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warnings and cautions
5 WARNINGS AND PRECAUTIONS L i f e - T h r e at e nin g R e s pi r a t or y D e p r e ss i o n i n P a t i e nt s w ith C h ro n i c P u l m o na r y D i s e a se o r i n E l d e rl y , Ca c h e ct i c , or D e bi l i t at e d P a t i e nt s: Monitor closely, particularly during initiation and titration. ( 5.8 ) A d r e na l I n s u ff ici e nc y : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.10 ) S e v e r e H y p o t e n s i o n : Monitor during dosage initiation and titration. Avoid use of Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules in patients with circulatory shock. ( 5.11 ) Ri s k s o f U se i n P a ti e n t s w i t h I nc r e a s ed I nt r ac r a n ial Pr e ss u r e , B r a i n T u m or s, H e a d I nju r y , o r I m pai r e d C o n s c i o u s n e ss: Monitor for sedation and respiratory depression. Avoid use of Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules in patients with impaired consciousness or coma. ( 5.12 ) 5.1 Addiction, Abuse, and Misuse Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules contain codeine. Codeine in combination with butalbital, acetaminophen, and caffeine is a Schedule III controlled substance. As Butalbital, Acetaminophen, and Caffeine with 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, and Caffeine with Codeine Phosphate Capsules. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules, and monitor all patients receiving Butalbital, Acetaminophen, and Caffeine with 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, and Caffeine with Codeine Phosphate Capsules, but use in such patients necessitates intensive counseling about the risks and proper use of Butalbital, Acetaminophen, and Caffeine with 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, Acetaminophen, and Caffeine with 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 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 (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Butalbital, Acetaminophen, and Caffeine with 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, Acetaminophen, and Caffeine with Codeine Phosphate Capsules. To reduce the risk of respiratory depression, proper dosing and titration of Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules are essential [see Dosage and Administration ( 2.2 )] . Overestimating the Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of (or exposure to) Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules, especially by children, can result in respiratory depression and death due to an overdose of codeine and butalbital. 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, and Caffeine with 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 [ s e e Drug I nt e ra c tions ( 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, Acetaminophen, and Caffeine with 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 ), Patient Counseling Information ( 17 )] . 5.4 Neonatal Opioid Withdrawal Syndrome Prolonged use of Butalbital, Acetaminophen, and Caffeine with 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 )]. 5.5 Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see Contraindications ( 4 )]. Respiratory depression and death have occurred in children who received codeine in the post- operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra- rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine. 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 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. 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). Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. 5.6 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, and Caffeine with 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, and Caffeine with 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, and Caffeine with 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, Acetaminophen, and Caffeine with Codeine Phosphate Capsules and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Butalbital, Acetaminophen, and Caffeine with 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, and Caffeine with 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, Acetaminophen, and Caffeine with 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, Acetaminophen, and Caffeine with 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, Acetaminophen, and Caffeine with Codeine Phosphate Capsules and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Butalbital, Acetaminophen, and Caffeine with 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, Acetaminophen, and Caffeine with Codeine Phosphate Capsules dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules dosage and follow the patient for signs and symptoms of respiratory depression or sedation [see Drug Interactions ( 7 )] . 5.7 Hepatotoxicity Butalbital, Acetaminophen, and Caffeine with 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. 5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Butalbital, Acetaminophen, and Caffeine with 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, and Caffeine with 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, and Caffeine with 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 )]. Monitor such patients closely, particularly when initiating and titrating Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules and when Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules are given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 )]. 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, Acetaminophen, and Caffeine with 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, Acetaminophen, and Caffeine with 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, Acetaminophen, and Caffeine with Codeine Phosphate Capsules. In patients with circulatory shock, Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Butalbital, Acetaminophen, and Caffeine with 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, Acetaminophen, and Caffeine with 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, and Caffeine with Codeine Phosphate Capsules. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules in patients with impaired consciousness or coma. 5.13 Risks of Use in Patients with Gastrointestinal Conditions Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The codeine in Butalbital, Acetaminophen, and Caffeine with 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. 5.14 Increased Risk of Seizures in Patients with Seizure Disorders The codeine in Butalbital, Acetaminophen, and Caffeine with 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, Acetaminophen, and Caffeine with Codeine Phosphate Capsules therapy. 5.15 Withdrawal 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, and Caffeine with 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, and Caffeine with Codeine Phosphate Capsules, in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration ( 2.3 )] . Do not abruptly discontinue Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules in these patients. Abrupt discontinuation of butalbital can cause seizures [see Drug Abuse and Dependence ( 9.3 )] . 5.16 Risks of Driving and Operating Machinery Butalbital, Acetaminophen, and Caffeine with 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, and Caffeine with Codeine Phosphate Capsules and know how they will react to the medication. 5.17 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. 5.18 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, and Caffeine with Codeine Phosphate Capsules immediately and seek medical care if they experience these symptoms. Do not prescribe Butalbital, Acetaminophen, and Caffeine with Codeine Phosphate Capsules for patients with acetaminophen allergy. 5.19 Drug/Laboratory Test Interactions C od e in e : Codeine may increase serum amylase levels. A ce t a minoph e n: Acetaminophen may produce false positive test results for urinary 5-hydroxyindoleacetic acid.