1 Name of Medicine
Ephedrine hydrochloride.
2 Qualitative and Quantitative Composition
Ephedrine-hameln is a colourless, clear solution containing the active ingredient ephedrine hydrochloride. Ephedrine-hameln comes in one strength containing 30 mg/1 mL.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Ephedrine hydrochloride is a white to almost white crystalline powder or colourless crystals. Ephedrine-hameln is a sterile solution.
4.1 Therapeutic Indications
Ephedrine-hameln is indicated in the treatment of hypotension secondary to spinal anaesthesia.
4.2 Dose and Method of Administration
Ephedrine-hameln is not approved for use in children (see Section 4.4 Special Warnings and Precautions for Use).
Ephedrine-hameln must be diluted prior to administration.
Ephedrine-hameln is administered by the intravenous route. The injection should be given slowly. Care should be taken to avoid extravasation, since this may result in tissue necrosis and sloughing. Ephedrine hydrochloride should be administered in the lowest effective dose. The parenteral adult dose should not exceed 150 mg in 24 hours.
A lack of efficacy after 30 mg should lead to reconsideration of the choice of the therapeutic agent.
Product is for single use in one patient only. Discard any residue.
As a pressor.
Adult dose.
Dilute 1 mL of Ephedrine-hameln to 10 mL with 0.9% Sodium chloride to produce a 3 mg/mL solution. After the development of hypotension, this medicine should be administered immediately after dilution by slow intravenous administration. Up to 30 mg in increments of 3 to 7.5 mg may be administered (maximum of 10 mg).
Patients with renal or hepatic impairment.
There are no specific dosage recommendations for patients with renal or hepatic impairment.
Compatibilities.
Ephedrine-hameln is reported to be compatible with 0.9% sodium chloride, lactated Ringer's injection, 5% and 10% glucose in water.
Incompatibilities.
Ephedrine hydrochloride is reported to be physically incompatible with the phenobarbital (phenobarbitone) sodium, pentobarbitone sodium, quinalbarbitone sodium and thiopentone sodium, and with hydrocortisone sodium succinate in some infusion solutions.4.3 Contraindications
Ephedrine-hameln is contraindicated in:
closed angle glaucoma, since ephedrine may exacerbate the condition;
patients with pheochromocytoma, since severe hypertension may result;
patients with asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis) since the obstruction may increase as myocardial contractility improves;
patients undergoing therapy with monoamine oxidase inhibitors (MAO inhibitors), or within 14 days of ceasing such therapy, since MAO inhibitors may prolong and intensify the cardiac and pressor effects of ephedrine;
patients undergoing general anaesthesia with cyclopropane or halothane or other halogenated hydrocarbons, since anaesthesia may increase cardiac irritability which may lead to arrhythmias;
patients with tachyarrhythmias, coronary thrombosis or ventricular fibrillation, since exacerbation of these conditions may occur;
patients with hypersensitivity to ephedrine and in patients with psychoneurosis;
patients using linezolid.
4.4 Special Warnings and Precautions for Use
The use of ephedrine as a pressor agent is not a substitute for replacement of blood, plasma, fluids and/or electrolytes. Blood volume depletion should be corrected as fully as possible before ephedrine therapy is instituted. In an emergency, ephedrine may be used as an adjunct to fluid volume replacement or as a temporary supportive measure to maintain coronary and cerebral artery perfusion until volume replacement therapy can be completed, but ephedrine must not be used as sole therapy in hypovolaemic patients.
Ephedrine may deplete noradrenaline stores in sympathetic nerve endings resulting in reduced cardiac and pressor effects of the drug. Consequently, it may be necessary to administer noradrenaline to replace tissue stores for restoration of the pressor effects of ephedrine.
Caution should be exercised if a dose greater than the maximum recommended bolus is administered as this may lead to undesirable hypertension.
Prolonged administration of pressor agents has been associated with oedema, haemorrhage, focal myocarditis, subpericardial haemorrhage, necrosis of the intestine and hepatic and renal necrosis. Since these effects have generally been observed in patients with severe shock and it is not clear if the drug or the shock state itself was responsible, they should therefore be taken into consideration before ephedrine hydrochloride is used.
Hypoxia, hypercapnia and acidosis may also reduce the effectiveness or increase the incidence of adverse effects of ephedrine, and should be identified and corrected prior to or concurrently with administration of the drug.
Ephedrine-hameln should be used with caution, if at all, in patients with hypertension or hyperthyroidism, since there is an increased risk of adverse effects in these patients.
Ephedrine-hameln should also be used with caution in:
geriatric males, especially those with prostatic hypertrophy, since ephedrine may cause acute urinary retention;
diabetic patients since drug induced hyperglycaemia may result in loss of diabetic control;
patients with cardiovascular disease including angina, cardiac arrhythmia and coronary insufficiency, since the cardiovascular effects of ephedrine may exacerbate these conditions. Ephedrine may intensify the ischaemia in myocardial infarction by increasing myocardial oxygen demands.
Athletes.
Warning, this product contains an active ingredient that may cause a positive reaction in anti-doping tests.
Patient monitoring.
Cardiovascular parameters, including blood pressure and ECG should be monitored during therapy with ephedrine. Urinary output should also be monitored.
Use in the elderly.
No data available.
Paediatric use.
Ephedrine-hameln is not approved for use in paediatric patients.
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
Alpha blockers.
Alpha blockers may decrease the vasopressor effect of ephedrine.
Atropine sulphate.
Atropine sulphate may increase the vasopressor effect of ephedrine.
Beta blockers.
Beta blockers may inhibit the cardiac and bronchodilator effects of ephedrine.
Cardiac glycosides.
Concurrent use of cardiac glycosides and ephedrine may increase the risk of arrhythmias.
Ergotamine, ergometrine, methylergometrine, oxytocin.
Concurrent use of these drugs with ephedrine hydrochloride may result in a potentiation of the pressor effect of ephedrine. Concurrent use of ergotamine and ephedrine sulfate may also produce peripheral vascular ischaemia and gangrene.
Guanethidine.
Ephedrine hydrochloride may decrease the antihypertensive effect of guanethidine.
Hydrocarbon inhalation anaesthetics, such as cyclopropane, halothane.
These drugs may increase cardiac irritability, and concurrent use with ephedrine hydrochloride may lead to increased risk of arrhythmia (see Section 4.3 Contraindications).
Indirect sympathomimetic agents (phenylpropanolamine, pseudoephedrine, phenylephrine, methylphenidate).
Risk of vasoconstriction and/or of acute episodes of hypertension.
Methyldopa.
Concurrent use of methyldopa with ephedrine hydrochloride may result in a reduced pressor effect.
Moclobemide.
Risk of headache and palpitations, and/or hypertension with an increase in systolic blood pressure and diastolic blood pressure.
Monoamine oxidase (MAO) inhibitors.
Concurrent use of MAO inhibitors and ephedrine sulfate may result in potentiation of the cardiac and pressor effects of ephedrine (see Section 4.3 Contraindications).
Noradrenergic-serotoninergic antidepressants (milnacipran, venlafaxine).
Paroxysmal hypertension with possibility of arrhythmia (inhibition of adrenaline or noradrenaline entry in sympathetic fibres).
Linezolid.
By extrapolation from non-selective MAO inhibitors. Risk of vasoconstriction and/or episodes of hypertension.
Reserpine.
Concurrent use of reserpine with ephedrine hydrochloride may result in a reduced pressor effect.
Sympathomimetic agents.
Concurrent use of ephedrine hydrochloride and other sympathomimetics may result in increased cardiovascular and pressor effects and an increased risk of adverse effects.
Tricyclic antidepressants.
Concurrent use of tricyclic antidepressant and ephedrine may result in potentiation of the cardiovascular and pressor effects of ephedrine.
Clonidine.
Pre-treatment with clonidine may increase the pressor effect of ephedrine.
Urinary alkalinizers, such as acetazolamide, dichlorphenamide, sodium bicarbonate and sodium citrate.
These drugs may increase the half-life and decrease the elimination of ephedrine leading to enhanced therapeutic or toxic effects of ephedrine.
Theophylline.
Concurrent use of ephedrine and theophylline may result in an increased incidence of adverse effects than when either drug is used alone. Adverse effects include those in the central nervous and the gastrointestinal systems.
Corticosteroids.
Ephedrine has been shown to increase the clearance of dexamethasone.
Antiepileptics.
Increased plasma concentration of phenytoin and possibly of phenobarbital (phenobarbitone) and primidone.
Ergot alkaloids (dopaminergic action).
Risk of vasoconstriction and/or episodes of hypertension.
Sibutramine.
Paroxysmal hypertension with possibility of arrhythmia (inhibition of adrenaline or noradrenaline entry in sympathetic fibres).
Doxapram.
Risk of hypertension.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
The effects of ephedrine hydrochloride on male and female fertility have not been investigated in animal studies.
(Category A1)
Ephedrine hydrochloride injection may accelerate the foetal heart rate when used to control maternal hypotension during spinal anaesthesia for delivery. Ephedrine-hameln should not be used if the maternal blood pressure is greater than 130/80 mmHg.
Ephedrine has been shown to cross the placenta and undergo early metabolism and/or redistribution in the foetus. Ephedrine has been associated with an increased risk of mild metabolic acidosis with increased umbilical plasma concentrations of lactate, glucose, epinephrine, and norepinephrine and greater UV pCO2.
Despite the transplacental passage of ephedrine and notable effects on the cord blood pH; it is uncertain whether this has the potential to affect clinical outcome on the neonate. Other studies have not demonstrated significant effects on neonatal outcomes.
Ephedrine hydrochloride is distributed into breast milk, and therefore Ephedrine-hameln is not recommended for use during lactation because of the risk of adverse effects in the infant. It should be avoided or used with caution and administered to a breast-feeding woman only if necessary.
1 Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.4.7 Effects on Ability to Drive and Use Machines
The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
4.8 Adverse Effects (Undesirable Effects)
Very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ≥ 1/10,000 to < 1/1,000; very rare: < 1/10,000; not known: cannot be estimated from the available data.
Body as a whole.
Pallor, fever, headache, dryness of nose, mouth and throat.
Ephedrine is reported to cause physical addiction after excessive long-term use. Addiction is more likely to occur after oral use, since intramuscular, subcutaneous or intravenous administration of ephedrine would not normally occur over long periods.
Blood and lymphatic system disorders.
Not known: primary haemostasis modifications.
Immune system disorders.
Not known: hypersensitivity.
Nervous system disorders.
Common: nervousness, anxiety, depression, confusion, irritability, restlessness, weakness, insomnia, sweating.
Not known: trembling, mood or mental changes. psychotic states, fear.
Large doses may cause dizziness, light-headedness, weakness, vertigo, confusion, delirium, euphoria. Long term therapy in large doses may lead to psychosis characterized by paranoia, hallucinations, bizarre mentation.
Eye disorders.
Not known: episodes of angle-closure glaucoma.
Cardiovascular system disorders.
Common: palpitations, hypertension, tachycardia.
Rare: cardiac arrest.
Not known: angina, bradycardia, hypotension, extrasystole and precordial pain.
Arrhythmias, including ventricular fibrillation, may occur, especially in patients with organic heart disease or those receiving other drugs that sensitise the heart to arrhythmias.
Vascular disorders.
Not known: cerebral haemorrhage.
Respiratory system.
Common: dyspnoea.
Not known: pulmonary oedema, shortness of breath, respiratory difficulty.
Gastrointestinal disorders.
Common: nausea, vomiting.
Not known: Mild epigastric distress, reduced appetite, hypersalivation.
Renal and urinary disorders.
Not known: difficult or painful urination, acute urinary retention (especially with prostatic hypertrophy).
Skin and appendages.
Sweating.
Investigations.
Not known: hypokalaemia, changes in blood glucose levels.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration of the medical 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 at http://www.tga.gov.au/reporting-problems.4.9 Overdose
Due to the rapid onset, but short duration of the drug, it is rarely necessary to actively manage adverse effects, as they tend to be of short duration and self-limiting.
Clinical features.
Symptoms associated with overdosage of ephedrine include headache, severe nausea or vomiting, chills or fever, dizziness or light-headedness, anxiety, nervousness, restlessness, mood changes, convulsions, severe weakness, blurred vision or enlarged pupils, ongoing fast heartbeat, severe or ongoing chest pain, severe hypertension or hypotension, and severe breathing difficulties.
Paranoid psychosis, delusions and hallucinations may also follow ephedrine overdosage.
Treatment.
Treatment of overdose involves the following measures:
reduce dosage or discontinue administration of ephedrine;
general supportive therapy, including monitoring and maintaining vital signs, blood gases, electrolytes and ECG.
The following additional measures may need to be considered:
beta blockers (e.g. propranolol) to control tachycardia and arrhythmia;
phentolamine or nitroprusside to reduce severe hypertension;
diazepam to control convulsions. General anaesthesia and neuromuscular blocking agents may need to be considered to treat refractory seizures;
dexamethasone to treat pyrexia.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Ephedrine is a sympathomimetic which stimulates both alpha- and beta-adrenergic receptors, and also releases noradrenaline from storage site. The main effects of therapeutic doses of ephedrine are relaxation of bronchial smooth muscle, cardiac stimulation and increased systolic and usually diastolic blood pressure via an increase in cardiac output and peripheral vasoconstriction. Ephedrine also decreases intestinal tone and motility, relaxes the bladder wall, contracts the sphincter muscle, relaxes the detrusor muscle, and decreases uterine activity. Ephedrine also has central nervous system stimulant effects. Tachyphylaxis to the effects of ephedrine may also occur after use for a short while possibly due to the depletion of noradrenaline stores.
Clinical trials.
The supporting evidence for the use of ephedrine in the treatment of hypotension secondary to spinal anaesthesia is based on published literature, predominantly in patients undergoing spinal anaesthesia for caesarean section. In one study the frequency of reactive hypertension was 0% in the patients receiving 10 mg ephedrine, and 13.3% and 46.7% respectively in patients receiving a 15 mg or 20 mg bolus. In a second study reactive hypertension was observed in 5% of patient receiving 10 mg ephedrine, and 25% and 45%, respectively, in patient receiving a 20 mg or 30 mg bolus. Overall the body of literature evidence supports the use of ephedrine in the treatment of hypotension secondary to spinal anaesthesia administered as an IV bolus dose with additional incremental rescue boluses as required.
5.2 Pharmacokinetic Properties
The duration of pressor and cardiac responses to ephedrine is 1 hour after intravenous administration of 10 to 25 mg. Small quantities of ephedrine are metabolised in the liver, but the majority of ephedrine is excreted unchanged in the urine. The plasma half-life of ephedrine is 3 to 6 hours. Elimination of ephedrine is increased (and hence the half-life is decreased) with decreasing pH of the urine. Ephedrine is presumed to cross the placenta, and to be excreted into breast milk.
5.3 Preclinical Safety Data
Genotoxicity.
Ephedrine sulfate was not mutagenic in four strains of Salmonella typhimurium (TA100, TA1535, TA97, or TA98) with or without Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9 activation. Ephedrine sulfate did not induce sister-chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells.
Carcinogenicity.
Carcinogenesis studies of ephedrine were conducted by administering 0, 125, or 250 ppm of ephedrine sulfate to groups of rats and mice for 103 weeks. Neoplasms that occurred in these studies were not considered to be related to administration of the drug. Two high dose female mice had ovarian granulose cell tumours, and luteomas were found in one low dose and one high dose female mouse. Because of the low incidence, these uncommon, benign tumours could not be clearly related to ephedrine sulfate administration.
Under the conditions of these studies, there was no evidence of carcinogenicity for rats or mice of either sex receiving 125 or 250 ppm ephedrine sulfate in the diet for 2 years.6 Pharmaceutical Particulars
6.1 List of Excipients
Ephedrine-hameln contains the inactive ingredient water for injections.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C.
6.5 Nature and Contents of Container
Solution for injection, 30 mg/mL ephedrine hydrochloride: Type I clear glass ampoule containing 1 mL of solution. Packs of 5 or 10 ampoules.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
Chemical structure.
CAS number.
50-98-6.
Chemical name: (1R,2S)-2-(Methylamino)-1-phenylpropan-1-ol hydrochloride.
Molecular formula: C10H16ClNO.
Molecular weight: 201.7.
Ephedrine hydrochloride is freely soluble in water and soluble in ethanol (96%). The mass of ephedrine in one ampoule is 24.6 mg.7 Medicine Schedule (Poisons Standard)
S4 (Prescription Only Medicine).
