Acetaminophen, isometheptene, and dichloralphenazone

Acetaminophen, isometheptene, and dichloralphenazone: Drug information
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(For additional information see “Acetaminophen, isometheptene, and dichloralphenazone: Patient drug information”)

Brand Names: U.S. Epidrin [DSC]; Midrin® [DSC]
Pharmacologic Category Analgesic, Miscellaneous; Sedative; Sympathomimetic
Dosing: Adult
Migraine headache: Oral: 2 capsules to start, followed by 1 capsule every hour until relief is obtained (maximum: 5 capsules/12 hours)

Tension headache: Oral: 1-2 capsules every 4 hours (maximum: 8 capsules/24 hours)

Dosing: Geriatric Refer to adult dosing.
Dosing: Hepatic Impairment 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.
Dosage Forms: U.S. Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule: Acetaminophen 325 mg, isometheptene mucate 65 mg, dichloralphenazone 100 mg [DSC]

Epidrin, Midrin®: Acetaminophen 325 mg, isometheptene mucate 65 mg, and dichloralphenazone 100 mg [DSC]

Generic Equivalent Available: U.S. Yes
Use Relief of migraine and tension headache
Medication Safety Issues
Sound-alike/look-alike issues:
Midrin® may be confused with midodrine, Mydfrin®

Other safety concerns:
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.

Adverse Reactions Significant Frequency not defined.
Central nervous system: Dizziness (transient)

Dermatological: Rash

Contraindications Hypersensitivity to acetaminophen, isometheptene, dichloralphenazone, or any component of the formulation; glaucoma; severe renal disease; hypertension; organic heart disease; hepatic disease; MAO inhibitor therapy
Warnings/Precautions
Concerns related to adverse events:

• Hepatotoxicity: May cause severe hepatotoxicity on acute overdose.

• Hypersensitivity/ anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported with acetaminophen use; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur.

Disease-related concerns:

• Cardiovascular disease: Use caution in patients with cardiovascular disease, including hypertension and peripheral vascular disease.

• G6PD deficiency: Use with caution in patients with known G6PD deficiency; rare reports of hemolysis have occurred with acetaminophen use.

• Hepatic impairment: Use with caution in patients with hepatic impairment or active liver disease.

Controlled Substance C-IV
Metabolism/Transport Effects Acetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)
Drug Interactions
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
Antacids: May decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Aluminum Hydroxide. 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

Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. 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

Beta-Blockers: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Risk D: Consider therapy modification

Bromocriptine: Alpha-/Beta-Agonists may enhance the adverse/toxic effect of Bromocriptine. Including increased blood pressure, ventricular arrhythmias, and seizure. Risk C: Monitor therapy

Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. 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

Carbonic Anhydrase Inhibitors: May decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Brinzolamide; Dorzolamide. 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

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Imatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

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

MAO Inhibitors: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Primarily with oral administration of phenylephrine. Risk D: Consider therapy modification

Metyrapone: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk C: Monitor therapy

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

Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Risk D: Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Risk D: Consider therapy modification

SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Spironolactone: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Risk C: Monitor therapy

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Risk D: Consider therapy modification

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: Excessive intake of ethanol may increase the risk of acetaminophen-induced hepatotoxicity. Avoid ethanol or limit to <3 drinks/day.
Pregnancy Implications Refer to Acetaminophen monograph.
Lactation Excretion in breast milk unknown/use caution
Breast-Feeding Considerations Acetaminophen and dichloralphenazone are excreted in breast milk; excretion of isometheptene is not known.
Pricing: U.S. (www.drugstore.com)
Capsules (Epidrin)

325-65-100 mg (100): $93.77

Capsules (Isometheptene-APAP-Dichloral)

65-325-100 mg (30): $42.99

Monitoring Parameters Relief of pain
Mechanism of Action
Acetaminophen: Although not fully elucidated, believed to inhibit the synthesis of prostaglandins in the central nervous system and work peripherally to block pain impulse generation; produces antipyresis from inhibition of hypothalamic health-regulating center

Dichloralphenazone: Prodrug, converted to chloral hydrate (sedative) and antipyrine (analgesic/antipyretic) that reduces patient’s emotional response to painful stimuli

Isometheptene: A sympathomimetic that reduces stimuli leading to vascular headaches via constriction of dilated cranial and cerebral arterioles

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