Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules: Dark blue, opaque cap is imprinted with “WATSON” in light blue. White, opaque body is imprinted with “3220” in red. Bottles of 100 are supplied with child-resistant closures (NDC 0591-3220-01). Store below 30°C (86°F); and dispense in a tight container. Store Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules securely and dispose of properly.; Package/Label Display Panel NDC 0591- 3220 -01 CIII 50mg, 325mg, 40mg, 30mg Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules Medication Guide Required: Dispense the accompanying Medication Guide to each patient. Actavis 100 Capsules Rx Only image
- 16 HOW SUPPLIED/STORAGE AND HANDLING Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules: Dark blue, opaque cap is imprinted with “WATSON” in light blue. White, opaque body is imprinted with “3220” in red. Bottles of 100 are supplied with child-resistant closures (NDC 0591-3220-01). Store below 30°C (86°F); and dispense in a tight container. Store Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules securely and dispose of properly.
- Package/Label Display Panel NDC 0591- 3220 -01 CIII 50mg, 325mg, 40mg, 30mg Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules Medication Guide Required: Dispense the accompanying Medication Guide to each patient. Actavis 100 Capsules Rx Only image
Overview
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: Acetaminophen (4'hydroxyacetanilide), is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula: Caffeine (1,3,7trimethylxanthine), a methylxanthine, is a central nervous system stimulant. It has the following structural formula: 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: Inactive Ingredients: colloidal silicon dioxide, magnesium stearate, pregelatinized starch. Gelatin capsules contain D&C Red No. 33, FD&C Blue No. 1, gelatin, and titanium dioxide. The capsules are printed with edible inks containing D&C Red No. 7 Calcium Lake, FD&C Blue No. 1 Aluminum Lake, and titanium dioxide. chem-structure-but.jpg chem-structure-acet.jpg chem-structure-caff.jpg chem-structure-cod.jpg
Indications & Usage
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are indicated for the management of the symptom complex of tension (or muscle contraction) headache when non-opioid analgesic and alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration, and persist over the course of therapy, [see Warnings and Precautions ( 5.1 )], reserve opioid analgesics, including Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsule is a combination product of butalbital, a barbiturate; acetaminophen; caffeine, a methylxanthine; and codeine phosphate, an opioid agonist; and is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when other non-opioid analgesic and alternative treatments are inadequate. ( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration, and persist over the course of therapy, reserve opioid analgesics, including Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 )
Dosage & Administration
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate capsules, 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 ) 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Total daily dosage should not exceed 6 capsules. ( 2.3 , 5 ) Periodically reassess patients receiving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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. ( 2.4 ) Do not rapidly reduce or abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 , 5.18 ) 2.1 Important Dosage and Administration Instructions Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5.2 )]. 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 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 , 5.2 , 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. 2.4 Titration and Maintenance of Therapy Individually titrate Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 , 5.18 )] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules Do not rapidly reduce or abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, there are a variety of factors that should be considered, including the total daily dose of opioid (including 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, evaluate 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 an extended period of time 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 ( 5.18 ), Drug Abuse and Dependence ( 9.3 )] .
Warnings & 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. ( 5.9 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate patients, particularly during initiation and titration. ( 5.10 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.12 ) Severe Hypotension: Regularly evaluate patients during dosage initiation and titration. Avoid use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with circulatory shock. ( 5.13 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with impaired consciousness or coma. ( 5.14 ) 5.1 Addiction, Abuse, and Misuse Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain codeine. Codeine in combination with butalbital, acetaminophen, and caffeine is a Schedule III controlled substance. As Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain butalbital and codeine, they expose users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6 )] . Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, and reassess all patients receiving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules but use in such patients necessitates intensive counseling about the risks and proper use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )] . Opioids and barbiturates are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drug . Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents, depending on the patient’s clinical status [see Overdosage ( 10 )] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are essential [see Dosage and Administration ( 2.3 )]. Overestimating the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, especially by children, can result in respiratory depression and death due to an overdose of codeine and butalbital. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.5 )]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.3 ) . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage ( 10 )] . 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7 )]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ), Overdosage ( 10 )] . Advise both patients and caregivers about the risks of respiratory depression and sedation when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7 ). 5.4 Neonatal Opioid Withdrawal Syndrome Use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1 ). 5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. 5.6 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. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years of age appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. 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. As with adults, when prescribing codeine for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [see Use in Specific Populations ( 8 ), Overdosage ( 10 )] . Nursing Mothers At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules [see Use in Specific Populations ( 8.2 )] . CYP2D6 Genetic Variability: Ultra-rapid metabolizer Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see Overdosage ( 10 )] . Therefore, individuals who are ultra-rapid metabolizers should not use Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. 5.7 Risks of 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 require careful consideration of the effects on codeine and the active metabolite, morphine. Cytochrome P450 3A4 Interaction The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Evaluate patients receiving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and any CYP3A4 inhibitor or inducer at frequent intervals for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are used in conjunction with inhibitors and inducers of CYP3A4. If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage until stable drug effects are achieved. Evaluate patients at frequent intervals for signs of opioid withdrawal [see Drug Interactions ( 7 )] . Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. Evaluate patients receiving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and any CYP2D6 inhibitor at frequent intervals for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are used in conjunction with inhibitors of CYP2D6. If concomitant use with a CYP2D6 inhibitor is necessary, evaluate patients at frequent intervals for signs of reduced efficacy or opioid withdrawal and consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage and evaluate patients at frequent intervals for signs and symptoms of respiratory depression or sedation [see Drug Interactions ( 7 )] . 5.8 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 4000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well. 5.9 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. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence ( 9.3 )]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.18 )]. 5.10 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules [see Warnings and Precautions ( 5.2 )]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions ( 5.2 )] . Regularly evaluate such patients, particularly when initiating and titrating Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.11 Interaction with Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules should not be used in patients taking MAOIs or within 14 days of stopping such treatment. 5.12 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.13 Severe Hypotension Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions ( 7 )]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. In patients with circulatory shock, Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with circulatory shock. 5.14 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with impaired consciousness or coma. 5.15 Risks of Gastrointestinal Complications Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The codeine in Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology ( 12.2 )] . 5.16 Hypersensitivity/Anaphylaxis There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules immediately and seek medical care if they experience these symptoms. Do not prescribe Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules for patients with acetaminophen allergy. 5.17 Increased Risk of Seizures in Patients with Seizure Disorders The codeine in Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules therapy. 5.18 Withdrawal Do not rapidly reduce or abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine in a patient physically dependent on opioids. Rapid tapering of Butalbital, Acetaminophen, Caffeine, and Codeine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration ( 2.5 ), Drug Abuse and Dependence ( 9.3 )] . Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. When discontinuing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration ( 2.5 )] . Abrupt discontinuation of butalbital can cause seizures [see Drug Abuse and Dependence ( 9.3 )] . 5.19 Risks of Driving and Operating Machinery Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and know how they will react to the medication. 5.20 Serious Skin Reactions Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. 5.21 Drug/Laboratory Test Interactions Codeine: Codeine may increase serum amylase levels. Acetaminophen: Acetaminophen may produce false positive test results for urinary 5‑hydroxyindoleacetic acid.
Boxed Warning
SERIOUS AND LIFE-THREATENING RISKS FROM USE OF BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE CAPSULES Addiction, Abuse, and Misuse Because the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules exposes 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 and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are essential [see Warnings and Precautions ( 5.2 )]. 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 codeine [see Warnings and Precautions ( 5.2 )]. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )]. Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions ( 5.4 )]. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions ( 5.5 )]. 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 ( 5.6 )] . 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. 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 )] . WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE CAPSULES 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 reassess regularly for these behaviors and conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation and following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are essential. ( 5.2 ) Accidental ingestion of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, especially by children, can result in fatal overdose. Keep out of reach of children. ( 5.2 ) 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. ( 5.3 , 7 ) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.4 ) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. ( 5.5 ) 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. ( 5.6 ). 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. 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 )
Contraindications
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for: All children younger than 12 years of age [see Warnings and Precautions ( 5.6 )] Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions ( 5.6 )] Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.10 )] Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.11 ), Drug Interactions ( 7 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.15 )] Known intolerance or hypersensitivity to acetaminophen, caffeine, butalbital, or codeine or to the components of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules Porphyria Children younger than 12 years of age. ( 4 ) Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. ( 4 ) Significant respiratory depression. ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Intolerance or hypersensitivity to acetaminophen, caffeine, butalbital or codeine, or components of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. ( 4 ) Porphyria. ( 4 )
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 )] Interactions with Benzodiazepines and other CNS Depressants [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.6 )] Hepatotoxicity [see Warnings and Precautions ( 5.8 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.9 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.12 )] Severe Hypotension [see Warnings and Precautions ( 5.13 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.15 )] Anaphylaxis [see Warnings and Precautions ( 5.16 )] Seizures [see Warnings and Precautions ( 5.17 )] Withdrawal [see Warnings and Precautions ( 5.18 )] Serious Skin Reactions [see Warnings and Precautions ( 5.20 )] The following adverse reactions associated with the use of butalbital, acetaminophen, caffeine, and codeine phosphate were identified in clinical studies or post-marketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Frequently Observed The most frequently reported adverse reactions were drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, abdominal pain, and intoxicated feeling. Infrequently Observed All adverse events tabulated below are classified as infrequent. Central Nervous : headache, shaky feeling, tingling, agitation, fainting, fatigue, heavy eyelids, high energy, hot spells, numbness, sluggishness, seizure. Mental confusion, excitement or depression can also occur due to intolerance, particularly in elderly or debilitated patients, or due to overdosage of butalbital. Autonomic Nervous : dry mouth, hyperhidrosis. Gastrointestinal : difficulty swallowing, heartburn, flatulence, constipation. Cardiovascular : tachycardia. Musculoskeletal: leg pain, muscle fatigue. Genitourinary: diuresis. Miscellaneous : pruritus, fever, earache, nasal congestion, tinnitus, euphoria, allergic reactions. The following adverse reactions have been voluntarily reported as temporally associated with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, a related product containing aspirin, butalbital, caffeine, and codeine phosphate. Central Nervous : abuse, addiction, anxiety, disorientation, hallucination, hyperactivity, insomnia, libido decrease, nervousness, neuropathy, psychosis, sexual activity increase, slurred speech, twitching, unconsciousness, vertigo. Autonomic Nervous : epistaxis, flushing, miosis, salivation. Gastrointestinal : anorexia, appetite increased, diarrhea, esophagitis, gastroenteritis, gastrointestinal spasms, hiccup, mouth burning, pyloric ulcer. Cardiovascular : chest pain, hypotensive reaction, palpitations, syncope. Skin : erythema, erythema multiforme, exfoliative dermatitis, hives, rash, toxic epidermal necrolysis. Urinary : kidney impairment, urinary difficulty. Miscellaneous : allergic reaction, anaphylactic shock, cholangiocarcinoma, drug interaction with erythromycin (stomach upset), edema. The following adverse reactions have been reported with the components of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Potential effects of high dosage are listed in the OVERDOSAGE section. Acetaminophen : allergic reactions, rash, thrombocytopenia, agranulocytosis. Caffeine : cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia. Codeine : nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus. Several cases of dermatological reactions, including toxic epidermal necrolysis and erythema multiforme, have been reported for butalbital, acetaminophen, and caffeine tablets, USP. Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.9 )]. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.15 )] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one of more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 )] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies. 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 Actavis Pharma LLC at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice CYP3A4 Inducers Clinical Impact: The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and CYP3A4 inducers can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [see Warnings and Precautions ( 5.7 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the codeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use of a CYP3A4 inducer is necessary, evaluate the patient at frequent intervals for reduced efficacy and signs of opioid withdrawal and consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage as needed. If a CYP3A4 inducer is discontinued, consider lowering Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage until stable drug effects are achieved. Evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Inhibitors of CYP2D6 Clinical Impact: Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and CYP2D6 inhibitors can increase the plasma concentration of codeine, but can decrease the plasma concentrations of active metabolite morphine, which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules is achieved [see Clinical Pharmacology ( 12.3 )] . After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression [see Clinical Pharmacology ( 12.3 )] . Intervention: If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and evaluate patients at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, evaluate the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and evaluate the patient at frequent intervals for signs and symptoms of respiratory depression or sedation. Examples: paroxetine, fluoxetine, bupropion, quinidine Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.3 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.11 )]. Intervention: Do not use Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydromorphone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. 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: Because respiratory depression may be greater than otherwise expected, 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 recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.3 )]. Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate 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: Evaluate 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 )
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