Promethazine is a phenothiazine that possesses antihistamine, sedative, anti-emetic, and anticholinergic effects. Unlike other drugs in its class, it is not used as an anti-psychotic. Promethazine can be used in endoscopic sedation as an adjunct to benzodiazepines and narcotics for hard-to-sedate patients who cannot be given droperidol. However, promethazine may produce a longer sedative effect than diphenhydramine, also used for this purpose. Other clinical uses for promethazine include the management of allergic reactions and anaphylaxis, treatment of post-operative nausea and vomiting, and as an adjuvant for post-operative pain.
Promethazine Dosing for Endoscopic Sedation
- One time dose: 12.5- 50 mg
- Onset of action: 2-5 minutes
- Peak effect: Unknown
- Duration of effect: More than 120 minutes
*Dosing information for promethazine in pediatric populations has not been well studied.
- Promethazine may be combined with analgesics and hypnotic medication and atropine-like drugs as desired. Dosage of concomitant medications should be reduced accordingly.
- Promethazine hydrochloride is not recommended for use in pediatric patients less than 2 years of age.
- When used intravenously, promethazine should be given in a concentration no greater than 25 mg per mL
- Promethazine is a clear, colorless solution. The product is light sensitive. It should be inspected before use and discarded if either color or particulate is observed.
- To avoid the possibility of physical and/or chemical incompatibility, consult specialized literature before diluting with any injectable solution or combining with any other medication.
- Promethazine should not be given by the subcutaneous route; evidence of chemical irritation has been noted, and necrotic lesions have resulted following subcutaneous injection or extravasion with infiltrated IV.
- Signs and symptoms of overdosage range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes (Babinski reflex).
- Stimulation may be evident, especially in pediatric patients and geriatric patients.
- Convulsions may rarely occur.
- A paradoxical-type reaction has been reported in pediatric patients receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares.
- Atropine-like signs and symptoms-dry mouth; fixed, dilated pupils; flushing; etc., as well as gastrointestinal symptoms, may occur.
- Treatment of overdosage is essentially symptomatic and supportive.
- Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation.
- Diazepam may be used to control convulsions. Acidosis and electrolyte losses should be corrected.
- Note that any depressant effects of promethazine are not reversed by naloxone.
- Avoid central nervous system stimulants which may cause convulsions.
- The treatment of choice for resulting hypotension is administration of intravenous fluids, accompanied by repositioning the patient if indicated. In the event that vasopressors are considered for the management of severe hypotension which does not respond to intravenous fluids and repositioning, the administration of norepinephrine or phenylephrine should be considered. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure.
- Extrapyramidal reactions may be treated with anticholinergic antiparkinson agents, diphenhydramine, or barbiturates.
- Oxygen may also be administered.
- Limited experience with dialysis indicates that it is not helpful as treatment for overdose.
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- Carcinogenesis, mutagenesis, impairment of fertility: Long-term animal studies have not been performed to assess the carcinogenic potential of promethazine, nor are there other animal or human data concerning carcinogenicity, mutagenicity, or impairment of fertility. Promethazine was nonmutagenic in the Salmonella test system of Ames.
- Use in Pregnancy: Pregnancy Category C.
- Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg (approximately 2.1 and 4.2 times the maximum recommended human daily dose) of promethazine. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats.
- There are no adequate and well-controlled studies of promethazine in pregnant women. Because animal reproduction studies are not always predictive of human response, promethazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Adequate studies to determine the action of the drug on parturition, lactation and development of the animal neonate have not been conducted.
- Promethazine administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.
- Use in Nursing Mothers: It is not known whether promethazine is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from promethazine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
- Use in Pediatric Patients:
- PROMETHAZINE IS CONTRAINDICATED FOR USE IN PEDIATRIC PATIENTS LESS THAN TWO YEARS OF AGE. (see Black Box Warning)
- Promethazine should be used with caution in pediatric patients 2 years of age and older.
- Use in Geriatric Patients (patients approximately 60 years or older). Since therapeutic requirements for sedative drugs tend to be less in geriatric patients, the dosage should be reduced for these patients.
- Drug Interactions.
- CNS Depressants: Promethazine may increase, prolong, or intensify the sedative action of central-nervous-system depressants, such as alcohol, sedative/hypnotics (including barbiturates), general anesthetics, narcotics, narcotic analgesics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine. When given concomitantly with promethazine, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of promethazine relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain.
- Epinephrine: Because of the potential for promethazine to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine overdose.
- Anticholinergics: Concomitant use of other agents with anticholinergic properties should be undertaken with caution.
- Monoamine Oxidase Inhibitors (MAOI): Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly. This possibility should be considered with promethazine.
- Drug/Laboratory Test Interactions. The following laboratory tests may be affected in patients who are receiving therapy with promethazine:
- Pregnancy Tests: Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations.
- Glucose Tolerance Test: An increase in blood glucose has been reported in patients receiving promethazine.
- Central Nervous System: Drowsiness is the most prominent CNS effect of this drug. Sedation, somnolence, blurred vision, dizziness, confusion, disorientation, and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion; lassitude, tinnitus, incoordination, fatigue, euphoria, nervousness, diplopia, insomnia, tremors, convulsive seizures, excitation, catatonic-like states, hysteria. Hallucinations have also been reported.
- Increased or decreased blood pressure, tachycardia, bradycardia, faintness. Thrombophlebitis, venous thrombosis, and phlebitis at the injection site have been reported and in some cases have required surgical intervention.
- INTRA-ARTERIAL INJECTION MAY RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.
- Dermatologic: Dermatitis, photosensitivity, urticaria.
- Hematologic: Leukopenia, thrombocytopenia, thrombocytopenic purpura, agranulocytosis.
- Gastrointestinal: Dry mouth, nausea, vomiting, jaundice.
- Respiratory: Asthma, nasal stuffiness, respiratory depression (potentially fatal) and apnea (potentially fatal).
- Paradoxical Reactions:
- Hyperexcitability and abnormal movements have been reported in patients following a single administration of promethazine.
- Consideration should be given to the discontinuation of promethazine and to the use of other drugs if these reactions occur.
- Respiratory depression, nightmares, delirium, and agitated behavior have also been reported in some of these patients.
- Other Adverse Reactions:
- Angioneurotic edema.
- Neuroleptic malignant syndrome (potentially fatal) has also been reported.
- Administration of promethazine has resulted in nerve damage ranging from temporary sensory loss to palsies and paralysis.
- Injection into or near a nerve may result in permanent tissue damage. Subcutaneous injection has resulted in tissue necrosis.
- Injection site reactions including burning, erythema, pain, and edema have been reported.
- Administration of promethazine has resulted in abscesses and/or tissue necrosis and gangrene, regardless of the route of administration. In some cases, surgical intervention (including fasciotomy, skin graft, and/or amputation) may be required.
The significant side effects of promethazine include the risks of hypotension, respiratory depression, and extrapyramidal effects.
Black Box Warning
PROMETHAZINE HYDROCHLORIDE SHOULD NOT BE USED IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE BECAUSE OF THE POTENTIAL FOR FATAL RESPIRATORY DEPRESSION. POSTMARKETING CASES OF RESPIRATORY DEPRESSION, INCLUDING FATALITIES, HAVE BEEN REPORTED WITH USE OF PROMETHAZINE HYDROCHLORIDE IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE. A WIDE RANGE OF WEIGHT-BASED DOSES OF PROMETHAZINE HYDROCHLORIDE HAVE RESULTED IN RESPIRATORY DEPRESSION IN THESE PATIENTS. CAUTION SHOULD BE EXERCISED WHEN ADMINISTERING PROMETHAZINE HYDROCHLORIDE TO PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER. IT IS RECOMMENDED THAT THE LOWEST EFFECTIVE DOSE OF PROMETHAZINE HYDROCHLORIDE BE USED IN PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER AND CONCOMITANT ADMINISTRATION OF OTHER DRUGS WITH RESPIRATORY DEPRESSANT EFFECTS BE AVOIDED.
- Sulfite Sensitivity: Promethazine contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthma episodes, in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
- CNS Depression: 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 impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedative/hypnotics (including barbiturates), general anesthetics, narcotics, narcotic analgesics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of promethazine.
- Respiratory Depression:
Promethazine may lead to potentially fatal respiratory depression.
Use of promethazine in patients with compromised respiratory function (e.g. COPD, sleep apnea) should be avoided.
- Lower Seizure Threshold: Promethazine may lower seizure threshold and should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.
- Bone-Marrow Depression: Promethazine should be used with caution in patients with bone-marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine has been used in association with other known marrow-toxic agents.
- Neuroleptic Malignant Syndrome:
A potentially fatal symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported in association with promethazine alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of promethazine, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine should be carefully considered.
- Use in Pediatric Patients:
- PROMETHAZINE IS CONTRAINDICATED FOR USE IN PEDIATRIC PATIENTS LESS THAN TWO YEARS OF AGE.
- CAUTION SHOULD BE EXERCISED WHEN ADMINISTERING INJECTION TO PEDIATRIC PATIENTS 2 YEARS OF AGE AND OLDER BECAUSE OF THE POTENTIAL FOR FATAL RESPIRATORY DEPRESSION. RESPIRATORY DEPRESSION AND APNEA, SOMETIMES ASSOCIATED WITH DEATH, ARE STRONGLY ASSOCIATED WITH PROMETHAZINE PRODUCTS AND NOT FIRMLY WEIGHT-RELATED, WHICH MIGHT OTHERWISE PERMIT SAFE ADMINISTRATION OF INDIVIDUALIZED DOSING.
- CONCOMITANT ADMINISTRATION OF PROMETHAZINE PRODUCTS WITH OTHER RESPIRATORY DEPRESSANTS HAS AN ASSOCIATION WITH RESPIRATORY DEPRESSION, AND SOMETIMES DEATH, IN PEDIATRIC PATIENTS.
- ANTIEMETICS ARE NOT RECOMMENDED FOR TREATMENT OF UNCOMPLICATED VOMITING IN PEDIATRIC PATIENTS, AND THEIR USE SHOULD BE LIMITED TO PROLONGED VOMITING OF KNOWN ETIOLOGY.
- THE EXTRAPYRAMIDAL SYMPTOMS WHICH CAN OCCUR SECONDARY TO PROMETHAZINE INJECTION ADMINISTRATION MAY BE CONFUSED WITH THE CNS SIGNS OF UNDIAGNOSED PRIMARY DISEASE, E.G., ENCEPHALOPATHY OR REYE'S SYNDROME. THE USE OF PROMETHAZINE INJECTION SHOULD BE AVOIDED IN PEDIATRIC PATIENTS WHOSE SIGNS AND SYMPTOMS MAY SUGGEST REYE'S SYNDROME OR OTHER HEPATIC DISEASES.
- Excessively large dosages of antihistamines, including promethazine in pediatric patients may cause sudden death (hallucinations and convulsions have occurred with therapeutic doses and overdoses of promethazine in pediatric patients).
In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine.
- Injection Site Reactions:
- Promethazine can cause severe chemical irritation and damage to tissues, regardless of the route of administration. Irritation and damage can also result from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration.
- Signs, symptoms, and manifestations of severe tissue irritation include burning, pain, erythema, swelling, severe spasm of distal vessels, thrombophlebitis, venous thrombosis, phlebitis, abscesses, tissue necrosis, and gangrene.
- Administration of promethazine has resulted in nerve damage ranging from temporary sensory loss to palsies and paralysis. Injection into or near a nerve may result in permanent tissue damage. In some cases, surgical intervention (including fasciotomy, skin graft, and/or amputation) may be required.
- Inadvertent Intra-Arterial Injection:
- Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or unintentional intra-arterial injection.
- Reports compatible with unintentional intra-arterial injection of promethazine, usually in conjunction with other drugs intended for intravenous use, suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.
- There is no proven successful management of unintentional intra-arterial injection or perivascular extravasation after it occurs. Sympathetic block and heparinization have been employed during the acute management of unintentional intra-arterial injection, because of the results of animal experiments with other known arteriolar irritants.
- Aspiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with promethazine HCl. Use of syringes with rigid plungers or of small-bore needles might obscure typical arterial backflow if this is relied upon alone.
- When used intravenously, promethazine should be given in a concentration no greater than 25 mg per mL. When administering any irritant drug intravenously, it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. In the event that a patient complains of pain during intended intravenous injection of promethazine, the injection should be stopped immediately to provide for evaluation of possible arterial placement or perivascular extravasation.
- Visual Inspection: This product is light sensitive and should be inspected before use and discarded if either color or particulate is observed.
- Other Considerations:
- Sedative drugs or CNS depressants should be avoided in patients with a history of sleep apnea.
- Administration of promethazine has been associated with reported cholestatic jaundice.
- Promethazine is contraindicated for use in pediatric patients less than two years of age.
- Promethazine is contraindicated in comatose states and in patients who have demonstrated an idiosyncratic reaction or hypersensitivity to promethazine or other phenothiazines.
- Under no circumstances should promethazine be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene.
- Promethazine should not be given by the subcutaneous route; evidence of chemical irritation has been noted, and necrotic lesions have resulted following subcutaneous injection. The preferred parenteral route of administration is by deep intramuscular injection.
Cohen LB, DeLegge MH, Aisenberg J, Brill JV, Inadomi JM, et al. AGA Institute review of endoscopic sedation. Gastroenterology. 2007 Aug;133(2):675-701.
Phenergan (Promethazine hydrochloride) Injection, Solution, [package insert]. Baxter Health Care Corporation. December 2006. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=2643 Accessed April 16, 2008.
Rex DK. Sedation for endoscopy. Gastroenterology & Hepatology Annual Review. 2006;1. http://www.gastro.org/user-assets/Documents/08_Publications/06_GIHep_Annual_Review/Articles/Rex.pdf Accessed April 16, 2008.