Butalbital, Aspirin, Caffeine and Codeine Phosphate (codeine phosphate 30 mg butalbital 50 mg caffeine 40 mg aspirin 325 mg) Dailymed

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. (2.1)
• Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1)
• Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Consider prescribing naloxone based on the patient’s risk factors for overdose (2.2, 5.1, 5.3, 5.4).
• Initiate treatment with one or two capsules every 4 hours. Total daily dosage should not exceed 6 capsules. (2.3)  
• Do not abruptly discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.4)

2.1

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5.1 )] .

Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see   Warnings and Precautions ( 5.1 )].

2.2

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP [see Warnings and Precautions ( 5.3 ), Patient Counseling Information ( 17 )]. 



Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).



Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.1 , 5.3 , 5.4 )].



Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

2.3

One or two capsules every 4 hours. Total daily dosage should not exceed 6 capsules.

Do not abruptly discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid dependent patient taking Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, there are a variety of factors that should be considered, including the dose of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and reaulic. 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 speciaul.

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, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.15 ), Drug Abuse and Dependence ( 9.3 )].

3

Capsules: Butalbital, 50 mg, Aspirin, 325 mg, Caffeine, 40 mg, Codeine Phosphate, 30 mg

Blue cap with a yellow body. Cap is imprinted with “WATSON” in red. Body is imprinted with “3546” in red.

• Capsules: 50 mg butalbital, 325 mg aspirin, 40 mg caffeine, and 30 mg codeine phosphate (3)

 

4

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP are contraindicated for:

• All children younger than 12 years of age [see Warnings and Precautions ( 5.5 )]
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions ( 5.5 )]

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP are also contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions ( 5.8 )]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.8 )]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.9 ) ,   Drug Interactions ( 7 )]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions   ( 5.13 )]
• Hypersensitivity or intolerance to aspirin, caffeine, butalbital, or codeine. 
• Hemophilia [see Warnings and Precautions ( 5.18 )]
• Reye’s Syndrome [see Warnings and Precautions ( 5.19 )]
• Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions ( 5.21 )]
• Syndrome of asthma, rhinitis, and nasal polyps [see Warnings and Precautions ( 5.21 )]

• Children younger than 12 years of age (4)
• Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (4)
• Significant respiratory depression (4)
• Acute or severe bronchial asthma (4)
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (4)
• Known or suspected gastrointestinal obstruction, including paralytic ileus (4)
• Hypersensitivity to aspirin, caffeine, butalbital, or codeine (4)
• Hemophilia (4)
• Reye’s Syndrome (4)
• Known allergy to NSAIDs (4)
• Syndrome of asthma, rhinitis, and nasal polyps (4)

5

• 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 Hypotensi on: Monitor during dose initiation and titration. Avoid use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, USP in patients with impaired consciousness or coma. (5.12)
• Fetal Toxicity: Limit use of NSAIDs, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.16, 8.1).
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically (5.20).

5.

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP contain codeine. Codeine in combination with butalbital, aspirin, and caffeine is a Schedule III controlled substance. As Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, USP. 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, USP, and monitor all patients receiving Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, but use in such patients necessitates intensive counseling about the risks and proper use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP along with intensive monitoring for signs of addiction, abuse, and misuse.

Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )].

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, USP. 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

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 ul 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.

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, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, 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, USP.

To reduce the risk of respiratory depression, proper dosing and titration of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP are essential [see Dosage and Administration ( 2.1 )]. Overestimating the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, especially by children, can result in respiratory depression and death due to an overdose of codeine and butalbital.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17 )].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.4 )].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information ( 17 )].



Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions ( 5.1 , 5.4 ), Patient Counseling Information ( 17 )] .

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )].

Advise both patients and caregivers about the risks of respiratory depression and sedation when Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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 [ s e e   Drug I nt e r a c tions   ( 7 )   and Pati e nt C ouns e ling I nformation ( 17 ) ].

5.

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, USP are contraindicated for all children younger than 12 years of age [see   Contraindications ( 4 )].
• Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, USP 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, USP 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 ), Overd osag e ( 10 )].

N ursing M oth e rs

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, USP [s e e   Use   in S p ec ific   Populations ( 8.2 )].

C Y P2D6 G e n e tic   Variabilit y :   Ultra - rapid m e taboliz e r

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) [ s ee Ove rdosage ( 10 )]. Therefore, individuals who are ultra-rapid metabolizers should not use Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP.

Prolonged use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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 [s e e   Use   in Sp e c ific   Po p ulations ( 8.1 , 8.2 ) , Pati e nt C ouns e ling I nformatio n ( 17 ) ].

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, USP requires 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, USP 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, USP 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, USP 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, USP 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, USP 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, USP 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, USP 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, USP and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, USP dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage and follow the patient for signs and symptoms of respiratory depression or sedation [see Drug Interactions ( 7 )].

5.

The use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, USP -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, USP [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, USP and when Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP are 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.

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, USP should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

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.

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, USP. In patients with circulatory shock, Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in patients with circulatory shock.

5.

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may reduce respiratory drive, and the resultant CO₂ 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, USP.

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, USP in patients with impaired consciousness or coma.

5.

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The codeine in Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, USP 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.

The codeine in Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, USP therapy.

5.

Do not abruptly discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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 ( 2.4 ), 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, USP. 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, USP in a physically dependent patient, gradually taper the dosage [see Dosage and Administration ( 2.4 )]. Abrupt discontinuation of butalbital can cause seizures [see Drug Abuse and Dependence ( 9.3 )].

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, in pregnant women at about 30 weeks gestation and later. NSAIDs, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.



Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.



If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP treatment extends beyond 48 hours. Discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations ( 8.1 )].

5.

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP 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, USP and know how they will react to the medication.

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.

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.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Some of these events have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and evaluate the patient immediately.

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).

DRUG & OR LABORATORY TEST INTERACTIONS SECTION

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.