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Butalbital and Acetaminophen

Pronunciation

(byoo TAL bi tal & a seet a MIN oh fen)

Index Terms

  • Acetaminophen and Butalbital
  • Butalbital/Acetaminophen

Dosage Forms

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

Tablet, oral:

Allzital: Butalbital 25 mg and acetaminophen 325 mg

Bupap: Butalbital 50 mg and acetaminophen 300 mg

Bupap: Butalbital 50 mg and acetaminophen 650 mg [DSC]

Marten-Tab: Butalbital 50 mg and acetaminophen 325 mg

Orbivan CF: Butalbital 50 mg and acetaminophen 300 mg [DSC]

Promacet: Butalbital 50 mg and acetaminophen 650 mg [DSC]

Generic: Butalbital 50 mg and acetaminophen 325 mg

Capsule, oral:

Phrenilin Forte: Butalbital 50 mg and acetaminophen 650 mg [may contain benzyl alcohol] [DSC]

Brand Names: U.S.

  • Allzital
  • Bupap
  • Marten-Tab
  • Orviban CF [DSC]
  • Phrenilin Forte [DSC]
  • Promacet [DSC]

Pharmacologic Category

  • Analgesic, Nonopioid
  • Barbiturate

Pharmacology

Butalbital: Short- to intermediate-acting barbiturate; depresses the sensory cortex, decreases motor activity, alters cerebellar function, and produces drowsiness, sedation, hypnosis, and dose-dependent respiratory depression.

Acetaminophen: Inhibits the synthesis of prostaglandins in the central nervous system and peripherally blocks pain impulse generation.

Absorption

Butalbital: Well absorbed

Excretion

Butalbital: Urine (59% to 88% as unchanged drug or metabolites)

Half-Life Elimination

Butalbital: ~35 hours

Protein Binding

Butalbital: 45%

Use: Labeled Indications

Tension or muscle contraction headache: Relief of the symptomatic complex of tension or muscle contraction headache

Contraindications

Hypersensitivity to butalbital, acetaminophen, or any component of the formulation; porphyria

Dosing: Adult

Tension or muscle contraction headache: Oral:

Butalbital 25 mg/acetaminophen 325 mg: 2 tablets every 4 hours as needed (maximum: 12 tablets [butalbital 300 mg/acetaminophen 3,900 mg] per 24 hours).

Butalbital 50 mg/acetaminophen 300 to 325 mg: 1 or 2 tablets every 4 hours as needed (maximum: 6 tablets [butalbital 300 mg/acetaminophen 1,950 mg] per 24 hours).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Tension or muscle contraction headache: Children ≥12 years and Adolescents: Oral: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution in severe impairment.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution in severe impairment.

Storage

Store at 20ºC to 25ºC (68ºF to 77ºF). Protect from light and moisture.

Drug Interactions

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

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

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

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

Beta-Blockers: Barbiturates may decrease the serum concentration of Beta-Blockers. Exceptions: Atenolol; Levobunolol; Metipranolol; Nadolol. Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Blood Pressure Lowering Agents: Barbiturates may enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

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

Calcium Channel Blockers: Barbiturates may increase the metabolism of Calcium Channel Blockers. Management: Monitor for decreased therapeutic effects of calcium channel blockers with concomitant barbiturate therapy. Calcium channel blocker dose adjustments may be necessary. Nimodipine Canadian labeling contraindicates concomitant use with phenobarbital. Exceptions: Clevidipine. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. 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

Chloramphenicol: May decrease the metabolism of Barbiturates. Barbiturates may increase the metabolism of Chloramphenicol. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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

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

Contraceptives (Estrogens): Barbiturates may diminish the therapeutic effect of Contraceptives (Estrogens). Contraceptive failure is possible. Management: Use of a non-hormonal contraceptive is recommended. Consider therapy modification

Contraceptives (Progestins): Barbiturates may diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Consider therapy modification

CycloSPORINE (Systemic): Barbiturates may increase the metabolism of CycloSPORINE (Systemic). 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. Consider therapy modification

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

Doxycycline: Barbiturates may decrease the serum concentration of Doxycycline. Consider therapy modification

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. 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

Felbamate: May increase the serum concentration of Barbiturates. Barbiturates may decrease the serum concentration of Felbamate. Management: Monitor for elevated barbiturate concentrations/toxicity if felbamate is initiated/dose increased, or reduced concentrations/effects if felbamate is discontinued/dose decreased. Refer to phenobarbital dosing guidelines for patients receiving that agent. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

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

Griseofulvin: Barbiturates may decrease the serum concentration of Griseofulvin. Monitor therapy

Hemin: Barbiturates may diminish the therapeutic effect of Hemin. 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

HydrOXYzine: May enhance the CNS depressant effect of Barbiturates. Management: Consider a decrease in the barbiturate dose, as appropriate, when used together with hydroxyzine. With concurrent use, monitor patients closely for excessive response to the combination. Consider therapy modification

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

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

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

LamoTRIgine: Barbiturates may decrease the serum concentration of LamoTRIgine. Management: See lamotrigine prescribing information for specific age-dependent dosing guidelines regarding concurrent use with a barbiturate, as well as for adjusting lamotrigine dosing if concurrent barbiturate therapy is discontinued. Consider therapy modification

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

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

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. 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

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

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Mianserin: May enhance the CNS depressant effect of Barbiturates. Mianserin may diminish the therapeutic effect of Barbiturates. Barbiturates may decrease the serum concentration of Mianserin. Avoid combination

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

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

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Barbiturates. Monitor therapy

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

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

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

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

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

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

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. 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

Primidone: May enhance the adverse/toxic effect of Barbiturates. Primidone is converted to phenobarbital, and thus becomes additive with existing barbiturate therapy. 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. Consider therapy modification

Propacetamol: Barbiturates may increase the metabolism of Propacetamol. This may 1) diminish the desired effects of propacetamol; and 2) increase the risk of liver damage. Monitor therapy

Pyridoxine: May increase the metabolism of Barbiturates. Apparent in high pyridoxine doses (eg, 200 mg/day) Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Barbiturates. 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

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

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

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 Acetate: May enhance the adverse/toxic effect of Barbiturates. Specifically, Somatostatin Acetate may enhance or prolong Barbiturate effects, including sedative effects. Avoid combination

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

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

Teniposide: Barbiturates may decrease the serum concentration of Teniposide. Management: Consider alternatives to combined treatment with barbiturates and teniposide due to the potential for decreased teniposide concentrations. If the combination cannot be avoided, monitor teniposide response closely. Consider therapy modification

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

Theophylline Derivatives: Barbiturates may decrease the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Barbiturates may enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tricyclic Antidepressants: Barbiturates may increase the metabolism of Tricyclic Antidepressants. Consider therapy modification

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

Ulipristal: Barbiturates may decrease the serum concentration of Ulipristal. Avoid combination

Valproate Products: May increase the serum concentration of Barbiturates. Barbiturates may decrease the serum concentration of Valproate Products. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Barbiturates may increase the metabolism of Vitamin K Antagonists. Management: Monitor INR more closely. An anticoagulant dose increase may be needed after a barbiturate is initiated or given at an increased dose. Anticoagulant dose decreases may be needed following barbiturate discontinuation or dose reduction. Consider therapy modification

Voriconazole: Barbiturates may decrease the serum concentration of Voriconazole. 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

Acetaminophen may produce false-positive tests for urinary 5-hydroxyindoleacetic acid.

Adverse Reactions

Frequency not defined.

Cardiovascular: Tachycardia

Central nervous system: Agitation, confusion, depression, dizziness, drowsiness, euphoria, excitement, headache, increased energy, intoxicated feeling, lethargy, numbness, paresthesia, sedation, seizure, shakiness

Dermatologic: Hyperhidrosis, pruritus

Endocrine & metabolic: Hot flash

Gastrointestinal: Abdominal pain, constipation, dysphagia, flatulence, heartburn, nausea, vomiting, xerostomia

Genitourinary: Diuresis

Hypersensitivity: Hypersensitivity reaction

Neuromuscular & skeletal: Leg pain, muscle fatigue

Otic: Otalgia, tinnitus

Respiratory: Dyspnea, nasal congestion

Miscellaneous: Fever, heavy eyelids

<1% (Limited to important or life-threatening): Erythema multiforme, toxic epidermal necrolysis

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 mg per day, and often involve more than one acetaminophen-containing product.

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 that require mental alertness (eg, operating machinery, driving).

• Hepatotoxicity: [US 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, 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/anaphylactic reactions: 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:

• Abdominal conditions: Use with caution in patients with acute abdominal conditions.

• 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 per day may increase the risk of liver damage.

• G6PD deficiency: Use with caution in patients with known G6PD deficiency.

• Hepatic impairment: Use with caution in patients with severe hepatic impairment.

• Renal impairment: Use with caution in patients with severe renal impairment.

• Respiratory disease: Use with caution in patients with preexisting respiratory compromise (hypoxia and/or hypercapnia), chronic obstructive pulmonary disease (COPD) or other obstructive pulmonary disease, and kyphoscoliosis or other skeletal disorder which may alter respiratory function; critical respiratory depression may occur, even at therapeutic dosages.

Concurrent drug therapy issues:

• 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:

• 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.

Other warnings/precautions:

• Dosage limit: Limit acetaminophen dose from all sources (prescription and OTC) to <4 g/day.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. Withdrawal seizures were reported in an infant 2 days after birth following maternal use of a butalbital product during the last 2 months of pregnancy; butalbital was detected in the newborns serum. Also refer to acetaminophen monograph for information specific to acetaminophen.

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 fatigue, abdominal pain, vomiting, or nausea. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), change in balance, confusion, loss of strength and energy, severe dizziness, passing out, mood changes, burning or numbness feeling, seizures, shortness of breath, bruising, bleeding, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (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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