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Special Alerts
Promethazine Injection: Serious Tissue Injury - September 2009
The U.S. Food and Drug Administration (FDA) is requiring manufacturers to revise the labeling for promethazine injection and is alerting healthcare professionals to new prescribing information.
The FDA has received reports of severe tissue injury (including gangrene) requiring fasciotomy, skin graft, and/or amputation following the intravenous administration of promethazine. Severe tissue injury can occur from perivascular extravasation, unintentional intra-arterial administration, and intraneuronal or perineuronal infiltration. In addition, the agency has received numerous reports of injection site pain, phlebitis, cyanosis, swelling, blistering, necrosis, and nerve damage with promethazine administration.
As a result, the FDA has requested that a Boxed Warning emphasizing the risk of serious tissue injury be added to the labeling and that the Dosage and Administration section be revised. Due to the risk of tissue injury, deep intramuscular injection is the preferred route of administration. Intra-arterial and subcutaneous administration of promethazine are contraindicated. In addition, promethazine should not be administered to patients <2 years of age because of the risk of fatal respiratory depression.
If intravenous administration is required, the recommended maximum concentration is 25 mg/mL and the maximum rate of administration is 25 mg/minute into a properly functioning I.V. line. Healthcare providers should monitor patients for signs and symptoms of potential tissue injury including burning or pain at the injection site, phlebitis, swelling, and blistering. The injection should be discontinued immediately if the patient complains of pain during administration. Side effects may occur immediately or may develop hours to days after an injection.
For more information, U.S. healthcare professionals may refer to the following FDA website: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm182500.htm
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.
Medication Safety Issues
Sound-alike/look-alike issues:
Promethazine may be confused with chlorproMAZINE, predniSONE, promazine
Phenergan® may be confused with Phenaphen®, PHENobarbital, Phrenilin®, Theragran®
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication (I.V. formulation) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Administration issues:
To prevent or minimize tissue damage during I.V. administration, the Institute for Safe Medication Practices (ISMP) has the following recommendations:
Limit concentration available to the 25 mg/mL product
Consider limiting initial doses to 6.25-12.5 mg
Further dilute the 25 mg/mL strength into 10-20 mL NS
Administer through a large bore vein (not hand or wrist)
Administer via running I.V. line at port farthest from patient's vein
Consider administering over 10-15 minutes
Instruct patients to report immediately signs of pain or burning
Pronunciation
(proe METH a zeen)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Symptomatic treatment of various allergic conditions; antiemetic; motion sickness; sedative
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects were not observed in animal studies. Crosses the placenta. 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
Warnings/Precautions
Boxed warnings:
• Pediatrics: See “Special populations” 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).
• 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).
• 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.
• 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: Use with caution 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: Use caution as may cause confusion and oversedation.
• 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.
Other warnings/precautions:
• Appropriate administration: Not for SubQ or intra-arterial administration. I.M. is the preferred route of parenteral administration. I.V. use has been associated with severe tissue damage; unintentional intra-arterial administration/infiltration has been associated with severe tissue necrosis and loss of digits/limb. In some institutions, I.V administration may be avoided or specific administration techniques may be used to minimize risk. Discontinue immediately if burning or pain occurs with I.V. administration.
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, hyperglycemia
Gastrointestinal: Xerostomia, constipation, nausea, vomiting
Genitourinary: Urinary retention, ejaculatory disorder, impotence
Hematologic: Agranulocytosis, eosinophilia, leukopenia, hemolytic anemia, aplastic anemia, thrombocytopenia, thrombocytopenic purpura
Hepatic: Jaundice
Local: Venous thrombosis; injection site reactions (burning, erythema, pain, edema)
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 (major) of CYP2B6, 2D6; Inhibits CYP2D6 (weak)
Drug Interactions
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: Paliperidone. 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 effect of Orthostasis Producing Agents. 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
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination
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 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, oral solution: 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, bivalirudin, ciprofloxacin, cisatracurium, cisplatin, cladribine, cyclophosphamide, cytarabine, dexmedetomidine, docetaxel, doxorubicin hydrochloride, etoposide phosphate, fenoldopam, filgrastim, fluconazole, fludarabine, gatifloxacin, gemcitabine, granisetron, linezolid, melphalan, ondansetron, oxaliplatin, palonosetron, pemetrexed, remifentanil, sargramostim, teniposide, thiotepa, vinorelbine. Incompatible: Aldesleukin, allopurinol, amphotericin B cholesteryl sulfate complex, cefazolin, cefepime, cefoperazone, cefotetan, doxorubicin liposome, foscarnet, furosemide, lansoprazole, 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, ceftriaxone, chloroquine, dexamethasone, 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, cimetidine, dopamine, glycopyrrolate, hydromorphone, morphine, netilmicin, procainamide, prochlorperazine, vancomycin, vinorelbine, vitamin B complex with C. Incompatible: Aminophylline, ampicillin, cefazolin, cefotetan, ceftriaxone, chloramphenicol, chlordiazepoxide, chlorothiazide, codeine, floxacillin, furosemide, heparin, hydrocortisone sodium succinate, ketorolac, meperidine, methylprednisolone, methohexital, pentobarbital, phenobarbital, phenytoin, sodium bicarbonate, thiopental. Variable (consult detailed reference): Dimenhydrinate, 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; 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.: 3-5 minutes
Peak effect: Cmax: 9.04 ng/mL (suppository); 19.3 ng/mL (syrup)
Duration: Usually 4-6 hours (up to 12 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: 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
Test Interactions
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
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 increase CNS depression. 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.
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.
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.
Nursing: Physical Assessment/Monitoring
Assess patient carefully for use cautions prior to beginning treatment. Assess potential for interactions with other pharmacological agents and herbal products patient may be taking. Note Administration specifics for I.V. and I.M. use (do not give SubQ or intra-arterially; necrotic lesions may occur). Assess for effectiveness (according to purpose for use) and adverse response (eg, sedation, bradycardia, akathisia, delirium, extrapyramidal symptoms, dermatitis, gastrointestinal upset, urinary retention, blurred vision, respiratory depression). May be sedating and impair physical or mental abilities; use and teach sedation safety measures (eg, side rails up, call light within reach). Teach patient appropriate use (oral), interventions to reduce side effects, and adverse symptoms to report.
Oncology: Vesicant
Yes; see Management of Drug Extravasations.
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, as hydrochloride: 6.25 mg/5 mL (120 mL, 480 mL)
Tablet, as hydrochloride: 12.5 mg, 25 mg, 50 mg
Pricing: U.S. (www.drugstore.com)
Solution (Promethazine HCl)
50 mg/mL (25): $69.99
Suppository (Promethazine HCl)
12.5 mg (12): $29.99
Suppository (Promethegan)
25 mg (12): $58.71
50 mg (12): $75.99
Syrup (Promethazine HCl)
6.25 mg/5 mL (118): $12.99
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.
Parkman HP, Hasler WL, Fisher RS, “American Gastroenterological Association Medical Position Statement: Diagnosis and Treatment of Gastroparesis,” Gastroenterology, 2004, 127(5):1589-91.
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.
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 October 2009
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