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Promethazine

Class: First Generation Antihistamines
VA Class: CN309
CAS Number: 58-33-3
Brands: Phenadoz, Phenergan, Promethegan

Medically reviewed by Drugs.com on Sep 14, 2021. Written by ASHP.

Warning

    Children <2 Years of Age
  • Promethazine is contraindicated in pediatric patients <2 years of age, because of risk of developing potentially fatal respiratory depression.

    Respiratory Depression in Children <2 Years of Age
  • Postmarketing reports of respiratory depression, including fatalities, in pediatric patients <2 years of age receiving a wide range of weight-adjusted doses.

    Children ≥2 Years of Age
  • Administer with caution.

  • Use the lowest effective dose.

  • Avoid concomitant use with other respiratory depressant drugs.

    Warnings Regarding Parenteral Administration
  • Because of risk of severe tissue injury, including gangrene requiring amputation, following IV administration of promethazine, FDA states that the preferred route of administration is deep IM injection.

    Perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration of promethazine may result in irritation and tissue damage. Healthcare professionals should be alert for signs and symptoms of potential tissue injury, including burning or pain at the site of injection, phlebitis, swelling, and blistering. (See IV Administration under Dosage and Administration and see Precautions Associated with Parenteral Administration under Cautions.)

  • FDA has notified healthcare professionals that a Boxed Warning describing these risks is being added to the prescribing information for promethazine hydrochloride.

Introduction

An ethylamino derivative of phenothiazine with potent first generation antihistaminic properties.

Uses for Promethazine

Nasal Allergies and the Common Cold

Management of seasonal allergic rhinitis (e.g., hay fever) and perennial (nonseasonal) allergic rhinitis.

Management of seasonal nonallergic (vasomotor) rhinitis.

Symptomatic relief of rhinorrhea and sneezing associated with the common cold.

Other Allergic Conditions

Adjunct to epinephrine and other standard measures in the treatment of anaphylactic reactions after the acute manifestations have been controlled.

Used IM for management of other uncomplicated allergic reactions of the immediate type when oral therapy is impossible or contraindicated.

Prevention and treatment of mild, uncomplicated skin manifestations of urticaria and angioedema.

Management of allergic conjunctivitis caused by foods or inhaled allergens.

Treatment of mild transfusion reactions not caused by ABO incompatibility or pyrogens.

Treatment of dermatographism.

Sedation

Treatment to produce sedation in surgery and obstetrics (during labor); reduces preoperative tension and anxiety, facilitates sleep.

Routine sedation.

Pain

Adjunct to analgesics (e.g., opiates) for management of pain (e.g., postoperative).

Used IV as adjunct to analgesics (e.g., opiates) and anesthesia during surgery (e.g., bronchoscopy, ophthalmic surgery) and in poor-risk patients.

Motion Sickness

Prevention and treatment of nausea, vomiting, and/or vertigo associated with motion sickness.

Nausea and Vomiting

Prevention and management of nausea and vomiting of various etiologies (e.g., anesthesia, surgery, postoperative).

Hemolytic Disease of the Newborn†

May ameliorate hemolytic disease of the newborn (erythroblastosis fetalis) when administered during pregnancy in Rh-sensitized women.

Promethazine Dosage and Administration

Administration

Administer orally, rectally, or by deep IM injection. Also administered by IV injection. However, FDA states that deep IM injection is the preferred method for administration of promethazine hydrochloride injection because of risks associated with IV administration (see Warnings Regarding Parenteral Administration under Boxed Warning).

FDA states that sub-Q or intra-arterial injection is contraindicated. In addition, some medication safety experts (e.g., the Institute for Safe Medication Practices [ISMP]) recommend avoiding parenteral administration of promethazine hydrochloride and use of safer alternative therapies (e.g., a 5-HT3 receptor antagonist such as ondansetron). (See Precautions Associated with Parenteral Administration under Cautions.)

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

If IV administration is required, administer through tubing of an IV infusion set that is known to be correctly functioning.

If patient complains of pain at the injection site during presumed IV injection, immediately discontinue injection and evaluate the possibility of intra-arterial placement of the needle or perivascular extravasation.

Promethazine hydrochloride injection is commercially available in 2 strengths: 25 mg/mL and 50 mg/mL. FDA states that the preparation containing 50 mg/mL is for IM injection only; the preparation containing 25 mg/mL may be administered by IM or IV injection.

Maximum concentration of the injection is 25 mg/mL.

Rate of Administration

Maximum rate of IV administration is 25 mg/minute. (See Cardiovascular Effects under Cautions.)

Dosage

Dosages of promethazine hydrochloride by the various routes of administration are identical.

Parenteral and rectal routes are used when oral administration is not feasible; institute oral therapy as soon as possible.

When used for management of common cold, administer only for short-term due to toxic potential of long-term therapy.

When used for allergic conditions, administer at bedtime because of pronounced sedative effects; adjust dosage to the smallest amount adequate to relieve symptoms.

Pediatric Patients

Common Cold
Oral

Children 2 to <6 years of age (as directed by a clinician): 1.56 mg every 4–6 hours. (See Pediatric Use under Cautions.)

Children 6 to <12 years of age: 3.125 mg every 4–6 hours.

Children ≥12 years of age: 6.25 mg every 4–6 hours.

Allergic Conditions
Oral

Children ≥2 years of age: up to 25 mg at bedtime or up to 12.5 mg 3 times daily (should be adjusted to age and weight). Alternatively, 0.5 mg/kg at bedtime or 0.125 mg/kg as needed.

Rectal , IM, or IV

May be administered rectally, by deep IM, or IV in dosages identical to oral dosages.

Sedation
Preoperative or Postoperative Sedation
Oral, Rectal, IM, or IV

Children ≥2 years of age: 12.5–25 mg or 0.5–1.1 mg/kg.

Routine Sedation
Oral or Rectal

Children ≥2 years of age: 12.5–25 mg or 0.5–1.1 mg/kg.

Pain
Adjunct to Analgesics
Oral, Rectal, IM, or IV

Children ≥2 years of age: 12.5–25 mg or 0.5–1.1 mg/kg; reduce analgesic dosage accordingly.

Motion Sickness
Oral or Rectal

Children ≥2 years of age: 12.5–25 mg or 0.5 mg/kg administered at least 30–60 minutes prior to departure. Administer a second dose 8–12 hours later if necessary; additional doses may be given on arising in the morning and before the evening meal for the duration of the journey.

Nausea and Vomiting
Oral or Rectal

Children ≥2 years of age: Usually, 1.1 mg/kg; should be adjusted to age, weight, and severity of condition. Alternatively, 0.25–0.5 mg/kg or 7.5–15 mg/m2 4–6 times daily.

IM or IV

Children ≥2 years of age: 0.25–0.5 mg/kg or 7.5–15 mg/m2 4–6 times daily.

Adults

Common Cold
Oral

6.25 mg every 4–6 hours.

Allergic Conditions
Oral

25 mg before retiring. Alternatively, 12.5 mg administered before meals and on retiring.

Rectal, IM, or IV

25 mg; dose may be repeated within 2 hours if necessary.

Transfusion Reactions

25 mg administered prior to or during a blood transfusion.

Sedation
Preoperative or Postoperative Sedation
Oral or Rectal

For preoperative sedation, a 50-mg dose may be administered the night before surgery and 50 mg usually is given before surgery.

For postoperative sedation, 25–50 mg is used.

IM or IV

25–50 mg.

Routine Sedation
Oral, Rectal, IM, or IV

25–50 mg.

Sedation in Obstetric Patients
IM or IV

50 mg administered during the early stage of labor. When labor is established, 25–75 mg is given with a reduced dose of an opiate agonist. 25–50 mg doses may be repeated once or twice at 4-hour intervals if necessary.

Pain
Adjunct to Analgesics
Oral, Rectal, IM or IV

25–50 mg; reduce analgesic dosage accordingly.

Motion Sickness
Oral

25 mg administered at least 30–60 minutes prior to departure. Administer 25 mg 8–12 hours later if necessary; additional doses may be given on arising in the morning and before the evening meal for the duration of the journey.

Nausea and Vomiting
Oral, Rectal, IM, or IV

12.5–25 mg; administer additional doses of 12.5–25 mg every 4–6 hours if necessary; reduce dosage of analgesics and barbiturates accordingly.

Hemolytic Disease of the Newborn†
Oral

3.7–5 mg/kg daily (given to the nearest 25-mg multiple) has been given initially in 4 divided doses after the first trimester or the 16th week of gestation in Rh-sensitized pregnant women. In extremely severe cases, maintenance dosage as high as 6.5 mg/kg daily has been used.

Prescribing Limits

Pediatric Patients

Common Cold
Oral

Maximum 9.36 mg in 24 hours for children 2 to <6 years of age. (See Pediatric Use under Cautions.)

Maximum 18.75 mg in 24 hour for children 6 to <12 years of age.

Maximum 37.5 mg in 24 hours for children ≥12 years of age.

Adults

Common Cold
Oral

Maximum 37.5 mg in 24 hours.

Sedation
Sedation in Obstetric Patients
IM or IV

Maximum 100 mg during a 24-hour period of labor.

Special Populations

Geriatric Patients

Use caution in dosage selection. Parenteral dosage should be reduced.

Cautions for Promethazine

Contraindications

  • Pediatric patients <2 years of age. (See Boxed Warning.)

  • Concomitant administration of large doses of other CNS depressants. (See Specific Drugs and Laboratory Tests under Interactions.)

  • Comatose patients.

  • Known hypersensitivity or idiosyncrasy to promethazine or other phenothiazines.

  • Treatment of lower respiratory symptoms (e.g., asthma).

  • FDA states that sub-Q or intra-arterial injection is contraindicated. (See Precautions Associated with Parenteral Administration under Cautions.)

  • Some manufacturers state that promethazine also is contraindicated in patients with bone marrow depression, angle-closure glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, or bladder neck obstruction; others state that the drug may be used with caution in these patients.

Warnings/Precautions

Warnings

Nervous System Effects

Possible impairment of ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).

Possible extrapyramidal reactions with high doses.

Possible increased severity of seizures in epileptic patients; use with caution, if at all, in patients with seizure disorders.

Possible neuroleptic malignant syndrome (NMS), characterized by hyperpyrexia, muscle rigidity, altered mental status, evidence of autonomic instability (e.g., irregular pulse or BP, tachycardia, diaphoresis, cardiac dysrhythmias). Immediately discontinue therapy and initiate supportive and symptomatic therapy if NMS develops.

Respiratory Effects

Possible fatal respiratory depression.

Possible suppression of cough reflex.

Use with caution in patients who are having an asthmatic attack and in those with acute or chronic respiratory impairment (e.g., COPD), particularly children. (See Pediatric Use under Cautions.)

Use with caution, if at all, in patients with a history of sleep apnea.

Hematologic Effects

Possible leukopenia, agranulocytosis, and thrombocytopenic purpura.

Precautions Associated with Parenteral Administration

Severe chemical irritation and damage to tissues (e.g., burning, pain, erythema, swelling, severe spasm of distal vessels, thrombophlebitis, venous thrombosis, phlebitis, abscesses, tissue necrosis, gangrene) may occur with administration of the injection, regardless of the route of administration.

Because IV administration has been associated with severe tissue injury, including gangrene requiring amputation, FDA states that deep IM injection is the preferred method for administration.

Possible irritation and damage from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration.

Possible nerve damage (ranging from temporary sensory loss to palsies and paralysis). Injection near or into a nerve may result in permanent tissue damage. Surgical intervention (e.g., fasciotomy, skin graft, amputation) may be needed.

Possible severe chemical irritation following unintentional intra-arterial administration; may result in impairment of circulation and gangrene requiring amputation.

If IV administration is required, use extreme care when administering IV; avoid extravasation or unintentional intra-arterial injection. (See IV Administration under Dosage and Administration.)

Because of the risk of severe tissue injury and amputations because of inadvertent intra-arterial injection or extravasation, some medication safety experts (e.g., ISMP) recommend avoiding parenteral administration of promethazine hydrochloride and use of safer alternative therapies (e.g., a 5-HT3 receptor antagonist such as ondansetron).

FDA states that sub-Q or intra-arterial administration of promethazine hydrochloride is contraindicated. Intra-arterial administration may cause chemical irritation that may be severe and cause severe arteriospasm, possibly resulting in impairment of circulation and gangrene requiring amputation.

Because promethazine discolors blood on contact; aspiration of dark blood at the site of injection does not rule out the possibility of intra-arterial placement of the needle.

During IV administration, observe for signs and symptoms of potential tissue injury, including burning or pain at the site of injection, phlebitis, swelling, and blistering; inform patients that adverse effects may occur immediately (i.e., while receiving the injection) or may develop hours to days after an injection of promethazine.

Immediately stop injection if pain at the injection site occurs during presumed IV injection; evaluate the possibility of intra-arterial placement of the needle or perivascular extravasation.

Sympathetic block and administration of heparin may be used for acute management of extravasation or inadvertent intra-arterial injection.

Hepatic Effects

Possible obstructive jaundice; usually reversible following discontinuance of therapy.

Possible cholestatic jaundice.

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Possible photosensitivity; further therapy may be contraindicated if this effect develops.

Possible urticaria, dermatitis, dermatologic reactions, and angioedema.

Sulfite Sensitivity

Some commercially available formulations of promethazine injection may contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.

General Precautions

Cardiovascular Effects

Possible tachycardia, bradycardia, and faintness with parenteral use.

Rapid IV administration may produce a transient fall in BP; administer slowly.

Use with caution in patients with cardiovascular disease.

Possible increased BP; administer with extreme caution, if at all, to patients in hypertensive crisis.

Other Precautions

Shares the toxic potentials of antihistamines and phenothiazines; observe the usual precautions of these agents.

Use of Fixed Combination

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether promethazine is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Use of promethazine is contraindicated in pediatric patients <2 years of age, because of risk of developing potentially fatal respiratory depression. (See Boxed Warning.)

Excessively high dosages may cause sudden death in pediatric patients. Possible cardiac arrest, hallucinations, oversedation, agitation, dystonic reactions, apnea, dermatologic reactions, neuroleptic malignant syndrome, and seizures with therapeutic doses and overdosage.

Use with caution in pediatric patients ≥2 years of age.

Avoid concomitant use with other respiratory depressant drugs in children ≥2 years of age, because respiratory depression and death may occur.

In children ≥2 years of age, the drug may be used for prolonged vomiting of known etiology; use not recommended in children with vomiting of unknown etiology.

Possible increased susceptibility to dystonias in acutely ill or dehydrated children; use not recommended in these children.

Avoid use in children ≥2 years of age with signs and symptoms suggestive of Reye’s syndrome or other hepatic disease.

Use not recommended in children ≥2 years of age with asthma, liver disease, seizure disorder, or glaucoma, unless otherwise directed by a clinician.

Possible sleep apnea and sudden infant death syndrome (SIDS) in infants and young children. (See Respiratory Effects under Cautions.) Use with caution in children with a history of sleep apnea, those with a family history of SIDS, and those who are less prone than usual to spontaneous arousal from sleep.

Possible marked drowsiness that may be potentiated by other CNS depressants (e.g., sedatives, tranquilizers); use these drugs only under the direction of a clinician. (See Nervous System Effects under Cautions.)

Possible increased risk of CNS stimulant effects; close supervision recommended for children performing hazardous activities (e.g., bike riding).

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.

Increased risk of sedative effects and confusion. Select dosage with caution (usually starting at low end of dosage range) because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. Dosage of the injection should be reduced.

Close observation recommended.

Hepatic Impairment

Use with caution.

Common Adverse Effects

Pronounced sedative effects, drowsiness, confusion, disorientation.

Interactions for Promethazine

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Anticholinergic agents

Additive anticholinergic effects

Use with caution

CNS depressants

Additive effects

Either avoid concomitant use or reduce barbiturate dosage by ≥50% and narcotic dosage by 25–50% if administered concomitantly

Epinephrine

Reversal of vasopressor effect of epinephrine

Administer norepinephrine or phenylephrine if a vasopressor agent is required; epinephrine should not be used

Immunologic urinary pregnancy tests

Possible test interference: false-positive Gravindex test and false-negative Prepurex and Dap test

MAO inhibitors

Increased extrapyramidal effects

Promethazine Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract and from parenteral sites.

Onset

Onset of sedative effects occurs within 20 minutes following oral, rectal, or IM administration; following IV administration, sedative effects occur within 3–5 minutes.

Duration

Duration of sedative effects usually about 2–8 hours (depending on the dose and route of administration); effects may persist for 12 hours.

Distribution

Extent

Widely distributed in body tissues.

Compared with other organs, lower concentrations of the drug are found in the brain, but this concentration is higher than the plasma concentration.

Readily crosses the placenta.

It is not known if promethazine is distributed into milk.

Plasma Protein Binding

93% protein bound (determined by gas chromatography) and 76–80% bound (determined by high-performance liquid chromatography).

Elimination

Metabolism

Metabolized in the liver.

Elimination Route

Excreted slowly in urine (mainly) and feces, principally as inactive promethazine sulfoxide and glucuronides.

Half-life

9–16 hours (following IV use) and about 9.8 hours (following IM use).

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25°C. Protect from light.

Solution

Tight, light-resistant containers at 15–30°C. Protect from light. Avoid freezing.

Parenteral

Injection

Tight, light-resistant containers preferably at 20–25°C (may be exposed to 15–30°C).

Rectal

Suppositories

Well-closed containers at 2–8°C. Protect from light.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Dextrose–Ringer’s injection combinations

Dextrose–Ringer’s injection, lactated, combinations

Dextrose–saline combinations

Dextrose 2.5, 5, or 10% in water

Ionosol products

Ringer’s injection

Ringer’s injection, lactated

Sodium chloride 0.45 or 0.9%

Sodium lactate 1/6M

Drug Compatibility
Admixture CompatibilityHID

Compatible

Amikacin sulfate

Ascorbic acid injection

Hydromorphone HCl

Incompatible

Aminophylline

Chloramphenicol sodium succinate

Chlorothiazide sodium

Furosemide

Heparin sodium

Hydrocortisone sodium succinate

Methohexital sodium

Penicillin G sodium

Pentobarbital sodium

Phenobarbital sodium

Variable

Penicillin G potassium

Y-Site CompatibilityHID

Compatible

Amifostine

Aztreonam

Bivalirudin

Ceftaroline fosamil

Ciprofloxacin

Cisatracurium besylate

Cladribine

Dexmedetomidine HCI

Docetaxel

Etoposide phosphate

Fenoldopam mesylate

Filgrastim

Fluconazole

Fludarabine phosphate

Gemcitabine HCl

Granisetron HCl

Hetastarch in lactated electrolyte injection (Hextend)

Linezolid

Melphalan HCl

Ondansetron HCl

Oxaliplatin

Palonosetron HCl

Pemetrexed disodium

Remifentanil HCl

Sargramostim

Teniposide

Thiotepa

Vinorelbine tartrate

Incompatible

Aldesleukin

Allopurinol sodium

Amphotericin B cholesteryl sulfate complex

Cefotetan disodium

Doxorubicin HCl liposome injection

Foscarnet sodium

Piperacillin sodium–tazobactam sodium

Variable

Heparin sodium

Hydrocortisone sodium succinate

Potassium chloride

Actions

  • Blocks H1-receptor sites, but does not block release of histamine.

  • Produces either CNS stimulation or CNS depression (sedation); CNS depression is more common with therapeutic doses.

  • Exhibits antiemetic, anticholinergic, and local anesthetic effects; also exhibits antimotion sickness action.

  • Precise mechanism of the CNS effects unknown. Antimotion sickness action apparently related to central anticholinergic effects.

  • Slight antitussive activity may result from anticholinergic and CNS-depressant effects.

  • Inhibits collagen-induced platelet aggregation in neonates whose mothers had received the drug during labor.

  • Inhibits the ability of fetal macrophages to bind Rh-positive erythrocytes.

  • Inhibits phagocytosis and hexose monophosphate shunt activity in polymorphonuclear leukocytes.

  • Inhibits lysis of fetal Rh-positive erythrocytes mediated by lymphocytes and polymorphonuclear leukocytes.

  • Stabilizes the erythrocyte membrane against hemolysis.

Advice to Patients

  • Importance of informing parents and caregivers that promethazine should not be used in pediatric patients <2 years of age.

  • Importance of informing parents and caregivers to use the drug with caution and obtain a clinician's advice about administration of any promethazine dosage form in pediatric patients ≥2 years of age.

  • Risk of drowsiness; avoid alcohol and other CNS depressants and use caution when driving, operating machinery, or engaging in other hazardous tasks.

  • Importance of informing caregivers that pediatric patients performing hazardous activities (e.g., bike riding) should be closely supervised, because children may be at increased risk for experiencing CNS stimulant effects.

  • Importance of informing clinicians of any involuntary muscle movements or unusual sensitivity to sunlight.

  • Importance of avoiding prolonged exposure to sun.

  • Importance of promptly informing clinicians of any pain at the injection site during IV injection or other symptoms (e.g., erythema, swelling, blistering) occurring within days of IV injection.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Promethazine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

6.25 mg/5 mL*

Tablets

12.5 mg*

Phenergan (scored)

Wyeth

Promethazine Hydrochloride Tablets

25 mg*

Phenergan (scored)

Wyeth

Promethazine Hydrochloride Tablets

50 mg*

Phenergan

Wyeth

Promethazine Hydrochloride Tablets

Parenteral

Injection

25 mg/mL*

Promethazine Hydrochloride Injection

Injection, for IM use only

50 mg/mL*

Promethazine Hydrochloride Injection

Rectal

Suppositories

12.5 mg*

Phenadoz

Paddock

Phenergan

Wyeth

Promethazine Hydrochloride Suppositories

25 mg*

Phenadoz

Paddock

Phenergan

Wyeth

Promethazine Hydrochloride Suppositories

50 mg*

Phenergan

Wyeth

Promethazine Hydrochloride Suppositories

Promethegan

G&W

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Promethazine Hydrochloride Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

6.25 mg/5 mL with Phenylephrine Hydrochloride 5 mg/5 mL*

Prometh VC Syrup

Alpharma

AHFS DI Essentials™. © Copyright 2022, Selected Revisions September 24, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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