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Promethazine

Pronunciation

Pronunciation

(proe METH a zeen)

Index Terms

  • Promethazine HCl
  • Promethazine Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection, as hydrochloride:

Phenergan: 50 mg/mL (1 mL) [contains edetate disodium, phenol, sodium metabisulfite]

Phenergan: 25 mg/mL (1 mL) [pyrogen free; contains edetate disodium, phenol, sodium metabisulfite]

Generic: 25 mg/mL (1 mL); 50 mg/mL (1 mL)

Solution, Oral, as hydrochloride:

Generic: 6.25 mg/5 mL (118 mL, 473 mL)

Suppository, Rectal, as hydrochloride:

Phenadoz: 12.5 mg (12 ea); 25 mg (12 ea)

Phenergan: 12.5 mg (12 ea); 25 mg (12 ea); 50 mg (12 ea)

Promethegan: 12.5 mg (12 ea); 25 mg (12 ea, 1000 ea); 50 mg (12 ea)

Generic: 12.5 mg (1 ea, 12 ea); 25 mg (1 ea, 12 ea); 50 mg (12 ea)

Syrup, Oral, as hydrochloride:

Generic: 6.25 mg/5 mL (118 mL, 473 mL)

Tablet, Oral, as hydrochloride:

Generic: 12.5 mg, 25 mg, 50 mg

Brand Names: U.S.

  • Phenadoz
  • Phenergan
  • Promethegan

Pharmacologic Category

  • Antiemetic
  • Histamine H1 Antagonist
  • Histamine H1 Antagonist, First Generation
  • Phenothiazine Derivative

Pharmacology

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

Absorption

Oral: Rapid and complete; large first pass effect limits systemic bioavailability (Sharma, 2003)

Distribution

Vd: 13.4 ± 3.6 L/kg (Brunton 2011)

Metabolism

Hepatic; hydroxylation via CYP2D6 and N-demethylation via CYP2B6; significant first-pass effect (Sharma, 2003)

Excretion

Urine, feces as inactive metabolites

Onset of Action

Oral, IM: ~20 minutes; IV: ~5 minutes

Time to Peak

Maximum serum concentration (Brunton 2011): Oral (syrup): 2.8 ± 1.4 hours; Rectal: 8.2 ± 3.4 hours

Duration of Action

Usually 4 to 6 hours (up to 12 hours)

Half-Life Elimination

IM: ~10 hours; IV: 9 to 16 hours; Suppositories, syrup: 16 to 19 hours (range: 4 to 34 hours) (Strenkoski-Nox, 2000)

Protein Binding

93% (Brunton 2011)

Use: Labeled Indications

Allergic conditions, treatment: Perennial and seasonal allergic rhinitis; vasomotor rhinitis; allergic conjunctivitis due to inhalant allergens and foods; mild, uncomplicated allergic skin manifestations of urticaria and angioedema; amelioration of allergic reactions to blood or plasma; dermographism; anaphylactic reactions, as adjunctive therapy to epinephrine and other standard measures, after the acute manifestations have been controlled

Nausea and vomiting: Prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery; antiemetic therapy in postoperative patients

Motion sickness: Active and prophylactic treatment of motion sickness

Surgical analgesia/hypnotic; pre-/postoperative adjunct: Adjunctive therapy with analgesics and/or anesthesia

Sedation: Preoperative, postoperative, and obstetric sedation; for sedation, relief of apprehension, and production of light sleep from which the patient can be easily aroused

Use: Unlabeled

Treatment of nausea and vomiting of pregnancy (NVP)

Contraindications

Hypersensitivity or idiosyncratic reaction to promethazine, other phenothiazines, or any component of the formulation; coma; treatment of lower respiratory tract symptoms, including asthma; children <2 years of age; intra-arterial or subcutaneous administration

Dosing: Adult

Allergic conditions, treatment:

Oral, rectal: 25 mg at bedtime or 12.5 mg before meals and at bedtime (usual range: 6.25 to 12.5 mg 3 times daily)

IM, IV: 25 mg, may repeat in 2 hours when necessary; switch to oral route as soon as feasible

Motion sickness: Oral, rectal: Initial: 25 mg 30 to 60 minutes before departure; repeat 8 to 12 hours later as needed; maintenance: 25 mg twice daily.

Nausea and vomiting: Oral, IM, IV, rectal: 12.5 to 25 mg every 4 to 6 hours as needed

Obstetrics (labor) analgesia adjunct: IM, IV: Early labor: 50 mg; Established labor: 25 to 75 mg in combination with analgesic at reduced dosage; may repeat every 4 hours for up to 2 additional doses (maximum: 100 mg/day while in labor)

Surgical analgesia/hypnotic; pre-/postoperative adjunct : IM, IV: 25 to 50 mg in combination with analgesic or hypnotic (at reduced dosage)

Sedation: Oral, IM, IV, rectal: 25 to 50 mg/dose

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Allergic conditions, treatment: Children ≥2 years and Adolescents: Oral: 0.125 mg/kg/dose (maximum dose: 12.5 mg) every 6 hours during the day as needed and 0.5 mg/kg/dose (maximum dose: 25 mg) at bedtime as needed. Note: Not typically a first-line option for allergic conditions; other agents may be more effective with fewer adverse effects.

Motion sickness: Children ≥2 years and Adolescents: Oral, rectal: 0.5 mg/kg/dose (maximum dose: 25 mg) 30 minutes to 1 hour before departure, then every 12 hours as needed (Kleigman 2007)

Nausea and vomiting: Children ≥2 years and Adolescents: Oral, IM, IV, rectal: 0.25 to 1 mg/kg/dose (maximum dose: 25 mg) every 4 to 6 hours as needed (Kliegman 2007) Note: Expert recommendations for postoperative nausea and vomiting (PONV) management do not include promethazine as an option for the prevention or treatment of PONV in pediatric patients; use replaced by newer agents (SAA [Gan 2014]; WHO 2011).

Surgical analgesia/hypnotic; pre-/postoperative adjunct: Children ≥2 years and Adolescents: IM, IV: 0.25 to 1.1 mg/kg once in combination with an analgesic or hypnotic (at reduced dosage; low end of range) and with an atropine-like agent (at appropriate dosage) (Kliegman, 2007). Promethazine dosage should not exceed 12.5 to 25 mg (ie, half of suggested adult dosage).

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

Adults: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution (cholestatic jaundice has been reported with use).

Children ≥2 years and Adolescents: The manufacturer recommends avoiding use in pediatric patients with signs and symptoms of hepatic disease (extrapyramidal symptoms caused by promethazine may be confused with CNS signs of hepatic disease).

Reconstitution

Parenteral: IV: Although IV administration should be avoided, promethazine has been administered IV in select patients. Solution for injection may be administered at a maximum concentration of 25 mg/mL; however, to minimize phlebitis further dilution is recommended. Some have suggested further diluting the 25 mg/mL with 10 to 20 mL NS (ISMP 2006).

Administration

Oral: Administer with food, water, or milk to decrease GI distress. Measure and administer prescribed dose of oral solution using dosing syringe, dosing spoon, or dosing cup.

Parenteral: Not for SubQ administration; promethazine is a chemical irritant which may produce necrosis.

IM: Preferred route of administration; administer as a deep IM injection

IV: IV use should be avoided when possible since severe tissue damage has occurred with IV administration; in selected patients, promethazine has been diluted and infused at a maximum rate of 25 mg/minute. To minimize phlebitis, consider administering over 10 to 15 minutes, limiting initial dose to 1/4 or 1/2 the usual dose (eg, in adults 6.25 to 12.5 mg), further diluting the 25 mg/mL strength in 10 to 20 mL NS, and administering through a large bore vein (not hand or wrist) or via a running IV line at port farthest from patient's vein (ISMP 2006).

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. Discontinue immediately if burning or pain occurs with administration; evaluate for inadvertent arterial injection or extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Apply dry cold compresses (Hurst 2004).

Dietary Considerations

Increase dietary intake of riboflavin.

Compatibility

Stable in D5W, D10W, D5LR, D51/4NS, D51/2NS, D5NS, LR, R, SL.

Y-site administration: Incompatible with aldesleukin, allopurinol, amphotericin B cholesteryl sulfate complex, cefepime, cefotetan, ceftriaxone, dimenhydrinate, doxorubicin liposome, foscarnet, furosemide, hydromorphone, ketamine, morphine, piperacillin/tazobactam.

Compatibility in syringe: Incompatible with cefotetan, ceftriaxone, dexamethasone sodium phosphate, heparin, iodipamide meglumine 52%, iothalamate meglumine 60%, iothalamate sodium 80%, ketorolac, pentobarbital, thiopental.

Storage

Injection, oral solution, tablets: Store between 20°C and 25°C (68°F and 77°F). Protect from light.

Suppositories: Store refrigerated between 2°C and 8°C (36°F and 46°F).

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. Consider therapy modification

AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy

Acetylcholinesterase Inhibitors: Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Anti-Parkinson Agents (Monoamine Oxidase Inhibitor): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity if selegiline or rasagiline is combined with a serotonin modulator. Use of transdermal selegiline with serotonin modulators is contraindicated. Consider therapy modification

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Monitor therapy

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

CYP2B6 Inducers (Moderate): May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Dimethindene (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination

EPINEPHrine (Nasal): Promethazine may diminish the vasoconstricting effect of EPINEPHrine (Nasal). Monitor therapy

EPINEPHrine (Oral Inhalation): Promethazine may diminish the therapeutic effect of EPINEPHrine (Oral Inhalation). Monitor therapy

Epinephrine (Racemic): Promethazine may diminish the vasoconstricting effect of Epinephrine (Racemic). Management: Monitor for diminished vasoconstrictive effects of racemic epinephrine (e.g., diminished efficacy when used for gingival retraction). This interaction is likely of less concern in patients receiving epinephrine for other purposes (e.g., bronchodilation). Monitor therapy

EPINEPHrine (Systemic): Promethazine may diminish the vasoconstricting effect of EPINEPHrine (Systemic). Management: When vasoconstrictive effects are desired in patients receiving promethazine, consider alternatives to epinephrine. Consider use of norepinephrine or phenylephrine, and avoid epinephrine, when treating hypotension associated with promethazine overdose. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Avoid combination

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination

Linezolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Due to a risk of serotonin syndrome/serotonin toxicity, discontinue serotonin modulators 2 weeks prior to the administration of linezolid. If urgent initiation of linezolid is needed, discontinue serotonin modulators immediately and monitor closely. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Metoclopramide: May enhance the adverse/toxic effect of Promethazine. Avoid combination

MetyroSINE: May enhance the adverse/toxic effect of Promethazine. Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Avoid combination

OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy

RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to secretin. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thiotepa: May increase the serum concentration of CYP2B6 Substrates. Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

Pregnancy tests (hCG-based) may result in false-negatives or false-positives; increased serum glucose may be seen with glucose tolerance tests; may result in false-positives with urine detection of amphetamine/methamphetamine (Melanson 2006); may alter the flare response in intradermal allergen tests (Melanson 2006)

Adverse Reactions

Frequency not defined.

Cardiovascular: Bradycardia, ECG changes (nonspecific QT changes) hypertension, hypotension, local thrombophlebitis, localized phlebitis, orthostatic hypotension, tachycardia, vasospasm (distal to injection site), venous thrombosis (local)

Central nervous system: Agitation, akathisia, ataxia, catatonia, confusion, delirium, disorientation, dizziness, drowsiness, dystonia, euphoria, excitement, extrapyramidal reaction, fatigue, hallucination, hysteria, insomnia, lassitude, paralysis (local), Parkinsonian-like syndrome, tardive dyskinesia, nervousness, neuroleptic malignant syndrome, nightmares, sedation, seizure, sensory disturbance (local sensory loss)

Dermatologic: Dermatitis, gangrene of skin or other tissue (local), skin photosensitivity, skin pigmentation (slate gray), urticaria

Endocrine & metabolic: Amenorrhea, gynecomastia, hyperglycemia

Gastrointestinal: Constipation, nausea, vomiting, xerostomia

Genitourinary: Breast engorgement, ejaculatory disorder, impotence, lactation, urinary retention

Hematologic & oncologic: Agranulocytosis, immune thrombocytopenia, leukopenia, thrombocytopenia

Hepatic: Jaundice

Hypersensitivity: Angioedema

Local: Abscess at injection site, injection site reaction (burning sensation at injection site, edema at injection site, erythema at injection site, pain at injection site), local tissue necrosis

Neuromuscular & skeletal: Tremor

Ophthalmic: Blurred vision, corneal changes, diplopia, epithelial keratopathy, lens disease (changes), retinitis pigmentosa

Otic: Tinnitus

Respiratory: Apnea, asthma, nasal congestion, respiratory depression

ALERT: U.S. Boxed Warning

Respiratory depression - Pediatrics:

Promethazine should not be used in pediatric patients younger than 2 years because of the potential for fatal respiratory depression.

Postmarketing cases of respiratory depression, including fatalities, have been reported with the use of promethazine in pediatric patients younger than 2 years. A wide range of weight-based doses of promethazine have resulted in respiratory depression in these patients.

Exercise caution when administering promethazine to pediatric patients 2 years and older. It is recommended that the lowest effective dose of promethazine be used in pediatric patients 2 years and older and that coadministration with other drugs with respiratory-depressant effects be avoided.

Severe tissue injury, including gangrene (injection):

Promethazine can cause severe chemical irritation and damage to tissues regardless of the route of administration. Irritation and damage can result from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration. Adverse reactions include burning, pain, thrombophlebitis, tissue necrosis, and gangrene. In some cases, surgical intervention, including fasciotomy, skin graft, and/or amputation have been required.

Due to the risks of intravenous (IV) injection, the preferred route of administration of promethazine is deep intramuscular (IM) injection. Subcutaneous injection is contraindicated.

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: May alter cardiac conduction (life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines).

• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, pyloroduodenal obstruction, urinary retention, bladder neck obstruction, BPH, xerostomia, or visual problems.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• 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.

• Serious tissue injury: [US 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, 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 (IM) 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. Vesicant; for IV administration (not the preferred route of administration), ensure proper needle or catheter placement prior to and during administration; avoid extravasation.

• 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 cardiovascular disease.

• Glaucoma: Use with caution in patients with narrow-angle glaucoma; condition may be exacerbated by cholinergic blockade.

• Hepatic impairment: Use with caution in patients with hepatic impairment; cholestatic jaundice has been reported with use. Avoid use in pediatric patients with signs and symptoms of hepatic disease (extrapyramidal symptoms caused by promethazine may be confused with CNS signs of hepatic disease).

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; condition may be exacerbated by cholinergic blockade.

• Parkinson disease: Use with caution in patients with Parkinson disease; may have increased risk of tardive dyskinesia.

• Respiratory disease: Avoid use in patients with compromised respiratory function or in patients at risk for respiratory failure (eg, 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:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: [US Boxed Warning]: Respiratory depression, including 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. Antiemetics are not recommended for the treatment of uncomplicated vomiting in pediatric patients; limit use to prolonged vomiting of known etiology. Avoid use in children who may have Reye syndrome or hepatic disease as adverse reactions caused by promethazine may be confused with signs of primary disease.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP 1997; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

• Sodium metabisulfite: Injection may contain sodium metabisulfite; may cause allergic reaction.

Monitoring Parameters

Relief of symptoms, mental status, and CNS effects (including sedation, akathisia, delirium, extrapyramidal symptoms); signs and symptoms of tissue injury (burning or pain at injection site, phlebitis, edema) with IV administration

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects have not been observed in animal reproduction studies. Promethazine crosses the placenta (Potts 1961). Platelet aggregation may be inhibited in newborns following maternal use of promethazine within 2 weeks of delivery. Promethazine is approved for use as an antiemetic; however, other agents are recommended as initial therapy for the treatment of nausea and vomiting of pregnancy (ACOG 2015). Promethazine is indicated for use during labor for obstetric sedation and may be used alone or as an adjunct to opioid analgesics. Although promethazine is approved for the treatment of allergic conditions (eg, allergic rhinitis, urticaria), other agents are preferred for use in pregnant women (Scadding 2008; Wallace 2008; Zuberbier 2014).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, blurred vision, dry mouth, nausea, vomiting, or insomnia. Have patient report immediately to prescriber signs of infection, bradycardia, tachycardia, abnormal movements, twitching, change in balance, dysphagia, difficulty speaking, severe dizziness, passing out, severe headache, tremors, difficulty moving, rigidity, loss of strength and energy, illogical thinking, hallucinations, mood changes, severe anxiety, tinnitus, seizures, bruising, bleeding, jaundice, vision changes, difficulty breathing, slow breathing, shallow breathing, signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, very bad headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot), or severe injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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