Active ingredients: Propafenone (Propafenone hydrochloride)
Rytmonorm 150 mg Coated tablets
Rytmonorm 300 mg Coated tablets
Rytmonorm 325 mg Prolonged-release hard capsules
Rytmonorm 425 mg Prolonged-release hard capsules
Rytmonorm package inserts are available for pack sizes: - Rytmonorm 150 mg Coated tablets, Rytmonorm 300 mg Coated tablets, Rytmonorm 325 mg Prolonged-release capsules, Rytmonorm 425 mg Prolonged-release capsules, hard
- Rytmonorm 70 mg / 20 ml Solution for injection for intravenous use
Why is Rytmonorm used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antiarrhythmic, class IC
THERAPEUTIC INDICATIONS
Prevention and treatment of ventricular and supraventricular tachycardias and tachyarrhythmias, including W.P.W.syndrome, when associated with disabling symptoms.
Contraindications When Rytmonorm should not be used
Hypersensitivity to the active substance (propafenone hydrochloride), or to other closely related substances from a chemical point of view or to any of the excipients.
Known Brugada syndrome, manifest heart failure. Significant structural heart disease such as: myocardial infarction episode in the last three months, uncontrolled congestive heart failure in which the output (ejection fraction) of the left ventricle is less than 35%, cardiogenic shock (except that caused by arrhythmia), severe symptomatic bradycardia, severe pre-existing atrial, atrioventricular and intraventricular excitation conduction disturbances, sinus node disease (bradycardiatachycardia syndrome), atrial conduction defects, second degree or major atrioventricular block or bundle branch block or block distal in the absence of an artificial pacemaker, marked hypotension. Manifest disturbances of the electrolyte balance (e.g. potassium metabolism disorders), severe obstructive pulmonary disease, myasthenia gravis. Generally contraindicated in pregnancy (see "Special Warnings").
Contraindicated during lactation (see "Special Warnings"). Co-administration of propafenone hydrochloride and ritonavir is contraindicated (see "Interactions")
Precautions for use What you need to know before taking Rytmonorm
It is essential to electrocardiographically and clinically evaluate each patient given propafenone hydrochloride before and during therapy to determine whether the response to propafenone hydrochloride is sufficient to warrant continued use. Brugada Syndrome or Brugada-like changes in the electrocardiogram (ECG) may be caused after administration of propafenone in previously asymptomatic carriers of the syndrome. Once therapy with propafenone is initiated, an ECG should be performed to rule out changes indicative of the Brugada syndrome. Brugada Propafenone hydrochloride can worsen myasthenia gravis.
The frequency and sensitivity threshold of pace-makers may be altered during therapy with propafenone. Therefore the functioning of the pace-makers will have to be properly verified during the therapy and if necessary reprogrammed.
There is a potential for conversion of paroxysmal atrial fibrillation to atrial flutter resulting in 2: 1 conduction block or 1: 1 conduction (see "Side Effects"). As with other class 1C antiarrhythmic drugs, severe adverse events are more likely to occur in patients with significant structural heart disease taking this drug, therefore propafenone hydrochloride is contraindicated in these patients (see "Contraindications").
In the event of a previous myocardial infarction, the use of Rytmonorm tablets and capsules should be limited to the treatment of life-threatening ventricular arrhythmias.
In patients with impaired liver or kidney function, drug accumulation may occur even with the administration of therapeutic doses of Rytmonorm tablets and capsules. However, under constant ECG monitoring, these patients can be treated with reduced dose Rytmonorm tablets and capsules. .
Propafenone hydrochloride should be used with caution in patients with airway obstruction (eg asthma) due to beta-blocking activity. Administer with caution in patients with obstructive pulmonary disease as the beta-blocking activity of propafenone may increase resistance. respiratory tract.
Interactions Which medications or foods may change the effect of Rytmonorm
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those without a prescription.
In the case of simultaneous use of local anesthetics (for example during the implantation of pacemakers, surgical or dental procedures) as well as other drugs that have an inhibitory effect on heart rate and / or myocardial contractility (for example beta-blockers, tricyclic antidepressants) the possibility of potentiation of the side effects of Rytmonorm tablets and capsules should be considered.
Increases in plasma levels of cyclosporine, theophylline, desipramine, propranolol, metoprolol and digoxin have been found following co-administration of these drugs with propafenone. Doses of these medicinal products should be reduced as needed if signs of overdose are observed.
Concomitant use of propafenone and phenobarbital and / or rifampicin (inducers of CYP3A4) may reduce the antiarrhythmic efficacy of propafenone as a result of decreased plasma concentration of propafenone. Close monitoring of response to propafenone therapy is required during chronic co-administration with phenobarbital and / or rifampicin.
Oral anticoagulants can interact with propafenone, with consequent enhancement of the anticoagulant effect.
It is therefore recommended to carefully control the coagulation parameters of those patients treated simultaneously with oral anticoagulants (for example, phenprocoumon, warfarin) and propafenone as the latter can enhance the efficacy of these drugs by causing an increase in prothrombin time. The doses of these medicines should be adjusted if necessary. Drugs that inhibit CYP2D6, CYP1A2 and CYP3A4 such as ketoconazole, cimetidine, quinidine, erythromycin and grapefruit juice can cause an increase in propafenone levels. When propafenone is administered with inhibitors of these enzymes, patients should be closely monitored and the dose adjusted accordingly.
Co-administration of propafenone with drugs metabolised by CYP2D6 (such as venlafaxine) may cause the levels of these drugs to increase.
Propafenone is contraindicated when co-administered with ritonavir due to the potential for increased plasma concentrations of propafenone (see "Contraindications").
Combination therapy of amiodarone and propafenone can affect cardiac conduction and repolarization and lead to potentially proarrhythmic abnormalities. Dosage adjustments may be required for both compounds based on therapeutic response.
Concomitant use of propafenone and lidocaine did not show significant effects on pharmacokinetics. However, co-administration of propafenone and intravenous lidocaine has been reported to increase the risk of lidocaine-associated central nervous system adverse reactions.
Elevated plasma levels of propafenone can occur when administered concomitantly with SSRIs, such as fluoxetine and paroxetine.
Co-administration of propafenone hydrochloride and fluoxetine in extensive metabolisers increases the Cmax and AUC of S-propafenone by 39% and 50% and the Cmax and AUC of R-propafenone by 71% and 50%, respectively.
Low doses of propafenone may be sufficient to elicit the desired therapeutic response.
Pediatric population
Interaction studies have only been performed in adults. It is not known whether the extent of interactions in pediatric age is similar to that in adults.
Warnings It is important to know that:
Pregnancy
Ask your doctor or pharmacist for advice before taking any medicine
There are no adequate and well-controlled studies in pregnant women.
Propafenone should only be taken during pregnancy if the potential benefit justifies the potential risk to the fetus.
Propafenone hydrochloride is known to be able to cross the placental barrier in humans.
The concentration of propafenone in the umbilical cord appears to be about 30% of that in maternal blood.
The intake of Rytmonorm during pregnancy must be carried out in cases of recognized and effective necessity, under direct medical supervision.
Feeding time
There are no studies concerning the excretion of propafenone in breast milk.
Limited data suggest that propafenone can be excreted in breast milk.
Propafenone should be used with caution in nursing mothers
Because of the potential serious side effects on the newborn, the physician should decide whether to discontinue breastfeeding or use of the drug, considering the importance of the latter for the mother.
Effects on ability to drive and use machines
The product, in some patients, can cause blurred vision, dizziness, fatigue or postural hypotension; these symptoms may affect the patient's reaction rate and impair the individual's ability to use machines or motor vehicles.
Important information about some of the ingredients
Rytmonorm 150 mg and 300 mg Coated tablets contain 10 mg and 20 mg sodium per tablet respectively. To be taken into consideration in people with reduced kidney function or who follow a low sodium diet.
Dosage and method of use How to use Rytmonorm: Dosage
- 150 mg and 300 mg Coated tablets
Due to their bitter taste and due to the local numbing effect of Propafenone, the tablets should be swallowed whole (without being chewed) with a sip of liquid. The dose should be adapted to the individual needs of the patients.
Adults
For initial and maintenance treatment, the recommended daily dose is 450-600 mg (one 150 mg tablet three times a day or one 300 mg tablet twice a day).
Occasionally, an increase in the daily dose up to 900 mg (one 300 mg tablet or two 150 mg tablets three times a day) may be needed.
This daily dose can only be exceeded in exceptional cases under strict cardiological control.
These dosages refer to patients with a body weight of approximately 70 kg. Daily doses should be reduced proportionally for patients with lower body weight.
Dosage increases should not be made until the patient has taken the treatment for 3 to 4 days.
In patients presenting with significant enlargement of the QRS complex or second or third degree AV block, a dose reduction should be considered.
The individual maintenance dose should be determined under specialist cardiac control including ECG monitoring and repeated blood pressure checks (titration phase).
Senior citizens
Overall, no differences in safety or efficacy were observed between elderly patients. However, increased sensitivity of some older subjects cannot be ruled out, therefore these patients should be carefully monitored. Treatment should be started gradually and with particular caution in small incremental doses. The same is true for maintenance therapy. Any increase in dosage, which may be required, should be started after at least 5 - 8 days of treatment.
Hepatic / renal insufficiency
In patients with impaired hepatic and / or renal function, drug accumulation may occur after administration of standard therapeutic doses. However, in patients with these conditions the dose of propafenone hydrochloride can be further titrated under ECG control and by monitoring plasma levels.
- 325 mg and 425 mg Prolonged-release capsules, hard
The capsules should be swallowed whole with a sip of liquid. Do not crush or further divide the contents of the capsules.
The prolonged-release dose of propafenone should be individually titrated based on response and tolerability.
For initial and maintenance treatment, the recommended daily dose is 650 mg (one hard prolonged-release capsule of 325 mg twice daily).
If an additional therapeutic effect is required, the dose of propafenone hydrochloride (prolonged-release capsules) can be increased to 425 mg administered every twelve hours, after at least 5 days.
The individual maintenance dose should be determined under specialist cardiological control including repeated electrocardiographic evaluations and blood pressure measurements (dose adjustment phase).
If the duration of the QRS interval is prolonged or the rate-corrected QT interval is prolonged by more than 20%, the dose should be reduced or suspended until the electrocardiograph is normalized.
In patients with second or third degree AV block, a dose reduction should be considered.
Senior citizens
Overall, no differences in safety or efficacy were observed between elderly patients. However, increased sensitivity of some older subjects cannot be ruled out, therefore these patients should be carefully monitored. Dose titration in these patients should be done with particular caution.
In elderly patients or in patients with severe myocardial damage, as well as for other antiarrhythmic drugs, the dose should be gradually increased by carrying out special monitoring during the initial phase of treatment.
Kidney failure
The elimination of the major metabolite of propafenone is affected by renal insufficiency, therefore prolonged-release propafenone hydrochloride should be administered with caution to patients with renal insufficiency.
Hepatic insufficiency
Dosage should be appropriate for patients with hepatic insufficiency.
Prolonged-release propafenone hydrochloride is extensively metabolised via saturable hepatic oxidase. Due to the increased bioavailability and elimination half-life of propafenone hydrochloride, a reduction in the recommended dose may be required.
Children
Prolonged-release propafenone hydrochloride has not been studied in children and adolescents.
Overdose What to do if you have taken too much Rytmonorm
If you accidentally take an overdose of Rytmonorm, notify your doctor immediately or go to the nearest hospital.
Symptoms of overdose:
If symptoms of overdose occur, plasma concentrations of the drug should be determined and the doses administered should be appropriately reduced.
Myocardial symptoms: The effects of propafenone hydrochloride overdose on the myocardium manifest as impulse and conduction disorders such as PQ prolongation, QRS enlargement, sinus node automatism block, atrioventricular block, ventricular tachycardia, ventricular flutter and ventricular fibrillation.
Reduced contractility (negative inotropic effect) can cause hypotension which, in severe cases, can lead to cardiovascular shock.
Non-cardiac symptoms: Headache, dizziness, blurred vision, paraesthesia, tremors, nausea, constipation and dry mouth can occur frequently in the event of an overdose. In extremely rare cases of overdose, seizures and death can occur.
In severe cases of poisoning, tonic-clonic seizures, paraesthesia, somnolence, coma and respiratory arrest can occur.
Treatment: In addition to general emergency measures, the patient's vital signs should be monitored in the ICU, and adjusted as appropriate.
Defibrillation as well as infusion of dopamine and isoproterenol have been effective in controlling rhythm and blood pressure. Seizures have been relieved with intravenous diazepam. General supportive measures such as respiratory mechanical assistance and massage may be needed. external cardiac.
In the event of propafenone hydrochloride overdose, due to high protein binding (> 95%) and large volume of distribution, hemodialysis is ineffective and attempts at elimination by haemoperfusion have limited efficacy.
If you have any questions about the use of Rytmonorm, ask your doctor or pharmacist.
Side Effects What are the side effects of Rytmonorm
Like all medicines, Rytmonorm can cause side effects, although not everybody gets them. The most frequent and very common adverse reactions related to Propafenone therapy are: dizziness, cardiac conduction disturbances and palpitations. Summary table of adverse reactions The following table shows the adverse reactions that occurred in at least one of the 885 patients treated with prolonged-release propafenone hydrochloride in five phase II and two phase III studies.
For immediate-release formulations of propafenone hydrochloride, adverse reactions and frequency of occurrence are expected to be similar.
The following table also includes adverse reactions reported from post-marketing experience.
Reactions considered at least possibly related to the intake of propafenone hydrochloride are described by system organ class and frequency using the following convention: very common (≥1 / 10), common (≥1 / 100 to
1 Cholestasis, blood dyscrasias and skin rash may occur
2 Excluding vertigo
3 Including sinoatrial block, atrioventricular block and intraventricular block
4 Propafenone may be associated with proarrhythmic effects manifesting as an increase in heart rate (tachycardia) or ventricular fibrillation. Some of these arrhythmias can be life-threatening and may require resuscitation to avoid a life-threatening outcome
5 An aggravation of pre-existing heart failure may occur
6 This term includes abnormal liver function tests such as increased aspartate aminotransferase, increased alanine aminotransferase, increased gamma-glutamyltransferase and increased blood alkaline phosphatase.
7 The decrease in sperm count is reversible after discontinuation of propafenone
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse." information on the safety of this medicine ".
Expiry and Retention
Expiry: see the expiry date printed on the package.
The expiry date refers to the product in intact packaging, correctly stored. Warning: do not use the medicine after the expiry date shown on the package.
150 mg and 300 mg coated tablets: This medicinal product does not require any special storage conditions.
Prolonged-release 325 mg and 425 mg capsules, hard: Store the medicine below 30 ° C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Keep this medicine out of the sight and reach of children.
COMPOSITION
Rytmonorm 150 mg Coated tablets
One coated tablet contains:
Active principle: propafenone hydrochloride 150 mg.
Excipients: Pre-gelled starch, copovidone, crospovidone, hypromellose, macrogol 6000, magnesium stearate, sodium lauryl sulfate, talc, titanium dioxide.
Rytmonorm 300 mg Coated tablets
One coated tablet contains:
Active principle: propafenone hydrochloride 300 mg.
Excipients: Pre-gelled starch, copovidone, crospovidone, hypromellose, macrogol 6000, magnesium stearate, sodium lauryl sulfate, talc, titanium dioxide.
Rytmonorm 325 mg Prolonged-release hard capsules
One prolonged-release capsule, hard contains:
Active principle: propafenone hydrochloride 325 mg.
Excipients: hypromellose, magnesium stearate. Composition of the capsule: gelatin, red iron oxide (E 172), sodium lauryl sulfate, titanium dioxide (E 171).
Rytmonorm 425 mg Prolonged-release hard capsules
One prolonged-release capsule, hard contains:
Active principle: propafenone hydrochloride 425 mg.
Excipients: hypromellose, magnesium stearate. Composition of the capsule: gelatin, red iron oxide (E 172), sodium lauryl sulfate, titanium dioxide (E 171).
PHARMACEUTICAL FORM AND CONTENT
- 150 mg coated tablets:
Box of 30 tablets
Box of 60 tablets (*)
- 300 mg coated tablets:
Box of 30 tablets
Box of 60 tablets (*) (*) not on the market
- 325 mg prolonged-release hard capsules:
Box of 28 capsules
- 425 mg prolonged-release hard capsules:
Box of 28 capsules
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
RYTMONORM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Rytmonorm 150 mg Coated tablets
One coated tablet contains:
Active principle: propafenone hydrochloride 150 mg
Excipients: Each 150 mg tablet contains up to 10.0 mg of sodium
For the full list of excipients, see section 6.1
Rytmonorm 300 mg Coated tablets
One coated tablet contains:
Active principle: propafenone hydrochloride 300 mg
Excipients: Each 300 mg tablet contains up to 20.0 mg of sodium
For the full list of excipients, see section 6.1
Rytmonorm 325 mg Prolonged-release hard capsules
One prolonged-release capsule, hard contains:
Active principle: propafenone hydrochloride 325 mg
Excipients: Each 325 mg capsule contains up to 0.2200 mg of sodium
For the full list of excipients, see section 6.1
Rytmonorm 425 mg Prolonged-release hard capsules
One prolonged-release capsule, hard contains:
Active principle: propafenone hydrochloride 425 mg
Excipients: Each 425 mg capsule contains up to 0.1520 mg of sodium
For the full list of excipients, see section 6.1
Rytmonorm 70mg / 20ml Solution for injection for intravenous use
One 20ml vial contains:
Active principle: propafenone hydrochloride 70 mg
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Coated tablets.
Prolonged-release hard capsules.
Solution for injection for intravenous use.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
• Rytmonorm 150 mg and 300 mg Coated tablets
• Rytmonorm 325 mg and 425 mg Prolonged-release hard capsules
Prevention and treatment of ventricular and supraventricular tachycardias and tachyarrhythmias, including W.P.W.syndrome, when associated with disabling symptoms.
• Rytmonorm 70 mg / 20 ml Solution for injection for intravenous use
Rapid control or short-term prophylaxis of ventricular and supraventricular tachycardias and tachyarrhythmias, including W.P.W.syndrome, when associated with disabling symptoms.
04.2 Posology and method of administration
The dosage should be as indicated below, unless changed by the doctor.
• Rytmonorm 150 mg and 300 mg Coated tablets
The dose should be adapted to the individual needs of the patients.
Adults
For initial and maintenance treatment, the recommended daily dose is 450-600 mg (one 150 mg tablet three times a day or one 300 mg tablet twice a day).
Occasionally, an increase in the daily dose up to 900 mg (one 300 mg tablet or two 150 mg tablets three times a day) may be needed.
This daily dose can only be exceeded in exceptional cases under strict cardiological control.
These dosages refer to patients with a body weight of approximately 70 kg. Daily doses should be reduced proportionally for patients with lower body weight. Dosage increases should not be made until the patient has taken the treatment for 3 to 4 days.
In patients presenting with significant enlargement of the QRS complex or second or third degree AV block, a dose reduction should be considered.
The individual maintenance dose should be determined under specialist cardiac control including ECG monitoring and repeated blood pressure checks (titration phase).
Senior citizens
Overall, no differences in safety or efficacy were observed between elderly patients. However, increased sensitivity of some older subjects cannot be ruled out, therefore these patients should be carefully monitored.
Treatment should be started gradually and with particular caution in small incremental doses. The same is true for maintenance therapy. Any increase in dosage, which may be required, should be started after at least 5 - 8 days of treatment.
Hepatic / renal insufficiency
In patients with impaired hepatic and / or renal function, drug accumulation may occur after administration of standard therapeutic doses. However, in patients with these conditions the dose of propafenone hydrochloride can be further titrated under ECG control and by monitoring plasma levels (see section 5.2).
Method of administration
Due to their bitter taste and due to the local numbing effect of propafenone, the tablets should be swallowed whole (without being chewed) with a sip of liquid.
• Rytmonorm 325 mg and 425 mg Prolonged-release hard capsules
Dosage
The prolonged-release dose of propafenone should be individually titrated based on response and tolerability.
For initial and maintenance treatment, the recommended daily dose is 650 mg (one 325 mg prolonged-release capsule twice a day).
If an additional therapeutic effect is required, the dose of propafenone hydrochloride (prolonged-release capsules) can be increased to 425 mg administered every twelve hours, after at least 5 days.
The individual maintenance dose should be determined under specialist cardiological control including repeated electrocardiographic evaluations and blood pressure measurements (dose adjustment phase).
If the duration of the QRS interval is prolonged or the rate-corrected QT interval is prolonged by more than 20%, the dose should be reduced or suspended until the electrocardiograph is normalized. In patients with second or third degree AV block, a dose reduction should be considered.
Hepatic insufficiency
Prolonged-release propafenone hydrochloride is extensively metabolised via "saturable hepatic oxidase. Due to the increased bioavailability and elimination half-life of propafenone hydrochloride, a reduction in the recommended dose may be required (see section 5.2).
Kidney failure
The elimination of the major metabolite of prolonged-release propafenone hydrochloride is affected by renal insufficiency, therefore propafenone hydrochloride should be administered with caution (see section 5.2).
Senior citizens
Overall, no differences in safety or efficacy were observed between elderly patients. However, increased sensitivity of some older subjects cannot be ruled out and therefore these patients should be carefully monitored. Dose titration in these patients should be done with particular caution.
In elderly patients or in patients with severe myocardial damage, as well as for other antiarrhythmic drugs, the dose should be gradually increased by carrying out special monitoring during the initial phase of treatment.
Pediatric population
Prolonged-release propafenone hydrochloride has not been studied in children and adolescents.
Method of administration
The capsules should be swallowed whole with a sip of liquid. Do not crush or further divide the contents of the capsules.
• Rytmonorm 70 mg / 20 ml Solution for injection for intravenous use
Dosage
Dosage should be individualized and determined under ECG control and blood pressure monitoring. When administering solutions for infusion, careful monitoring of ECG (QRS interval, PR and QTc) and circulatory parameters is required.
Single dose intravenous administration is 1 mg / kg body weight (corresponding to a 20 ml vial in patients with a body weight of 70 kg).
Often the desired therapeutic effect can already be achieved with a dose of 0.5 mg / kg body weight (corresponding to 10 ml of solution). If necessary, the single dose can be increased to 2 mg / kg body weight ( corresponding to 40 ml of solution).
Treatment should be started with the lowest possible dose, keeping the patient under careful observation and close monitoring of electrocardiography and blood pressure.
Method of administration
The slow intravenous injection should be given over a 3-5 minute period.
The interval between two injections should not be less than 90-120 minutes. If the QRS interval is prolonged or if a lengthening of the frequency corrected QT interval of more than 20% is observed, dosing should be stopped immediately.
Short-lasting infusion
For short duration infusion (1-3 hours) the infusion rate is 0.5-1 mg / min. of Rytmonorm 70 mg / 20 ml Injectable solution.
Slow intravenous infusion
For slow intravenous infusion, the maximum daily dose is generally 560 mg (corresponding to 160 ml of solution). A 5% glucose or fructose solution should be used to prepare the infusion. Due to the potential for precipitation, saline is not suitable for preparing the solution for infusion.
Kidney failure
Propafenone hydrochloride should be administered with caution in patients with renal insufficiency.
Hepatic insufficiency
Dosage should be appropriate for patients with hepatic insufficiency.
04.3 Contraindications
Hypersensitivity to the active substance (propafenone hydrochloride), to other closely related substances from a chemical point of view or to any of the excipients listed in section 6.1.
Known Brugada syndrome, manifest heart failure. Significant structural heart disease such as: myocardial infarction episode in the last three months, uncontrolled congestive heart failure in which the output (ejection fraction) of the left ventricle is less than 35%, cardiogenic shock (except that caused by arrhythmia), severe symptomatic bradycardia, severe pre-existing atrial, atrioventricular and intraventricular excitation conduction disturbances, sinus node disease (bradycardia-tachycardia syndrome), atrial conduction defects, second degree or major atrioventricular block or bundle branch block or distal block in the absence of an artificial pacemaker, marked hypotension. Manifest disturbances of the electrolyte balance (e.g. potassium metabolism disorders), severe obstructive pulmonary disease, myasthenia gravis. Generally contraindicated in pregnancy (see 4.6). Contraindicated during lactation (see 4.6).
Co-administration of propafenone hydrochloride and ritonavir is contraindicated (see section 4.5).
04.4 Special warnings and appropriate precautions for use
It is essential to electrocardiographically and clinically evaluate each patient given propafenone hydrochloride before and during therapy to determine whether the response to propafenone hydrochloride is sufficient to warrant continued use.
Brugada Syndrome or Brugada-like changes in the electrocardiogram (ECG) may be caused after administration of propafenone in previously asymptomatic carriers of the syndrome. Once therapy with propafenone is initiated, an ECG should be performed to rule out changes indicative of the Brugada syndrome. Brugada.
Propafenone hydrochloride can worsen myasthenia gravis.
Rytmonorm solution for injection contains glucose and is therefore not suitable for people with glucose / galactose malabsorption syndrome.
The frequency and sensitivity threshold of pace-makers may be altered during therapy with propafenone. Therefore the functioning of the pace-makers will have to be properly verified during the therapy and if necessary reprogrammed.
There is a potential for conversion of paroxysmal atrial fibrillation to atrial flutter resulting in 2: 1 conduction block or 1: 1 conduction block (see section 4.8).
As with other class 1C antiarrhythmic drugs, severe adverse events are more likely to occur in patients with significant structural heart disease, therefore, propafenone hydrochloride is contraindicated in these patients (see section 4.3).
In the event of a previous myocardial infarction, use of Rytmonorm should be limited to the treatment of life-threatening ventricular arrhythmias.
In patients with impaired hepatic or renal function, drug accumulation may occur even with the administration of therapeutic doses of Rytmonorm.
However, under constant ECG monitoring, these patients can be treated with Rytmonorm in reduced doses.
Propafenone hydrochloride should be used with caution in patients with airway obstruction (eg asthma) due to beta-blocking activity. Administer with caution in patients with obstructive pulmonary disease as the beta-blocking activity of propafenone may increase resistance. respiratory tract.
During continuous infusion, careful monitoring of the electrocardiographic trace and the blood pressure value is recommended.
04.5 Interactions with other medicinal products and other forms of interaction
In case of simultaneous use of local anesthetics (for example during the implantation of pace-makers, surgical or dental procedures) as well as other drugs that determine an inhibitory effect on heart rate and / or myocardial contractility (for example beta-blockers , tricyclic antidepressants) the possibility of potentiation of the side effects of Rytmonorm should be considered.
Increases in plasma levels of cyclosporine, theophylline, desipramine, propranolol, metoprolol and digoxin have been found following co-administration of these drugs with propafenone. Doses of these medicinal products should be reduced as needed if signs of overdose are observed.
Concomitant use of propafenone and phenobarbital and / or rifampicin (inducers of CYP3A4) may reduce the antiarrhythmic efficacy of propafenone as a result of decreased plasma concentration of propafenone. Close monitoring of response to propafenone therapy is required during chronic co-administration with phenobarbital and / or rifampicin.
Oral anticoagulants can interact with propafenone, with consequent enhancement of the anticoagulant effect.
It is therefore recommended to carefully control the coagulation parameters of those patients treated simultaneously with oral anticoagulants (for example, phenprocoumon, warfarin) and propafenone as the latter can enhance the efficacy of these drugs by causing an increase in prothrombin time. The doses of these medicines should be adjusted if necessary.
Drugs that inhibit CYP2D6, CYP1A2 and CYP3A4 such as ketoconazole, cimetidine, quinidine, erythromycin and grapefruit juice can cause an increase in propafenone levels. When propafenone is administered with inhibitors of these enzymes, patients should be closely monitored and the dose adjusted accordingly.
Co-administration of propafenone with drugs metabolised by CYP2D6 (such as venlafaxine) may cause the levels of these drugs to increase.
Propafenone is contraindicated in co-administration with ritonavir due to the potential for increased plasma concentrations of propafenone (see section 4.3).
Combination therapy of amiodarone and propafenone can affect cardiac conduction and repolarization and lead to potentially proarrhythmic abnormalities. Dosage adjustments may be required for both compounds based on therapeutic response.
Concomitant use of propafenone and lidocaine did not show significant effects on pharmacokinetics. However, co-administration of propafenone and intravenous lidocaine has been reported to increase the risk of lidocaine-associated central nervous system adverse reactions.
Elevated plasma levels of propafenone can occur when administered concomitantly with SSRIs, such as fluoxetine and paroxetine. Co-administration of propafenone hydrochloride and fluoxetine in extensive metabolisers increases the Cmax and AUC of S-propafenone by 39% and 50% and the Cmax and AUC of R-propafenone by 71% and 50%, respectively.
Low doses of propafenone may be sufficient to elicit the desired therapeutic response.
Pediatric population
Interaction studies have only been performed in adults. It is not known whether the extent of interactions in pediatric age is similar to that in adults.
04.6 Pregnancy and lactation
Pregnancy
There are no adequate and well-controlled studies in pregnant women.
Propafenone should only be taken during pregnancy if the potential benefit justifies the potential risk to the fetus.
Propafenone hydrochloride is known to be able to overcome the placental barrier in humans.
The concentration of propafenone in the umbilical cord appears to be about 30% of that in maternal blood.
The intake of Rytmonorm during pregnancy must be carried out in cases of recognized and effective necessity, under direct medical supervision.
Feeding time
There are no studies concerning the excretion of propafenone in breast milk.
Limited data suggest that propafenone can be excreted in breast milk. Propafenone should be used with caution in nursing mothers.
Because of the potential serious side effects on the newborn, the physician should decide whether to discontinue breastfeeding or use of the drug, considering the importance of the latter for the mother.
04.7 Effects on ability to drive and use machines
The product, in some patients, can cause blurred vision, dizziness, fatigue or postural hypotension; these symptoms may affect the patient's reaction rate and impair the individual's ability to use machines or motor vehicles.
04.8 Undesirable effects
The most frequent and very common adverse reactions related to propafenone therapy are: dizziness, cardiac conduction disturbances and palpitations.
Summary table of adverse reactions
The following table shows the adverse reactions that occurred in at least one of the 885 patients treated with prolonged-release propafenone hydrochloride in five phase II and two phase III studies. For immediate-release formulations of propafenone hydrochloride, adverse reactions and frequency of occurrence are expected to be similar.
The following table also includes adverse reactions reported from post-marketing experience. Reactions considered at least possibly related to taking propafenone hydrochloride are described by system organ class and frequency using the following convention: very common (≥1 / 10), common (≥1 / 100 to
1 Cholestasis, blood dyscrasias and skin rash may occur
2 Excluding vertigo
3 Including sinoatrial block, atrioventricular block and intraventricular block.
4Propafenone may be associated with proarrhythmic effects manifesting as an increase in heart rate (tachycardia) or ventricular fibrillation. Some of these arrhythmias can be life-threatening and may require resuscitation to avoid a life-threatening outcome
5 An aggravation of pre-existing heart failure may occur
6 This term includes abnormal liver function tests such as increased aspartate aminotransferase, increased alanine aminotransferase, increased gamma-glutamyltransferase and increased blood alkaline phosphatase.
7 The decrease in sperm count is reversible after discontinuation of propafenone
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address" www.agenziafarmaco.gov.it/it/responsabili ".
04.9 Overdose
Symptoms of overdose
If symptoms of overdose occur, plasma concentrations of the drug should be determined and the doses administered should be appropriately reduced.
Myocardial symptoms:
The effects of propafenone hydrochloride overdose on the myocardium manifest as impulse and conduction disorders such as PQ prolongation, QRS enlargement, sinus node automatism block, atrioventricular block, ventricular tachycardia, ventricular flutter and ventricular fibrillation.
Reduced contractility (negative inotropic effect) can cause hypotension which, in severe cases, can lead to cardiovascular shock.
Non-cardiac symptoms:
Headache, dizziness, blurred vision, paraesthesia, tremors, nausea, constipation and dry mouth can occur frequently in the event of an overdose.
In extremely rare cases of overdose, seizures and death can occur.
In severe cases of poisoning, tonic-clonic seizures, paraesthesia, somnolence, coma and respiratory arrest can occur.
Treatment:
In addition to general emergency measures, the patient's vital signs should be monitored in the ICU and adjusted as appropriate.
Defibrillation as well as infusion of dopamine and isoproterenol have been effective in controlling rhythm and blood pressure. Seizures have been relieved with intravenous diazepam. General supportive measures such as respiratory mechanical assistance and massage may be needed. external cardiac.
In the event of propafenone hydrochloride overdose, due to high protein binding (> 95%) and large volume of distribution, hemodialysis is ineffective and attempts at elimination by haemoperfusion have limited efficacy.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiarrhythmics, class IC.
ATC code: C01BC03
Mechanism of action and pharmacodynamic effects
Propafenone hydrochloride is a very effective antiarrhythmic drug, with a local anesthetic action and a stabilizing effect on the myocardial cell membrane, and blocking sodium channels (Vaughan Williams, Class 1C).
This drug also has a mild beta-blocker efficacy (class II according to Vaughan Williams).
Propafenone hydrochloride reduces the rate of increase of the action potential and consequently slows down the conduction of the impulse (negative dromotropic effect). It prolongs the atrial and ventricular refractory period in proportion to the dosage employed. Propafenone hydrochloride prolongs the refractory periods in the accessory bundles in the WPW syndrome patients Therefore Rytmonorm has a powerful and effective effect in cardiac arrhythmias of various origins.
05.2 Pharmacokinetic properties
Propafenone is a racemic mixture of propafenone S and R.
Phase b half-life: 3.6 ± 0.2 hours.
Plasma protein binding: 97%.
It undergoes an important first pass hepatic metabolism; the share of unchanged drug excreted via the kidney is 1% in 24 hours.
For oral administration :
Absorption
Rytmonorm 150 mg and 300 mg Coated tablets :
After a rapid onset (approximately 30 minutes), maximum plasma concentration is reached after 2-3 hours administration of immediate-release propafenone hydrochloride and the effect persists for more than 8 hours. Propafenone is known to undergo widespread presystemic biotransformation and saturable (CYP2D6 hepatic first pass effect) leading to absolute dose- and pharmaceutical form-dependent bioavailability.
Although food increased maximum plasma concentration and bioavailability in a single dose study, during multiple dose administration of propafenone to healthy subjects, food did not significantly change bioavailability.
Rytmonorm 150 mg and 300 mg Coated tablets it is well absorbed from the gastrointestinal tract and its bioavailability is 49%.
Rytmonorm 325 mg and 425 mg Prolonged-release hard capsules :
the maximum level of plasma concentration is reached after 3-8 hours and the effect, thanks to the prolonged release of the active principle, persists for more than 12 hours. The characteristic of the prolonged release also guarantees, with only two daily administrations, blood concentrations of propafenone more constant than those obtained with Rytmonorm 150 mg and 300 mg Coated tablets taken three times a day.
Rytmonorm 325 mg and 425 mg Prolonged-release hard capsules it is well absorbed from the gastrointestinal tract and its bioavailability is 32%.
Distribution
Propafenone is rapidly distributed. The steady-state volume of distribution is 1.9 to 3.0 L / kg. The degree of plasma protein binding of propafenone is concentration dependent and decreases from 97.3% with 0.25 ng / mL to 91.3% with 100 ng / mL.
Biotransformation and elimination
There are two genetically determined types of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolised with an "elimination half-life of 2 to 10 hours (rapid metabolisers). These patients metabolize propafenone into two active metabolites: 5-hydroxypropafenone which is formed. from CYP2D6 and "N-depropylpropafenone (norpropafenone) which is formed from both CYP3A4 and CYP1A2. In less than 10% of patients, the metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed at all or is poorly formed (poor metabolisers). In patients with poor drug metabolism, the elimination half-life of both immediate-release and prolonged-release propafenone hydrochloride is between 10 and 32 hours.
The clearance of propafenone ranges from 0.67 to 0.81 L / h / kg.
Since propafenone is subject to first-pass hepatic metabolism and has a non-linear (exponential) kinetics, with the prolonged-release formulation, the amount of drug available in the blood appears to be, at the same dosage, lower than that obtainable. after administration of Rytmonorm 150 mg and 300 mg Coated tablets.
In order to achieve equal exposure, higher daily dosages are therefore required for the prolonged release formulation compared to the immediate release formulation.
Bioequivalence studies have shown that 650 mg or 850 mg of Rytmonorm 325 mg and 425 mg Prolonged-release hard capsules(corresponding to a 325 mg or 425 mg prolonged-release capsule twice a day) guarantee blood levels equivalent to those obtained with 450 mg or 600 mg of Rytmonorm 150 mg and 300 mg respectively Coated tablets.
Linearity / non-linearity
In extensive metabolisers, the saturable hydroxylation cycle (CYP2D6) exhibits non-linear pharmacokinetics. In poor metabolisers, the pharmacokinetics of propafenone are linear. Since steady state is reached in three to four days for immediate-release propafenone (four to five days for prolonged-release propafenone) after taking the drug in all patients, the recommended dosing schedule when taking propafenone immediate-release and prolonged-release hydrochloride are the same for all patients.
Inter / intravariability of subjects
With propafenone, there is a considerable degree of individual variability in pharmacokinetics which is largely due to the hepatic first pass effect and non-linear pharmacokinetics in patients with intensive metabolism. The wide variability in blood levels requires careful titration. of dosage in all patients and a "particular attention to clinical and electrocardiographic tests of toxicity.
Elderly population
Exposure to propafenone in elderly subjects with normal renal function is highly variable, and is not significantly different in healthy young subjects. Exposure to 5-hydroxypropafenone is similar, but exposure to propafenone glucuronides is doubled.
Kidney failure
In patients with renal insufficiency, exposure to propafenone and 5-hydroxypropafenone is similar to that observed in healthy controls, while accumulation of glucuronide metabolites was observed. Propafenone hydrochloride should be administered with caution in patients with renal insufficiency.
Hepatic insufficiency
Propafenone exhibits increased oral bioavailability and half-life in patients with hepatic insufficiency. Dosage should be adjusted for patients with hepatic insufficiency.
Pediatric population
The (apparent) clearance of propafenone in infants and children aged 3 days to 7.5 years varies from 0.13 to 2.98 L / h / kg after intravenous and oral administration, with no clear relationship to age. .
Steady-state concentrations of dose-normalized oral propafenone in 47 children aged 1 day to 10.3 years (median 2.2 months) were 45% higher in children older than 1 year compared to subjects less than one year old. Although there is considerable intersubject variability, for dose adjustment, ECG monitoring seems more appropriate than that of plasma concentrations of propafenone.
For parenteral administration :
The onset of action occurs either during or shortly after the injection. The effect reaches its maximum a few minutes after the injection and persists for more than four hours.
05.3 Preclinical safety data
Non-clinical data do not show that the intake of this drug may pose a particular danger to humans according to conventional studies conducted on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or reproductive toxicity. .
Acute toxicity
Toxicological tests have shown that propafenone is well tolerated in the most common laboratory animals (LD50 rat p.o. 913 mg / kg; Mus Musculus p.o. 728 mg / kg without substantial differences between the two sexes).
Subacute and chronic toxicity
Subacute and chronic toxicity studies did not show any functional or histological alteration of the uropoietic, hepatic and medullary systems in the treated animals. It was also found to be neither mutagenic nor teratogenic.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Rytmonorm 150 mg and 300 mg Coated tablets
Pre-gelled starch, copovidone, crospovidone, hypromellose, macrogol 6000, magnesium stearate, silicone antifoam emulsion (polydimethylsiloxane, polyglycolstearyl ether), sodium lauryl sulfate, talc, titanium dioxide.
Rytmonorm 325 mg Prolonged-release hard capsules
Hypromellose, magnesium stearate.
Composition of the capsule: gelatin, red iron oxide (E 172), sodium lauryl sulfate, titanium dioxide (E 171).
Rytmonorm 425 mg Prolonged-release hard capsules
Hypromellose, magnesium stearate.
Composition of the capsule: gelatin, red iron oxide (E 172), sodium lauryl sulfate, titanium dioxide (E 171).
Rytmonorm 70 mg / 20 ml Solution for injection for intravenous use
Water for injections, glucose.
06.2 Incompatibility
When the drug is administered by long-lasting infusion, mixtures with physiological saline solutions should be avoided as precipitates may appear under certain temperature and concentration conditions.
06.3 Period of validity
Rytmonorm 150 mg and 300 mg Coated tablets and 325 mg and 425 mg Prolonged-release hard capsules: 5 years
Rytmonorm 70 mg / 20 ml Solution for injection for intravenous use: 3 years
06.4 Special precautions for storage
Coated tablets
Prolonged-release hard capsules
Store the medicine below 30 ° C.
Solution for injection for intravenous use
Store the medicine between 15 ° C and 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Carton containing 30 150 mg coated tablets in aluminum / PVC blister
Carton containing 60 coated tablets of 150 mg in aluminum / PVC blister
Carton containing 30 coated tablets of 300 mg in aluminum / PVC blister
Carton containing 60 coated tablets of 300 mg in aluminum / PVC blister
Carton containing 28 prolonged-release hard capsules of 325 mg in PVC / PVDC / Alu blisters
Carton containing 28 prolonged-release hard capsules of 425 mg in PVC / PVDC / Alu blisters
Carton containing 5 vials (20 ml each) of 70 mg
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
ABBOTT S.r.l - S.R. 148 Pontina km 52 snc - 04011 Campoverde di Aprilia (LT)
08.0 MARKETING AUTHORIZATION NUMBER
Rytmonorm 150 mg Coated tablets, 30 tablets - A.I.C .: No. 024862017
Rytmonorm 150 mg Coated tablets, 60 tablets - A.I.C .: No. 024862070 *
Rytmonorm 300 mg Coated tablets, 30 tablets - A.I.C .: No. 024862029
Rytmonorm 300 mg Coated tablets, 60 tablets - A.I.C .: No. 024862082 *
Rytmonorm 325 mg Prolonged-release capsules, hard, 28 capsules - A.I.C .: No. 024862094
Rytmonorm 425 mg Prolonged-release capsules, hard, 28 capsules - A.I.C .: No. 024862106
Rytmonorm 70 mg / 20 ml Solution for injection for intravenous use, 5 ampoules -
A.I.C .: n. 024862031
* not on the market
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Rytmonorm 150 mg Coated tablets, 30 tablets: 15.12.1982
Rytmonorm 150 mg Coated tablets, 60 tablets: 28.01.2000
Rytmonorm 300 mg Coated tablets, 30 tablets: 15.12.1982
Rytmonorm 300 mg Coated tablets, 60 tablets: 28.01.2000
Rytmonorm 325 mg Prolonged-release capsules, hard, 28 capsules: 09.06.2006
Rytmonorm 425 mg Prolonged-release capsules, hard, 28 capsules: 09.06.2006
Rytmonorm 70 mg / 20 ml Solution for injection for intravenous use, 5 ampoules: 15.12.1982
Authorization renewal: 01.06.2010
10.0 DATE OF REVISION OF THE TEXT
AIFA V&A Resolution no. 1796/2014 of 09.09.2014
