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.
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.
Note: IV and IM administration is generally avoided due to risk of severe tissue injury. When parenteral therapy is indicated, other parenteral antiemetics with less risk of tissue injury are preferred (Ref). Do not administer SUBQ, which can cause severe tissue necrosis.
Nausea and/or vomiting, acute:
Note: May use short-term (eg, up to 48 to 72 hours) for self-limiting nausea/vomiting (eg, postoperative rescue therapy, acute vertigo) (Ref).
Oral, rectal: 12.5 to 25 mg every 4 to 6 hours as needed. To avoid intolerable adverse effects, some experts recommend a maximum dose of 50 mg/day (Ref).
IM or IV (alternative routes): Note: IV and IM administration is generally avoided due to risk of severe tissue injury. When parenteral therapy is indicated, other parenteral antiemetics with less risk of tissue injury are preferred (Ref).
12.5 to 25 mg IM or IV every 4 to 6 hours as needed (Barrett 2011; Braude 2008; manufacturer's labeling); for postoperative rescue, may administer 6.25 mg IV as a single dose (Ref). To avoid intolerable adverse effects, some experts recommend a maximum dose of 50 mg/day (Ref).
Peripartum management, adjunct to opioids:
Note: Other parenteral antiemetics with less risk of tissue injury are preferred (Ref). May be used to potentiate opioid analgesia and decrease side effects (eg, nausea and vomiting) (Ref).
IM (preferred route), IV (alternative route): 25 mg once; may repeat every 4 hours for up to 2 additional doses.
Pregnancy-associated nausea and vomiting (off-label use):
Note: Safety: IV and IM administration is generally avoided due to risk of severe tissue injury. When parenteral therapy is indicated, other parenteral antiemetics with less risk of tissue injury are preferred (Ref). Use: May use as add-on therapy when symptoms persist following initial pharmacologic treatment (Ref).
Patients without hypovolemia : Oral, rectal, IM (alternative route): 12.5 to 25 mg every 4 to 6 hours as needed (Ref).
Patients with hypovolemia (alternative agent, alternative route):
Note: Consider for persistent nausea and vomiting in addition to treatment of hypovolemia (eg, IV fluids) (Ref).
IV: 12.5 to 25 mg every 4 to 6 hours (Ref).
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (only 0.6% of an administered dose excreted in the urine unchanged) (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (large Vd): No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: Unlikely to be dialyzed (large Vd): No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution (cholestatic jaundice has been reported with use).
(For additional information see "Promethazine: Pediatric drug information")
Note: Use with extreme caution and utilize the lowest effective dose to reduce the risk of adverse effects with all routes of administration. Use has generally been replaced by agents that are more effective with fewer adverse events. Due to risk of severe tissue injury, IV and IM administration is generally avoided.
Nausea and vomiting:
Note: Promethazine has been used as an antiemetic for various presenting conditions (eg, postoperative nausea/vomiting, chemotherapy-induced nausea/vomiting, cyclic vomiting syndrome, migraine). In most clinical situations, routine use has been replaced by alternate agents from other therapeutic classes; however, promethazine may be necessary in refractory situations or as rescue therapy; may consider concomitant diphenhydramine to decrease risk of dystonic adverse effects (Ref).
Children ≥2 years and Adolescents: Oral, IM, IV, rectal: Usual range: 0.25 to 0.5 mg/kg/dose every 4 to 6 hours as needed; doses up to 1.1 mg/kg/dose may be necessary in some patients; do not exceed usual adult dose of 6.25 to 25 mg/dose (Ref).
Preprocedure sedation, adjunct: Children ≥2 years and Adolescents: Oral, IM, IV: 0.5 to 1.1 mg/kg once 30 minutes prior to procedure as part of an appropriate combination regimen; maximum dose: 12.5 to 25 mg/dose; manufacturer recommends in combination with a reduced dose of opioid or barbiturate and an appropriate dosage of an atropine-like drug if appropriate; however, other combination regimens have been described (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥2 years and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling.
Children ≥ 2 years and Adolescents: The manufacturer recommends to 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).
Avoid use (Ref).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Injection, as hydrochloride:
Phenergan: 50 mg/mL (1 mL) [contains edetate (edta) disodium, phenol, sodium metabisulfite]
Phenergan: 25 mg/mL (1 mL) [pyrogen free; contains edetate (edta) 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 [DSC], 473 mL)
Suppository, Rectal, as hydrochloride:
Phenadoz: 12.5 mg (12 ea [DSC]); 25 mg (12 ea [DSC])
Promethegan: 12.5 mg (1 ea, 12 ea); 25 mg (12 ea); 50 mg (1 ea, 12 ea)
Generic: 12.5 mg (1 ea, 12 ea); 25 mg (1 ea, 12 ea); 50 mg (12 ea [DSC])
Syrup, Oral, as hydrochloride:
Generic: 6.25 mg/5 mL (473 mL)
Tablet, Oral, as hydrochloride:
Generic: 12.5 mg, 25 mg, 50 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Injection, as hydrochloride:
Generic: 25 mg/mL ([DSC])
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: The Institute for Safe Medication Practices does not recommend the use of injectable promethazine (any route) due to the risk of severe tissue damage (Ref). Do not administer SUBQ; may cause severe tissue necrosis.
IM: Administer as a deep IM injection.
IV: Due to risk of severe tissue damage, use a concentration ≤25 mg/mL and infuse at a maximum rate of 25 mg/minute. To minimize phlebitis, consider administering over 10 to 15 minutes, using a low initial dose, 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 (Ref).
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. Information conflicts regarding the use of dry warm or dry cold compresses (Ref).
Oral: 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; ISMP discourages use of injectable promethazine (any route) (Ref).
IM: Administer as a deep IM injection.
IV: IV use should be avoided when possible since severe tissue damage has occurred with IV administration. If used, promethazine should be administered diluted (eg, minibag or the 25 mg/mL preparation in at least 10 to 20 mL NS) and infused over 10 to 15 minutes or at a rate not to exceed 25 mg/minute; administer through a large bore vein (not hand or wrist) or via a running IV line at port farthest from patient's vein to reduce risk of phlebitis (Ref).
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. 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. Information varies regarding the use of dry warm or dry cold compresses (Ref).
Nausea and/or vomiting, acute: Prevention and control of nausea and/or vomiting.
Peripartum management, adjunct to opioids: May be used to potentiate opioid analgesia.
Pregnancy-associated nausea and vomiting
Promethazine may be confused with chlorproMAZINE, predniSONE
Phenergan may be confused with PHENobarbital, Phrenilin, Theragran
The Institute for Safe Medication Practices (ISMP) includes this medication (injectable formulation) among its list of drugs that have a heightened risk of causing significant patient harm when used. ISMP strongly discourages use of injectable promethazine (any route) and suggests facilities remove from all areas (including pharmacy) and not allow practitioners to order (ISMP 2020).
Beers Criteria: Promethazine, a first-generation antihistamine, is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to its potent anticholinergic properties resulting in increased risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity; use should also be avoided due to reduced clearance with advanced age and tolerance associated with use as a hypnotic (Beers Criteria [AGS 2019]).
Pharmacy Quality Alliance (PQA): Promethazine, as a single agent or as part of a combination, is identified as a high-risk medication in patients 65 years and older on the PQA's Use of High-Risk Medications in the Elderly (HRM) performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) for Medicare plans (PQA 2017).
KIDs List: Dopamine antagonists, when used in pediatric patients <18 years of age, are identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list; use should be avoided in infants and used with caution in children and adolescents due to risk of acute dystonia (dyskinesia), and with intravenous administration an increased risk of respiratory depression, extravasation, and death (strong recommendation; moderate quality of evidence) (PPA [Meyers 2020]).
Sominex: Brand name for promethazine in Great Britain, but also is a brand name for diphenhydrAMINE in the US
Phenothiazines, including promethazine, may cause anticholinergic adverse effects such as blurred vision, confusion, constipation, dry eye, urinary retention, and xerostomia. Promethazine is included in the Beers Criteria of Potentially Inappropriate Medication Use in Older Adults (Ref).
Mechanism: Dose-related; related to the pharmacologic action (ie, muscarinic receptor antagonism) (Ref).
Onset: Rapid; occurs within 1 to 2 hours of administration (Ref).
Risk factors:
• Age ≥65 years (Ref)
• Concurrent use of other anticholinergic agents (Ref)
Promethazine use has been associated with dizziness, drowsiness, delirium, motor dysfunction (motor sensory instability), and sedated state in adult (including pregnant women) (Ref) and pediatric patients (Ref). Promethazine is included in the Beers Criteria of Potentially Inappropriate Medication Use in Older Adults (Ref).
Onset: Rapid; may occur within 30 minutes of ingestion and up to 24 hours after cessation. A delay in cognitive reaction time may be observed within 1 hour of ingestion (Ref).
Risk factors:
• In overdose, ingestion of >250 mg increases risk for delirium (Ref)
• Pediatric patients and older adults (Ref)
• Concurrent use of other CNS depressants (eg, alcohol, opioids) (Ref)
Extrapyramidal reactions (EPS), including akathisia, acute dystonia, drug-induced parkinsonism, and tardive dyskinesia, have occurred with the use of promethazine and other dopamine receptor antagonist neuroleptic agents in adult and pediatric patients (Ref). Symptoms of EPS may be confused with other conditions, such as Reye syndrome or other encephalopathy. Acute akathisia is typically transient and resolves with drug discontinuation, but delayed akathisia may be permanent (Ref). Resolution of acute dystonia occurs quickly after drug discontinuation and with supportive care (Ref). Symptoms of drug-induced parkinsonism typically resolve within 7 months of drug discontinuation but may persist for 18 months or longer (Ref). The use of dopamine receptor antagonists, such as promethazine, may unmask undiagnosed idiopathic Parkinson disease (Ref). Tardive dyskinesia may be irreversible; earlier drug discontinuation increases the likelihood of symptom resolution (Ref).
Mechanism: Dose-related; related to the pharmacologic action (ie, dopamine D2 receptor antagonism leading to imbalance in dopamine and acetylcholine in the striatum) (Ref).
Onset:
• Akathisia: Rapid; usually occurs within the first 72 hours of therapy initiation (data with prochlorperazine) (Ref); however, delayed (tardive) akathisia may occur (Ref).
• Dystonia: Rapid; usually occurs within the first 5 days after therapy initiation or large dose increase (Ref).
• Drug-induced parkinsonism: Varied; onset may be delayed from days to weeks, with 50% to 75% of cases occurring within the first month and 90% within the first 3 months of therapy (Ref).
• Tardive dyskinesia: Delayed; symptoms usually occur after at least 3 months of therapy and may occur up to 3 months after therapy discontinuation (Ref).
Risk factors:
• Akathisia
- Age <18 years (increasing with decreasing age) (Ref)
- IV administration (data with prochlorperazine) (Ref)
- Pregnancy (Ref)
• Dystonia
- Age <19 years (increasing with decreasing age) (Ref)
- Males (Ref)
- Use of agents with high dopamine D2 receptor affinity (Ref)
- History of acute dystonia (Ref)
- Underweight or normal body weight (Ref)
- Cocaine use (Ref)
- Pediatric: Acute illness associated with dehydration
• Drug-induced parkinsonism
- Age >60 years (Ref)
- Females (Ref)
- Preexisting movement disorder (Ref)
- Cigarette smoking (Ref)
- Genetic variants (Ref)
• Tardive dyskinesia
- Higher cumulative doses (Ref)
- Longer durations of therapy (Ref)
- Age ≥65 years (Ref)
- Females (Ref)
- Diabetes (Ref)
Neuroleptic malignant syndrome (NMS) has been associated with the use of dopamine receptor antagonist neuroleptics, including promethazine. Recovery generally occurs after drug discontinuation and with supportive care; however, some cases have been fatal (Ref). Cases with promethazine have been reported following single doses, alone or in combination with other medications and has occurred in patients who have previously received promethazine without incident. Resolution onset has occurred 5 to 7 days after diagnosis (Ref).
Mechanism: Non–dose-related; idiosyncratic (Ref).
Onset: Rapid; has been reported within 1 to 2 days (Ref).
Risk factors:
- Higher doses (suggested risk factor, but development of NMS is not dose-dependent) (Ref)
- Rapid dose escalation (Ref)
- Concurrent use of dopamine antagonists may increase risk (Ref)
- Use of agents with high D2 receptor affinity (Ref)
- IV administration (Ref)
- Use of depot formulation (Ref)
- Genetic polymorphism (Ref)
- Catatonia may increase risk (Ref)
Phenothiazines, including promethazine, may cause orthostatic hypotension (Ref). Orthostatic hypotension may increase the risk for falls in older patients; this risk may be augmented by the sedative effects of promethazine.
Mechanism: Dose-related; related to the pharmacologic action (ie, alpha1-adrenergic receptor blockade and anticholinergic effects) (Ref).
Onset: Rapid; may occur immediately following IV infusion or following excessive doses (Ref).
Risk factors:
- Age ≥65 years
- Higher doses
- Parenteral administration
- Concurrent use of thiazide diuretics (Ref)
- Mitral insufficiency
- Pheochromocytoma
Rare but fatal respiratory depression in neonates and children may occur. An FDA black box warning exists for children <2 years of age; however, it may occur in adults, especially patients with compromised respiratory function (Ref).
Mechanism: Unknown; may be due to sedation secondary to H1 antagonism.
Onset: Rapid; can occur within minutes to hours (Ref).
Risk factors:
• Age <2 years
• Excessive doses (Ref)
• Concurrent use of medications that cause respiratory depression (Ref)
• Patients with compromised respiratory function (eg, COPD, sleep apnea)
Unintentional intraarterial administration and perivascular extravasation have been associated with local tissue necrosis and subsequent hand and digit amputation in case reports (Ref). ISMP discourages the use of injectable promethazine (any route) because of the risk of severe tissue damage (Ref).
Mechanism: Non–dose-related; the acidic pH (4 to 5.5) of promethazine induces cellular and tissue necrosis, leading to complications such as inflammation, vasoconstriction, and thrombosis (Ref).
Onset: Varied; pain during IV infusion can occur during administration. Skin discoloration and tissue necrosis have occurred immediately following injection and up to 2 weeks after administration (Ref).
Risk factors:
• Dehydration may make IV access challenging, increasing the risk for extravasation (Ref)
• Concentrations >25 mg/mL and rapid administration (<10 minutes) increase the risk for extravasation (Ref)
• Intraarterial administration increases the likelihood of necrosis and amputation (Ref)
• IV placement in small veins (eg, hand and wrist) increases the risk for inadvertent intraarterial administration (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined.
Cardiovascular: Bradycardia, decreased blood pressure, local thrombophlebitis (injection), localized phlebitis (injection), peripheral vasospasm (injection), venous thrombosis (injection)
Dermatologic: Dermatitis, skin photosensitivity, urticaria
Gastrointestinal: Nausea, vomiting
Hematologic & oncologic: Immune thrombocytopenia, leukopenia, thrombocytopenia
Hepatic: Cholestatic jaundice, jaundice
Hypersensitivity: Angioedema
Local: Abscess at injection site, erythema at injection site, swelling at injection site
Nervous system: Abnormal sensory symptoms (injection), ataxia, catatonia, disorientation, euphoria, excitement, fatigue, hysteria, insomnia, lassitude, nervousness, paralysis (injection), sedated state, seizure
Neuromuscular & skeletal: Tremor
Ophthalmic: Blurred vision, diplopia
Otic: Tinnitus
Respiratory: Apnea, asthma, nasal congestion
Postmarketing:
Cardiovascular: Increased blood pressure (Tsay 2015), orthostatic hypotension (Shi 2011), tachycardia (Tsay 2015)
Dermatological: Gangrene of skin and/or other subcutaneous tissues (injection) (Keene 2006)
Gastrointestinal: Xerostomia (Brown 1997)
Hematologic & oncologic: Agranulocytosis
Local: Burning sensation at injection site (Keene 2006), local tissue necrosis (injection) (Keene 2006), pain at injection site (Keene 2006)
Nervous system: Agitation (Tsay 2015), confusion (Tsay 2015), delirium (Page 2009), dizziness (Brown 1997), drowsiness (Naicker 2013), extrapyramidal reaction (Musco 2019), hallucination (Tsay 2015), hyperexcitability, motor dysfunction (Kavanagh 2012), neuroleptic malignant syndrome (Mendhekar 2005), nightmares, slurred speech (Tsay 2015)
Respiratory: Respiratory depression (Tsay 2015)
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
Concerns related to adverse effects:
• Altered cardiac conduction: May alter cardiac conduction (life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines).
• Photosensitivity: May cause photosensitivity; avoid prolonged sun exposure.
• 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.
• GI motility: Use with caution in patients with decreased GI motility or pyloroduodenal obstruction as anticholinergic effects may exacerbate underlying condition.
• 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.
• Ophthalmic conditions: Use with caution in patients with certain ophthalmic conditions (eg, narrow angle glaucoma, visual problems) as anticholinergic effects may exacerbate underlying condition.
• 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).
• 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.
• Urinary tract conditions: Use with caution in patients with urinary retention, benign prostatic hyperplasia (BPH), or bladder neck obstruction, as anticholinergic effects may exacerbate underlying condition.
Special populations:
• Pediatric: 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.
• Ethanol: Oral solution contains 7% ethyl alcohol.
• Sodium metabisulfite: Injection may contain sodium metabisulfite; may cause allergic reaction.
Substrate of CYP2B6 (minor), CYP2D6 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the adverse/toxic effect of Promethazine. Risk X: Avoid combination
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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 at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Risk X: Avoid combination
CloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
EPINEPHrine (Nasal): Promethazine may diminish the vasoconstricting effect of EPINEPHrine (Nasal). Risk C: Monitor therapy
EPINEPHrine (Oral Inhalation): Promethazine may diminish the therapeutic effect of EPINEPHrine (Oral Inhalation). Risk C: 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). Risk C: Monitor therapy
EPINEPHrine (Systemic): Promethazine may diminish the vasoconstricting effect of EPINEPHrine (Systemic). Management: Avoid epinephrine and consider norepinephrine or phenylephrine when treating hypotension due to promethazine overdose. Consider alternative vasocontrictors in patients treated with promethazine. This combination may be indicated in anaphylaxis treatment. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor therapy
Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Risk X: Avoid combination
Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Haloperidol: Promethazine may enhance the anticholinergic effect of Haloperidol. Promethazine may enhance the CNS depressant effect of Haloperidol. Promethazine may increase the serum concentration of Haloperidol. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Risk X: Avoid combination
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Promethazine. Risk X: Avoid combination
MetyroSINE: May enhance the adverse/toxic effect of Promethazine. Risk C: Monitor therapy
Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Risk C: 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. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pitolisant: Promethazine may diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: 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. Risk X: Avoid combination
Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Risk X: Avoid combination
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: 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. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Risk X: Avoid combination
Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Following use of promethazine, hCG-based pregnancy tests may result in false-negatives or false-positives.
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 indicated for use during labor for obstetric sedation and may be used alone or as an adjunct to opioid analgesics. Promethazine may be used as adjunctive therapy in the management of nausea and vomiting of pregnancy when the preferred agents do not provide initial symptom improvement or when symptoms persist despite other therapies (ACOG 189 2018). Although promethazine is approved for the treatment of allergic conditions (eg, allergic rhinitis, urticaria), other agents are preferred for use in pregnancy (BSACI [Powell 2015]; BSACI [Scadding 2017]; Zuberbier 2018).
It is not known if promethazine is present in breast milk.
Drowsiness and irritability have been reported in breastfed infants exposed to other antihistamines (Ito 1993). Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother. Single maternal doses of promethazine may be compatible with breastfeeding; repeated doses should be avoided (WHO 2002). In general, first generation antihistamines should be used with caution in breastfeeding women and breastfed infants should be monitored for irritability or drowsiness (Butler 2014; WHO 2002).
When treatment with an antihistamine is needed in breastfeeding women, second generation antihistamines are preferred (BSACI [Powell 2015]; Butler 2014; Zuberbier 2018).
Antihistamines may decrease maternal serum prolactin concentrations when administered prior to the establishment of lactation (Messinis 1985).
Increase dietary intake of riboflavin.
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 parenteral administration.
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
Onset of action: Oral, IM: ~20 minutes; IV: ~5 minutes
Duration: Usually 4 to 6 hours (up to 12 hours)
Absorption: Oral: Rapid and complete; large first pass effect limits systemic bioavailability (Sharma 2003)
Distribution: Vd: 13.4 ± 3.6 L/kg (Brunton 2011)
Protein binding: 93% (Brunton 2011)
Metabolism: Hepatic; hydroxylation via CYP2D6 and N-demethylation via CYP2B6; significant first-pass effect (Sharma 2003)
Bioavailability: Oral: ~25% (Sharma 2003); Rectal: 21.7% to 23.4% (Brunton 2011)
Half-life elimination: IM: ~10 hours; IV: 9 to 16 hours; Suppositories, syrup: 16 to 19 hours (range: 4 to 34 hours) (Strenkoski-Nix 2000)
Time to maximum serum concentration (Brunton 2011): Oral (syrup): 2.8 ± 1.4 hours; Rectal: 8.2 ± 3.4 hours
Excretion: Urine, feces as inactive metabolites
Solution (Phenergan Injection)
25 mg/mL (per mL): $4.04
50 mg/mL (per mL): $5.60
Solution (Promethazine HCl Injection)
25 mg/mL (per mL): $2.09 - $2.50
50 mg/mL (per mL): $3.02 - $4.62
Suppository (Promethazine HCl Rectal)
12.5 mg (per each): $17.71
25 mg (per each): $17.71
Suppository (Promethegan Rectal)
12.5 mg (per each): $17.71
25 mg (per each): $17.71
50 mg (per each): $35.77
Syrup (Promethazine HCl Oral)
6.25 mg/5 mL (per mL): $0.05 - $0.10
Tablets (Promethazine HCl Oral)
12.5 mg (per each): $0.49
25 mg (per each): $0.10 - $0.95
50 mg (per each): $0.42 - $0.78
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