Butalbital, Acetaminophen, Caffeine and Codeine Phosphate

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 reported adverse reactions are drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, abdominal pain, and intoxicated feeling. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 chronic use of opioids [see Clinical Pharmacology (12.2) ] .

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 )

11 DESCRIPTION Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are supplied in capsule form for oral administration. Each capsule contains: Butalbital, USP 50 mg Acetaminophen, USP 325 mg Caffeine, USP 40 mg Codeine phosphate, USP 30 mg Butalbital (5-allyl-5-isobutylbarbituric acid), is a short-to intermediate-acting barbiturate. It has the following structural formula: C 11 H 16 N 2 O 3 MW 224.26 Acetaminophen (4'hydroxyacetanilide), is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula: C 8 H 9 NO 2 MW 151.16 Caffeine (1,3,7-trimethylxanthine), a methylxanthine, is a central nervous system stimulant. It has the following structural formula: C 8 H 10 N 4 O 2 MW 194.19 Codeine phosphate (7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1)(salt) hemihydrate) is an opioid agonist. It has the following structural formula: C 18 H 24 NO 7 P anhydrous MW 397.37 Inactive Ingredients: Microcrystalline Cellulose, Sodium Lauryl Sulfate, Stearic Acid, Talc. The gelatin capsules are printed with edible inks containing Titanium Dioxide, Gelatin, FD&C Blue No. 1, FD&C Red No. 40, and FD&C Yellow No. 5 [see Warnings and Precautions (5.21) ]. Chemical Structure Chemical Structure Chemical Structure Chemical Structure

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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.16) , Drug Abuse and Dependence (9.3) ] .

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. 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. 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.

9.2 Abuse Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contains codeine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) ]. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are for oral use only. Abuse of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules poses a risk of overdose and death. The risk is increased with concurrent use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with alcohol and other central nervous system depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Butalbital Barbiturates may be habit-forming: Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. The average daily dose for the barbiturate addict is usually about 1,500 mg. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than twofold. As this occurs, the margin between an intoxication dosage and fatal dosage becomes smaller. The lethal dose of a barbiturate is far less if alcohol is also ingested. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. One method involves initiating treatment at the patient's regular dosage level and gradually decreasing the daily dosage as tolerated by the patient.

9.1 Controlled Substance Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain codeine. Codeine in combination with butalbital, acetaminophen, and caffeine is a Schedule III controlled substance.

9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Do not abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in a patient physically dependent on opioids. Rapid tapering of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in a patient physically dependent on opioids may lead to 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. When discontinuing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.4) , Warnings and Precautions (5.16) ] . Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ] .

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain codeine. Codeine in combination with butalbital, acetaminophen, and caffeine is a Schedule III controlled substance. 9.2 Abuse Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contains codeine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) ]. All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are for oral use only. Abuse of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules poses a risk of overdose and death. The risk is increased with concurrent use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with alcohol and other central nervous system depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Butalbital Barbiturates may be habit-forming: Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. The average daily dose for the barbiturate addict is usually about 1,500 mg. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than twofold. As this occurs, the margin between an intoxication dosage and fatal dosage becomes smaller. The lethal dose of a barbiturate is far less if alcohol is also ingested. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. One method involves initiating treatment at the patient's regular dosage level and gradually decreasing the daily dosage as tolerated by the patient. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. Do not abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in a patient physically dependent on opioids. Rapid tapering of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in a patient physically dependent on opioids may lead to 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. When discontinuing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.4) , Warnings and Precautions (5.16) ] . Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ] .

10 OVERDOSAGE Clinical Presentation Acute overdose with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2) ] . Signs and Symptoms Symptoms attributable to acute barbiturate poisoning include drowsiness, confusion, and coma; respiratory depression; hypotension; and hypovolemic shock. Toxicity from codeine poisoning includes the opioid triad of: pinpoint pupils, depression of respiration, and loss of consciousness. Convulsions may occur. In acetaminophen overdosage: dose dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Acute caffeine poisoning may cause insomnia, restlessness, tremor, and delirium, tachycardia, and extrasystoles. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist. Because the duration of opioid reversal is expected to be less than the duration of action of codeine in Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist. A single or multiple drug overdose with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to codeine, parenteral naloxone is a specific and effective antagonist. Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration. Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.

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 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 monitor patients closely at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and monitor the patient 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. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.3 , 5.4) ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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, carefully observe 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 (5.10) ]. 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. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2) , Warnings and Precautions (5.3 , 5.4) ] . Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are used concomitantly with anticholinergic drugs. Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules because they may reduce analgesic effect of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules or precipitate withdrawal symptoms. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics Effects on the Central Nervous System Butalbital, a barbiturate, is a central nervous system (CNS) depressant that can produce sedation, respiratory depression, and euphoria. The potential impact of butalbital on painful stimuli is not clear and in some individuals barbiturates may increase reaction to painful stimuli. Codeine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and to electrical stimulation. Codeine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Acetaminophen has been shown to have analgesic activity in animal and human studies. Effects on the Gastrointestinal Tract and Other Smooth Muscle Codeine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Butalbital may decrease blood pressure and heart rate when administered at sedative and hypnotic doses. Codeine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6) ] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of codeine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.3) ] . Concentration–Adverse Reaction Relationships There is a relationship between increasing codeine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.3 , 2.4) ] . 12.3 Pharmacokinetics The behavior of the individual components is described below. Butalbital Absorption Butalbital is well absorbed from the gastrointestinal tract. Distribution Butalbital is expected to distribute to most tissues in the body. Barbiturates in general may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility. The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5 to 20 mcg/mL. This falls within the range of plasma protein binding (20% to 45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells. Elimination Elimination of butalbital is primarily via the kidney (59% to 88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products include parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5-(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% is conjugated. [See Overdosage (10) for toxicity information]. Acetaminophen Absorption Acetaminophen is rapidly absorbed from the gastrointestinal tract. Metabolism Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways. Distribution Acetaminophen is distributed throughout most body tissues. A small fraction (10-25%) of acetaminophen is bound to plasma proteins. Elimination Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. [See Overdosage (10) for toxicity information]. Caffeine Absorption Like most xanthines, caffeine is rapidly absorbed. Distribution Caffeine is distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk. Elimination Caffeine is cleared through metabolism and excretion in the urine. Metabolism Caffeine is mainly metabolized by CYP1A2. Other enzymes, including CYP2E1, CYP3A4, CYP2C8 and CYP2C9 may play a minor role in its metabolism. Hepatic biotransformation prior to excretion results in about equal amounts of 1-methylxanthine and 1-methyluric acid. Excretion Of the 70% of the dose that is recovered in the urine, only 3% is unchanged drug. The plasma half-life is about 3 hours. [See Overdosage (10) for toxicity information]. Codeine Absorption Codeine is readily absorbed from the gastrointestinal tract. At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. Distribution Codeine is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain; however, codeine is not bound to plasma proteins and does not accumulate in body tissues. Elimination Metabolism About 70-80% of administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G) and via O -demethylation to morphine (about 5-10%) and N -demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucuronidation of codeine to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of codeine to morphine and P450 3A4 is the major enzyme mediating conversion of codeine to norcodeine. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G are known to have analgesic activity in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G are generally not considered to possess analgesic properties. Excretion The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (about 4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces. [See Overdosage (10) for toxicity information].

12.1 Mechanism of Action 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.

12.2 Pharmacodynamics Effects on the Central Nervous System Butalbital, a barbiturate, is a central nervous system (CNS) depressant that can produce sedation, respiratory depression, and euphoria. The potential impact of butalbital on painful stimuli is not clear and in some individuals barbiturates may increase reaction to painful stimuli. Codeine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and to electrical stimulation. Codeine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Acetaminophen has been shown to have analgesic activity in animal and human studies. Effects on the Gastrointestinal Tract and Other Smooth Muscle Codeine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Butalbital may decrease blood pressure and heart rate when administered at sedative and hypnotic doses. Codeine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6) ] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of codeine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.3) ] . Concentration–Adverse Reaction Relationships There is a relationship between increasing codeine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.3 , 2.4) ] .

12.3 Pharmacokinetics The behavior of the individual components is described below. Butalbital Absorption Butalbital is well absorbed from the gastrointestinal tract. Distribution Butalbital is expected to distribute to most tissues in the body. Barbiturates in general may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility. The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5 to 20 mcg/mL. This falls within the range of plasma protein binding (20% to 45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells. Elimination Elimination of butalbital is primarily via the kidney (59% to 88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products include parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5-(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% is conjugated. [See Overdosage (10) for toxicity information]. Acetaminophen Absorption Acetaminophen is rapidly absorbed from the gastrointestinal tract. Metabolism Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: conjugation with glucuronide; conjugation with sulfate; and oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways. Distribution Acetaminophen is distributed throughout most body tissues. A small fraction (10-25%) of acetaminophen is bound to plasma proteins. Elimination Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. [See Overdosage (10) for toxicity information]. Caffeine Absorption Like most xanthines, caffeine is rapidly absorbed. Distribution Caffeine is distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk. Elimination Caffeine is cleared through metabolism and excretion in the urine. Metabolism Caffeine is mainly metabolized by CYP1A2. Other enzymes, including CYP2E1, CYP3A4, CYP2C8 and CYP2C9 may play a minor role in its metabolism. Hepatic biotransformation prior to excretion results in about equal amounts of 1-methylxanthine and 1-methyluric acid. Excretion Of the 70% of the dose that is recovered in the urine, only 3% is unchanged drug. The plasma half-life is about 3 hours. [See Overdosage (10) for toxicity information]. Codeine Absorption Codeine is readily absorbed from the gastrointestinal tract. At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours. Distribution Codeine is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain; however, codeine is not bound to plasma proteins and does not accumulate in body tissues. Elimination Metabolism About 70-80% of administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G) and via O -demethylation to morphine (about 5-10%) and N -demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucuronidation of codeine to C6G. Cytochrome P450 2D6 is the major enzyme responsible for conversion of codeine to morphine and P450 3A4 is the major enzyme mediating conversion of codeine to norcodeine. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Morphine and M6G are known to have analgesic activity in humans. The analgesic activity of C6G in humans is unknown. Norcodeine and M3G are generally not considered to possess analgesic properties. Excretion The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (about 4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces. [See Overdosage (10) for toxicity information].

20210527

8

3 DOSAGE FORMS AND STRENGTHS Capsules: Butalbital 50 mg, Acetaminophen 325 mg, Caffeine 40 mg, Codeine Phosphate 30 mg Blue, opaque cap with a gray, opaque body, and body is imprinted with "B073" in black ink. Capsules: 50 mg butalbital, 325 mg acetaminophen, 40 mg caffeine, and 30 mg codeine phosphate.

Butalbital, Acetaminophen, Caffeine and Codeine Phosphate Butalbital, Acetaminophen, Caffeine and Codeine Phosphate Butalbital Butalbital Acetaminophen Acetaminophen Caffeine Caffeine Codeine Phosphate CODEINE ANHYDROUS FD&C Blue No. 1 FD&C Red No. 3 FD&C Red No. 40 FD&C Yellow No. 5 GELATIN, UNSPECIFIED MICROCRYSTALLINE CELLULOSE Sodium Lauryl Sulfate Stearic Acid Talc Titanium Dioxide B073

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of the combination of butalbital, acetaminophen, caffeine, and codeine or butalbital alone have not been conducted. Two-year carcinogenicity studies with codeine sulfate have been conducted in F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of codeine sulfate (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m 2 basis) for two years. Similarly, there was no evidence of carcinogenicity activity in male and female mice at dietary doses up to 400 mg/kg/day of codeine sulfate (approximately 10 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m 2 basis) for two years. Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 1.6 times the maximum human daily dose (MHDD) of 1950 mg/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats that received up to 1.4 times or mice at up to 2.4 to 2.8 times the MHDD, based on a body surface area comparison. In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 4 and 7 times, respectively, the maximum human daily dose on a mg/m 2 basis). In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses up to 55 mg/kg (equivalent to the MHDD on a mg/m 2 basis). Mutagenesis There are no genetic toxicology data for butalbital. Codeine sulfate was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay. In the published literature, acetaminophen has been reported to be clastogenic when administered at 1500 mg/kg/day to the rat model (7.2-times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (3.6-times the MHDD, based on a body surface area comparison), suggesting a threshold effect. Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation (5-fold) in folate-deficient mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary cell (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/hypoxanthine guanine phosphoribosyltransferase (HGPRT) gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay. Caffeine was negative in the in vitro bacterial reverse mutation assay (Ames test). Impairment of Fertility No adequate studies have been conducted in animals to characterize the impact of the combinations of butalbital, acetaminophen, caffeine, and codeine on fertility. There are also no data on butalbital alone or codeine alone. In studies conducted by the National Toxicology Program, fertility assessments with acetaminophen have been completed in Swiss CD-1 mice via a continuous breeding study. There were no effects on fertility parameters in mice consuming up to 3.4 times the MHDD of acetaminophen, based on a body surface area comparison. Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 3.6 times the MHDD (based on a body surface comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing. Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 2.4 times the MHDD and greater (based on a body surface comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. The clinical significance of these findings is not known. Caffeine (as caffeine base) administered to male rats at 50 mg/kg/day subcutaneously (2 times the MHDD on a mg/m 2 basis) for 4 days prior to mating with untreated females, caused decreased male reproductive performance in addition to causing embryotoxicity. In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of the combination of butalbital, acetaminophen, caffeine, and codeine or butalbital alone have not been conducted. Two-year carcinogenicity studies with codeine sulfate have been conducted in F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of codeine sulfate (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m 2 basis) for two years. Similarly, there was no evidence of carcinogenicity activity in male and female mice at dietary doses up to 400 mg/kg/day of codeine sulfate (approximately 10 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m 2 basis) for two years. Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 1.6 times the maximum human daily dose (MHDD) of 1950 mg/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats that received up to 1.4 times or mice at up to 2.4 to 2.8 times the MHDD, based on a body surface area comparison. In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 4 and 7 times, respectively, the maximum human daily dose on a mg/m 2 basis). In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses up to 55 mg/kg (equivalent to the MHDD on a mg/m 2 basis). Mutagenesis There are no genetic toxicology data for butalbital. Codeine sulfate was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay. In the published literature, acetaminophen has been reported to be clastogenic when administered at 1500 mg/kg/day to the rat model (7.2-times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (3.6-times the MHDD, based on a body surface area comparison), suggesting a threshold effect. Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation (5-fold) in folate-deficient mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary cell (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/hypoxanthine guanine phosphoribosyltransferase (HGPRT) gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay. Caffeine was negative in the in vitro bacterial reverse mutation assay (Ames test). Impairment of Fertility No adequate studies have been conducted in animals to characterize the impact of the combinations of butalbital, acetaminophen, caffeine, and codeine on fertility. There are also no data on butalbital alone or codeine alone. In studies conducted by the National Toxicology Program, fertility assessments with acetaminophen have been completed in Swiss CD-1 mice via a continuous breeding study. There were no effects on fertility parameters in mice consuming up to 3.4 times the MHDD of acetaminophen, based on a body surface area comparison. Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 3.6 times the MHDD (based on a body surface comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing. Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 2.4 times the MHDD and greater (based on a body surface comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. The clinical significance of these findings is not known. Caffeine (as caffeine base) administered to male rats at 50 mg/kg/day subcutaneously (2 times the MHDD on a mg/m 2 basis) for 4 days prior to mating with untreated females, caused decreased male reproductive performance in addition to causing embryotoxicity. In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration.

ANDA076560

Butalbital, Acetaminophen, Caffeine and Codeine Phosphate

Butalbital, Acetaminophen, Caffeine and Codeine Phosphate

51991-073

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 100 Capsule Bottle Label NDC 51991-073-01 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules CIII 50 mg/325 mg/40 mg/30 mg Each Capsule Contains: Butalbital, USP 50 mg Acetaminophen, USP 325 mg Caffeine, USP 40 mg Codeine Phosphate, USP 30 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient. breckenridge A Towa Company Rx only 100 Capsules PRINCIPAL DISPLAY PANEL - 100 Capsule Bottle Label

Dosage and Administration ( 2.2 ) 03/2021 Warnings and Precautions ( 5.1 , 5.3 , 5.4 ) 03/2021

Manufactured by: LGM Pharma Solutions, LLC Irvine, CA 92614 Manufactured for: Breckenridge Pharmaceutical, Inc. Berlin, CT 06037 6670 Rev. 04/2021

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1 , 5.3) , Drug Abuse and Dependence (9.2) ]. Inform patients that leaving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules unsecured can pose a deadly risk to others in the home. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that medicine take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take back programs or DEA-registered collectors are available, instruct patients to dispose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules by following these four steps: Mix Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules (do not crush) with an unpalatable substance such as dirt, cat litter, or used coffee grounds; Place the mixture in a container such as a sealed plastic bag; Throw the container in the household trash; Delete all personal information on the prescription label of the empty bottle Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1) ]. Instruct patients not to share Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with others and to take steps to protect Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules or when the dosage is increased, and that it can occur even at recommended dosages. 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 [see Warnings and Precautions (5.3) ] . Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. 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) [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) ]. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone's effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10) ] . If naloxone is prescribed, also advise patients and caregivers: How to treat with naloxone in the event of an opioid overdose. To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency. To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Accidental Ingestion Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.3) ] . Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (Including Alcohol) Inform patients and caregivers that potentially fatal additive effects may occur if Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4) , Drug Interactions (7) ]. Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children Advise caregivers that Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12-18 years of age receiving codeine to monitor for signs of respiratory depression [see Warnings and Precautions (5.5) ] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions (7) ] . MAOI Interaction Inform patients not to take Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules [see Drug Interactions (7) ]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.11) ] . Important Administration Instructions Instruct patients how to properly take Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, including the following: To take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed [see Dosage and Administration (2.1 , 2.3) ]. Do not take more than 4000 milligrams of acetaminophen per day and to call their healthcare provider if they took more than the recommended dose. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.4) ]. Severe Hypotension Inform patients that Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.12) ] . Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4) , Adverse Reactions (6) ]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.6) , Use in Specific Populations (8.1) ]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ]. Lactation Advise women that breastfeeding is not recommended during treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules [see Use in Specific Populations (8.2) ] . Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6) ]. Risks of Driving and Operating Heavy Machinery Inform patients that Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.17) ] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6) ] .

Medication Guide Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, C III Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are: A strong prescription pain medicine that contains an opioid (narcotic) that is indicated for the relief of the symptom complex of tension (or muscle contraction) headache, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules: Get emergency help or call 911 right away if you take too much Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules (overdose) . When you first start taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. Taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. They could die from taking it. Selling or giving away Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules is against the law. Store Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Get emergency help right away if you take more than 4,000 mg of acetaminophen in 1 day. Taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with other products that contain acetaminophen can lead to serious liver problems and death. Important Information Guiding Use in Pediatric Patients: Do not give Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules to a child younger than 12 years of age. Do not give Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids. Avoid giving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems. Do not take Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules if you have: severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines. Before taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, tell your healthcare provider if you have a history of: head injury, seizures problems urinating abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Have been told by your healthcare provider that you are a "rapid metabolizer" of certain medicines liver, kidney, thyroid problems pancreas or gallbladder problems Tell your healthcare provider if you are: pregnant or planning to become pregnant. Prolonged use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding. Not recommended; may harm your baby. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with certain other medicines can cause serious side effects that could lead to death. When taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules: Do not change your dose. Take Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. Take your prescribed dose of 1 or 2 capsules every 4 hours. Total daily dosage should not exceed 6 capsules. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. Call your healthcare provider if the dose you are taking does not control your pain. If you have been taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules regularly, do not stop taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules without talking to your healthcare provider. After you stop taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, dispose the unused Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in accordance with the local state guidelines and/or regulations. Dispose of expired, unwanted, or unused Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules by taking your drug to an authorized DEA-registered collector or drug take-back program. If one is not available, you can dispose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules by mixing the product with dirt, cat litter, or coffee grounds; placing the mixture in a sealed plastic bag, and throwing the bag in your trash. While taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules DO NOT: Drive or operate heavy machinery, until you know how Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules affect you. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause you to overdose and die. The possible side effects of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you: have trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. are a nursing mother taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, and your breastfeeding baby has increased sleepiness, confusion, difficulty breathing, shallow breathing, limpness, or difficulty breastfeeding. These are not all the possible side effects of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov Manufactured by: LGM Pharma Solutions, LLC, Irvine, CA 92614 Manufactured for: Breckenridge Pharmaceutical, Inc., Berlin, CT 06037 This Medication Guide has been approved by the U.S. Food and Drug Administration. 6670 Rev. 04/2021

8.5 Geriatric Use Clinical studies of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Butalbital is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients (aged 65 years or older) may have increased sensitivity to Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules slowly in geriatric patients and monitor closely for signs of respiratory depression [see Warnings and Precautions (5.9) ]. Components of this product are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.4 Pediatric Use The safety and effectiveness of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in pediatric patients have not been established. Life-threatening respiratory depression and deaths have occurred in children who received codeine [see Warnings and Precautions (5.5) ] . In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life-threatening respiratory depression and death: Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for all children younger than 12 years of age [see Contraindications (4) ] . Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4) ] . Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression [see Warnings and Precautions (5.5) ].

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 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/m 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. These effects did not occur in animals that received oral acetaminophen at doses 0.6 times the MHDD, based on a body surface area comparison. In a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.86, 1.7, and 3.4 times the MHDD, respectively, based on a body surface area comparison. A dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. Animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups. Caffeine In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained release pellets at 50 mg/kg (less than the maximum recommended daily dose on a mg/m 2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses.

8 USE IN SPECIFIC POPULATIONS 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 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 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/m 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. These effects did not occur in animals that received oral acetaminophen at doses 0.6 times the MHDD, based on a body surface area comparison. In a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.86, 1.7, and 3.4 times the MHDD, respectively, based on a body surface area comparison. A dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. Animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups. Caffeine In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained release pellets at 50 mg/kg (less than the maximum recommended daily dose on a mg/m 2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. 8.2 Lactation Risk Summary 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 the effects of the codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules [see Warnings and Precautions (5.5) ] . Acetaminophen is present in human milk in small quantities after oral administration. Based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 to 2% of the maternal dose. There is one well-documented report of a rash in a breastfed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. Barbiturates and caffeine are also excreted in breast milk in small amounts. Because of potential for serious adverse reactions in nursing infants from Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Clinical Considerations If infants are exposed to Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6) , Clinical Pharmacology (12.2) , Nonclinical Pharmacology (13.1) ]. Published literature indicates that acetaminophen affects sperm development in mice with consequent reduction in litter size in a multigeneration study [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in pediatric patients have not been established. Life-threatening respiratory depression and deaths have occurred in children who received codeine [see Warnings and Precautions (5.5) ] . In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life-threatening respiratory depression and death: Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for all children younger than 12 years of age [see Contraindications (4) ] . Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4) ] . Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression [see Warnings and Precautions (5.5) ]. 8.5 Geriatric Use Clinical studies of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Butalbital is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients (aged 65 years or older) may have increased sensitivity to Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules slowly in geriatric patients and monitor closely for signs of respiratory depression [see Warnings and Precautions (5.9) ]. Components of this product are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Hepatic Impairment No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of butalbital, codeine, and acetaminophen in this patient population are unknown. Start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. 8.7 Renal Impairment Codeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. In patients with renal disease, monitor effects of therapy with serial renal function tests.

16 HOW SUPPLIED/STORAGE AND HANDLING Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are dark blue, opaque cap with a gray, opaque body. The body is imprinted with "B 073" in black ink. Bottles of 100 (NDC 51991-073-01) Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]; and Dispense in a tight, light-resistant container. Store Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules securely and dispose of properly [see Patient Counseling Information (17) ]. Rx only Keep this and all medication out of the reach of children.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]; and Dispense in a tight, light-resistant container. Store Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules securely and dispose of properly [see Patient Counseling Information (17) ]. Rx only Keep this and all medication out of the reach of children.

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY See full prescribing information for complete boxed warning. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules expose users to the 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. ( 5.1 ) 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. ( 5.2 ) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. ( 5.3 ) Accidental ingestion of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, especially by children, can result in fatal overdose. Keep out of reach of children. ( 5.3 ) Concomitant use of opioids or a barbiturate with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.4 , 7 ) Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. ( 5.5 ). Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy ( 4 ). Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Prolonged use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. ( 5.6 ) 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, and Codeine Phosphate Capsules requires careful consideration of the effects on codeine, and the active metabolite, morphine. ( 5.7 , 7 ) Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. ( 5.8 ) Addiction, Abuse, and Misuse Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules expose 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 Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) ] . 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 REMS for these products [see Warnings and Precautions (5.2) ] . 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 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. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Monitor for respiratory depression, especially during initiation of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules or following a dose increase [see Warnings and Precautions (5.3) ] . Accidental Ingestion Accidental ingestion of even one dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, especially by children, can result in a fatal overdose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate [see Warnings and Precautions (5.3) ] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids or a barbiturate with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.4) , Drug Interactions (7) ] . Reserve concomitant prescribing of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children 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 an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism [see Warnings and Precautions (5.5) ] . Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4) ] . Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Neonatal Opioid Withdrawal Syndrome Prolonged use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 [see Warnings and Precautions (5.6) ] . Interactions with Drugs Affecting Cytochrome P450 Isoenzymes 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, and Codeine Phosphate Capsules requires careful consideration of the effects on codeine, and the active metabolite, morphine [see Warnings and Precautions (5.7) ] . Hepatotoxicity Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product [see Warnings and Precautions (5.8) ] .