Butalbital, Aspirin, Cafeine, and Codeine Phosphate

INDICATIONS AND USAGE Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when non-opioid analgesic and alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [ see Warnings and Precautions (5.1) ], reserve opioid analgesics, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is a combination of butalbital, a barbiturate, aspirin, a nonsteroidal anti-inflammatory drug, 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 analgesics and alternative treatments are inadequate. Limitations of Use : Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 )

DOSAGE AND ADMINISTRATION Periodically reassess patients receiving Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.1 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available, ( 2.1 ) Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Initiate treatment with one or two capsules every 4 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Total daily dose should not exceed 6 capsules. ( 2 , 5 ) Do not rapidly reduce or abruptly discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.4 , 5.16 ) 2.1 Important Dosage and Administration Instructions Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is a variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )] . 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Dosing Information One or two capsules every 4 hours as needed for pain. Total daily dosage should not exceed 6 capsules. Use the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. 2.4 Safe Reduction or Discontinuation of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP Do not rapidly reduce or abruptly discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt 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, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, there are a variety of factors that should be considered, including the total daily dose of opioid (including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP) 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 used disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. Ther

WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.8 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate closely, particularly during initiation and titration. ( 5.9 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. ( 5.11 ) Severe Hypotension : Regularly evaluate during dose initiation and titration. Avoid use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in patients with circulatory shock. ( 5.12 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Reguarly evaluate for sedation and respiratory depression. Avoid use of Butalbital, Aspirin, Caffeine, and Codeine Capsules, USP in patients with impaired consciousness or coma. ( 5.13 ) Fetal Toxicity : Limit use of NSAIDs, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus ( 5.17 , 8.1 ). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically ( 5.22 ). 5.1 Addiction, Abuse, and Misuse Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP contains codeine. Codeine in combination with butalbital, aspirin, and caffeine is a Schedule III controlled substance. As Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP contains butalbital and codeine, it exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 ) ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6.2 )] . Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP, and reassess all patients receiving Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, but use in such patients necessitates intensive counseling about the risks and proper use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and P recautions ( 5.2 )] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5. 2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid reversal agents, depending on the patient’s clinical status [see Overdosage ( 10 ) ] . Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP are essential [see Dosage and Administration ( 2.1 )]. Overestimating the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, especially by children, can result in respiratory depression and death due to an overdose of codeine and butalbital. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17 )] . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.4 )] . Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.3 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered

CONTRAINDICATIONS Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is contraindicated for: All children younger than 12 years of age [see Warnings and Precautions ( 5.6 ) ] Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions ( 5.6 ) ]. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.9 ) ] 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 )] Hypersensitivity or intolerance to aspirin, caffeine, butalbital, or codeine. Hemophilia [see Warnings and Precautions ( 5.19 ) ] Reye’s Syndrome [see Warnings and Precautions ( 5.20 ) ] Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions ( 5.23 ) ] Syndrome of asthma, rhinitis, and nasal polyps [see Warnings and Precautions ( 5.23 ) ] 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 ( 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 ) Hypersensitivity to aspirin, caffeine, butalbital, or codeine ( 4 ) Hemophilia ( 4 ) Reye’s Syndrome ( 4 ) Known allergy to NSAIDs ( 4 ) Syndrome of asthma, rhinitis, and nasal polyps ( 4 )

DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Table 1: Clinically Significant Drug Interactions with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP Inhibitors of CYP3A4 Clinical Impact: The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is achieved. 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, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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 ( 5.16 ) ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the codeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see Clinical Pharmacology ( 12.3 ) ] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use of a CYP3A4 inducer is necessary, evaluate patients at frequent intervals for reduced efficacy and signs of opioid withdrawal and consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage as needed. If a CYP3A4 inducer is discontinued, consider Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage reduction, and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Inhibitors of CYP2D6 Clinical Impact: Codeine in Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is metabolized by CYP2D6 to form morphine. The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and evaluate patients at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, evaluate patients for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and evaluate patients at frequent intervals for signs and symptoms of respiratory depression or sedation. Examples: paroxetine, fluoxetine, bupropion, quinidine Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose. 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, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP immediately if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT 3 receptor antagonists, drugs that effect 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, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, 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, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine, Muscle Relaxants Clinical Impact: Codeine may enhance the neuromuscula

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 ( 5.2 ) Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [ see Warnings and Precautions ( 5.6 ) ] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.8 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.11 ) ] Severe Hypotension [see Warnings and Precautions ( 5.12 ) ] Risk of Use in Patients with Gastrointestinal Conditions Including Peptic Ulcer Disease [see Warnings and Precautions ( 5.14 )] Increase Risk of Seizures in Patients with Seizure Disorders [see Warnings and Precautions ( 5.15 )] Withdrawal [see Warnings and Precautions ( 5.16 ) ] Coagulation Abnormalities and Bleeding Risks [see Warnings and Precautions ( 5.19 ) ] Reye’s Syndrome [see Warnings and Precautions ( 5.20 ) ] Serious Skin Reactions [see Warnings and Precautions ( 5.21 )] Allergy [see Warnings and Precautions ( 5.23 ) ] Most common adverse reactions (incidence > 1%) are nausea and/or abdominal pain, drowsiness, and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact LGM Pharma Solutions, LLC at 1-877-288-1495 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Incidence in Controlled Clinical Trials : The following table summarizes the incidence rates of the adverse events reported by at least 1% of the Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules treated patients in controlled clinical trials comparing Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules to placebo, and provides a comparison to the incidence rates reported by the placebo-treated patients. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. Adverse Events Reported by at Least 1% of Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules Treated Patients During Placebo Controlled Clinical Trials Incidence Rate of Adverse Events Body System/Adverse Event Butalbital, Aspirin, Caffeine, and Placebo Codeine Phosphate, USP (N =377) Capsules (N=382) Central Nervous Drowsiness 2.4% 0.5% Dizziness/Lightheadedness 2.6% 0.5% Intoxicated Feeling 1.0% 0% Gastrointestinal Nausea/Abdominal Pain 3.7% 0.8% Other Adverse Events Reported During Controlled Clinical Trials The listing that follows represents the proportion of the 382 patients exposed to Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules while participating in the controlled clinical trials who reported, on at least one occasion, an adverse event of the type cited. All reported adverse events, except those already presented in the previous table, are included. It is important to emphasize that, although the adverse events reported did occur while the patient was receiving Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules, the adverse events were not necessarily caused by Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules. Adverse events are classified by body system and frequency. “Frequent” is defined as an adverse event which occurred in at least 1/100 (1%) of the patients; all adverse events listed in the previous table are frequent. “Infrequent” is defined as an adverse event that occurred in less than 1/100 patients but at least 1/1000 patients. 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, and sluggishness. Autonomic Nervous : dry mouth and hyperhidrosis. Gastrointestinal : vomiting, difficulty swallowing, and heartburn. Cardiovascular : tachycardia. Musculoskeletal : leg pain and muscle fatigue. Genitourinary : diuresis. Miscellaneous : pruritus, fever, earache, nasal congestion, and tinnitus. The following adverse drug reactions have been reported with the components of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Potential effects of high dosage are listed in the [see Overdosage ( 10 ) ] section of this insert. Aspirin : occult blood loss, hemolytic anemia, iron deficiency anemia, gastric distress, heartburn, nausea, peptic ulcer, prolonged bleeding time, acute airway obstruction, renal toxicity when taken in high doses for prolonged periods, impaired urate excretion, hepatitis. Caffeine : cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia. Codeine : nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules. Because these reactions are 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. Central Nervous : abuse, addiction, anxiety, depression, disorientation, hallucination, hyperactivity, insomnia, libido decrease, nervousness, neuropathy, psychosis, sedation, sexual activity increase, slurred speech, twitching, unconsciousness, vertigo. Autonomic Nervous : epistaxis, flushing, miosis, salivation. Gastrointestinal : anorexia, appetite increased, constipation, diarrhea, esophagitis, gastroenteritis, gastrointestinal spasm, hiccup, mouth burning, pyloric ulcer. Cardiovascular : chest pain, hypotensive reaction, palpitations, syncope. Skin : erythema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), hives, rash, toxic epidermal necrolysis, and fixed drug eruption (FDE). Urinary : kidney impairment, urinary difficulty. Miscellaneous : allergic reaction, anaphylactic shock, cholangiocarcinoma, drug interaction with erythromycin (stomach upset), edema. 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. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.8 )] . Hyp o glycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.14 )] . Adverse Reactions from Observ

Mechanism of Action Butalbital, a barbiturate, is a GABA A receptor agonist and may inhibit excitatory AMPA receptors. Aspirin is a nonsteroidal anti-inflammatory drug and a non-selective irreversible inhibitor of cyclooxygenases. 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.