Butalbital, Acetaminophen, Caffeine, and Codeine

Dosage Forms

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

Capsule, Oral:

Fioricet/Codeine: Butalbital 50 mg, acetaminophen 300 mg, caffeine 40 mg, and codeine phosphate 30 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow #6 (sunset yellow)]

Generic: Butalbital 50 mg, acetaminophen 300 mg, caffeine 40 mg, and codeine phosphate 30 mg, Butalbital 50 mg, acetaminophen 325 mg, caffeine 40 mg, and codeine phosphate 30 mg

Pharmacology

Mechanism of Action

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.

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.

Caffeine: CNS stimulant; use with acetaminophen and dihydrocodeine increases the level of analgesia provided by each agent.

Codeine: Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression.

Use: Labeled Indications

Tension or muscle contraction headache: Management of the symptom complex of tension (muscle contraction) headache when nonopioid analgesic and alternative treatments are inadequate.

Limitations of use: Reserve for use in patients for whom alternative treatment options (eg, nonopioid, non-barbiturate analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

Contraindications

Known intolerance or hypersensitivity to butalbital, codeine, caffeine, acetaminophen, or any component of the formulation; pediatric patients <12 years; postoperative management in pediatric patients <18 years who have undergone tonsillectomy and/or adenoidectomy; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days; GI obstruction, including paralytic ileus (known or suspected); porphyria.

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.

Dosage and Administration

Dosing: Adult

Note: Limit butalbital use to ≤3 days per month to avoid medication overuse headache (Garza 2006); studies have found increased risk with use ≥5 days per month (Da Silva 2014).

Tension or muscle contraction headache: Oral:

Butalbital 50 mg/acetaminophen 300 mg/caffeine 40 mg/codeine 30 mg: 1 to 2 capsules every 4 hours as needed; maximum dose: 6 capsules (butalbital 300 mg/acetaminophen 1,800 mg/caffeine 240 mg/codeine 180 mg) per day.

Butalbital 50 mg/acetaminophen 325 mg/caffeine 40 mg/codeine 30 mg: 1 to 2 capsules every 4 hours as needed; maximum dose: 6 capsules (butalbital 300 mg/acetaminophen 1,950 mg/caffeine 240 mg/codeine 180 mg) per day.

Discontinuation of therapy: When discontinuing chronic opioid therapy, the dose should be gradually tapered down. An optimal universal tapering schedule for all patients has not been established (CDC [Dowell 2016]). Proposed schedules range from slow (eg, 10% reductions per week) to rapid (eg, 25% to 50% reduction every few days) (CDC 2015). Tapering schedules should be individualized to minimize opioid withdrawal while considering patient-specific goals and concerns as well as the pharmacokinetics of the opioid being tapered. An even slower taper may be appropriate in patients who have been receiving opioids for a long duration (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse events (CDC [Dowell 2016]). Monitor carefully for signs/symptoms of opioid withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt withdrawal symptoms (Berna 2015; CDC [Dowell 2016]). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Berna 2015; Sevarino 2018). For low butalbital doses or less frequent use, consider abrupt discontinuation of therapy or a gradual taper over 2 to 4 weeks. If use is frequent or at high doses or if a patient has developed chronic migraine, discontinuing the butalbital-containing product and replacing with a gradual (eg, over 2 to 4 weeks) phenobarbital taper is advised to avoid withdrawal symptoms (ie, worsened headache, nausea/vomiting, restlessness, anxiety, diaphoresis, disturbed sleep, seizures). Consider providing bridge therapy with a medication to treat acute headaches and optimizing a preventative regimen to avoid rebound headache (Boes 2006; Garza 2019).

Dosing: Geriatric

Avoid use (Beers Criteria [AGS 2019]).

Storage

Store below 30°C (86°F).

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

Acebrophylline: May enhance the stimulatory effect of CNS Stimulants. Avoid combination

Adenosine: Caffeine and Caffeine Containing Products may diminish the therapeutic effect of Adenosine. Management: Monitor for decreased effect of adenosine if patient is receiving caffeine. Discontinue caffeine in advance of scheduled diagnostic use of adenosine whenever possible. Consider therapy modification

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

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

Alvimopan: Opioid Agonists 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

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Monitor therapy

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

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

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

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

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

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

Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy

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

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

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

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

Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). 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 (Systemic): May decrease the metabolism of Barbiturates. Barbiturates may increase the metabolism of Chloramphenicol (Systemic). Consider therapy modification

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

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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

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

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

CYP1A2 Inducers (Moderate): May decrease the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

CYP1A2 Inhibitors (Moderate): May increase the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

CYP1A2 Inhibitors (Strong): May increase the serum concentration of Caffeine and Caffeine Containing Products. 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

CYP3A4 Inducers (Moderate): May decrease serum concentrations of the active metabolite(s) of Codeine. Monitor therapy

CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Codeine. Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of Codeine. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Codeine. Monitor therapy

Dacomitinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Consider therapy modification

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

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

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

Desmopressin: Opioid Agonists 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 Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Monitor therapy

Doxofylline: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Doxofylline. Avoid combination

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

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 (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Avoid combination

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

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

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

Formoterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Formoterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Formoterol. 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

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

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

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

Indacaterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Indacaterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Indacaterol. Monitor therapy

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

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

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lithium: Caffeine and Caffeine Containing Products may decrease the serum concentration of Lithium. 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

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. 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

Methoxyflurane: Barbiturates may enhance the nephrotoxic effect of Methoxyflurane. Barbiturates may increase the metabolism of Methoxyflurane. Avoid combination

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

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

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

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

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

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

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

Norfloxacin: May increase the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

Olodaterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Olodaterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Olodaterol. Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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 Agonists. 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

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). Monitor therapy

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 Agonists 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

PHENobarbital: May enhance the CNS depressant effect of Codeine. PHENobarbital may decrease the serum concentration of Codeine. Management: Avoid use of codeine and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased codeine efficacy and withdrawal if combined. Consider therapy modification

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

Pipemidic Acid: May increase the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. 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 CNS depressant effect of Codeine. Primidone may decrease the serum concentration of Codeine. Management: Avoid use of codeine and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased codeine efficacy and withdrawal if combined. Consider therapy modification

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

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

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

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Monitor therapy

Regadenoson: Caffeine and Caffeine Containing Products may diminish the vasodilatory effect of Regadenoson. Management: Avoiding using caffeine or other methylxanthine containing products (e.g., theophylline) for at least 12 hours prior to the administration of regadenoson. Consider therapy modification

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

Serotonergic Agents (High Risk): Opioid Agonists may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. 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

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

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

Solriamfetol: CNS Stimulants may enhance the hypertensive effect of Solriamfetol. Monitor therapy

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

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

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

Stiripentol: May increase the serum concentration of Caffeine and Caffeine Containing Products. Avoid combination

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. 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

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

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

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

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

Tetrahydrocannabinol and Cannabidiol: 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

Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tobacco (Smoked): May decrease the serum concentration of Caffeine and Caffeine Containing Products. Monitor therapy

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

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

See individual agents.

Adverse Reactions

Frequency not defined.

Cardiovascular: Syncope, tachycardia

Central nervous system: Agitation, confusion, depression, dizziness, drowsiness, euphoria, excitement, fatigue, 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

Postmarketing and/or case reports: Hypogonadism (Brennan 2013; Debono 2011)

Note: Potential reactions associated with components of Fioricet with Codeine include agranulocytosis, cardiac stimulation, dependence, erythema multiforme, hyperglycemia, irritability, nephrotoxicity, rash, thrombocytopenia, toxic epidermal necrolysis, tremor

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, driving).
• Constipation: May cause or aggravate constipation.
• Hepatotoxicity: [US Boxed Warning]: 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 >4 g/day, and often involve more than one acetaminophen-containing product. 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.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.
• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (eg. hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).
• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur with use. Monitor for respiratory depression, especially during initiation of therapy or following a dose increase. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
• Skin reactions: Serious and potentially fatal skin reactions such as acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred rarely with acetaminophen. Discontinue treatment at the first appearance of skin rash (or any other sign of hypersensitivity).

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO₂ retention.
• Delirium tremens: Use with caution in patients with delirium tremens.
• 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 acetaminophen with caution in patients with known G6PD deficiency.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Seizure disorder: Use with caution in patients with a history of seizure disorder; may cause or exacerbate preexisting seizures.
• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2016]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

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. Reserve concomitant prescribing of butalbital/acetaminophen/caffeine/codeine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.
• Cytochrome P450 interactions: [US Boxed Warning]: The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with butalbital/acetaminophen/caffeine/codeine requires careful consideration of the effects on 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 from codeine 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 in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Elderly: Use with caution in the elderly; may be more sensitive to adverse effects, such as respiratory depression. Consider the use of alternative nonopioid analgesics in these patients.
• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.
• Pediatric: [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 ultra-rapid metabolizers of codeine due to a CYP-450 2D6 polymorphism. Butalbital/acetaminophen/caffeine/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 butalbital/acetaminophen/caffeine/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 nursing infants after being exposed to high concentrations of morphine because the mothers were ultra-rapid metabolizers.

Other warnings/precautions:

• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances; provide care as needed. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist analgesics (eg, buprenorphine) may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.
• Abuse/misuse/diversion: [US Boxed Warning]: Use exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for the development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk for misuse include younger age, concomitant depression (major), and psychotropic medication use.
• Accidental ingestion: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of codeine.
• Appropriate use: Limit butalbital use to ≤3 days per month to avoid medication overuse headache (Garza 2006); studies have found increased risk with use ≥5 days per month (Da Silva 2014).
• Caffeine: May cause CNS and cardiovascular stimulation, as well as GI irritation in high doses.
• Discontinuation of therapy: When discontinuing chronic or high-dose treatment with butalbital, or if a patient has developed chronic migraine on butalbital, discontinuing butalbital and replacing with a gradual phenobarbital taper is advised to avoid barbiturate withdrawal symptoms (ie, anxiety, diaphoresis, disturbed sleep, nausea/vomiting, restlessness, seizures, worsened headache). These patients will likely require bridge therapy with a medication to treat acute headaches and may benefit from an optimized preventative regimen (Boes 2006; Garza 2019).
• Dosage limit: Limit acetaminophen dose from all sources (prescription and OTC) to <4 g/day.
• REMS: [US Boxed Warning]: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.

Monitoring Parameters

Relief of symptoms; respiratory and mental status, blood pressure, heart rate; bowel function; signs/symptoms of misuse, abuse, and addiction; hepatic and renal function tests (in patients with impairment); signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013)

Pregnancy

Pregnancy Considerations

[US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Refer to the acetaminophen/butalbital, caffeine, or codeine monographs for additional information.

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, headache, 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 yellow skin), signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), severe dizziness, passing out, sexual dysfunction (males), no menstrual periods, decreased sex drive, trouble getting pregnant, confusion, intoxicated feeling, loss of strength and energy, severe constipation, abdominal pain, chills, sore throat, bruising, bleeding, mood changes, seizures, difficulty breathing, slow breathing, shallow breathing, noisy breathing, chest pain, fast heartbeat, severe fatigue, tremors, signs of serotonin syndrome (dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), 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.