Butalbital, Aspirin, Caffeine, and Codeine Phosphate: Package Insert and Label Information

BUTALBITAL, ASPIRIN, CAFFEINE, AND CODEINE PHOSPHATE- butalbital, aspirin, caffeine and codeine phosphate capsule
Mayne Pharma Inc.

WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES

Addiction, Abuse, and Misuse

Butalbital, aspirin, caffeine, and codeine phosphate capsules expose 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 butalbital, aspirin, caffeine, and codeine phosphate capsules, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

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 REMS for these products [see Warnings and Precautions (5.2)]. 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

  • complete a REMS-compliant education program,
  • counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
  • emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
  • consider other tools to improve patient, household, and community safety

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of butalbital, aspirin, caffeine, and codeine phosphate capsules. Monitor for respiratory depression, especially during initiation of butalbital, aspirin, caffeine, and codeine phosphate capsules or following a dose increase [see Warnings and Precautions (5.3)].

Accidental Ingestion

Accidental ingestion of even one dose of butalbital, aspirin, caffeine, and codeine phosphate capsules, especially by children, can result in a fatal overdose of butalbital, aspirin, caffeine, and codeine phosphate capsules [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.4 , 5.8), Drug Interactions (7)].

  • Reserve concomitant prescribing of butalbital, aspirin, caffeine, and codeine phosphate capsules and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.

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 (5.5)]. Butalbital, aspirin, 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, 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.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of butalbital, aspirin, caffeine, and codeine phosphate capsules during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.6)].

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 [see Warnings and Precautions (5.7 , 5.8), Drug Interactions (7)].

1 INDICATIONS AND USAGE

Butalbital, aspirin, 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, and misuse with opioids and butalbital, even at recommended doses [see Warnings and Precautions (5.1)] , reserve butalbital, aspirin, caffeine, and codeine phosphate capsules for use in patients for whom alternative treatment options (e.g., non-opioid, non-barbiturate analgesics):

  • Have not been tolerated, or are not expected to be tolerated,
  • Have not provided adequate analgesia, or are not expected to provide adequate analgesia

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

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 Dosing Information

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

2.3 Safe Reduction or Discontinuation of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules

Do not abruptly discontinue butalbital, aspirin, caffeine, and codeine phosphate capsules 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, there are a variety of factors that should be considered, including the dose of butalbital, aspirin, 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, aspirin, 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, 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 DOSAGE FORMS AND STRENGTHS

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

Purple cap with a yellow body. Body is imprinted with “312” in black.

4 CONTRAINDICATIONS

Butalbital, aspirin, caffeine, and codeine phosphate capsules are contraindicated for:

Butalbital, aspirin, caffeine, and codeine phosphate capsules are also contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

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 (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, 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)].

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