General Articles

Acetaminophen, codeine, and doxylamine

MEDICATION SAFETY ISSUES
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

PHARMACOLOGIC CATEGORY
Analgesic, Miscellaneous
Analgesic, Opioid
Antitussive
Histamine H1 Antagonist
Histamine H1 Antagonist, First Generation

DOSING: ADULTS — Oral: 1-2 tablets every 4 hours as needed; total dose should not exceed 12 tablets in a 24-hour period

DOSING: PEDIATRIC — Children >12 years: Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — No dosage adjustment required.

DOSING: HEPATIC IMPAIRMENT
Acetaminophen: Use with caution. Limited, low-dose therapy usually well tolerated in hepatic disease/cirrhosis. However, cases of hepatotoxicity at daily acetaminophen dosages <4 g/day have been reported. Avoid chronic use in hepatic impairment. Codeine: Dosage adjustment of codeine is probably necessary in hepatic insufficiency; no specific guidelines available. DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [CAN] = Canadian brand name Tablet:
Mersyndol® With Codeine [CAN]: Acetaminophen 325 mg, codeine 8 mg, and doxylamine 5 mg [not available in the U.S.]

DOSAGE FORMS: CONCISE — [CAN] = Canadian brand name

Tablet:
Mersyndol® With Codeine [CAN]: Acetaminophen 325 mg, codeine 8 mg, and doxylamine 5 mg [not available in the U.S.]

USE — Relief of headache, cold symptoms, neuralgia, and muscular aches/pain

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — Hypersensitivity to acetaminophen, codeine, doxylamine, or any component of the formulation; significant respiratory depression (in unmonitored settings); acute or severe bronchial asthma; hypercapnia

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Hepatotoxicity: Acetaminophen may cause severe hepatic toxicity on acute overdose; in addition, chronic daily dosing in adults has resulted in liver damage in some patients. Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).

Disease-related concerns: Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison’s disease. Cardiovascular disease: Use with caution in patients with cardiovascular disease (including hypertension/hypotension and tachycardia). CNS depression/coma: Use with caution in patients with CNS depression or coma. Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use. Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥ 3 alcoholic drinks/day may increase the risk of liver damage. G6PD deficiency: Use with caution in patients with known G6PD deficiency. Gastrointestinal motility disorders: Use with caution in patients with gastrointestinal motility disorders; avoid in paralytic ileus. Glaucoma: Use with caution in patients with angle-closure glaucoma and/or increased intraocular pressure. Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure; exaggerated elevation of ICP may occur. Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture. Pyloroduodenal obstruction: Use with caution in patients with pyloroduodenal obstruction (including stenotic peptic ulcer). Seizure disorder: Use with caution in patients with a history of seizure disorder. Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

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Concurrent drug therapy issues: Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations: Debilitated patients: Use with caution in debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Elderly: Use with caution in the elderly; may be more sensitive to adverse effects. Pediatrics: Safety and efficacy have not been established in children <12 years of age. Surgical patients: Use with caution in postoperative patients following thoracotomy or laparotomy due to suppression of cough. Other warnings/precautions: Dosage limit: Limit total acetaminophen dose to <4 g/day. RESTRICTIONS — CDSA-1; Not available in U.S. METABOLISM / TRANSPORT EFFECTS
Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

Codeine: Substrate of CYP2D6 (major), 3A4 (minor); Inhibits CYP2D6 (weak)

DRUG INTERACTIONS
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy

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

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Alvimopan: Analgesics (Opioid) 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. Risk D: Consider therapy modification

Ammonium Chloride: May increase the excretion of Analgesics (Opioid). Risk C: Monitor therapy

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Risk C: Monitor therapy

Amphetamines: May diminish the sedative effect of Antihistamines. Risk C: Monitor therapy

Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Paliperidone. Risk C: Monitor therapy

Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Betahistine: Antihistamines may diminish the therapeutic effect of Betahistine. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification

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

CYP2D6 Inhibitors (Moderate): May diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabo

lic conversion of codeine to its active metabolite morphine. Risk C: 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. Risk D: Consider therapy modification

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Imatinib: May increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy

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

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: Analgesics (Opioid) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Risk C: Monitor therapy

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

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Risk C: Monitor therapy

Thiazide Diuretics: Analgesics (Opioid) may enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS
Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: Avoid valerian, St John’s wort, kava kava, gotu kola (may increase CNS depression).

PREGNANCY IMPLICATIONS — There are no adequate and well-controlled studies in pregnant women. Should not be used in pregnancy unless the potential benefit to the mother justifies possible harm to the fetus. Refer to Codeine monograph.

LACTATION — No data available.

BREAST-FEEDING CONSIDERATIONS — Doxylamine may be excreted in breast milk, potentially resulting in sedative effects in nursing infants. Refer to Codeine monograph.

MONITORING PARAMETERS — Relief of pain, respiratory and mental status, blood pressure, bowel function

CANADIAN BRAND NAMES — Mersyndol® With Codeine

INTERNATIONAL BRAND NAMES — Mersyndol With Codeine (CA)

MECHANISM OF ACTION — Acetaminophen inhibits the synthesis of prostaglandins in the central nervous system and peripherally blocks pain impulse generation; produces antipyresis from inhibition of hypothalamic heat-regulating center. Codeine binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough supression by direct central action in the medulla; produces generalized CNS depression. Doxylamine competes with histamine for H1-receptor sites on effector cells; blocks chemoreceptor trigger zone, diminishes vestibular stimulation, and depresses labyrinthine function through its central anticholinergic activity.

PHARMACODYNAMICS / KINETICS — See individual agents.