Ephedrine Biotika Injection


SUMMARY OF PRODUCT CHARACTERISTICS


1. NAME OF THE MEDICINAL PRODUCT
                                              EPHEDRIN Biotika

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
                        Ephedrine hydrochloride 50 mg in 1 ml 

3. PHARMACEUTICAL  FORM 
                             Solution for injections. 
                                Clear, colourless solution. 

4. CLINICAL PARTICULARS 

4.1 Therapeutic indications 
Circulation: vasomotor collapse, sinus bradycardia (in inclination to syncopes)
Allergic statuses (asthma, allergic rhinitis, urticaria, angioneurotic oedemas, drug exanthemas)
Central: enuresis nocturna, narcolepsy

4.2 Posology and method of administration 
Ephedrine should be dosed individually according to circulatory parameters. 

Dosage for children 
5 mg (0.1 ml) exceptionally subcutaneously or 2.5 mg (0.05 ml) intravenously, 
1 to 2-times daily is administered for children up to 1 year of age. 
For children 1 to 6 years of age 12.5 mg (0.25 ml) subcutaneously or 5 mg (0.1 ml) intravenously is administered 1 to 2-times daily
For children 6 to 15 years of age 25 mg (0.5 ml) subcutaneously or 10 mg (0.2 ml) intravenously is administered 1 to 2-tlmes daily. 

Dosage for adults 
In collapse statuses 25-50 mg (0.5 to 1 ml) subcutaneously or intramuscularly is administered. When an intravenous administration is necessary, the dose of 0.4 ml (20mg) is diluted with sodium chloride isotonic solution up to 20 ml and it is applied very slowly. 
The maximal single dose in subcutaneous and intramuscular administration is 50 mg. 
The maximal daily dose in subcutaneous and intramuscular administration is 150 mg. 
The preparation is recommended to apply in the morning and afternoon, not in the evening, because it can cause insomnia. 

4.3 Contraindications 
Hypersensitivity to ephedrine and other sympathomimetic agents.Arterial hypertension, cardiac insufficiency, ischaemic heart disease, myocardial infarction, hyperthyreosis, traumatic shock, sinus tachycardia. 

4.4 Special warnings and precautions for use
Ephedrine is not allowed to be administered as a monotherapy in hypovolemic patients. Only in absolutely inevitable cases, ephedrine can be administered with total volume replacement preparation together or to maintain coronary and cerebral perfusion during volume depletion. Even in the smmallest doses, ephedrin causes vasoconstriction. It irritates cortex and subcortical centers. When administered due to its peripheral effect, central stimulating effect is often considered as a side effect.
Caution is needed in patients with diabetes mellitus, aneurysm, prostatic hypertrophy and atherosclerosis. Due to the tolerance which is developed, long term use of ephedrine in grams doses that usually cause circulation and nervous disorders, are known.

1 Decrease venal perfusion due to vasoconstrictions. Should be avoided or use after risk and benefit consideration in patients with venal impairment. 
2 Constricting per.vessels Ephedrine accelerates heart rate (by acting on preceptors). Use of ephedrin in cases assotiated with tachycardia the selective a adrenergic agonists (e.g. methoxamine) is more appriopriative. 
3 Shock (collapse) could reduce SC absorption of drug. 
Drug addiction (ephedrinism) may develop and in long-term use of mainly higher doses toxic psychoses. Ephedrine is included into a group of precursors of narcotic drugs and psychotropic substances.

4.5 Interactions with other medicinal products and other forms of interaction
The most serious interactions are with MAO inhibitors and halothane (arrhythmia up to fibrillation) and care is requested in combination with cardio¬active pharmaca. The preparation potentiates the effect of digitalis glycosides. Combined with caffeine it may cause palpitation. Simultaneous administration of higher doses of theophylline and aminophylline increases ephedrine toxicity. 
Reserpine and oral contraceptives decrease ephedrine efficacy. In the case of ephedrine application, the response to catecholamines may be changed. 

4.6 Pregnancy and lactation 
Teratogenic potential has been proved In laboratory animals experiments. The damage is manifested by specific developmental abnormalities of cardiovascular system. This teratogenic influence has not been proved In humans in the meantime. In available literature sources and databases there are no information about mutageneity of ephedrine. 
In spite of the mentioned knowledge, care is necessary in ephedrine application to pregnant women and lactating mothers (irritability and disturbed sleep), because ephedrine passes the placental barrier and is present also in breast milk. The child may be influenced by the amount of ephedrine into breast milk. 

4.7.Effects on ability to drive and use machines 
Although ephedrine has central stimulative effects, they may be manifested by nervous Irritability, headache, therefore about the ability of the patient to participate in traffic and to operate machinery decides the physician. 

4.8 Undesirable effects 
They occur in about 5% and the most serious are: ataxia, headache, insomnia, restlessness, muscle weakness, tremor, sweating, palpitation, dysrhythmia, hypertension, paranoidal psychoses, disillusion, hallucination, urination disorders, nausea, vomiting, contact dermatitis, tachyphylaxis. 

4.9 0verdosage 
Ephedrine with Its pharmacological properties belongs to medium toxic 
substances. LD50 in man after oral administration is estimated at about 50 mg/kg. Acute ephedrine intoxication is similar to adrenaline one with overload of the cardiovascular system. 
Changes In myocardium and dystrophic changes in the tubular system of kidneys were ascertained in animals experiments. 
Ephedrine overdosage is manifested by a variable symptomatology as a consequence of sympathomimetic irritation of cardiovascular and nervous systems. Nausea, vomiting, pyrexia, hypertension, tachycardia, cardiac arrhythmia, precordial pain, palpitation, respiratory depression, convulsions, coma up to asystolla occur. Hypokalaemia and respiratory alkalosis may develop. Central effects include fear, anxiety, restlessness, tremor, insomnia, confusion, irritability. Paranoidal psychosis, disillusions and hallucinations occur. 
Treatment: Symptomatic, aimed at dampening of the central effects by neuroleptics and anxiolytics. Adjustment of severe hypokalaemia and respiratory alkalosis is necessary. In monitoring of cardiovascular functions, It is possible to adjust tachyarrythmia or hypertension by administration of alpha-blockers (fentolamine), beta-blockers (propanolol, esmolol), combined alpha-and beta-blockers (labetalol) or nitroprusside. 

5. PHARMACOLOGICAL PROPERTIES 
5.1 Pharmacodynamic properties 
Pharmacotherapeutic group: Sympathomimetic
ATC code: R03CA02

Mechanism of action
Ephedrine is a natural herbaceous alkaloid with combined, direct or Indirect sympathomimetic effects. It Is an effective agonist to alpha and beta adrenergic receptors and its action on target organs is complex. Beside the direct effect on receptors, ephedrine acts also by an indirect mechanism, by release of native noradrenaline from adrenergic nerve ends. The effect on heart, smooth muscles of vessels and bronchi and effects on CNS are the most important effects of ephedrine. In repeated administration of ephedrine tachyphylaxis occurs. Ephedrine has an positive inotropic, weak dromotropic, chronotropic and bathmotropic effects on the heart, It causes tachycardia. Even in smallest doses it acts vasoconstrictively and in therapeutic doses It increases the blood pressure. It influences the breathing by irritation of respiratory centre and simultaneously it causes dilation of bronchi. It acts irritatively on cerebral cortex and on subcortical centres. The central stimulative effect of ephedrine Is an adverse reaction in the utilisation of ephedrine peripheral effects. 
Ephedrine causes Inhibition of peristalsis and relaxation of Intestine musculature of intestinal system. The stomach emptying period and the intestinal passage get longer. The drug causes tonus increase of urinary sphincter, what in ephedrine treated patients, may cause difficulties In urination. 
On eye ephedrine causes dilation of pupils, what does not influence the intraocular pressure. 
The activity of uterus is usually decreased by ephedrine. 

5.2 Pharmacokinetic properties 
Ephedrine is well and completely absorbed from the gastrointestinal tract, from subcutis and muscle. It Is quickly distributed mainly Into the liver, lungs, kidneys, spleen and brain. The therapeutic serum level is In the range of 0.04 to 0.08 mg/ml. Ephedrine is strongly bound to human saliva, the binding Is not pH dependent. 
The biological half-life is 3-6 hours. The substance is resistant to the action of monoaminooxidase and it is prevailingly excreted in unchanged form in the urine (60-80%). A part of ephedrine (5%) is biotransformed by deamination and N-demethylation. The main metabolite, norephedrine, Is pharmacologically active, it has central stimulative effects and its biological half-life is 1.5 to 4 hours. 95% of the administered dose is excreted from the organism within 24 hours. 
If urine has acid pH, the elimination of ephedrine and the biological half-life gets adequately shorter. The elimination is slowed down in renal diseases. 

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients 
Water for injection. 

6.2 Incompatibilities 
Ephedrine is incompatible in solutions with hydrocortisone and some barbiturates. 

6.3 Shelf life
5 years

6.4 Special precaution for storage 
Store at 10-25°C. 

6.5 Nature and content of container 
Colourless glass ampoule with label, PVC mould with aluminium foil, paper folder, package insert. 
Size of the package: 10 ampoules of 1 ml 

7. MARKETING AUTHORIZATION HOLDER 
 BB Pharma Inc., Pod Višňovkou 1662/21, 140 00 Prague 4, Czech Republic 

8. MARKETING AUTHORIZATION NUMBER
78/765/92-S/C 
 
9. DATE OF FIRST AUTHORIZATION / RENEWAL OF THE AUTHORIZATION 
December 14th, 1992 / September 8th, 1999 
 
10. DATE OF REVISION OF THE TEXT