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Acetaminophen, Isometheptene, and Dichloralphenazone

Medically reviewed by Drugs.com. Last updated on Jun 16, 2020.

Pronunciation

(a seet a MIN oh fen, eye soe me THEP teen, & dye KLOR al FEN a zone)

Index Terms

  • Acetaminophen, Dichloralphenazone, and Isometheptene
  • Dichloralphenazone, Acetaminophen, and Isometheptene
  • Dichloralphenazone, Isometheptene, and Acetaminophen
  • Isomethept/Dichlphn/Acetaminop
  • Isometheptene, Acetaminophen, and Dichloralphenazone
  • Isometheptene, Dichloralphenazone, and Acetaminophen
  • Isometheptene/Apap/Dichlphen
  • Midrin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Nodolor: Acetaminophen 325 mg, isometheptene mucate 65 mg, and dichloralphenazone 100 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Generic: Acetaminophen 325 mg, isometheptene mucate 65 mg, and dichloralphenazone 100 mg [DSC]

Brand Names: U.S.

  • Nodolor [DSC]

Pharmacologic Category

  • Analgesic, Nonopioid
  • Sedative
  • Sympathomimetic

Pharmacology

Acetaminophen: Although not fully elucidated, the analgesic effects are believed to be due to activation of descending serotonergic inhibitory pathways in the CNS. Interactions with other nociceptive systems may be involved as well (Smith 2009). Antipyresis is produced from inhibition of the hypothalamic heat-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

Use: Labeled Indications

Headache: Relief of tension headache and vascular headache (potentially effective for relief of migraine headache).

Contraindications

Hypersensitivity to isometheptene, dichloralphenazone, acetaminophen, or any component of the formulation; cardiovascular or cerebrovascular insufficiency (eg, recent MI, stroke); glaucoma; severe renal disease; hypertension; organic heart disease; peripheral vascular disease; hepatic disease; concomitant monoamine oxidase inhibitor (MAOI) therapy

Dosing: Adult

Migraine headache: Oral: Two capsules to start, followed by 1 capsule every hour until relief is obtained (maximum: 5 capsules/12 hours).

Tension headache: Oral: 1 to 2 capsules every 4 hours (maximum: 8 capsules/day).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer without regard to food.

Storage

Store at 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alcohol (Ethyl): May enhance the hepatotoxic effect of Acetaminophen. Monitor therapy

Alpha1-Blockers: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Similarly, Alpha-/Beta-Agonists may antagonize Alpha1-Blocker vasodilation. Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. 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. Exceptions: Amobarbital; Butabarbital; Butalbital; Methohexital; PENTobarbital; Secobarbital; Thiopental. Monitor therapy

Busulfan: Acetaminophen may increase the serum concentration of Busulfan. Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. 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. Monitor therapy

Chloroprocaine: May enhance the hypertensive effect of Alpha-/Beta-Agonists. Monitor therapy

Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Management: Avoid coadministration of acetaminophen and dasatinib if possible. If coadministration is unavoidable, monitor for signs/symptoms of hepatotoxicity, particularly in patients with greater acetaminophen exposure. Consider therapy modification

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Ergot Derivatives: May enhance the hypertensive effect of Alpha-/Beta-Agonists. Ergot Derivatives may enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Exceptions: Ergoloid Mesylates; Nicergoline. Avoid combination

Flucloxacillin: May enhance the adverse/toxic effect of Acetaminophen. Specifically, the risk for high anion gap metabolic acidosis may be increased. Monitor therapy

Fosphenytoin-Phenytoin: May decrease the serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Monitor therapy

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Monitor therapy

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Monitor therapy

Isoniazid: May enhance the hepatotoxic effect of Acetaminophen. Isoniazid may increase the metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Monitor therapy

LamoTRIgine: Acetaminophen may decrease the serum concentration of LamoTRIgine. Monitor therapy

Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Monitor therapy

Lorlatinib: May decrease the serum concentration of Acetaminophen. Monitor therapy

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. Monitor therapy

Mipomersen: Acetaminophen may enhance the hepatotoxic effect of Mipomersen. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Isometheptene. Avoid combination

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Management: Concomitant use of ozanimod with sympathomimetic agents is not recommended. If combined, monitor patients closely for the development of hypertension, including hypertensive crises. Consider therapy modification

Phenylephrine (Systemic): Acetaminophen may increase the serum concentration of Phenylephrine (Systemic). Monitor therapy

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. 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. Management: Consider limiting acetaminophen use in combination with probenecid. Probenecid may reduce clearance of acetaminophen to one of its non-toxic metabolities, increasing the risk for acetaminophen toxicity, even a lower doses. Consider therapy modification

Procarbazine: May enhance the adverse/toxic effect of Sympathomimetics. Management: Consider alternatives to this combination when possible. Procarbazine prescribing information states that this combination should be avoided. 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. Management: If possible, avoid coadministration of direct-acting alpha-/beta-agonists and serotonin/norepinephrine reuptake inhibitors. If coadministered, monitor for increased sympathomimetic effects (eg, increased blood pressure, chest pain, headache). Consider therapy modification

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Monitor therapy

SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Management: Avoid coadministration of acetaminophen and sorafenib if possible. If coadministration is unavoidable, monitor for signs/symptoms of hepatotoxicity, particularly in patients with greater acetaminophen exposure. Consider therapy modification

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

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

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha-/Beta-Agonists. Management: Avoid, if possible, the use of alpha-/beta-agonists in patients receiving tricyclic antidepressants. If combined, monitor for evidence of increased pressor effects and consider reductions in initial dosages of the alpha-/beta-agonist. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive days. Monitor therapy

Test Interactions

Acetaminophen may cause false urine glucose, urine catecholamine, and urinary 5-hydroxyindoleacetic acid test results.

Adverse Reactions

Frequency not defined.

Central nervous system: Dizziness (transient)

Dermatologic: Skin rash

ALERT: U.S. Boxed Warning

Hepatotoxicity:

This product contains acetaminophen. Severe liver damage may occur if a person takes: more than 4,000 mg of acetaminophen in 24 hours; with other drugs containing acetaminophen; with 3 or more alcoholic drinks every day while using this product.

Warnings/Precautions

Concerns related to adverse events:

• 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 or driving).

• Hepatotoxicity: [U.S. Boxed Warning]: Acetaminophen may cause severe hepatotoxicity, potentially requiring liver transplant or resulting in death; hepatotoxicity is usually associated with excessive acetaminophen intake (>4 g/day). Risk is increased with alcohol use (eg, ≥3 drinks per day), preexisting liver disease, and intake of more than one source of acetaminophen-containing medications. Chronic daily dosing in adults has also resulted in liver damage in some patients.

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

• Skin reactions: Rarely, acetaminophen may cause serious and potentially fatal skin reactions such as acute generalized exanthematous pustulosis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Discontinue treatment if severe skin reactions develop.

Disease-related concerns:

• Cardiovascular disease: Use is contraindicated in cardiovascular or cerebrovascular insufficiency (eg, recent MI, stroke), hypertension, organic heart disease, 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 is contraindicated in patients with hepatic disease.

• Renal impairment: Use is contraindicated in patients with severe renal disease.

Other warning/precautions:

• Dosage limit: Limit acetaminophen dose from all sources (prescription, OTC) ≤4 g/day (adults).

Monitoring Parameters

Relief of pain

Pregnancy Considerations

Refer to individual monographs.

Patient Education

What is this drug used for?

• It is used to treat headaches.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness

• Fatigue

• Nausea

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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