Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate

1 INDICATIONS AND USAGE 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, and misuse with opioids and butalbital, even at recommended doses [see Warnings and Precautions ( 5.1 )], reserve Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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. 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, and misuse with opioids, even at recommended doses, reserve Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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.

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1 ) Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 ) Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with Butalbital, Acetaminophen, Caffeine and Codeine Phosphate Capsules. Consider prescribing naloxone based on the patient’s risk factors for overdose. ( 2.2 , 5.1 , 5.3 , 5.4 ) Initiate treatment with one or two capsules every 4 hours as needed for pain. Total daily dosage should not exceed 6 capsules. ( 2.3 ) Do not abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide ( 2.4 ). 2.1 Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )]. Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )]. Evidence supporting the efficacy and safety of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in the treatment of multiple recurrent headaches is unavailable. 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules [see Warnings and Precautions ( 5.3 ), Patient Counseling Information ( 17 )]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.1 , 5.3 , 5.4 )]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 2.3 Dosing Information One or two capsules every 4 hours as needed for pain. Total daily dosage should not exceed 6 capsules. 2.4 Safe Reduction or Discontinuation of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules Do not abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, there are a variety of factors that should be considered, including the dose of…

5 WARNINGS AND PRECAUTIONS Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.9 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.11 ) Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with circulatory shock. ( 5.12 ) 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. ( 5.13 ) 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. Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, and monitor 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 intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )] . Opioids and barbiturates are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. 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 the proper disposal of unused drug [see Patient Counseling Information ( 17 )]. 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 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (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 healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements o…

4 CONTRAINDICATIONS Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for: All children younger than 12 years of age [see Warnings and Precautions ( 5.5 )] . Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions ( 5.5 )] . Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.3 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.9 )] Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.10 ), Drug Interactions ( 7 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.14 )] 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 )

7 DRUG INTERACTIONS 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. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage until stable drug effects are achieved. Monitor 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, follow the patient 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage reduction, and monitor for signs of respiratory depression and sedation at frequent intervals. 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 me…

8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.6 )] . 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. 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 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or non-medical 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 ( 5.6 )] . 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 antagonist, such as naloxone, 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 …

6 ADVERSE REACTIONS 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 ( 5.3 )] Interactions with Benzodiazepines and other CNS Depressants [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 ( 5.5 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.6 )] Hepatotoxicity [see Warnings and Precautions ( 5.8 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.11 )] Severe Hypotension [see Warnings and Precautions ( 5.12 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.14 )] Seizures [see Warnings and Precautions ( 5.15 )] Withdrawal [see Warnings and Precautions ( 5.16 )] Serious Skin Reactions [see Warnings and Precautions ( 5.18 )] Anaphylaxis [see Warnings and Precautions ( 5.19 )] 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 multif…