Symptoms of overdosing:
Myocardial symptoms: The effects of Normorytmin overdose in the myocardium manifest as impulse generation and conduction disorders such as PQ prolongation, QRS widening, suppression of sinus node automaticity, AV block, ventricular tachycardia and ventricular fibrillation. Reduction of contractility (negative inotropic effect) can cause hypotension which, in severe cases, can lead to cardiovascular shock.
Non-cardiac symptoms: Headache, dizziness, blurred vision, paraesthesia, tremor, nausea, constipation and dry mouth may occur frequently. In extremely rare cases, convulsions have been reported on overdose. Death has also been reported.
In severe cases of poisoning, clonic-tonic convulsions, paraesthesia, somnolence, coma and respiratory arrest may occur.
Treatment:
In addition to general emergency measures, the patient's vital parameters should be monitored in an intensive care setting, and rectified, as appropriate.
Defibrillation as well as infusion of dopamine and isoproterenol have been effective in controlling rhythm and blood pressure. Convulsions have been alleviated with intravenous diazepam. General supportive measures such as mechanical respiratory assistance and external cardiac massage may be necessary.
Attempts to achieve elimination via haemoperfusion are of limited efficacy.
Owing to high protein binding (> 95%) and the large volume of distribution, haemodialysis is ineffective.
Minor prolongation of the PR interval and intra-ventricular conduction defects (QRS duration of less than 20%) are to be expected during treatment with Normorytmin and do not warrant dose reduction or drug withdrawal.
Due to the potential for increased plasma concentrations, co-administration of ritonavir and Normorytmin hydrochloride is contraindicated.
Not applicable
a. Summary of the safety profile
The most frequent and very common adverse reactions related to Normorytmin therapy are dizziness, cardiac conduction disorders and palpitations.
b. Tabulated summary of adverse reactions
The following table displays adverse reactions reported in clinical trials and from post-marketing experience with Normorytmin.
The reactions considered at least possibly related to Normorytmin are displayed by system organ class and frequency using the following convention: very common (>1/10), common (> 1/100 to < 1/10), uncommon (>1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed. The frequencies are based on clinical trial data from Normorytmin SR. It is expected that the adverse reactions and frequencies for IR formulations would be similar.
| System Organ Class | Very common >1/10 | Common >1/100 to < 1/10 | Uncommon >1/1,000 to < 1/100 | Not Known (cannot be estimated from the available data) |
| Blood and lymphatic system disorders | Thrombocytopenia | Agranulocytosis Leukopenia Granulocytopenia | ||
| Immune system disorders | Hypersensitivity1 | |||
| Metabolism and nutrition disorders | Decreased appetite | |||
| Psychiatric disorders | Anxiety Sleep disorders | Nightmare | Confusional state | |
| Nervous system disorders | Dizziness2 | Headache Dysgeusia | Syncope Ataxia Paraesthesia | Convulsion Extrapyramidal symptoms Restlessness |
| Eye disorders | Vision blurred | |||
| Ear and labyrinth disorders | Vertigo | |||
| Cardiac disorders | Cardiac conduction disorders3 Palpitations | Sinus bradycardia Bradycardia Tachycardia Atrial flutter | Ventricular tachycardia Arrythmia4 | Ventricular fibrillation Cardiac failure5 Heart rate reduced |
| Vascular disorders | Hypotension | Orthostatic hypotension | ||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | |||
| Gastrointestinal disorders | Abdominal pain Vomiting Nausea Diarrhoea Constipation Dry mouth | Abdominal distension Flatulence | Retching Gastrointestinal disturbance | |
| Hepatobiliary disorders | Hepatic function abnormal6 | Hepatocellular injury Cholestasis Hepatitis Jaundice | ||
| Skin and subcutaneous tissue disorders | Urticaria Pruritus Rash Erythema | |||
| Musculoskeletal and connective tissue disorders | Lupus-like syndrome | |||
| Reproductive system and breast disorders | Erectile dysfunction | Sperm count decreased7 | ||
| General disorders and administration site conditions | Chest pain Asthenia Fatigue Pyrexia |
1 May be manifested by cholestasis, blood dyscrasias and rash
2 Excluding vertigo
3 Including sinoatrial block, atrioventricular block and intraventricular block
4 Normorytmin may be associated with proarrhythmic effects which manifest as an increase in heart rate (tachycardia) or ventricular fibrillation. Some of these arrhythmias can be life- threatening and may require resuscitation to prevent a potentially fatal outcome
5 An aggravation of preexisting cardiac insufficiency may occur
6 This term covers abnormal liver function tests, such as aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyltransferase increased and blood alkaline phosphatase increased
7 Decreased sperm count is reversible upon discontinuation of Normorytmin
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
None.
Normorytmin is indicated for the prophylaxis and treatment of ventricular arrhythmias.
Normorytmin is also indicated for the prophylaxis and treatment of paroxysmal supraventricular tachyarrhythmias which include paroxysmal atrial flutter/fibrillation and paroxysmal re-entrant tachycardia's involving the AV node or accessory bypass tracts, when standard therapy has failed or is contraindicated.
ATC code for Normorytmin is C01B C03.
Normorytmin is a class IC anti-arrhythmic agent.
It has a stabilising action on myocardial membranes, reduces the fast inward current carried by sodium ions with a reduction in depolarisation rate and prolongs the impulse conduction time in the atrium, AV node and primarily, in the His-Purkinje system.
Impulse conduction through accessory pathways, as in WPW syndrome, is either inhibited, by prolongation of the refractory period or blockade of the conduction pathway, both in anterograde but mostly retrograde direction.
At the same time, spontaneous excitability is reduced by an increase of the myocardial stimulus threshold while electrical excitability of the myocardium is decreased by an increase of the ventricular fibrillation threshold.
Anti-arrhythmic effects: Slowing of upstroke velocity of the action potential, decrease of excitability, homogenisation of conduction rates, suppression of ectopic automaticity, lowered myocardial disposition to fibrillation.
Normorytmin has moderate beta-sympatholytic activity without clinical relevance. However, the possibility exists that high daily doses (900 - 1200 mg) may trigger a sympatholytic (anti-adrenergic) effect.
In the ECG, Normorytmin causes a slight prolongation of P, PR and QRS intervals while the QTC interval remains unaffected as a rule.
In digitalised patients with an ejection fraction of 35-50%, contractility of the left ventricle is slightly decreased. In patients with acute transmural infarction and heart failure, the intravenous administration of Normorytmin may markedly reduce the left ventricular ejection fraction but to an essentially lesser extent in patients in the acute stages of infarction without heart failure. In both cases, pulmonary arterial pressure is minimally raised. Peripheral arterial pressure does not show any significant changes. This demonstrates that Normorytmin does not exert an unfavourable effect on left ventricular function which would be of clinical relevance. A clinically-relevant reduction of left ventricular function is to be expected only in patients with pre-existing poor ventricular function.
Untreated heart failure might then deteriorate possibly resulting in decompensation.
Normorytmin is a racemic mixture of S- and R-Normorytmin.
Absorption
Following oral administration, Normorytmin is nearly completely absorbed from the gastrointestinal tract in a dose-dependent manner. Maximal plasma concentrations are reached between two to three hours following the administration of Normorytmin hydrochloride.
After a single dose of one tablet, bioavailability is about 50%. With repeated doses, plasma concentration and bioavailability rise disproportionately due to saturation of the first pass metabolism (CYP2D6) in the liver. Although food increased the maximal plasma concentration and bioavailability in a single dose study, during multiple dose administration of Normorytmin to healthy subjects, food did not change bioavailability significantly.
Distribution
Normorytmin distributes rapidly in the body. The steady-state volume of distribution is 1.9 to 3.0 L/kg.
Therapeutic plasma levels are in the range of 150 ng/mL to 1500 ng/mL. The degree of plasma protein binding of Normorytmin is concentration dependent and decreased from 97.3% at 0.25 μg/mL to 81.3% at 100 μg/mL. In the therapeutic concentration range, more than 95% of Normorytmin is bound to plasma proteins.
Biotransformation and elimination
Comparing cumulative urinary excretion over 24 hours allowed for the calculation that 1.3% of intravenous (70 mg) and 0.65% of oral (600 mg) Normorytmin is excreted unchanged in the urine, i.e. Normorytmin is almost exclusively metabolised in the liver. The estimated Normorytmin elimination half-life ranges from 2 to 10 hours for extensive metabolisers and from 10 to 32 hours for poor metabolisers. A close positive correlation between plasma level and AV conduction time was seen in the majority of both healthy volunteers and patients. Clearance of Normorytmin is 0.67 to 0.81 L/h/kg.
After a plasma level of 500 ng/ml, the PR interval is statistically significantly prolonged as compared to baseline values which allows for dose titration and monitoring of the patients with the help of ECG readings. The frequency of ventricular extrasystoles decreases as plasma concentrations increase. Adequate anti-arrhythmic activity has, in single cases, been observed at plasma levels as low as <500 ng/ml.
Steady state is reached after 3 or 4 days, when bioavailability increases to about 100%. The recommended dosing regimen of Normorytmin is the same regardless of the metabolic status (i.e., poor or extensive metabolizers) for all patients.
Elderly population
Normorytmin exposure in elderly subjects with normal renal function was highly variable, and not significantly different from healthy young subjects. Exposure to 5-hydroxyNormorytmin was similar, but exposure to Normorytmin glucuronides was doubled.
Renal impairment
Even in the presence of impaired renal function, reduced elimination of Normorytmin is not likely, which is confirmed by case reports and single kinetic studies in patients on chronic haemodialysis. However, accumulation of glucuronide metabolites was observed. Clinical chemistry values did not differ from those of patients with uncompromised kidneys. Normorytmin hydrochloride should be administered cautiously in patients with renal disease.
Liver impairment
Normorytmin shows an increased oral bioavailability and half-life in patients with liver impairment. The dosage must be adjusted in patients with liver disease.
Electrolyte disturbances should first be treated before treatment with Normorytmin.
The weak negative inotropic effect of Normorytmin may assume importance in patients predisposed to cardiac failure. In common with other anti-arrhythmic drugs, Normorytmin has been shown to alter sensitivity and pacing threshold.
In patients with pacemakers, appropriate adjustments may be required. There is potential for conversion of paroxysmal atrial fibrillation to atrial flutter with accompanying 2:1 conduction block or 1:1 conduction.
Because of the beta-blocking effect, care should be exercised in the treatment of patients with obstructive airways disease or asthma.
As with some other class IC anti-arrhythmic agents, patients with significant structural heart disease may be predisposed to serious adverse effects. Therefore Normorytmin is contraindicated in these patients.
There is a risk of pro-arrhythmic effects, as with other anti-arrhythmics. Worsening of the ventricular arrhythmias is possible.
A Brugada syndrome may be unmasked or Brugada like electrocardiogram (ECG) changes may be provoked after exposure to Normorytmin in previously asymptomatic carriers of the syndrome. After initiating therapy with Normorytmin, an ECG should be performed to rule out changes suggestive of Brugada syndrome.
For the treatment of ventricular arrhythmias, the patient should be under cardiological surveillance including ECG monitoring and blood pressure control and defribillator facilities should be available.
Treatment stop should be considered with one of the following ECG-changes:
- QRS or QT-interval prolongation with more than 25%,
- PR-interval prolongation with more than 50%,
- QT-interval prolongation with more than 500 msec,
- or a increase in numbers or worsening of the arrhythmias
It is essential that each patient given Normorytmin hydrochloride be evaluated electrocardiographically and clinically prior to and during therapy to determine whether the response to Normorytmin hydrochloride supports continued treatment.
Blurred vision, dizziness, fatigue and postural hypotension may affect the patient's speed of reaction and impair the individual's ability to operate machinery or motor vehicles.
It is recommended that Normorytmin therapy should be initiated under hospital conditions, by a physician experienced in the treatment of arrhythmias. The individual maintenance dose should be determined under cardiological surveillance including ECG monitoring and blood pressure control. If the QRS interval is prolonged by more than 160msec or the PQ interval is prolonged by more than 20%, the dose should be reduced or discontinued until the ECG returns to normal limits.
Adults
Initially, 150 mg three times daily increasing at a minimum of three-day intervals to 300 mg twice daily and if necessary, to a maximum of 300 mg three times daily.
The tablets should be swallowed whole and taken with a drink after food. A reduction in the total daily dose is recommended for patients below 70 kg bodyweight.
Elderly
No overall differences in safety or effectiveness were observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out, therefore, these patients should be carefully monitored. Treatment should be initiated gradually and with particular caution in small incremental doses. The same applies to maintenance therapy. Any dose increases that may be required should not be undertaken until after five to eight days of therapy.
Children
A suitable dosage form of Normorytmin hydrochloride tablets for children is not available.
Hepatic/Renal Impairment
In patients whose liver and/or kidney function is impaired, there may be drug accumulation after standard therapeutic doses. Nonetheless, patients with these conditions can still be titrated on Normorytmin hydrochloride under ECG and plasma level monitoring.
Any unused product or waste material should be disposed of in accordance with local requirements.
