Fuck it thought I might actually do some research. Here tis.
PROMETHAZINE HYDROCHLORIDE INJECTION B.P.
(DBL)
Composition:
Promethazine Hydrochloride B.P.
Description:
Promethazine Hydrochloride Injection B.P. is a clear, colourless solution of pH 5.0-6.0. Each mL of the solution contains 25.0 mg promethazine hydrochloride, 0.10 mg disodium edetate, 1.30 microlitre glacial acetic acid, 27.2 mg sodium acetate and 1.32 mg sodium metabisulfite in water for injections.
Pharmacology:
Promethazine is a phenothiazine derivative with potent antihistaminic and sedative-hypnotic effects. It also has antiemetic, antivertigo, anti-motion sickness, anticholinergic effects and local anaesthetic actions.
Antihistamines competitively and reversibly antagonise the effects of histamine at the H1-receptor sites on effector cells which are responsible for vasodilatation, increased capillary permeability, flare and itch reactions in the skin, and to some extent for contraction of smooth muscle in the bronchi and gastrointestinal tract (2).
The precise mechanism of the CNS effects of promethazine is unknown. The sedative effects may involve antagonism at central histamine, serotonin and acetylcholine receptors, or central alpha-adrenergic stimulation (1). However, paradoxical CNS stimulation may occur, especially in children, and at high doses may be attributable to antimuscarinic activity (2). The antiemetic, anti-motion sickness and antivertigo effects of promethazine are possibly a result of central anticholinergic actions on the vestibular apparatus and the integrative vomiting centre and medullary chemoreceptive trigger zone of the midbrain (1).
The anticholinergic (antimuscarinic) actions of promethazine provide a drying effect on the oral and nasal mucosa (1).
Pharmacokinetics: Promethazine is well absorbed from parenteral sites and the onset of antihistaminic properties occurs about 20 minutes after intramuscular injection and 3 to 5 minutes after intravenous injection. It has a prolonged antihistamine action, which may persist for 12 hours or more. The duration of sedative effects may range from 2-8 hours depending on the dose and route of administration.
Promethazine is widely distributed within body tissues. Promethazine crosses the blood/brain barrier, also the placenta and is excreted in breast milk (7). It is metabolised by the liver and excreted slowly in the urine and faeces mainly as inactive promethazine sulphoxide and glucuronides; elimination half lives of 7 to 14 hours have been reported (1).
Indications:
Promethazine Hydrochloride Injection is indicated for the following conditions:
Treatment of allergic reactions such as:
* uncomplicated allergic conditions of the immediate type, eg. Pruritus, urticaria and angioedema, when oral therapy is impossible or contra-indicated;
Treatment and prevention of vomiting including:
* motion sickness;
* drug induced nausea;
* prevention and control of nausea and vomiting associated with certain types of anaesthesia and surgery, such as procedures with a high incidence of postoperative vomiting (eg. gynaecological surgery, strabismus or middle ear surgery, and electroconvulsive therapy); in patients with a past history of motion sickness or post operative vomiting; and in patients in whom avoidance of vomiting is crucial (eg. Neurosurgery and eye surgery);
Promethazine has sedative effects and it is also used in:
* preoperative, postoperative and obstetric (during labour) sedation.
Contra-indications:
Promethazine is contra-indicated in patients who have exhibited hypersensitivity to the drug or other phenothiazine derivatives. Promethazine is also contra-indicated in the following patients:
* comatose
* after administration of large doses of other CNS depressants (eg. alcohol general anaesthetics, opioid analgesics, tranquillisers, etc.)
Promethazine injection must not be administered intra-arterially due to the likelihood of severe arteriospasm and the possibility of resultant gangrene. Promethazine injection should not be given subcutaneously, as the solution is irritant and may produce necrotic lesions.
Precautions:
The use of phenothiazine antihistamines is not recommended in newborn or premature infants because of the increased susceptibility of this age group to anticholinergic side effects, such as CNS excitation, and an increased tendency towards convulsions. Use is also not recommended in infants up to 3 months of age because of the possible absence or deficiency in detoxifying enzyme and inefficient renal function usually noted in this group.
Some studies have associated to the use of promethazine with sudden infant death syndrome (SIDS) and with an increase in infant sleep apnoea. Thus the use of promethazine is not recommended in children under 2 years of age (2).
Use of promethazine should be avoided in acutely ill or dehydrated children, since these patients have an increased susceptibility to dystonias. Use of the drug should also be avoided in children with signs and symptoms which suggest Reye's syndrome, since the potential extrapyramidal effects produced by the drug may obscure the diagnosis of, or be confused with the CNS signs and symptoms of this condition or other hepatic diseases. Excessively large doses in children may cause hallucinations, convulsions and sudden death (1).
As a result of its anticholinergic actions, promethazine should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction. It should also be used with caution in patients with bone-marrow depression, jaundice, impaired liver function, epilepsy, asthmatic attack, or cardiovascular disorders (2).
Promethazine may mask the adverse effects of ototoxic medications; eg. tinnitus, dizziness (1). Concurrent use of promethazine and other hypotension-producing medications may produce additive hypotensive effects. Concurrent use of promethazine with other hepatotoxic medications may increase the potential for hepatotoxicity, and patients should be carefully monitored (1).
Promethazine's anti-emetic action may mask the symptoms of acute appendicitis or overdose of other drugs.
Promethazine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a vehicle or operating machinery. The concomitant administration of alcohol, sedative-hypnotics, general anaesthetics, opioids, tranquillisers or other CNS depressants may have an additive sedative effect. Patients should be warned accordingly (4).
Promethazine Injection contains sodium metabisulfite, which may cause allergic-type reactions, including anaphylactic symptoms and life- threatening or less severe asthmatic episodes, in certain susceptible people (4).
Use in Pregnancy:
Category C. When given in high doses during late pregnancy, phenothiazines have cause prolonged extrapyramidal disturbances in the child (6).
Australian categorisation definition of:
Category C:
Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying text above should be consulted for further details.
Use in Lactation:
The exact amount of promethazine excreted into breast milk is unknown, but amounts are usually small. Promethazine should be used with caution in nursing women. The infant should be observed for side effects, especially sedation (7).
Drug Interactions:
Anticholinergics: Anticholinergic effects may be potentiated when these medications are used concurrently with promethazine. Patients should be advised to report occurrence of gastrointestinal problems promptly, since paralytic ileus may occur with concurrent therapy (1).
Anticonvulsants: As promethazine may lower the convulsion threshold, dosage adjustment of anticonvulsant medication may be required (1).
Antihypertensive agents: Concurrent use of promethazine with beta-blockers, especially propranolol, may result in increased plasma concentrations of each agent because of inhibition of metabolism. This may result in additive hypotensive effects, irreversible retinopathy, cardiac arrhythmias and tardive dyskinesia. The neuronal uptake of guanethidine may be inhibited when used with promethazine, causing a decrease in the antihypertensive effect (1).
Bromocriptine: Increase serum prolactin concentrations, thereby interfering with the effects of bromocriptine. Dosage adjustments of bromocriptine may be necessary.
CNS depressants: Promethazine may potentiate the sedative action of other CNS depressants such as barbiturates, antihistamines, tranquillisers, opioids, general anaesthetics, or alcohol (1).
Levodopa: The antiparkinsonian effects of levodopa may be inhibited when used concurrently with promethazine because of blockade of dopamine receptors in the brain (1).
Metrizamide: Concurrent use of intrathecal metrizamide with promethazine may lower the seizure threshold. Promethazine should be discontinued at least 48 hours before, and not resumed for at least 24 hours following myelography (1).
Monoamine oxidase (MAO) inhibitors: Concurrent use of MAO inhibitors with promethazine may prolong and intensify the anticholinergic and CNS depressant effects, and may increase the risk of hypotension and extrapyramidal reactions (1).
Phenothiazine derivatives: Concurrent use of other phenothiazine derivatives may increase the severity and frequency of extrapyramidal effects (1).
Quinidine: Concurrent use of promethazine with quinidine may result in additive cardiac effect (1).
Sympathomimetic agents: The alpha-adrenoceptor agonist effects of adrenaline may be blocked when it is used concurrently with promethazine, possibly resulting in severe hypotension and tachycardia. The alpha-adrenoceptor blocking activity of promethazine may also decrease the pressor response to ephedrine, metaraminol and methoxamine; decrease the stimulant effects of amphetamines; and antagonise the anorectic effect of the centrally acting appetite suppressants (1).
Tricyclic antidepressants: Concurrent use of tricyclic antidepressants may intensify the anticholinergic effects and increase the risk of hypotension and extrapyramidal effects.
Drug Incompatibilities: Solutions of promethazine hydrochloride are incompatible with alkaline substances, which precipitate the insoluble promethazine base. Promethazine has been reported to be incompatible with solutions containing the following compounds: aminophylline, benzylpenicillin salts, cefepime hydrochloride, cefotetan disodium, cephazolin, chloramphenicol sodium succinate, chloroquine phosphate, chlorothiazide sodium, dexamethasone sodium phosphate, dextran, dimenhydrinate, flocloxacillin sodium, foscarnet, frusemide, heparin sodium, hydrocortisone sodium succinate, ketorolac tromethamine, meglumine diatrizoate, meglumine iodipamide, methicillin sodium, methohexitone sodium, methotrexate sodium, morphine sulfate, nalbuphine hydrochloride (some formulations only), nitrofurantoin, penicillin G, pentobarbitone sodium, phenobarbitone sodium, phenytoin sodium, piperacillin, sodium bicarbonate, sodium diatizoate, sodium iothalamate, sulphafurazole, thiopentone sodium (2,5).
Effects on laboratory tests: Promethazine may interfere with diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG, and may cause an increase in glucose tolerance. Promethazine may produce false negative results in skin tests using allergen extracts. It is recommended that antihistamines are discontinued at least 72 hours before testing begins (1).
Adverse Reactions:
CNS: Sedation is the most prominent CNS effect promethazine. Extrapyramidal reactions may occur with high doses and usually subside with dosage reduction. Other reported reactions include dizziness, lassitude, tinnitus, confusion, disorientation, incoordination, fatigue, blurred vision, euphoria, diplopia, nervousness, irritability, tremors, convulsions, oculogyric crises, excitation, catatonic-like states, and hysteria.
Cardiovascular: Tachycardia, bradycardia, faintness, dizziness, transient minor increases in blood pressure, and hypotension have been reported following the use of promethazine hydrochloride injection. Venous thrombosis at the injection site has been reported.
Gastrointestinal: Nausea and vomiting have been reported, usually in association with surgical procedures and combination drug therapy. Loss of appetite, epigastric distress, constipation and diarrhoea have also been reported.
Allergic: Urticaria, dermatitis, asthma, photosensitivity, and angioneurotic oedema have been reported.
Other reported reactions: Leukopenia and agranulocytosis, usually when promethazine has been used in association with other known toxic agents; thrombocytopenic purpura; obstructive jaundice; tissue necrossis following subcutaneous injection, nasal stuffiness; and dry mouth (1,2,4).
Dosage and Administration:
The preferred route of administration of Promethazine Hydrochloride Injection is by deep intramuscular injection.
Intravenous administration of this product is generally well tolerated, however extreme care must be taken to avoid extravasation or intra-arterial injection (see Contra-indications). When given intravenously Promethazine Injection 25 mg/1mL should be diluted 1 in 10 with water for injections or preferably given through the tubing of a freely flowing I.V. infusion. It should be injected slowly at a rate of administration not greater than 25 mg/minute (ie. 10mL/minute of dilute solution (1,2,4). Rapid intravenous infusion may cause a transient fall in blood pressure (1). Promethazine should not be given intra-arterially or subcutaneously (see Contra-indications) (1).
Allergic Conditions:
Adults: 25 mg-50 mg by deep intramuscular injection or slow intravenous injection; may be repeated within two hours if necessary. Maximum dose up to 150 mg daily (1).
Antiemetic:
In established nausea or vomiting due to causes other than motion sickness:
Adults: 12.5 - 25 mg, by intramuscular or intravenous injection, every four hours as needed.
Children: 5-12 yrs old 12.5 mg by intramuscular injection.
Sedative/hypnotic:
Adults: 25-50 mg by intramuscular or intravenous injection.
Children: When oral route is not possible:
up to 12 months: 2.5 - 5 mg by intramuscular injection
1-5 yrs old: 7.5 - 10 mg by intramuscular injection
6-10 yrs old: 10 - 12.5 mg by intramuscular injection
Preoperative and postoperative sedation:
Adults: 25-50 mg by intramuscular or intravenous injection, usually with pethidine and atropine.
Obstetric Sedation:
Early stages of labour: 50 mg, by intramuscular injection.
Established labour: 25-75 mg, by intramuscular or intravenous injection, with an appropriately reduced dose of an opioid analgesic. May be repeated once or twice at four hourly intervals during the course of the labour, if necessary. Total dose should not exceed 100 mg in 24 hours (1,4).
Overdosage:
Symptoms: Symptoms of overdose range from mild depression of the CNS and cardiovascular system (drowsiness, bradycardia, tachycardia, and transient increases in blood pressure) to profound hypotension, respiratory depression, and unconsciousness. Paradoxical CNS stimulation (hallucinations, seizures, nightmares and trouble in sleeping) may be evident, especially in children and the elderly. Anticholinergic symptoms (severe dryness of mouth, nose or throat, flushing or redness of face, trouble in breathing), and extrapyramidal effects (muscle spasms, especially of the neck and back, restlessness tic-like movements of head and face, trembling of hands) may occur (1,2,4).
Treatment: Treatment of promethazine overdosage is similar to that of other phenothiazine derivatives. Symptomatic supportive therapy is indicated and general physiologic measures such as maintenance of adequate ventilation should be instituted if necessary. Analeptics may cause convulsions and should not be used. Convulsions may be controlled with diazepam or barbiturates. Anticholinergic antiparkinsonism agents may be used to treat severe extrapyramidal reactions. Severe hypotension may respond to administration of noradrenaline or phenylephrine, but should not be treated with adrenaline becuase it may lower the blood pressure further.
Storage:
Store below 25°C. Protect from light.
Pack:
Promethazine Hydrochloride Injection B.P. is available as follows:
Promethazine Hydrochloride 50 mg/2 mL: 5 x 2 mL Ampoules.
AUST R 16255
All States and A.C.T.-S.4.
References:
1. USP DI. 17th ed. United States Pharmacopeial Convention, Inc. 1997:501-507, 511-513. 2. Reynolds JEF, editor. Martindale: the extra pharmacopoeia. 31st ed. London: The Pharmaceutical Press; 1996: 380, 427-433, 450-451, 1198-1199. 3. Compendium of Pharmaceutical Specialities. 31st ed. Canadian Pharmaceutical Association, 1996: 156-157. 4. Physicians' Desk Reference, 51st ed. Montvale: Medical Economics Company, 1997: 2880-2883. 5. Trissel LA. Handbook on injectable drugs. 9th ed. Bethesda: American Society of Health System Pharmacists, 1996: 941-78 6. Australian Drug Evaluation Committee, Commonwealth Department of health and Family Services. Medicines in Pregnancy. An Australian categorisation of risk of drug use in pregnancy. Canberra: Australian Government Publishing Service; 1996. 7. Andriske L. Drugs and Breastfeeding 1997-98. Melbourne: Pharmacy Department, Royal Women's Hospital, Melbourne, 1997: 129.
29 April 1998
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Dancing, the eternal quest to mash my ankles into dust.
