Drug Safety-related Labeling Changes (SrLC)

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FIORICET W/ CODEINE (NDA-020232)

(ACETAMINOPHEN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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03/04/2021 (SUPPL-45)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

… Patients at increased risk may be prescribed opioids such as Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, but use in such patients necessitates intensive counseling about the risks and proper use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules along with 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)].

5.3 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

… Accidental ingestion of even one dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, especially by children, can result in respiratory depression and death due to an overdose of codeine and butalbital.

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

Newly added information:

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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. 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)].

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

… 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)].

7 Drug Interactions

Table 1: Clinically Significant Drug Interactions with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Under Intervention, the following language is added:

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3, 5.4)].

Muscle Relaxants

Under Intervention, the following language is added:

Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3, 5.4)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Important information about Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules:

Additions and/or revisions underlined:

  • Get emergency help or call 911 right away if you take too much Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules (overdose). When you first start taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.

Before taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, tell your healthcare provider if you have a history of:

  • abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.

Tell your healthcare provider if you are:

  • living in a household where there are small children or someone who has abused street or prescription drugs

Get emergency medical help or call 911 right away if you have:

PATIENT COUNSELING INFORMATION

Life-Threatening Respiratory Depression

Newly added information:

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 Warnings and Precautions (5.4)].

Newly added information:

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. 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) [see Dosage and Administrations (2.2), Warnings and Precautions (5.4)].Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].

If naloxone is prescribed, also advise patients and caregivers:

  • How to treat with naloxone in the event of an opioid overdose

  • To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency

  • To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

10/07/2019 (SUPPL-44)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Life-Threatening Respiratory Depression

Newly added information to end of subsection:

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.

Additions and/or revisions underlined:

5.16 Withdrawal

Do not abruptly discontinue BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE in a patient physically dependent on opioids. Rapid tapering of BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain.

Additionally, avoid the use of mixed agonist/antagonist …

7 Drug Interactions

Table 1: Clinically Significant Drug Interactions with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

Serotonergic Drugs

Additions and/or revisions underlined:

Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined in bulleted information:

Important information about BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE:

  • Store BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

When taking BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE:

  • Dispose of expired, unwanted, or unused Butalbital, Acetaminophen, Caffeine, and Codeine by taking your drug to an authorized DEA-registered collector or drug take-back program. If one is not available, you can dispose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules by mixing the product with dirt, cat litter, or coffee grounds; placing the mixture in a sealed plastic bag and throwing the bag in your trash.

PATIENT COUNSELING INFORMATION

Storage and Disposal:

Additions and/or revisions underlined:

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly.

Inform patients that medicine take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take back programs or DEA-registered collectors are available, instruct patients to dispose of Butalbital, Acetaminophen, Caffeine, and Codeine by following these four steps:

  • Mix Butalbital, Acetaminophen, Caffeine, and Codeine (do not crush) with an unpalatable substance such as dirt, cat litter, or used coffee grounds;

  • Place the mixture in a container such as a sealed plastic bag;

  • Throw the container in the household trash;

  • Delete all personal information on the prescription label of the empty bottle

  • Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

Newly added titled section:

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE without first discussing a tapering plan with the prescriber.

09/18/2018 (SUPPL-43)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

RISK EVALUATION AND MITIGATION STRATEGY (REMS)

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. 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.

5 Warnings and Precautions

5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

(Additions and/or revisions are underlined)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

      • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
      • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
      • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
      • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

08/29/2017 (SUPPL-41)

Approved Drug Label (PDF)

Boxed Warning

(additions underlined)

WARNING: ADDICTION, ABUSE, AND MISUSE; 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; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY

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. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate   Capsules are contraindicated in children younger than12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

4 Contraindications

(additions underlined)

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for:

    • children younger than 12 years of age

    • Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

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

  • Significant respiratory depression

5 Warnings and Precautions

5.4 Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children

(subsection revised)

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 of age appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the postoperative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:

  • Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for all children younger than 12 years of age.

  • Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

  • Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as 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 codeine for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose.

    Nursing Mothers

    At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules.

    CYP2D6 Genetic Variability: Ultra-rapid metabolizer

    Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican).

    These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see Overdosage (10)]. Therefore, individuals who are ultra-rapid metabolizers should not use Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules.

6 Adverse Reactions

(additions underlined)

  • Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

8 Use in Specific Populations

8.2 Lactation

(additions underlined)

Risk Summary

Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent.

There is no information on the effects of the codeine milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules.

8.4 Pediatric Use

(additions underlined)

The safety and effectiveness of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in pediatric patients have not been established.

Life-threatening respiratory depression and deaths have occurred in children who received codeine. In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children 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). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life-threatening respiratory depression and death:

  • Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for all children younger than 12 years of age.

  • Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

    Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

Ultra-Rapid Metabolism of Codeine and Risk Factors for Life-threatening Respiratory Depression in Children

Advise caregivers that Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12-18 years of age receiving codeine to monitor for signs of respiratory depression.

Lactation

Advise women that breastfeeding is not recommended during treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules.

12/16/2016 (SUPPL-40)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY


Addiction, Abuse, and Misuse

Butalbital, Acetaminophen, 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, and monitor all patients regularly for the development of these behaviors and conditions.


Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Monitor for respiratory depression, especially during initiation of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules or following a dose increase.


Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids or a barbiturate with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

  • Reserve concomitant prescribing of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.


Accidental Ingestion

Accidental ingestion of even one dose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, especially by children, can result in a fatal overdose of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate.


Neonatal Opioid Withdrawal Syndrome

Prolonged use of Butalbital, Acetaminophen, 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.


Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules requires careful consideration of the effects on codeine, and the active metabolite, morphine.

4 Contraindications

(Additions and/or revisions are underlined)

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated in patients with:

  • Significant respiratory depression
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
  • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days
  • Known or suspected gastrointestinal obstruction, including paralytic ileus
  • Known intolerance or hypersensitivity to acetaminophen, caffeine, butalbital, or codeine or to the components of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

(Newly added subsection)

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain codeine. Codeine in combination with butalbital, acetaminophen, and caffeine is a Schedule III controlled substance. As Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules contain butalbital and codeine, they expose users to the risks of addiction, abuse, and misuse.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, and monitor all patients receiving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, but use in such patients necessitates intensive counseling about the risks and proper use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules along with 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, 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. 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.

5.10 Adrenal Insufficiency

(Newly added subsection)

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

(Newly added subsection)

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. In patients with circulatory shock, Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with circulatory shock.

5.12 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

(Newly added subsection)

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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with impaired consciousness or coma.

5.13 Risks of Use in Patients with Gastrointestinal Conditions

(Newly added subsection)

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

The codeine in Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.14 Increased Risk of Seizures in Patients with Seizure Disorders

(Newly added subsection)

The codeine in Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures.

Monitor patients with a history of seizure disorders for worsened seizure control during Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules therapy.

5.15 Withdrawal

(Newly added subsection)

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, in a physically-dependent patient, gradually taper the dosage. Do not abruptly discontinue Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in these patients. Abrupt discontinuation of butalbital can cause seizures.

5.16 Risks of Driving and Operating Machinery

(Newly added subsection)

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and know how they will react to the medication.

5.2 Life-Threatening Respiratory Depression

(Newly added subsection)

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.

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, 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules.

To reduce the risk of respiratory depression, proper dosing and titration of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are essential [see Dosage and Administration (2.2)]. Overestimating the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of (or exposure to) Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, especially by children, can result in respiratory depression and death due to an overdose of codeine and butalbital.

5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

(Newly added subsection)

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Butalbital, Acetaminophen, 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.

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, Caffeine, and Codeine Phosphate Capsules are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

5.4 Neonatal Opioid Withdrawal Syndrome

(Newly added subsection)

Prolonged use of Butalbital, Acetaminophen, 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.

5.5 Death Related to Ultra-Rapid Metabolism of Codeine to Morphine

(Newly added subsection title; Additions and/or revisions are underlined)

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy...

5.6 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

(Newly added subsection)

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules require careful consideration of the effects on codeine and the active metabolite, morphine.


Cytochrome P450 3A4 Interaction

The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal.

Follow patients receiving Butalbital, Acetaminophen, 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, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are used in conjunction with inhibitors and inducers of CYP3A4.

If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules until stable drug effects are achieved. 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, Caffeine, and Codeine Phosphate Capsules dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.


Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors

The concomitant use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.

Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

Follow patients receiving Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are used in conjunction with inhibitors of CYP2D6.

If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules dosage and follow the patient for signs and symptoms of respiratory depression or sedation.

5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

(Newly added subsection)

The use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.


Patients with Chronic Pulmonary Disease: Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules.


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.

Monitor such patients closely, particularly when initiating and titrating Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules and when Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

5.9 Interaction with Monoamine Oxidase Inhibitors

(Newly added subsection)

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions are described, or described in greater detail, in other sections:

  • Addiction, Abuse, and Misuse
  • Life-Threatening Respiratory Depression
  • Interactions with Benzodiazepines and other CNS Depressants
  • Neonatal Opioid Withdrawal Syndrome
  • Death Related to Ultra-Rapid Metabolism of Codeine to Morphine
  • Hepatotoxicity
  • Adrenal Insufficiency
  • Severe Hypotension
  • Gastrointestinal Adverse Reactions
  • Seizures
  • Withdrawal
  • Serious Skin Reactions
  • Anaphylaxis

The following adverse reactions associated with the use of butalbital, acetaminophen, caffeine, and codeine phosphate were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure


Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.


Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.


Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.

7 Drug Interactions

(Additions and/or revisions are underlined)

Table 1 includes clinically significant drug interactions with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. (Table has been added; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion: Extensive changes; please refer to label)

8.2 Lactation

(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)

Risk Summary

Acetaminophen is present in human milk in small quantities after oral administration. Based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 to 2% of the maternal dose. There is one well-documented report of a rash in a breastfed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use.

 

Clinical Considerations

Infants exposed to Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined; Pregnancy and Lactation Labeling Rule (PLLR) Conversion)

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

Published literature indicates that acetaminophen affects sperm development in mice with consequent reduction in litter size in a multigeneration study.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Elderly patients (aged 65 years or older) may have increased sensitivity to Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate CapsulesRespiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules slowly in geriatric patients and monitor closely for signs of respiratory depression.

8.6 Hepatic Impairment

(Newly added subsection)

No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of butalbital, codeine, and acetaminophen in this patient population are unknown. Start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects.

8.7 Renal Impairment

(Newly added subsection)

Codeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. In patients with renal disease, monitor effects of therapy with serial renal function tests.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive changes; please refer to label)

Medication Guide

(Newly added subsection)

Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules are:

  • A strong prescription pain medicine that contains an opioid (narcotic) that is indicated for the relief of the symptom complex of tension (or muscle contraction) headache, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
  • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.

Important information about Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules:

  • Get emergency help right away if you take too much Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules (overdose). When you first start taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
  • Taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.
  • Never give anyone else your Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. They could die from taking it. Store Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules away from children and in a safe place to prevent stealing or abuse. Selling or giving away Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules is against the law.
  • Get emergency help right away if you take more than 4,000 mg of acetaminophen in 1 day. Taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with other products that contain acetaminophen can lead to serious liver problems and death.

Do not take Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules if you have:

  • severe asthma, trouble breathing, or other lung problems.
  • a bowel blockage or have narrowing of the stomach or intestines.
  • Do not give Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules to a child to treat pain after tonsillectomy and/or adenoidectomy surgery.

Before taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, tell your healthcare provider if you have a history of:

  • head injury, seizures
  • liver, kidney, thyroid problems
  • problems urinating
  • pancreas or gallbladder problems
  • abuse of street or prescription drugs, alcohol addiction, or mental health problems.
  • Have been told by your healthcare provider that you are a “rapid metabolizer” of certain medicines

Tell your healthcare provider if you are:

  • pregnant or planning to become pregnant. Prolonged use of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
  • breastfeeding. When taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, some or all of codeine in it changes into morphine in your body. In some women, this may happen very quickly. Codeine and morphine pass into your breast milk. A large amount of morphine can cause your baby to die.
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with certain other medicines can cause serious side effects that could lead to death.

When taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules:

  • Do not change your dose. Take Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
  • Take your prescribed dose of 1 or 2 capsules every 4 hours. Total daily dosage should not exceed 6 capsules. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • If you have been taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules regularly, do not stop taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules without talking to your healthcare provider.
  • After you stop taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, dispose the unused Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules in accordance with the local state guidelines and/or regulations.

While taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules DO NOT:

  • Drive or operate heavy machinery, until you know how Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules affect you. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules may cause you to overdose and die.

The possible side effects of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules:

  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help if you:

  • have trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.
  • are a nursing mother taking Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, and your breastfeeding baby has increased sleepiness, confusion, difficulty breathing, shallow breathing, limpness, or difficulty breastfeeding.

These are not all the possible side effects of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088. For more information go to dailymed.nlm.nih.gov

Distributed by: Actavis Pharma, Inc., Parsippany, NJ 07054

Other

(Physician Labeling Rule (PLR) conversion; please refer to label)

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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