Promethazine

Special Alerts

New Labeling Related to Pediatric Use - February 2005

A "Dear Healthcare Professional" letter has been distributed by the manufacturer (Wyeth) of Phenergan® (promethazine hydrochloride) concerning important revisions to the approved product labeling (tablets and suppositories). Due to the potential for severe, and potentially fatal respiratory depression, promethazine is contraindicated for use in pediatric patients <2 years of age. The revision was based on cases reported in postmarketing surveillance which included fatalities in this population. Caution should also be exercised when administering promethazine to pediatric patients >2 years of age. Changes were approved by the FDA, and incorporated into the Lexi-Comp monograph, in November, 2004. The letter was distributed in February, 2005 in an effort to ensure awareness of these revisions among healthcare providers.

Additional information is available at http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#phenergan, last accessed March 3, 2005.

Pronunciation

(proe METH a zeen)

U.S. Brand Names

Phenadoz™; Phenergan®; Promethegan™

Synonyms

Promethazine Hydrochloride

Generic Available

Yes

Canadian Brand Names

Phenergan®

Use

Symptomatic treatment of various allergic conditions; antiemetic; motion sickness; sedative; postoperative pain (adjunctive therapy); anesthetic (adjunctive therapy); anaphylactic reactions (adjunctive therapy)

Pregnancy Risk Factor

Pregnancy Implications

Crosses the placenta. Possible respiratory depression if drug is administered near time of delivery; behavioral changes, EEG alterations, impaired platelet aggregation reported with use 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

Warnings/Precautions

Not for SubQ or intra-arterial administration. Injection may contain sodium metabisulfite (may cause allergic reaction). May be sedating; use with caution in disorders where CNS depression is a feature. May impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Effects with other sedative drugs or ethanol may be potentiated. Use with caution in Parkinson's disease; hemodynamic instability; bone marrow suppression; subcortical brain damage; and in severe cardiac, hepatic, renal, or respiratory disease. Avoid use in Reye's syndrome. Respiratory fatalities have been reported in children <2 years of age. In children

2 years, use the lowest possible dose; other drugs with respiratory depressant effects should be avoided. May lower seizure threshold; use caution in persons with seizure disorders or in persons using narcotics or local anesthetics which may also affect seizure threshold. Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects. May alter cardiac conduction (life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines). May cause orthostatic hypotension; use with caution in patients at risk of hypotension or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease).

Phenothiazines may cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia. May be associated with neuroleptic malignant syndrome (NMS).

Adverse Reactions

Frequency not defined.

Cardiovascular: Bradycardia, hypertension, postural hypotension, tachycardia, nonspecific QT changes

Central nervous system: Akathisia, catatonic states, confusion, delirium, disorientation, dizziness, drowsiness, dystonias, euphoria, excitation, extrapyramidal symptoms, fatigue, hallucinations, hysteria, insomnia, lassitude, pseudoparkinsonism, tardive dyskinesia, nervousness, neuroleptic malignant syndrome, nightmares, sedation, seizure, somnolence

Dermatologic: Angioneurotic edema, photosensitivity, dermatitis, skin pigmentation (slate gray), urticaria

Endocrine & metabolic: Lactation, breast engorgement, amenorrhea, gynecomastia, hyper-/hypoglycemia

Gastrointestinal: Xerostomia, constipation, nausea, vomiting

Genitourinary: Urinary retention, ejaculatory disorder, impotence

Hematologic: Agranulocytosis, eosinophilia, leukopenia, hemolytic anemia, aplastic anemia, thrombocytopenia, thrombocytopenic purpura

Hepatic: Jaundice

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

Overdosage/Toxicology

Symptoms of overdose include CNS depression, respiratory depression, possible CNS stimulation, dry mouth, fixed and dilated pupils, and hypotension. Treatment is symptom-directed and supportive. Epinephrine should not be used. Hemodialysis: Not dialyzable (0% to 5%)

Drug Interactions

Substrate (major) of CYP2B6, 2D6; Inhibits CYP2D6 (weak)

Aluminum salts: May decrease the absorption of phenothiazines; monitor

Amphetamines: Efficacy may be diminished by antipsychotics; in addition, amphetamines may increase psychotic symptoms; avoid concurrent use

Anticholinergics: May inhibit the therapeutic response to phenothiazines and excess anticholinergic effects may occur; includes benztropine, trihexyphenidyl, biperiden, and drugs with significant anticholinergic activity (TCAs, antihistamines, disopyramide)

Antihypertensives: Concurrent use of phenothiazines with an antihypertensive may produce additive hypotensive effects (particularly orthostasis)

Bromocriptine: Phenothiazines inhibit the ability of bromocriptine to lower serum prolactin concentrations

CNS depressants: Sedative effects may be additive with phenothiazines; monitor for increased effect; includes barbiturates, benzodiazepines, narcotic analgesics, ethanol, and other sedative agents

CYP2B6 inducers: May decrease the levels/effects of promethazine. Example inducers include carbamazepine, nevirapine, phenobarbital, phenytoin, and rifampin.

CYP2B6 inhibitors: May increase the levels/effects of promethazine. Example inhibitors include desipramine, paroxetine, and sertraline.

CYP2D6 inhibitors: May increase the levels/effects of promethazine. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Epinephrine: Promethazine may diminish the pressor effects of epinephrine.

Guanethidine and guanadrel: Antihypertensive effects may be inhibited by phenothiazines

Levodopa: Phenothiazines may inhibit the antiparkinsonian effect of levodopa; avoid this combination

Lithium: Phenothiazines may produce neurotoxicity with lithium; this is a rare effect

Propranolol: Serum concentrations of phenothiazines may be increased; propranolol also increases phenothiazine concentrations

Polypeptide antibiotics: Rare cases of respiratory paralysis have been reported with concurrent use of phenothiazines

QTc-prolonging agents: Effects on QTc interval may be additive with phenothiazines, increasing the risk of malignant arrhythmias; includes type Ia antiarrhythmics, TCAs, and some quinolone antibiotics (sparfloxacin, moxifloxacin, and gatifloxacin)

Sulfadoxine-pyrimethamine: May increase phenothiazine concentrations

Tricyclic antidepressants: Concurrent use may produce increased toxicity or altered therapeutic response

Trazodone: Phenothiazines and trazodone may produce additive hypotensive effects

Valproic acid: Serum levels may be increased by phenothiazines

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).

Stability

Injection: Prior to dilution, store at room temperature; protect from light. Solutions in NS or D5W are stable for 24 hours at room temperature.

Suppositories: Store refrigerated at 2°C to 8°C (36°F to 46°F)

Tablets: Store at room temperature; protect from light

Compatibility

Stable in dextran 6% in dextrose, dextran 6% in NS, D5W, D10W, D5LR, D5¹ /4NS, D5¹ /2NS, D5NS, LR, ¹ /2NS, NS

Y-site administration: Compatible: Amifostine, amsacrine, aztreonam, ciprofloxacin, cisatracurium, cisplatin, cladribine, cyclophosphamide, cytarabine, docetaxel, doxorubicin, etoposide phosphate, filgrastim, fluconazole, fludarabine, gatifloxacin, gemcitabine, granisetron, linezolid, melphalan, ondansetron, remifentanil, sargramostim, teniposide, thiotepa, vinorelbine. Incompatible: Aldesleukin, allopurinol, amphotericin B cholesteryl sulfate complex, cefazolin, cefepime, cefoperazone, cefotetan, doxorubicin liposome, foscarnet, methotrexate, piperacillin/tazobactam. Variable (consult detailed reference): Cefazolin, ceftizoxime, 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, hydromorphone, hydroxyzine, meperidine, metoclopramide, midazolam, pentazocine, perphenazine, prochlorperazine edisylate, promazine, ranitidine, scopolamine. Incompatible: Cefotetan, chloroquine, diatrizoate sodium 75%, diatrizoate meglumine 52% with diatrizoate sodium 8%, diatrizoate meglumine 34.3% with diatrizoate sodium 35%, dimenhydrinate, heparin, iodipamide meglumine 52%, iothalamate meglumine 60%, iothalamate sodium 80%, ketorolac, pentobarbital, thiopental. Variable (consult detailed reference): Morphine, nalbuphine

Compatibility when admixed: Compatible: Amikacin, ascorbic acid injection, buprenorphine, butorphanol, chloroquine, hydromorphone, netilmicin, vitamin B complex with C. Incompatible: Aminophylline, chloramphenicol, chlorothiazide, dimenhydrinate, floxacillin, furosemide, heparin, hydrocortisone sodium succinate, methohexital, penicillin G sodium, pentobarbital, phenobarbital, phenytoin, thiopental. Variable (consult detailed reference): Penicillin G potassium

Mechanism of Action

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; reduces stimuli to the brainstem reticular system

Pharmacodynamics/Kinetics

Onset of action: I.M.: ~20 minutes; I.V.: 3-5 minutes

Peak effect: Cmax: 9.04 ng/mL (suppository); 19.3 ng/mL (syrup)

Duration: 2-6 hours

Absorption:

I.M.: Bioavailability may be greater than with oral or rectal administration

Oral: Rapid and complete; large first pass effect limits systemic bioavailability

Distribution: Vd: 171 L

Protein binding: 93%

Metabolism: Hepatic; primarily oxidation; forms metabolites

Half-life elimination: 9-16 hours

Time to maximum serum concentration: 4.4 hours (syrup); 6.7-8.6 hours (suppositories)

Excretion: Primarily urine and feces (as inactive metabolites)

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)

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

Sedation: Oral, I.M., I.V., rectal: 12.5-50 mg/dose

Administration

Formulations available for oral, rectal, I.M./I.V. administration; not for SubQ or intra-arterial administration. Administer I.M. into deep muscle (preferred route of administration). Due to the possibility of orthostatic hypotension, I.V. administration is not the preferred route. Solution for injection may be diluted in 25-100 mL NS or D5W (maximum concentration of 25 mg/mL) and infused over 15-30 minutes at a rate

25 mg/minute.

Monitoring Parameters

Relief of symptoms, mental status

Test Interactions

Alters the flare response in intradermal allergen tests; HCG-based pregnancy tests may result in false-negatives or false-positives; increased serum glucose may be seen with glucose tolerance tests

Dietary Considerations

Increase dietary intake of riboflavin.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber (especially anything that may cause CNS depression). Take this drug as prescribed; do not increase dosage. Avoid alcohol. May cause dizziness, drowsiness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or nausea, dry mouth, appetite disturbances (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Report unusual weight gain, unresolved nausea or diarrhea, chest pain or palpitations, excess sedation or stimulation, or sore throat or respiratory difficulty. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

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; orthostatic hypotension is due to alpha-receptor blockade, the elderly are at greater risk for orthostatic hypotension.

Tardive dyskinesia: Prevalence rate may be 40% in elderly; development of the syndrome and the irreversible nature are proportional to duration and total cumulative dose over time. Extrapyramidal reactions are more common in elderly with up to 50% developing these reactions after 60 years of age. Drug-induced Parkinson's syndrome occurs often; akathisia is the most common extrapyramidal reaction in elderly.

Increased confusion, memory loss, psychotic behavior, and agitation frequently occur as a consequence of anticholinergic effects. Antipsychotic associated sedation in nonpsychotic patients is extremely unpleasant due to feelings of depersonalization, derealization, and dysphoria.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

Most pharmacology textbooks state that in presence of phenothiazines, systemic doses of epinephrine paradoxically decrease the blood pressure. This is the so called "epinephrine reversal" phenomenon. This has never been observed when epinephrine is given by infiltration as part of the anesthesia procedure.

Oncology: Emetic Potential

Very low (<10%)

Oncology: Vesicant

Dosage Forms

[DSC] = Discontinued product

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 sodium metabisulfite]

Suppository, rectal, as hydrochloride: 12.5 mg, 25 mg, 50 mg

Phenadoz™: 12.5 mg, 25 mg

Phenergan®, Promethegan™: 12.5 mg, 25 mg, 50 mg

Syrup, as hydrochloride: 6.25 mg/5 mL (120 mL, 480 mL) [contains alcohol]

Tablet, as hydrochloride: 12.5 mg, 25 mg, 50 mg

Phenergan®: 12.5 mg [DSC], 25 mg, 50 mg [DSC]

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.

McGee JL and Alexander MR, "Phenothiazine Analgesia - Fact or Fantasy?" Am J Hosp Pharm , 1979, 36(5):633-40.

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.

Tortorice PV and O'Connell MB, "Management of Chemotherapy-Induced Nausea and Vomiting," Pharmacotherapy , 1990, 10(2):129-45.

International Brand Names

Allphen® (BD); Antiallersin® (BG); Atosil® (DE); Avomine® (AU, BD, GB, HK, IE, IN, NZ); Avopreg® (ID); Brunazine® (ZA); Closin® (DE); Cremefenergan® (BR); Daralix® (ZA); Diphergan® (PL); Eusedon® (DE); Farganesse® (IT); Fargan® (IT); Fenazil® (IT); Fenergan® (AR, BR, ES, PT); Fomergan® (RO); Frinova® (ES); Gold Cross Antihistamine Elixir® (AU); Histavil® (BD); Histazin® (JO, RO); Insomn-Eze® (AU); Intramed Promethazine Hydrochloride Injection® (ZA); Lenazine® (ZA); Lergigan® (SE); Otosil® (BD); Pamergan® (BR); Phenerex® (BD); Phenergan® (AU, BD, BE, CA, CZ, DK, EG); Phénergan® [compr.] (FR); Phénergan® (FR); Phenergan® (GB, HK, ID, IE, IN, LU, NL, NO, NZ, RO, TH, YU, ZA); Phenergan Nightime® (GB); Pipolphen® (HU, RU); Polfergan® (PL); Progan® (BD); Prohist® (ZA); Prometazina Cevallos® (AR); Prometazina Cloridrato® (IT); Prometazina Fada® (AR); Prometazina® (IT); Prometazina Larjan® (AR); Prometazin ERA® (DK); Promethazin® (CZ); Promethazine HCl-Fresenius® (ZA); Promethazine Hydrochloride BP® (AU); Promethazine Hydrochloride® (CY, NZ, SG); Promethazine® (IL, PL); Promethazin-neuraxpharm® (DE); Promodin® (BD); Proneurin® (DE); Prothazin® (CZ, DE); Prothiazine® (IL); Prozin® (BD); Receptozine® (ZA); Romergan® [inj.] (RO); Romergan® (RO); Sominex® (GB); Titanox® (TH)

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