butalbital/aspirin/caffeine/codeine (Rx)

Brand and Other Names:Fiorinal with Codeine
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

butalbital/aspirin/caffeine/codeine

capsule: Schedule III

  • 50mg/325mg/40mg/30mg

Tension Headache

1-2 tab/cap PO q4hr; not to exceed 6 tabs/caps per day

To discontinue therapy, decrease dose by 25% to 50% every 2-4 days; monitor for symptoms/signs of withdrawal; if withdrawal symptoms occur, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both; do not abruptly discontinue therapy in a physically dependent patient

Limitations of Use

Because of the risks of addiction, abuse, and misuse with opioids and butalbital, even at recommended doses, reserve therapy for use in patients for whom alternative treatment options [e.g., non-opioid, non-barbiturate analgesics] have not been tolerated, or are not expected to be tolerated, have not provided adequate analgesia, or are not expected to provide adequate analgesia

Dosing Considerations

Use lowest effective dosage for shortest duration consistent with individual patient treatment goals

Initiate dosing regimen for each patient individually, taking into account patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse

Evidence supporting efficacy and safety of drug in treatment of multiple recurrent headaches is unavailable

Dosage Forms & Strengths

capsule: Schedule III

  • 50mg/325mg/40mg/30mg

The FDA has recommended that codeine not be used in children <12 years and all pediatric patients undergoing tonsillectomy and/or adenoidectomy

Tension Headache

<16 years: Safety and efficacy not established

≥16 years: 1-2 tab/cap PO q4hr; not to exceed 6 tabs/caps per day

To discontinue therapy, decrease dose by 25% to 50% every 2-4 days; monitor for symptoms/signs of withdrawal; if withdrawal symptoms occur, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both; do not abruptly discontinue therapy in a physically dependent patient

Use caution; barbiturates not recommended in the elderly

Tension Headache

1-2 tab/cap PO q4hr; not to exceed 6 tabs/caps per day

To discontinue therapy, decrease dose by 25% to 50% every 2-4 days; monitor for symptoms/signs of withdrawal; if withdrawal symptoms occur, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both; do not abruptly discontinue therapy in a physically dependent patient

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Interactions

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            Adverse Effects

            >10%

            Codeine

            • Constipation
            • Drowsiness

            1-10%

            Codeine

            • Hypotension, tachycardia or bradycardia, confusion, dizziness, false feeling of well being, headache, lightheadedness, malaise, paradoxical CNS stimulation, restlessness, rash, urticaria, anorexia, nausea, vomiting, xerostomia, ureteral spasm, urination decreased, LFT's increased, weakness, blurred vision, dyspnea, histamine-release

            Frequency Not Defined

            Butalbital

            • Drowsiness, sedation
            • Lightheadedness, dizziness
            • Shortness of breath
            • Nausea, vomiting
            • Abdominal pain
            • Intoxicated feeling

            Aspirin

            • Stomach pain
            • Heartburn
            • Nausea, vomiting
            • Dyspepsia
            • Tinnitus (high or chronic dose)
            • Rash
            • Urticaria

            Caffeine

            • Insomnia, restlessness
            • Nervousness, irritability
            • Tremor
            • Tinnitus
            • Nausea, vomiting
            • Diarrhea
            • Tachycardia
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            Warnings

            Black Box Warnings

            Opioid analgesic risk evaluation and mitigation strategy (REMS)

            • To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products; under requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers
            • Healthcare 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
              • Consider other tools to improve patient, household, and community safety

            Addiction and abuse

            • Therapy exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death; assess patient’s risk before prescribing and monitor regularly for these behaviors and conditions

            Life threatening respiratory depression

            • Serious, life-threatening, or fatal respiratory depression may occur; monitor closely, especially upon initiation or following a dose increase

            Accidental ingestion

            • Accidental ingestion of drug, especially by children, can result in fatal overdose

            Neonatal opioid withdrawal syndrome

            • Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management 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

            Postoperative pain in children

            • Deaths have occurred in children with obstructive sleep apnea who receive codeine for postoperative pain following tonsillectomy and/or adenoidectomy
            • Codeine is converted to morphine by the liver; these children had evidence of being ultra-rapid metabolizers (via CYP2D6) of codeine, which is an inherited (genetic) ability that causes codeine to be converted rapidly into life-threatening or fatal amounts of morphine (see Pharmacology)
            • ontraindicated in children younger than 12 years ; life-threatening respiratory depression and death have occurred in children who received codeine; codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to active metabolite morphine; children < 12 years appear to be more susceptible to respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression; many reported cases of death occurred in postoperative period following tonsillectomy and/or adenoidectomy, and many of children had evidence of being ultra-rapid metabolizers of codeine
            • Avoid use in adolescents 12-18 years of age who have other risk factors that may increase sensitivity to respiratory depressant effects of codeine unless benefits outweigh risks; 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; when prescribing codeine for adolescents, healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about risks and the signs of morphine overdose

            Coadministration with benzodiazepines

            • Risks from concomitant use with benzodiazepines or other CNS depressants; concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death; reserve concomitant prescribing of this drug combination and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to minimum required; follow patients for signs and symptoms of respiratory depression and sedation

            Interactions with drugs affecting cytochrome P450 isoenzymes

            • Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine sulfate requires careful consideration of effects on parent drug, codeine, and active metabolite, morphine

            Contraindications

            Hypersensitivity

            Children <12 years (increased risk of death from opioid)

            Postoperative management in children <18 years following tonsillectomy and/or adenoidectomy

            Children <16 years because of potential for Reye syndrome

            Postoperative use in children following tonsillectomy and/or adenoidectomy (see Black Box Warnings)

            Bronchospastic reaction to aspirin

            Syndrome of asthma, rhinitis, and nasal polyps

            Significant respiratory depression

            Peptic ulcer disease

            Known allergy to NSAIDs

            Within 14 days of taking MAOIs

            Hemophilia

            Repeated administration in patients with anemia, cardiovascular, pulmonary, or renal disease

            Porphyria

            Cautions

            Gastrointestinal bleeding; particular caution in patients with history of GI bleed, alcoholism, or bleeding disorders

            Avoid driving car or operating machinery

            Reye syndrome may occur in children because of aspirin component; do not use for chickenpox or flu symptoms

            Avoid in severe renal impairment (ie, CrCl <10 mL/min)

            Avoid use of mixed agonist/antagonist (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms

            May increase respiratory depressant effects; caution with head injury, COPD, or other conditions with decreased respiratory drive

            As butalbital, aspirin, caffeine, and codeine phosphate drug dosage forms contain butalbital and codeine, they expose users to the risks of addiction, abuse, and misuse; assess each patient’s risk for addiction, abuse, or misuse prior to prescribing therapy, and monitor all patients receiving drug for development of addiction behaviors and conditions

            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, and codeine phosphate combination require careful consideration of effects on codeine and active metabolite, morphine

            Codeine may cause tolerance/dependency; assess each patient’s risk for addiction, abuse, or misuse prior to prescribing drug, and monitor all patients for development of behaviors and conditions associated with addiction

            Life-threatening respiratory depression and death have occurred in children who received codeine; codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to active metabolite morphine; children <12 years and pediatric patients <18 years, following tonsillectomy and/or adenoidectomy, appear to be more susceptible to respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression; many reported cases of death occurred in postoperative period following tonsillectomy and/or adenoidectomy, and many of children had evidence of being ultra-rapid metabolizers of codeine

            Avoid use of drug combination in adolescents 12-18 years of age who have other risk factors that may increase sensitivity to respiratory depressant effects of codeine unless benefits outweigh risks; 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; when prescribing codeine for adolescents, healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about risks and the signs of morphine overdose

            At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine; breastfeeding is not recommended during treatment

            Serious, life-threatening, or fatal respiratory depression may occur; monitor closely, especially upon initiation or following a dose increase

            Low doses of aspirin can inhibit platelet function leading to an increase in bleeding time; this can adversely affect patients with inherited (i.e. hemophilia) or acquired (i.e. liver disease or vitamin K deficiency) bleeding disorders; aspirin is contraindicated in patients with hemophilia

            Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses; aspirin administered pre-operatively may prolong bleeding time

            Adrenal Insufficiency may occur; if diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid

            In patients who may be susceptible to intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), butalbital, aspirin, caffeine, and codeine phosphate drug combination may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor for sedation and respiratory depression

            Opioids may obscure clinical course in patient with a head injury; avoid use of butalbital, aspirin, caffeine, and codeine phosphate drug combination in patients with impaired consciousness or coma

            Butalbital, aspirin, caffeine, and codeine phosphate drug combination may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs; monitor these patients for signs of hypotension after initiating or titrating dosage

            The codeine in butalbital, aspirin, caffeine, and codeine phosphate drug combination may increase frequency of seizures in patients with seizure disorders and may increase risk of seizures occurring in other clinical settings associated with seizures; monitor patients with a history of seizure disorders for worsened seizure control during butalbital, aspirin, caffeine, and codeine phosphate drug combination

            Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients; to reduce risk of respiratory depression, proper dosing and titration are essential

            Profound sedation, respiratory depression, coma, and death may result from concomitant with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate

            Monoamine oxidase inhibitors (MAOIs) may potentiate effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion; drug should not be used in patients taking MAOIs or within 14 days of stopping such treatment

            Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding.

            Opioid analgesic risk evaluation and mitigation strategy (REMS)

            • To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products
            • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed; use the following link to obtain the Patient Counseling Guide (PCG): www.fda.gov/OpioidAnalgesicREMSPCG
            • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them
            • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities
            • To obtain further information on opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com; the FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint
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            Pregnancy & Lactation

            Pregnancy

            Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome; available data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage

            Labor and delivery

            • Use of codeine during labor may lead to respiratory depression in the neonate; opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate; use is not recommended in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by increased rate of cervical dilation, which tends to shorten labor; monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression

            Lactation

            Codeine and its active metabolite, morphine, are present in human milk; there are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk; women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants; in women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent

            There is no information on effects of codeine milk production; because of potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, breastfeeding is not recommended during treatment

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Butalbital: Barbiturate; elicits generalized CNS depressant effects

            Aspirin: Acts on hypothalamus to produce antipyresis; anti-inflammatory properties attributed to prostaglandin synthetase inhibition resulting in decreased formation of thromboxane A2

            Caffeine: Vasoconstrictive properties of cerebral blood vessels may be helpful when treating headaches

            Codeine: Opioid agonist; analgesia

            Pharmacogenomics

            10% of codeine is metabolized to morphine by CYP2D6; the active morphine metabolite has a higher affinity for opioid receptors

            CYP2D6 poor metabolizers may not achieve adequate analgesia

            Ultra-rapid metabolizers (up to 7% of Caucasians and up to 30% of Asian and African populations) may have increased toxicity due to rapid conversion

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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