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warnings and cautions
5 WARNINGS AND PRECAUTIONS Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.8 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. ( 5.10 ) Severe Hypotension : Monitor during dose initiation and titration. Avoid use of butalbital, aspirin, caffeine, and codeine phosphate capsules in patients with circulatory shock. ( 5.11 ) 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, aspirin, caffeine, and codeine phosphate capsules in patients with impaired consciousness or coma. ( 5.12 ) 5.1 Addiction, Abuse, and Misuse Butalbital, aspirin, caffeine, and codeine phosphate capsules contain codeine. Codeine in combination with butalbital, aspirin, and caffeine is a Schedule III controlled substance. As butalbital, aspirin, caffeine, and codeine phosphate capsules contain 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. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient's risk for addiction, abuse, or misuse prior to prescribing butalbital, aspirin, caffeine, and codeine phosphate capsules, and monitor all patients receiving butalbital, aspirin, 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, aspirin, caffeine, and codeine phosphate capsules, but use in such patients necessitates intensive counseling about the risks and proper use of butalbital, aspirin, caffeine, and codeine phosphate capsules along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids and barbiturates are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing butalbital, aspirin, caffeine, and codeine phosphate capsules. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17) ] . Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Healthcare 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 . 5.3 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 antagonists, 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, aspirin, caffeine, and codeine phosphate capsules, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of butalbital, aspirin, caffeine, and codeine phosphate capsules. To reduce the risk of respiratory depression, proper dosing and titration of butalbital, aspirin, caffeine, and codeine phosphate capsules are essential [see Dosage and Administration (2.1) ] . Overestimating the butalbital, aspirin, 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 butalbital, aspirin, caffeine, and codeine phosphate capsules, especially by children, can result in respiratory depression and death due to an overdose of codeine and butalbital. 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 (2.3) ] . 5.4 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, aspirin, caffeine, and codeine phosphate capsules with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). 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. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when butalbital, aspirin, caffeine, and codeine phosphate capsules is 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) and Patient Counseling Information (17) ]. 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. 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 postmarketing reports, children younger than 12 years old 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, aspirin, caffeine, and codeine phosphate capsules are contraindicated for all children younger than 12 years of age [see Contraindications (4) ] . Butalbital, aspirin, 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, aspirin, 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 postoperative 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 butalbital, aspirin, caffeine, and codeine phosphate capsules 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 (8.4) , 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, aspirin, 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/*1×N or *1/*2×N). 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, aspirin, caffeine, and codeine phosphate capsules. 5.6 Neonatal Opioid Withdrawal Syndrome Prolonged use of butalbital, aspirin, caffeine, and codeine phosphate capsules 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 a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1 , 8.2) , Patient Counseling Information (17) ] . 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, aspirin, 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, aspirin, 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, aspirin, 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. Follow patients receiving butalbital, aspirin, caffeine, and codeine phosphate capsules and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when butalbital, aspirin, caffeine, and codeine phosphate capsules is 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, aspirin, caffeine, and codeine phosphate capsules until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the butalbital, aspirin, caffeine, and codeine phosphate capsules dosage until stable drug effects are achieved. Monitor 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, aspirin, 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. Follow patients receiving butalbital, aspirin, caffeine, and codeine phosphate capsules and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when butalbital, aspirin, caffeine, and codeine phosphate capsules are used in conjunction with inhibitors of CYP2D6. If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the butalbital, aspirin, caffeine, and codeine phosphate capsules dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the butalbital, aspirin, caffeine, and codeine phosphate capsules dosage and follow the patient for signs and symptoms of respiratory depression or sedation [see Drug Interactions (7) ] . 5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of butalbital, aspirin, 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, aspirin, 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, aspirin, caffeine, and codeine phosphate capsules [see Warnings and Precautions (5.8) ] . 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 (5.8) ]. Monitor such patients closely, particularly when initiating and titrating butalbital, aspirin, caffeine, and codeine phosphate capsules and when butalbital, aspirin, caffeine, and codeine phosphate capsules is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3) ] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.9 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, aspirin, caffeine, and codeine phosphate capsules should not be used in patients taking MAOIs or within 14 days of stopping such treatment. 5.10 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. 5.11 Severe Hypotension Butalbital, aspirin, 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) ] . Monitor these patients for signs of hypotension after initiating or titrating the dosage of butalbital, aspirin, caffeine, and codeine phosphate capsules. In patients with circulatory shock, butalbital, aspirin, caffeine, and codeine phosphate capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of butalbital, aspirin, caffeine, and codeine phosphate capsules in patients with circulatory shock. 5.12 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness 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, aspirin, 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, aspirin, caffeine, and codeine phosphate capsules. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of butalbital, aspirin, caffeine, and codeine phosphate capsules in patients with impaired consciousness or coma. 5.13 Risks of Use in Patients with Gastrointestinal Conditions Including Peptic Ulcer Disease Butalbital, aspirin, caffeine, and codeine phosphate capsules are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The codeine in butalbital, aspirin, caffeine, and codeine phosphate capsules may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. The aspirin in butalbital, aspirin, caffeine, and codeine phosphate capsules can cause GI side effects including stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. 5.14 Increased Risk of Seizures in Patients with Seizure Disorders The codeine in butalbital, aspirin, 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. Monitor patients with a history of seizure disorders for worsened seizure control during butalbital, aspirin, caffeine, and codeine phosphate capsules therapy. 5.15 Withdrawal Do not abruptly discontinue butalbital, aspirin, caffeine, and codeine phosphate capsules in a patient physically dependent on opioids. Rapid tapering of butalbital, aspirin, caffeine, and codeine phosphate capsules in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.3) , 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, aspirin, 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 [see Drug Interactions (7) ] . When discontinuing butalbital, aspirin, caffeine, and codeine phosphate capsules in a physically dependent patient, gradually taper the dosage [see Dosage and Administration (2.3) ]. Abrupt discontinuation of butalbital can cause seizures [see Drug Abuse and Dependence (9.3) ]. 5.16 Risks of Driving and Operating Machinery Butalbital, aspirin, 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, aspirin, caffeine, and codeine phosphate capsules and know how they will react to the medication. 5.17 Coagulation Abnormalities and Bleeding Risks Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (i.e. hemophilia) or acquired (i.e. liver disease or vitamin K deficiency) bleeding disorders. Aspirin is contraindicated in patients with hemophilia. Aspirin administered pre-operatively may prolong the bleeding time. Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. 5.18 Reye's Syndrome Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye's syndrome with concomitant use of aspirin in certain viral illnesses. 5.19 Allergy Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products (NSAIDs) and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). 5.20 Drug/Laboratory Test Interactions Aspirin: Aspirin may interfere with the following laboratory determinations in blood: serum amylase, fasting blood glucose, cholesterol, protein, serum glutamic-oxalacetic transaminase (SGOT), uric acid, prothrombin time and bleeding time. Aspirin may interfere with the following laboratory determinations in urine: glucose, 5-hydroxy-indoleacetic acid, Gerhardt ketone, vanillylmandelic acid (VMA), uric acid, diacetic acid, and spectrophotometric detection of barbiturates. Codeine: Codeine may increase serum amylase levels.