and 50%, respectively. Thus, the desirable therapeutic effect can be reached at use of a propafenon in smaller doses.

Contraindications:

The known hypersensitivity to a propafenon or any other component of drug.
Brugad's syndrome
Considerable organic changes of a myocardium, such as refractory chronic heart failure less than 35% and cardiogenic shock with fraction of emission of a left ventricle, except for arhythmic shock.
The expressed bradycardia.
Sick sinus syndrome, disturbances of intra-atrial conduction, AV blockade, blockade of legs of a ventriculonector or distal blockade (at patients without electrocardiostimulator).
The expressed arterial hypotension.
The expressed disturbances of water and electrolytic balance (for example, potassium metabolism disturbances).
Severe forms of the chronic obstructive pulmonary disease (COPD).
Simultaneous use of a ritonavir.
Age up to 18 years (efficiency and safety are not established).

With care: a myasthenia гравис, an abnormal liver function and/or kidneys, a paroxysmal ciliary arrhythmia (see. "Special instructions"), patients with electrocardiostimulators, advanced age, organic lesions of a myocardium (See the Route of administration and doses "), obstructive respiratory diseases, including.

bronchial asthma.

Pregnancy and period of a lactation

Adequate and well controlled researches at pregnant women were not conducted. Drug can be used at pregnancy only if the expected advantage for mother exceeds potential risk for a fruit. Propafenon gets through a placental barrier at the person. Concentration of a propafenon in an umbilical cord makes about 30% of concentration in mother's blood. As allocation of a propafenon in breast milk was not studied, but there are data on what пропафенон can be allocated with breast milk, the drug Ritmonorm® should be used with care during feeding by a breast.

Overdose:

Symptoms: lengthening of an interval of PQ, expansion of the QRS complex, suppression of automatism of a sinus node, AV blockade, ventricular tachycardia, fibrillation of ventricles, trembling of ventricles, can also appear the expressed decrease in the ABP, a spasm, drowsiness, death.

Treatment: symptomatic. As пропафенон has the large volume of distribution and high extent of linkng with proteins of a blood plasma (> 95%), the hemodialysis and hemoperfusion for removal of drug are not effective.

If necessary symptomatic therapy and/or the general supporting actions is applied.

Storage conditions:

To store at a temperature from 15 to 25 °C. To store in the place, unavailable to children. Period of validity of 5 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets are film coated, 150 mg.

On 10 tablets in the blister from foil PVC/Al. 2, 5 or 10 blisters with the application instruction in a cardboard pack.