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Promethazine and Codeine

Pronunciation

(proe METH a zeen & KOE deen)

Index Terms

  • Codeine and Promethazine
  • Promethazine HCl/Codeine
  • Promethazine/Codeine

Dosage Forms

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

Syrup, oral: Promethazine hydrochloride 6.25 mg and codeine phosphate 10 mg per 5 mL (5 mL, 118 mL, 473 mL)

Pharmacologic Category

  • Analgesic, Opioid
  • Antitussive
  • Histamine H1 Antagonist
  • Histamine H1 Antagonist, First Generation
  • Phenothiazine Derivative

Pharmacology

Codeine: Binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough suppression by direct central action in the medulla; produces generalized CNS depression.

Promethazine: 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.

Use: Labeled Indications

Cough and upper respiratory symptoms: Temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold.

Contraindications

Hypersensitivity to promethazine, codeine, other phenothiazines, or any component of the formulation; pediatric patients <12 years; postoperative management in pediatric patients <18 years of age who have undergone tonsillectomy and/or adenoidectomy; treatment of lower respiratory tract symptoms, including asthma; comatose states.

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Cough and upper respiratory symptoms: Oral: 5 mL (promethazine 6.25 mg/codeine 10 mg) every 4 to 6 hours (maximum: 30 mL [promethazine 37.5 mg/codeine 60 mg] per 24 hours)

Dosing: Geriatric

Refer to adult dosing. Use with caution; consider using decreased dose.

Dosing: Pediatric

Cough and upper respiratory symptoms: Oral: Children ≥12 years and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

There are no specific dosage adjustments provided in the manufacturer's labeling. Use with caution; reduce initial dose in significant renal impairment.

Dosing: Hepatic Impairment

Adults: There are no dosage adjustments provided in the manufacturer’s labeling. Cholestatic jaundice has been reported with promethazine use and codeine clearance may be reduced. Use with caution; reduce initial dose in significant hepatic impairment.

Children ≥6 years and Adolescents: Avoid use in pediatric patients with signs and symptoms of hepatic disease.

Administration

Administer with an accurate measuring device; do not use a household teaspoon (overdosage may occur).

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). 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: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

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

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Alvimopan: Opioid Analgesics may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification

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

Amifampridine: May diminish the anticholinergic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Amifampridine. Monitor therapy

Amphetamines: May enhance the analgesic effect of Opioid Analgesics. Monitor therapy

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

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Analgesics. Specifically, the risk for constipation and urinary retention may be increased with this combination. 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, rasagiline, or safinamide is combined with a serotonin modulator. Use of transdermal selegiline with serotonin modulators is contraindicated. Consider therapy modification

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). 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

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

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 CNS depressant effect of Opioid Analgesics. 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

Cobicistat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

CYP2D6 Inhibitors (Strong): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Consider therapy modification

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

Darunavir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Desmopressin: Opioid Analgesics may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

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

Diuretics: Opioid Analgesics may enhance the adverse/toxic effect of Diuretics. Opioid Analgesics may diminish the therapeutic effect of Diuretics. 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: Opioid Analgesics may enhance the constipating effect of Eluxadoline. Avoid combination

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

Gastrointestinal Agents (Prokinetic): Opioid Analgesics 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. Monitor therapy

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

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

Imatinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). 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

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

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

Methylphenidate: May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Monitor therapy

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

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

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

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Codeine. Monitor therapy

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

Nalmefene: May diminish the therapeutic effect of Opioid Analgesics. Management: Avoid the concomitant use of nalmefene and opioid analgesics. Discontinue nalmefene 1 week prior to any anticipated use of opioid analgesics. If combined, larger doses of opioid analgesics will likely be required. Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Analgesics. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

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. Monitor therapy

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

Opioid Analgesics: CNS Depressants may enhance the CNS depressant effect of Opioid Analgesics. 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

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Analgesics. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination

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

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

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. 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 (High risk with Inhibitors). 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 (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Pegvisomant: Opioid Analgesics may diminish the therapeutic effect of Pegvisomant. 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 (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. 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

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. 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

QuiNINE: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

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

Ramosetron: Opioid Analgesics 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 concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of 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

Serotonin Modulators: Opioid Analgesics may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. 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

Somatostatin Analogs: May decrease the metabolism of Codeine. The formation of two major codeine metabolites (morphine and norcodeine) may be impaired by somatostatin analogs. Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Analgesics. Monitor therapy

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

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

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

Refer to individual agents.

Adverse Reactions

Also see individual agents.

Limited to important or life-threatening: Hypogonadism (Brennan 2013; Debono 2011)

ALERT: U.S. Boxed Warning

Respiratory depression in children:

Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine.

Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children:

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Promethazine/codeine is contraindicated in pediatric patients <12 years of age and pediatric patients <18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of promethazine/codeine in pediatric patients 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Risks from concomitant use with benzodiazepines or other CNS depressants

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

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, urinary retention, 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, driving).

• Constipation: May cause constipation, which may be problematic in patients with unstable angina and patients post-myocardial infarction.

• Extrapyramidal symptoms: May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs that may exaggerate hypotensive effects (including general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Use with caution in patients with circulatory shock.

• Neuroleptic malignant syndrome (NMS): Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity and/or autonomic instability.

• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).

• Photosensitivity: May cause photosensitivity; avoid prolonged sun exposure.

• Respiratory depression: Serious, life-threatening, or fatal respiratory depression may occur with codeine. Monitor closely for respiratory depression, especially during initiation. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

• 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:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions. Use with caution and with a reduced initial dose.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency; reduce initial dose in patients with Addison disease.

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause constriction of sphincter of Oddi.

• 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.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Fever: Use with caution in patients with fever; reduce initial dose.

• GI disease: Use with caution in patients with pyloroduodenal obstruction (including stenotic peptic ulcer).

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

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur.

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

• Inflammatory bowel disease: Use with caution in patients with inflammatory bowel disease; reduce initial dose in patients with ulcerative colitis.

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

• Obesity: Use with caution in patients who are morbidly obese.

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

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture. Reduce initial dose in patients with prostatic hypertrophy.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with renal impairment. Reduce initial dose in patients with significant renal impairment.

• Respiratory disease: Avoid use in patients with severe respiratory disease (COPD, sleep apnea) or at risk for respiratory depression (conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression); critical respiratory depression may occur, even at therapeutic dosages. Use contraindicated in patients with asthma.

• 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 that may lower seizure threshold; reduce initial dose in patients with convulsive disorders.

• Thyroid disease: Use with caution in patients with thyroid dysfunction; reduce initial dose.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

• CYP 3A4 interactions: The effects of concomitant use or discontinuation of CYP-450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of CYP-450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine requires careful consideration of the effects on the parent drug, codeine, and the active metabolite morphine.

• 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:

• CYP2D6 “ultrarapid metabolizers”: Use caution in patients with two or more copies of the variant CYP2D6*2 allele; may have extensive conversion to morphine and thus increased opioid-mediated effects. Avoid the use of codeine in these patients; consider alternative analgesics such as morphine or a nonopioid agent (Crews, 2012). The occurrence of this phenotype is seen in 0.5% to 1% of Chinese and Japanese, 0.5% to 1% of Hispanics, 1% to 10% of Caucasians, 3% of African-Americans, and 16% to 28% of North Africans, Ethiopians, and Arabs.

• Cachectic or debilitated patients: Use with caution cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Reduce initial dose in debilitated patients.

• Elderly: Use with caution in the elderly, may be more sensitive to adverse effects; reduce initial dose.

• Pediatric: [US Boxed Warning]: Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine. Hallucinations and convulsions have occurred with therapeutic doses and overdoses of promethazine in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias. Avoid use in children who may have Reye syndrome or hepatic disease. Use caution in atopic children. [US Boxed Warning]: Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Promethazine/codeine is contraindicated in pediatric patients <12 years of age and in pediatric patients <18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of promethazine/codeine in pediatric patients 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. Deaths have also occurred in breastfeeding infants after being exposed to high concentrations of morphine because the mothers were ultra-rapid metabolizers.

• Surgery: Reduce initial dosage and use with caution in patients with recent GI or urinary tract surgery.

Dosage forms 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 ["Inactive" 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.

Other warnings/precautions:

• Abuse/misuse/diversion: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists.

• Administration: Use an accurate measuring device; a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions.

• Appropriate use: Underlying cause of cough should be determined prior to prescribing. Use the lowest effective dose for the shortest period of time. Avoid use in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's respiratory function. Dose should not be increased if cough does not respond; reevaluate within 5 days for possible underlying pathology.

Monitoring Parameters

Relief of symptoms; respiratory and mental status; blood pressure; heart rate; signs of misuse, abuse, and addiction.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. See individual agents.

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 anxiety, flushing, sweating a lot, dry mouth, nausea, or vomiting. Have patient report immediately to prescriber signs of infection, dizziness, passing out, difficulty breathing, slow breathing, shallow breathing, noisy breathing, severe fatigue, severe headache, confusion, tachycardia, bradycardia, abnormal heartbeat, severe constipation, severe abdominal pain, difficult urination, severe loss of strength and energy, jaundice, abnormal movements, twitching, change in balance, difficulty swallowing, difficulty speaking, hallucinations, mood changes, agitation, tinnitus, seizures, bruising, bleeding, vision changes, or signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, tachycardia, abnormal heartbeat, or sweating a lot) (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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