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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(proe METH a zeen)
Generic Available (U.S.)
Yes
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Symptomatic treatment of various allergic conditions; antiemetic; motion sickness; sedative; adjunct to postoperative analgesia and anesthesia
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women. Crosses the placenta. Use during pregnancy only if benefits outweigh risk. May be used alone or as an adjunct to narcotic analgesics during labor.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to promethazine or any component of the formulation (cross-reactivity between phenothiazines may occur); coma; treatment of lower respiratory tract symptoms, including asthma; children <2 years of age; intra-arterial or subcutaneous administration
Warnings/Precautions
Boxed warnings:
• Pediatrics: See “Special populations” below.
• Serious tissue injury: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Altered cardiac conduction: May alter cardiac conduction (life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines).
• Anticholinergic effects: Phenothiazines may cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, gastrointestinal obstructions (partial or complete), urinary retention, urinary obstructions (partial or complete), BPH, xerostomia, or visual problems.
• Extrapyramidal symptoms: May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia.
• Neuroleptic malignant syndrome (NMS): Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity and/or autonomic instability.
• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
• Photosensitivity: May cause photosensitivity; avoid prolonged sun exposure.
• Sedation: May be sedating, use with caution in disorders where CNS depression is a feature; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Serious tissue injury: [U.S. Boxed Warning]: Promethazine injection can cause severe tissue injury (including gangrene) regardless of the route of administration. Tissue irritation and damage may result from perivascular extravasation, unintentional intra-arterial administration, and intraneuronal or perineuronal infiltration. In addition to gangrene, adverse events reported include tissue necrosis, abscesses, burning, pain, erythema, edema, paralysis, severe spasm of distal vessels, phlebitis, thrombophlebitis, venous thrombosis, sensory loss, paralysis, and palsies. Surgical intervention including fasciotomy, skin graft, and/or amputation have been necessary in some cases. The preferred route of administration is by deep intramuscular (I.M.) injection. Subcutaneous administration is contraindicated. Discontinue intravenous injection immediately with onset of burning and/or pain and evaluate for arterial injection or perivascular extravasation. Although there is no proven successful management of unintentional intra-arterial injection or perivascular extravasation, sympathetic block and heparinization have been used in the acute management of unintentional intra-arterial injection based on results from animal studies.
• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.
Disease-related concerns:
• Bone marrow suppression: Use with caution in patients with bone marrow suppression; leukopenia and agranulocytosis have been reported.
• Cardiovascular disease: Use with caution in patients with severe cardiovascular disease.
• Glaucoma: Use with caution in patients with narrow-angle glaucoma; condition may be exacerbated by cholinergic blockade. Screening is recommended.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment. Cholestatic jaundice has been reported with use.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; condition may be exacerbated by cholinergic blockade.
• Parkinson's disease: Use with caution in patients with Parkinson's disease; may have increased risk of tardive dyskinesia.
• Respiratory disease: Avoid use in patients with severe respiratory disease (asthma, COPD, sleep apnea); may lead to potentially fatal respiratory depression.
• Seizures: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.
Concurrent drug therapy issues:
• Antiemetic effects: May mask toxicity of other drugs or conditions (eg, intestinal obstruction, Reye's syndrome, brain tumor) due to antiemetic effects.
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• Elderly: May be inappropriate in this age group due to potent anticholinergic effects (Beers Criteria).
• Pediatrics: [U.S. Boxed Warning]: Respiratory fatalities have been reported in children <2 years of age. Use contraindicated in children <2 years. In children ≥2 years, use the lowest possible dose; other drugs with respiratory depressant effects should be avoided. Avoid use in children who may have Reyes' syndrome or hepatic disease as adverse reactions caused by promethazine may be confused with signs of primary disease.
Dosage form specific issues:
• Sodium metabisulfite: Injection may contain sodium metabisulfite; may cause allergic reaction.
Adverse Reactions
Frequency not defined.
Cardiovascular: Bradycardia, hyper-/hypotension, nonspecific QT changes, postural hypotension, tachycardia,
Central nervous system: Agitation akathisia, catatonic states, confusion, delirium, disorientation, dizziness, drowsiness, dystonias, euphoria, excitation, extrapyramidal symptoms, faintness, fatigue, hallucinations, hysteria, insomnia, lassitude, pseudoparkinsonism, tardive dyskinesia, nervousness, neuroleptic malignant syndrome, nightmares, sedation, seizure, somnolence
Dermatologic: Angioneurotic edema, dermatitis, photosensitivity, skin pigmentation (slate gray), urticaria
Endocrine & metabolic: Amenorrhea, breast engorgement, gynecomastia, hyperglycemia, lactation
Gastrointestinal: Constipation, nausea, vomiting, xerostomia
Genitourinary: Ejaculatory disorder, impotence, urinary retention
Hematologic: Agranulocytosis, leukopenia, thrombocytopenia, thrombocytopenic purpura
Hepatic: Jaundice
Local: Abscess, distal vessel spasm, gangrene, injection site reactions (burning, edema, erythema, pain), palsies, paralysis, phlebitis, sensory loss, thrombophlebitis, tissue necrosis, venous thrombosis
Neuromuscular & skeletal: Incoordination, tremor
Ocular: Blurred vision, corneal and lenticular changes, diplopia, epithelial keratopathy, pigmentary retinopathy
Otic: Tinnitus
Respiratory: Apnea, asthma, nasal congestion, respiratory depression
Metabolism/Transport Effects
Substrate of CYP2B6 (major), CYP2D6 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2D6 (weak)
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy
Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Levocabastine (Nasal); Paliperidone. Risk C: Monitor therapy
Antipsychotics: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Risk C: Monitor therapy
CYP2B6 Inducers (Strong): May increase the metabolism of CYP2B6 Substrates. Risk C: Monitor therapy
CYP2B6 Inhibitors (Moderate): May decrease the metabolism of CYP2B6 Substrates. Risk C: Monitor therapy
CYP2B6 Inhibitors (Strong): May decrease the metabolism of CYP2B6 Substrates. Risk D: Consider therapy modification
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Promethazine. Risk X: Avoid combination
Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification
Quazepam: May increase the serum concentration of CYP2B6 Substrates. Risk C: Monitor therapy
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Storage
Injection: Prior to dilution, store at 20°C to 25°C (68°F to 77°F). Protect from light. Solutions in NS or D5W are stable for 24 hours at room temperature.
Oral solution: Store at 15°C to 25°C (59°F to 77°F). Protect from light.
Suppositories: Store refrigerated at 2°C to 8°C (36°F to 46°F).
Tablets: Store at 20°C to 25°C (68°F to 77°F). Protect from light.
Compatibility
Stable in D5W, D10W, D5LR, D51/4NS, D51/2NS, D5NS, LR, 1/2NS, NS.
Y-site administration: Compatible: Amifostine, amsacrine, aztreonam, bivalirudin, ciprofloxacin, cisatracurium, cisplatin, cladribine, cyclophosphamide, cytarabine, dexmedetomidine, docetaxel, doxorubicin, etoposide phosphate, fenoldopam, filgrastim, fluconazole, fludarabine, gemcitabine, granisetron, hetastarch in lactate electrolyte injection (Hextend®), linezolid, melphalan, ondansetron, oxaliplatin, palonosetron, pemetrexed, remifentanil, sargramostim, teniposide, thiotepa, vinorelbine. Incompatible: Aldesleukin, allopurinol, amphotericin B cholesteryl sulfate complex, cefepime, cefotetan, doxorubicin liposome, foscarnet, furosemide, methotrexate, piperacillin/tazobactam. Variable (consult detailed reference): Cefazolin, heparin, hydrocortisone sodium succinate, potassium chloride, vitamin B complex with C.
Compatibility in syringe: Compatible: Atropine, atropine with meperidine, butorphanol, chlorpromazine, cimetidine, dihydroergotamine, diphenhydramine, droperidol, fentanyl, glycopyrrolate, hydroxyzine, meperidine, metoclopramide, midazolam, pentazocine, prochlorperazine edisylate, ranitidine, scopolamine. Incompatible: Cefotetan, ceftriaxone, dexamethasone sodium phosphate, dimenhydrinate, heparin, iodipamide meglumine 52%, iothalamate meglumine 60%, iothalamate sodium 80%, ketorolac, pentobarbital, thiopental. Variable (consult detailed reference): Hydromorphone, morphine, nalbuphine.
Mechanism of Action
Phenothiazine derivative; blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits a strong alpha-adrenergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones; competes with histamine for the H1-receptor; muscarinic-blocking effect may be responsible for antiemetic activity; reduces stimuli to the brainstem reticular system
Pharmacodynamics/Kinetics
Onset of action: Oral, I.M.: ~20 minutes; I.V.: ~5 minutes
Duration: Usually 4-6 hours (up to 12 hours)
Absorption: Oral: Rapid and complete; large first pass effect limits systemic bioavailability (Sharma, 2003)
Distribution: Vd: Syrup: 98 L/kg (range: 17-277 L/kg) (Strenkoski-Nox, 2000)
Metabolism: Hepatic; hydroxylation via CYP2D6 and N-demethylation via CYP2B6; significant first-pass effect (Sharma, 2003)
Bioavailability: Oral: ~25% (Sharma, 2003)
Half-life elimination: I.M.: ~10 hours; I.V.: 9-16 hours; Suppositories, syrup: 16-19 hours (range: 4-34 hours) (Strenkoski-Nox, 2000)
Time to maximum serum concentration: Suppositories: 6.7-8.6 hours; Syrup: 4.4 hours (Strenkoski-Nox, 2000)
Excretion: Urine
Dosage
Children ≥2 years:
Allergic conditions: Oral, rectal: 0.1 mg/kg/dose (maximum: 12.5 mg) every 6 hours during the day and 0.5 mg/kg/dose (maximum: 25 mg) at bedtime as needed
Antiemetic: Oral, I.M., I.V., rectal: 0.25-1 mg/kg 4-6 times/day as needed (maximum: 25 mg/dose)
Motion sickness: Oral, rectal: 0.5 mg/kg/dose 30 minutes to 1 hour before departure, then every 12 hours as needed (maximum dose: 25 mg twice daily)
Preoperative analgesia/hypnotic adjunct: I.M., I.V.: 1.1 mg/kg in combination with an analgesic or hypnotic (at reduced doses) and an atropine-like agent. Note: Dose should not exceed half of suggested adult dose.
Sedation: Oral, I.M., I.V., rectal: 0.5-1 mg/kg/dose every 6 hours as needed (maximum: 50 mg/dose)
Adults:
Allergic conditions (including allergic reactions to blood or plasma):
Oral, rectal: 25 mg at bedtime or 12.5 mg before meals and at bedtime (range: 6.25-12.5 mg 3 times/day)
I.M., I.V.: 25 mg, may repeat in 2 hours when necessary; switch to oral route as soon as feasible
Antiemetic: Oral, I.M., I.V., rectal: 12.5-25 mg every 4-6 hours as needed
Motion sickness: Oral, rectal: 25 mg 30-60 minutes before departure, then every 12 hours as needed
Obstetrics (labor) as adjunct to analgesia: I.M., I.V.: Early labor: 50 mg; Established labor: 25-75 mg; may repeat every 4 hours for up to 2 additional doses (maximum: 100 mg/day while in labor). Note: Dosage of concomitant analgesic should be reduced.
Pre-/postoperative analgesia/hypnotic adjunct: I.M., I.V.: 25-50 mg in combination with analgesic or hypnotic (at reduced dosage)
Sedation: Oral, I.M., I.V., rectal: 12.5-50 mg/dose
Administration: I.M.
Preferred route of administration; administer into deep muscle
Administration: I.V.
I.V. administration is not the preferred route; severe tissue damage may occur. Solution for injection should be administered in a maximum concentration of 25 mg/mL (more dilute solutions are recommended). Administer via running I.V. line at port farthest from patient's vein, or through a large bore vein (not hand or wrist). Consider administering over 10-15 minutes (maximum: 25 mg/minute). Discontinue immediately if burning or pain occurs with administration.
Administration: Other
Not for SubQ or intra-arterial administration.
Administration: I.V. Detail
Rapid I.V. administration may produce a transient fall in blood pressure.
pH: 4.0-5.5
Monitoring Parameters
Relief of symptoms, mental status; signs and symptoms of tissue injury (burning or pain at injection site, phlebitis, edema) with I.V. administration
Test Interactions
May interfere with urine detection of amphetamine/methamphetamine (false-positive); alters the flare response in intradermal allergen tests; hCG-based pregnancy tests may result in false-negatives or false-positives
Dietary Considerations
Increase dietary intake of riboflavin.
Patient Education
I.V.: Report immediately any pain or burning at infusion/injection site. Oral/suppository: Avoid alcohol; may increase CNS depression. May cause dizziness, drowsiness, blurred vision, orthostatic hypotension, photosensitivity, nausea, dry mouth, or appetite disturbances. Report unresolved nausea or diarrhea, palpitations, dizziness, excess/persistent sedation, changes in urination, sore throat, or respiratory difficulty.
Geriatric Considerations
Because promethazine is a phenothiazine (and can, therefore, cause side effects such as extrapyramidal symptoms), it is not considered an antihistamine of choice in the elderly.
This medication is considered to be potentially inappropriate in this patient population (Beers Criteria severity: High).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Significant hypotension may occur, especially when the drug is administered parenterally or following administration of local anesthetics containing vasoconstrictors (ie, epinephrine or levonordefrin); orthostatic hypotension is due to alpha-receptor blockade, the elderly are at greater risk for orthostatic hypotension.
Significant sedation can occur and may be increased in the elderly and in patients taking or administered other CNS depressants (ie, opioid analgesics or benzodiazepines).
Extrapyramidal effects including akathisia (motor restlessness), acute dystonia (spasmodic contractures), pseudoparkinsonism, and tardive dyskinesia can occur with a single dose. These effects are more likely in the elderly, patients taking other dopamine antagonists (including antipsychotic agents and some antiemetic agents), and patients with Parkinson's disease.
Promethazine is a less expensive alternative for moderate-to-severe postoperative nausea than ondansetron but with a greater chance of adverse effects and drug interactions especially with opioid analgesics.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Promethazine may lower seizure threshold; use caution administering promethazine in combination with other agents that reduce seizure threshold (ie, local anesthetics). Due to promethazine induced alpha-adrenergic blockade, administration of local anesthetics containing the vasoconstrictors epinephrine or levonordefrin, causes unopposed stimulation of beta-adrenergic receptors in heart and peripheral blood vessels that may result in tachycardia and peripheral vasodilation causing hypotension. Effects on blood pressure are greater in combination with epinephrine than levonordefrin.
Dental Comment
Sedation: When used alone as a sedative agent the degree of sedation is often mild. As a sedative agent, promethazine is effective in managing pediatric patients that require mild anxiety control. It is ineffective when used alone in children with extreme apprehension or for the disruptive, unmanageable child. A more profound sedation will occur if promethazine is administered in combination with an opioid or benzodiazepine. If promethazine is combined with an opioid, the dose of the opioid should be decreased by 25% to 50%.
Nursing: Physical Assessment/Monitoring
Assess patient carefully for contraindications or cautions prior to beginning treatment. I.M. is the preferred route of administration. I.V.: Infusion site must be monitored closely; severe tissue damage may result. Not for SubQ or intra-arterial use. Monitor for sedation, bradycardia, akathisia, delirium, extrapyramidal symptoms, gastrointestinal upset, urinary retention, blurred vision, and respiratory depression. May be sedating and impair physical or mental abilities; use sedation safety measures to prevent falls (eg, side rails up, call light within reach).
Oncology: Vesicant
Vesicant
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution, as hydrochloride: 25 mg/mL (1 mL); 50 mg/mL (1 mL)
Phenergan®: 25 mg/mL (1 mL); 50 mg/mL (1 mL) [contains edetate disodium, sodium metabisulfite]
Suppository, rectal, as hydrochloride: 12.5 mg (12s); 25 mg (12s)
Phenadoz®: 12.5 mg (12s); 25 mg (12s)
Promethegan™: 12.5 mg (12s); 25 mg (12s); 50 mg (12s)
Syrup, oral, as hydrochloride: 6.25 mg/5 mL (118 mL, 473 mL)
Tablet, oral, as hydrochloride: 12.5 mg, 25 mg, 50 mg
Pricing: U.S. (www.drugstore.com)
Solution (Promethazine HCl)
50 mg/mL (25): $59.99
Suppository (Promethazine HCl)
12.5 mg (12): $49.99
Suppository (Promethegan)
12.5 mg (12): $25.99
25 mg (12): $59.99
50 mg (12): $107.99
Syrup (Promethazine HCl)
6.25 mg/5 mL (118): $12.99
Tablets (Promethazine HCl)
12.5 mg (30): $15.99
25 mg (30): $21.99
50 mg (30): $21.99
References
Blanc VF, Ruest P, Milot J, et al, “Antiemetic Prophylaxis With Promethazine or Droperidol in Paediatric Outpatient Strabismus Surgery,” Can J Anaesth, 1991, 38(1):54-60.
Grunberg SM and Hesketh PJ, “Control of Chemotherapy-Induced Emesis,” N Engl J Med, 1993, 329(24):1790-6.
Institute for Safe Medication Practice, “Action Needed to Prevent Serious Tissue Injury With I.V. Promethazine.” Available at http://www.ismp.org/Newsletters/acutecare/articles/20060810.asp
McGee JL and Alexander MR, “Phenothiazine Analgesia - Fact or Fantasy?” Am J Hosp Pharm, 1979, 36(5):633-40.
Melanson SE, Lee-Lewandrowski E, Griggs DA, et al, “Reduced Interference by Phenothiazines in Amphetamine Drug of Abuse Immunoassays,” Arch Pathol Lab Med, 2006, 130(12):1834-8.
Parkman HP, Hasler WL, Fisher RS, “American Gastroenterological Association Medical Position Statement: Diagnosis and Treatment of Gastroparesis,” Gastroenterology, 2004, 127(5):1589-91.
Sharma A and Hamelin BA, "Classic Histamine H1 Receptor Antagonists: A Critical Review of Their Metabolic and Pharmacokinetic Fate from a Bird's Eye View," Curr Drug Metab, 2003, 4(2):105-29.
Starke PR, Weaver J, and Chowdhury BA, “Boxed Warning Added to Promethazine Labeling for Pediatric Use,” N Engl J Med, 2005, 352(25):2653.
Strenkoski-Nix LC, Ermer J, DeCleene S, et al, “Pharmacokinetics of Promethazine Hydrochloride After Administration of Rectal Suppositories and Oral Syrup to Healthy Subjects,” Am J Health Syst Pharm, 2000, 57(16):1499-505.
Tavorath R and Hesketh PJ, “Drug Treatment of Chemotherapy-Induced Delayed Emesis,” Drugs, 1996, 52(5):639-48.
Taylor G, Houston JB, Shaffer J, et al, “Pharmacokinetics of Promethazine and Its Sulphoxide Metabolite After Intravenous and Oral Administration To Man,” Br J Clin Pharmacol, 1983, 15(3):287-93.
Tortorice PV and O'Connell MB, “Management of Chemotherapy-Induced Nausea and Vomiting,” Pharmacotherapy, 1990, 10(2):129-45.
International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
Content last modified March 2012
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