Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are indicated for the management of the symptom complex of tension (or muscle contraction) headache when non-opioid analgesic and alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration, and persist over the course of therapy, [see Warnings and Precautions ( 5.1 )], reserve opioid analgesics, including Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsule is a combination product of butalbital, a barbiturate; acetaminophen; caffeine, a methylxanthine; and codeine phosphate, an opioid agonist; and is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when other non-opioid analgesic and alternative treatments are inadequate. ( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration, and persist over the course of therapy, reserve opioid analgesics, including Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 )

Capsules: Butalbital 50 mg, Acetaminophen 325 mg, Caffeine 40 mg, Codeine Phosphate 30 mg Dark blue, opaque cap is imprinted with “WATSON” in light blue. White, opaque body is imprinted with “3220” in red. Capsules: 50 mg butalbital, 325 mg acetaminophen, 40 mg caffeine, and 30 mg codeine phosphate. ( 3 )

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for: All children younger than 12 years of age [see Warnings and Precautions ( 5.6 )] Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions ( 5.6 )] Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.10 )] Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.11 ), Drug Interactions ( 7 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.15 )] Known intolerance or hypersensitivity to acetaminophen, caffeine, butalbital, or codeine or to the components of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules Porphyria Children younger than 12 years of age. ( 4 ) Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. ( 4 ) Significant respiratory depression. ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Intolerance or hypersensitivity to acetaminophen, caffeine, butalbital or codeine, or components of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. ( 4 ) Porphyria. ( 4 )

Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.9 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate patients, particularly during initiation and titration. ( 5.10 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.12 ) Severe Hypotension: Regularly evaluate patients during dosage initiation and titration. Avoid use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with circulatory shock. ( 5.13 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with impaired consciousness or coma. ( 5.14 )

5.1 Addiction, Abuse, and Misuse Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain codeine. Codeine in combination with butalbital, acetaminophen, and caffeine is a Schedule III controlled substance. As Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain butalbital and codeine, they expose users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6 )] . Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, and reassess all patients receiving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules but use in such patients necessitates intensive counseling about the risks and proper use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )] . Opioids and barbiturates are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drug . Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents, depending on the patient’s clinical status [see Overdosage ( 10 )] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are essential [see Dosage and Administration ( 2.3 )]. Overestimating the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, especially by children, can result in respiratory depression and death due to an overdose of codeine and butalbital. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.5 )]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.3 ) . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage ( 10 )] . […]

The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Interactions with Benzodiazepines and other CNS Depressants [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.6 )] Hepatotoxicity [see Warnings and Precautions ( 5.8 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.9 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.12 )] Severe Hypotension [see Warnings and Precautions ( 5.13 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.15 )] Anaphylaxis [see Warnings and Precautions ( 5.16 )] Seizures [see Warnings and Precautions ( 5.17 )] Withdrawal [see Warnings and Precautions ( 5.18 )] Serious Skin Reactions [see Warnings and Precautions ( 5.20 )] The following adverse reactions associated with the use of butalbital, acetaminophen, caffeine, and codeine phosphate were identified in clinical studies or post-marketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Frequently Observed The most frequently reported adverse reactions were drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, abdominal pain, and intoxicated feeling. Infrequently Observed All adverse events tabulated below are classified as infrequent. Central Nervous : headache, shaky feeling, tingling, agitation, fainting, fatigue, heavy eyelids, high energy, hot spells, numbness, sluggishness, seizure. Mental confusion, excitement or depression can also occur due to intolerance, particularly in elderly or debilitated patients, or due to overdosage of butalbital. Autonomic Nervous : dry mouth, hyperhidrosis. Gastrointestinal : difficulty swallowing, heartburn, flatulence, constipation. Cardiovascular : tachycardia. Musculoskeletal: leg pain, muscle fatigue. Genitourinary: diuresis. Miscellaneous : pruritus, fever, earache, nasal congestion, tinnitus, euphoria, allergic reactions. The following adverse reactions have been voluntarily reported as temporally associated with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, a related product containing aspirin, butalbital, caffeine, and codeine phosphate. Central Nervous : abuse, addiction, anxiety, disorientation, hallucination, hyperactivity, insomnia, libido decrease, nervousness, neuropathy, psychosis, sexual activity increase, slurred speech, twitching, unconsciousness, vertigo. Autonomic Nervous : epistaxis, flushing, miosis, salivation. Gastrointestinal : anorexia, appetite increased, diarrhea, esophagitis, gastroenteritis, gastrointestinal spasms, hiccup, mouth burning, pyloric ulcer. Cardiovascular : chest pain, hypotensive reaction, palpitations, syncope. Skin : erythema, erythema multiforme, exfoliative dermatitis, hives, rash, toxic epidermal necrolysis. Urinary : kidney impairment, urinary difficulty. Miscellaneous : allergic reaction, anaphylactic shock, cholangiocarcinoma, drug interaction with erythromycin (stomach upset), edema. The following adverse reactions have been reported with the components of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Potential effects of high dosage are listed in the OVERDOSAGE section. Acetaminophen : allergic reactions, rash, thrombocytopenia, agranulocytosis. Caffeine : cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia. Codeine : nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus. Several cases of dermatological reactions, including toxic epidermal necrolysis and erythema multiforme, have been reported for butalbital, acetaminophen, and caffeine tablets, USP. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.9 )]. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.15 )] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one of more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 )] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. […]

Table 1 includes clinically significant drug interactions with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Table 1: Clinically Significant Drug Interactions with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules Inhibitors of CYP3A4 Clinical Impact: The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with CYP3A4 inhibitors may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules is achieved [see Warnings and Precautions ( 5.7 )] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. Intervention: If concomitant use with CYP3A4 inhibitor is necessary, consider dosage reduction of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice CYP3A4 Inducers Clinical Impact: The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and CYP3A4 inducers can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [see Warnings and Precautions ( 5.7 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the codeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use of a CYP3A4 inducer is necessary, evaluate the patient at frequent intervals for reduced efficacy and signs of opioid withdrawal and consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage as needed. If a CYP3A4 inducer is discontinued, consider lowering Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage until stable drug effects are achieved. Evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Inhibitors of CYP2D6 Clinical Impact: Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and CYP2D6 inhibitors can increase the plasma concentration of codeine, but can decrease the plasma concentrations of active metabolite morphine, which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules is achieved [see Clinical Pharmacology ( 12.3 )] . After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression [see Clinical Pharmacology ( 12.3 )] . Intervention: If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and evaluate patients at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, evaluate the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and evaluate the patient at frequent intervals for signs and symptoms of respiratory depression or sedation. Examples: paroxetine, fluoxetine, bupropion, quinidine Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.3 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.11 )]. Intervention: Do not use Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydromorphone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. […]

Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Breastfeeding not recommended. ( 8.2 ) Geriatric: Respiratory depression has occurred after large initial doses were administered. Increase dosage slowly. ( 8.5 )

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )] . Available data with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and infant associated with use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules for an extended period of time during pregnancy (see Clinical Considerations). Animal reproduction studies have not been conducted with the combination of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules or with butalbital alone. In animal reproduction studies, codeine administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 2.8 times maximum recommended human dose (MRHD) of 180 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately 4 to 6 times the MRHD, and cranial malformations/cranioschisis in the offspring of hamsters between 2 and 8 times the MRHD. Reproductive and developmental studies in rats and mice from the published literature identified adverse events at clinically relevant doses with acetaminophen. Treatment of pregnant rats with doses of acetaminophen approximately 2 times the maximum human daily dose (MHDD) showed evidence of fetotoxicity and increases in bone variations in the fetuses. In another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses approximately 2 times the MHDD. In mice treated with acetaminophen at doses within the clinical dosing range, cumulative adverse effects on reproduction were seen in a continuous breeding study. A reduction in number of litters of the parental mating pair was observed as well as retarded growth and abnormal sperm in their offspring and reduced birth weight in the next generation [ see Data ]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4 )] . Labor or 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 overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, 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 an 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. Data Human Data Published data from a large population-based prospective cohort study and a population-based, case-control study do not clearly report an association with oral acetaminophen and major birth defects, miscarriage, or adverse maternal or fetal outcomes when acetaminophen is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including recall bias. Withdrawal seizures were reported in a two-day-old male infant whose mother had taken a butalbital containing drug during the last 2 months of pregnancy. Butalbital was found in the infant's serum. The infant was given phenobarbital 5 mg/kg, which was tapered without further seizure or other withdrawal symptoms. Animal Data Animal reproduction studies have not been conducted with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules or with butalbital alone. The following data are based on findings from studies performed with either codeine or acetaminophen alone. Codeine In a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 14 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m 2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on Gestation Day 8 (oral; approximately 4 to 16 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m 2 basis), reportedly produced cranioschisis in all of the fetuses examined. In studies in rats, doses at the 120 mg/kg level (oral; approximately 6 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m 2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 2.8 times the recommended daily dose of 180 mg/day for adults on a mg/mg 2 basis) administered between Gestation Day 7 and 12 reportedly resulted in delayed ossification in the offspring. No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m 2 basis) of codeine during organogenesis. Codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. This dose is 1.6 times the maximum recommended human dose of 180 mg/day on a body surface area comparison. Acetaminophen Studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 1.7 the maximum human daily dose (MHDD) of 1950 mg/day based on a body surface area comparison showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes). Offspring had no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at doses of 2.4 times the MHDD (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. […]

Butalbital, a barbiturate, is a GABA A receptor agonist and may inhibit excitatory AMPA receptors. The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to involve central actions. Caffeine is a methylxanthine and CNS stimulant. The exact mechanism with respect to the indication is not clear; however, the effects of caffeine may be due to antagonism of adenosine receptors. Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.