These Highlights Do Not Include All The Information Needed To Use Butalbital, Aspirin, Caffeine And Codeine Phosphate Capsules Safely And Effectively. See Full Prescribing Information For Butalbital, Aspirin, Caffeine And Codeine Phosphate.

Addiction, Abuse, and Misuse

Because the use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE exposes 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 and reassess all patients regularly for the development of these behaviors and conditions

[see Warnings and Precautions ( 5.1) ].

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE contains aspirin, butalbital, caffeine, and codeine phosphate, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE with alcohol and other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE abuse include those with a history of prolonged use of any opioid, including products containing aspirin, butalbital, caffeine, and codeine phosphate, those with a history of drug or alcohol abuse, or those who use BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in combination with other abused drugs.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

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).

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE USP is supplied in capsule form for oral administration.

Each capsule contains the following active ingredients:

Butalbital, USP……………..50 mg

Aspirin, USP………………..325 mg

Caffeine, USP………………40 mg

Codeine phosphate, USP…...30 mg

Butalbital (5-allyl-5-isobutyl-barbituric acid) is a short- to intermediate-acting barbiturate. It has the following structural formula:

Its molecular weight is 224.26 and its molecular formula is C₁₁H₁₆N₂O₃.

Aspirin (benzoic acid, 2-(acetyloxy)-) is a nonsteroidal anti-inflammatory drug. It has the following structural formula:

Its molecular weight is 180.16 and its molecular formula is C₉H₈O₄.

Caffeine (1,3,7-trimethylxanthine), a methylxanthine, is a central nervous system stimulant. It has the following structural formula:

Its molecular weight is 194.19 and its molecular formula is C₈H₁₀N₄O₂.

Codeine phosphate (7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate) is an opioid agonist. It has the following structural formula:

Its molecular weight is 397.37 and its molecular formula is C₁₈H₂₄NO₇P.

Inactive Ingredients: D&C Yellow #10, D&C Yellow #10 Aluminum Lake, D&C Red #33, D&C Red #28, FD&C Blue #1, FD&C Blue #1 Aluminum Lake, gelatin, microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide, stearic acid, colloidal silicon dioxide.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Do not rapidly reduce or abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in a patient physically dependent on opioids. Rapid tapering of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in a patient physically dependent on opioids may lead to 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.

When discontinuing BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, gradually taper the dosage using a patient-specific plan that considers the following: the dose of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.4 ), Warnings and Precautions (5.16)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1, 8.2)].

Do not rapidly reduce or abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration ( 2.4)]. Do not abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in these patients [see Drug Abuse and Dependence (9.2, 9.3)].

Preparations containing aspirin should be kept out of the reach of children. Reye's Syndrome is a rare condition that affects the brain and liver and is most often observed in children given aspirin during a viral illness. Safety and effectiveness in pediatric patients have not been established.

The safety and effectiveness of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in pediatric patients have not been established.

Life-threatening respiratory depression and death have occurred in children who received codeine [see Warnings and Precautions (5.6)]. 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, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is contraindicated for all children younger than 12 years of age [see Contraindications (4)].
• BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is 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 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. [see Warnings and Precautions (5.6)].

Clinical studies of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Butalbital is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

Elderly patients (aged 65 years or older) may have increased sensitivity to BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory 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, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9)].

Components of this product are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, dose selection should start at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions(5)].

Evidence supporting the efficacy of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is derived from 2 multi-clinic trials that compared patients with tension headache randomly assigned to 4 parallel treatments: BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, codeine, butalbital + aspirin + caffeine capsules, USP, and placebo. Response was assessed over the course of the first 4 hours of each of 2 distinct headaches, separated by at least 24 hours BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE proved statistically significantly superior to each of its components and to placebo on measures of pain relief.

Evidence supporting the efficacy and safety of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because codeine and butalbital are habit-forming and potentially abusable.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is contraindicated for:

• All children younger than 12 years of age [see Warnings and Precautions (5.6)]
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy[see Warnings and Precautions (5.6)].

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is also contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.9)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment[see Warnings and Precautions (5.9)]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.10)/Drug Interactions (7)].
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14)]
• Hypersensitivity or intolerance to aspirin, caffeine, butalbital, or codeine.
• Hemophilia [see Warnings and Precautions (5.19)]
• Reye's Syndrome [see Warnings and Precautions (5.20)]
• Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions (5.23)]
• Syndrome of asthma, rhinitis, and nasal polyps [see Warnings and Precautions (5.23)]

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

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions ((5.2)
• Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)
• Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions (5.6)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8)]
• Adrenal Insufficiency [see Warnings and Precautions (5.11)]
• Severe Hypotension [see Warnings and Precautions (5.12)]
• Risks of Use in Patients with Gastrointestinal Conditions Including Peptic Ulcer Disease [see Warnings and Precautions ( 5.14)]
• Increased Risk of Seizures in Patients with Seizure Disorders [see Warnings and Precautions (5.15)]
• Withdrawal [see Warnings and Precautions (5.16)]
• Coagulation Abnormalities and Bleeding Risks [see Warnings and Precautions (5.19)]
• Reye's Syndrome [see Warnings and Precautions (5.20)]
• Serious Skin Reactions [see Warnings and Precautions (5.21)]
• Allergy [see Warnings and Precautions (5.23)]

Table 2 includes clinically significant drug interactions with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE.

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.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE contains aspirin, which should be avoided in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).

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 BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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.

One or two capsules every 4 hours as needed for pain. Total daily dosage should not exceed 6 capsules. Use the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE.

No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of aspirin, codeine and butalbital in this patient population are unknown. Start these patients cautiously with lower doses of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. In patients with severe hepatic disease, monitor effects of therapy with serial liver function tests.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when non-opioid analgesic and alternative treatments are inadequate.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. In patients with circulatory shock, BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients with circulatory shock.

NDC 69238-1993-1

BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE CAPSULES USP, 50 mg/325 mg/40 mg/30 mg CIII

Rx ONLY

100 CAPSULES

Butalbital, a barbiturate, is a GABA_A receptor agonist and may inhibit excitatory AMPA receptors.

Aspirin is a nonsteroidal anti-inflammatory drug and a non-selective irreversible inhibitor of cyclooxygenases.

Caffeine is a methylxanthine and CNS stimulant. The exact mechanism with respect to the indication is not clear; however, the effects of caffeine may be due to antagonism of adenosine receptors.

Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE contains codeine. Codeine in combination with butalbital, aspirin, and caffeine is a Schedule III controlled substance.

• Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. (5.8)
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate, particularly during initiation and titration. (5.9)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. (5.11)
• Severe Hypotension: Regularly evaluate during dose initiation and titration. Avoid use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients with circulatory shock. (5.12)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Regularly evaluate for sedation and respiratory depression. Avoid use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients with impaired consciousness or coma. (5.13)
• Fetal toxicity: Limit use of NSAIDs, including BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, 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. (5.17, 8.1)
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. (5.21)

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.

• Periodically reassess patients receiving BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse.
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2.1, 5)
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse (2.1, 5.1)
• 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. Consider prescribing naloxone based on the patient's risk factors for overdose. (2.2, 5.1, 5.2, 5.3)
• Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (2.2, 5.1, 5.2, 5.3)
• BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. (2.1)
• Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. (2.1)
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2)
• Initiate treatment with one or two capsules every 4 hours as needed for pain and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Total daily dosage should not exceed 6 capsules. (2, 5)
• Do not rapidly reduce or abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.4, 5.16)

NSAIDs, including aspirin, a component of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE at the first appearance of skin rash or any other sign of hypersensitivity. BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS (4)].

Capsules : Butalbital, 50 mg, Aspirin, 325 mg, Caffeine, 40 mg, Codeine Phosphate, 30 mg Yellow and blue Capsule imprinted with JSP 507.

The following adverse reactions have been identified during post approval use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Because these reactions are 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.

Central Nervous: abuse, addiction, anxiety, depression, disorientation, hallucination, hyperactivity, insomnia, libido decrease, nervousness, neuropathy, psychosis, sedation, sexual activity increase, slurred speech, twitching, unconsciousness, vertigo.

Autonomic Nervous: epistaxis, flushing, miosis, salivation.

Gastrointestinal: anorexia, appetite increased, constipation, diarrhea, esophagitis, gastroenteritis, gastrointestinal spasm, hiccup, mouth burning, pyloric ulcer.

Cardiovascular: chest pain, hypotensive reaction, palpitations, syncope.

Skin: erythema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), hives, rash, toxic epidermal necrolysis, and fixed drug eruption (FDE).

Urinary: kidney impairment, urinary difficulty.

Miscellaneous: allergic reaction, anaphylactic shock, cholangiocarcinoma, drug interaction with erythromycin (stomach upset), edema.

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.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE.

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioidsfor an extended period of time. [see Clinical Pharmacology (12.2)].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.8 )]

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.14 )].

Adverse Reactions from Observational Studies

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90 day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months:

• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interviewbased measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 )], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days' supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

• Pregnancy: May cause fetal harm (8.1)
• Lactation: Breastfeeding not recommended. (8.2)

Pharmacist: Dispense Medication Guide found at www.dailymed.nlm.nih.gov and enter NDC 69238-1993-1

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE contains codeine. Codeine in combination with butalbital, aspirin, and caffeine is a Schedule III controlled substance. As BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE contains 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. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2)].

Assess each patient's risk for addiction, abuse, or misuse prior to prescribing BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, and reassess all patients receiving BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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, but use in such patients necessitates intensive counseling about the risks and proper use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Opioids and barbiturates are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and 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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Each yellow and blue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE Capsule USP 50 mg/325 mg/ 40 mg/30 mg is imprinted JSP 507

Bottles of 100 NDC 69238-1993-1

Store and Dispense

Below 25°C (77°F); in a tight, light resistant container.

Keep out of reach of children

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.

Use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1, 8.2), Patient Counseling Information (17)].

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 overdose reversal agents, 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, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE are essential [see Dosage and Administration (2.1)]. Overestimating the BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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, 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 )].

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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 and know how they will react to the medication.

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence ( 9.3 )]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.4); Warnings and Precautions (5.2)].

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.

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

• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.
• Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)].

The codeine in BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE therapy.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. 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 and evaluate the patient immediately.

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.opioidanalgesicrems.com/patientCounselingGuide.html
• 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 https://www.opioidanalgesicrems.com/home.html The FDA Blueprint can be found at "http://www.fda.gov/OpioidAnalgesicREMSBlueprint".

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 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 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 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.
  
  
  
  Evaluate patients receiving BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE and any CYP3A4 inhibitor or inducer at frequent intervals for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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 until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation.
  
  
  
  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 dosage until stable drug effects are achieved. Evaluate patients at frequent intervals 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 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.
  
  
  
  Evaluate patients receiving BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE and any CYP2D6 inhibitor at frequent intervals for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE are used in conjunction with inhibitors of CYP2D6.
  
  
  
  If concomitant use with a CYP2D6 inhibitor is necessary, evaluate patients at frequent intervals for signs of reduced efficacy or opioid withdrawal and consider increasing the BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE dosage and evaluate patients at frequent intervals for signs and symptoms of respiratory depression or sedation. [see Drug Interactions (7)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)].

Do not rapidly reduce or abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt 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, there are a variety of factors that should be considered, including the total daily dose of opioid (including BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE) 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 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, evaluate 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 an extended period of time, 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 (5.16), Drug Abuse and Dependence (9.3)].

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE

See full prescribing information for complete boxed warning.

• BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE exposes users to the risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor regularly for these behaviors and conditions. (5.1)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. (5.2)
• Accidental ingestion of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, especially by children, can result in fatal overdose. (5.2)
• 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 for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.3, 5.9, 7)
• Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (5.4)
• 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 (5.5)
• Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. (5.6) BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (4). Avoid the use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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.
• 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 requires careful consideration of the effects on codeine, and the active metabolite, morphine. (5.7, 5.9, 7)

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 is contraindicated for all children younger than 12 years of age [see Contraindications (4)].
• BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is 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 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 for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [see Use in Specific Populations (8.4), Overdosage (10)].

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 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.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients with impaired consciousness or coma.

The use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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 -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 [see Warnings and Precautions (5.9)].

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 (5.9)].

Regularly evaluate patients, particularly when initiating and titrating BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE and when BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Addiction, Abuse, and Misuse

Because the use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE exposes 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 and reassess all patients regularly for the development of these behaviors and conditions

[see Warnings and Precautions ( 5.1) ].

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE contains aspirin, butalbital, caffeine, and codeine phosphate, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE with alcohol and other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE abuse include those with a history of prolonged use of any opioid, including products containing aspirin, butalbital, caffeine, and codeine phosphate, those with a history of drug or alcohol abuse, or those who use BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in combination with other abused drugs.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

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).

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE USP is supplied in capsule form for oral administration.

Each capsule contains the following active ingredients:

Butalbital, USP……………..50 mg

Aspirin, USP………………..325 mg

Caffeine, USP………………40 mg

Codeine phosphate, USP…...30 mg

Butalbital (5-allyl-5-isobutyl-barbituric acid) is a short- to intermediate-acting barbiturate. It has the following structural formula:

Its molecular weight is 224.26 and its molecular formula is C₁₁H₁₆N₂O₃.

Aspirin (benzoic acid, 2-(acetyloxy)-) is a nonsteroidal anti-inflammatory drug. It has the following structural formula:

Its molecular weight is 180.16 and its molecular formula is C₉H₈O₄.

Caffeine (1,3,7-trimethylxanthine), a methylxanthine, is a central nervous system stimulant. It has the following structural formula:

Its molecular weight is 194.19 and its molecular formula is C₈H₁₀N₄O₂.

Codeine phosphate (7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate) is an opioid agonist. It has the following structural formula:

Its molecular weight is 397.37 and its molecular formula is C₁₈H₂₄NO₇P.

Inactive Ingredients: D&C Yellow #10, D&C Yellow #10 Aluminum Lake, D&C Red #33, D&C Red #28, FD&C Blue #1, FD&C Blue #1 Aluminum Lake, gelatin, microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide, stearic acid, colloidal silicon dioxide.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Do not rapidly reduce or abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in a patient physically dependent on opioids. Rapid tapering of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in a patient physically dependent on opioids may lead to 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.

When discontinuing BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, gradually taper the dosage using a patient-specific plan that considers the following: the dose of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.4 ), Warnings and Precautions (5.16)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1, 8.2)].

Do not rapidly reduce or abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration ( 2.4)]. Do not abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in these patients [see Drug Abuse and Dependence (9.2, 9.3)].

Preparations containing aspirin should be kept out of the reach of children. Reye's Syndrome is a rare condition that affects the brain and liver and is most often observed in children given aspirin during a viral illness. Safety and effectiveness in pediatric patients have not been established.

The safety and effectiveness of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in pediatric patients have not been established.

Life-threatening respiratory depression and death have occurred in children who received codeine [see Warnings and Precautions (5.6)]. 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, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is contraindicated for all children younger than 12 years of age [see Contraindications (4)].
• BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is 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 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. [see Warnings and Precautions (5.6)].

Clinical studies of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Butalbital is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

Elderly patients (aged 65 years or older) may have increased sensitivity to BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory 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, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9)].

Components of this product are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, dose selection should start at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions(5)].

Evidence supporting the efficacy of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is derived from 2 multi-clinic trials that compared patients with tension headache randomly assigned to 4 parallel treatments: BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, codeine, butalbital + aspirin + caffeine capsules, USP, and placebo. Response was assessed over the course of the first 4 hours of each of 2 distinct headaches, separated by at least 24 hours BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE proved statistically significantly superior to each of its components and to placebo on measures of pain relief.

Evidence supporting the efficacy and safety of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because codeine and butalbital are habit-forming and potentially abusable.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is contraindicated for:

• All children younger than 12 years of age [see Warnings and Precautions (5.6)]
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy[see Warnings and Precautions (5.6)].

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is also contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.9)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment[see Warnings and Precautions (5.9)]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions (5.10)/Drug Interactions (7)].
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14)]
• Hypersensitivity or intolerance to aspirin, caffeine, butalbital, or codeine.
• Hemophilia [see Warnings and Precautions (5.19)]
• Reye's Syndrome [see Warnings and Precautions (5.20)]
• Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions (5.23)]
• Syndrome of asthma, rhinitis, and nasal polyps [see Warnings and Precautions (5.23)]

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

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions ((5.2)
• Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)
• Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions (5.6)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8)]
• Adrenal Insufficiency [see Warnings and Precautions (5.11)]
• Severe Hypotension [see Warnings and Precautions (5.12)]
• Risks of Use in Patients with Gastrointestinal Conditions Including Peptic Ulcer Disease [see Warnings and Precautions ( 5.14)]
• Increased Risk of Seizures in Patients with Seizure Disorders [see Warnings and Precautions (5.15)]
• Withdrawal [see Warnings and Precautions (5.16)]
• Coagulation Abnormalities and Bleeding Risks [see Warnings and Precautions (5.19)]
• Reye's Syndrome [see Warnings and Precautions (5.20)]
• Serious Skin Reactions [see Warnings and Precautions (5.21)]
• Allergy [see Warnings and Precautions (5.23)]

Table 2 includes clinically significant drug interactions with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE.

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.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE contains aspirin, which should be avoided in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).

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 BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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.

One or two capsules every 4 hours as needed for pain. Total daily dosage should not exceed 6 capsules. Use the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE.

No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of aspirin, codeine and butalbital in this patient population are unknown. Start these patients cautiously with lower doses of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. In patients with severe hepatic disease, monitor effects of therapy with serial liver function tests.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when non-opioid analgesic and alternative treatments are inadequate.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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)]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. In patients with circulatory shock, BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients with circulatory shock.

NDC 69238-1993-1

BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE CAPSULES USP, 50 mg/325 mg/40 mg/30 mg CIII

Rx ONLY

100 CAPSULES

Butalbital, a barbiturate, is a GABA_A receptor agonist and may inhibit excitatory AMPA receptors.

Aspirin is a nonsteroidal anti-inflammatory drug and a non-selective irreversible inhibitor of cyclooxygenases.

Caffeine is a methylxanthine and CNS stimulant. The exact mechanism with respect to the indication is not clear; however, the effects of caffeine may be due to antagonism of adenosine receptors.

Codeine is an opioid agonist relatively selective for the mu-opioid receptor, but with a much weaker affinity than morphine. The analgesic properties of codeine have been speculated to come from its conversion to morphine, although the exact mechanism of analgesic action remains unknown.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE contains codeine. Codeine in combination with butalbital, aspirin, and caffeine is a Schedule III controlled substance.

• Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. (5.8)
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate, particularly during initiation and titration. (5.9)
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. (5.11)
• Severe Hypotension: Regularly evaluate during dose initiation and titration. Avoid use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients with circulatory shock. (5.12)
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Regularly evaluate for sedation and respiratory depression. Avoid use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients with impaired consciousness or coma. (5.13)
• Fetal toxicity: Limit use of NSAIDs, including BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, 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. (5.17, 8.1)
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. (5.21)

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.

• Periodically reassess patients receiving BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse.
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2.1, 5)
• Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse (2.1, 5.1)
• 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. Consider prescribing naloxone based on the patient's risk factors for overdose. (2.2, 5.1, 5.2, 5.3)
• Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (2.2, 5.1, 5.2, 5.3)
• BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. (2.1)
• Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. (2.1)
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.2)
• Initiate treatment with one or two capsules every 4 hours as needed for pain and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Total daily dosage should not exceed 6 capsules. (2, 5)
• Do not rapidly reduce or abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.4, 5.16)

NSAIDs, including aspirin, a component of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE at the first appearance of skin rash or any other sign of hypersensitivity. BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS (4)].

Capsules : Butalbital, 50 mg, Aspirin, 325 mg, Caffeine, 40 mg, Codeine Phosphate, 30 mg Yellow and blue Capsule imprinted with JSP 507.

The following adverse reactions have been identified during post approval use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Because these reactions are 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.

Central Nervous: abuse, addiction, anxiety, depression, disorientation, hallucination, hyperactivity, insomnia, libido decrease, nervousness, neuropathy, psychosis, sedation, sexual activity increase, slurred speech, twitching, unconsciousness, vertigo.

Autonomic Nervous: epistaxis, flushing, miosis, salivation.

Gastrointestinal: anorexia, appetite increased, constipation, diarrhea, esophagitis, gastroenteritis, gastrointestinal spasm, hiccup, mouth burning, pyloric ulcer.

Cardiovascular: chest pain, hypotensive reaction, palpitations, syncope.

Skin: erythema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), hives, rash, toxic epidermal necrolysis, and fixed drug eruption (FDE).

Urinary: kidney impairment, urinary difficulty.

Miscellaneous: allergic reaction, anaphylactic shock, cholangiocarcinoma, drug interaction with erythromycin (stomach upset), edema.

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.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE.

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioidsfor an extended period of time. [see Clinical Pharmacology (12.2)].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.8 )]

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.14 )].

Adverse Reactions from Observational Studies

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90 day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months:

• approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interviewbased measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and
• approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 )], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days' supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

• Pregnancy: May cause fetal harm (8.1)
• Lactation: Breastfeeding not recommended. (8.2)

Pharmacist: Dispense Medication Guide found at www.dailymed.nlm.nih.gov and enter NDC 69238-1993-1

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE contains codeine. Codeine in combination with butalbital, aspirin, and caffeine is a Schedule III controlled substance. As BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE contains 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. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2)].

Assess each patient's risk for addiction, abuse, or misuse prior to prescribing BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, and reassess all patients receiving BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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, but use in such patients necessitates intensive counseling about the risks and proper use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Opioids and barbiturates are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and 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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Each yellow and blue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE Capsule USP 50 mg/325 mg/ 40 mg/30 mg is imprinted JSP 507

Bottles of 100 NDC 69238-1993-1

Store and Dispense

Below 25°C (77°F); in a tight, light resistant container.

Keep out of reach of children

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.

Use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1, 8.2), Patient Counseling Information (17)].

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 overdose reversal agents, 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, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE are essential [see Dosage and Administration (2.1)]. Overestimating the BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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, 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 )].

BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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 and know how they will react to the medication.

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence ( 9.3 )]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.4); Warnings and Precautions (5.2)].

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.

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

• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
• There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.
• Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)].

The codeine in BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE therapy.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. 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 and evaluate the patient immediately.

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.opioidanalgesicrems.com/patientCounselingGuide.html
• 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 https://www.opioidanalgesicrems.com/home.html The FDA Blueprint can be found at "http://www.fda.gov/OpioidAnalgesicREMSBlueprint".

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 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 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 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.
  
  
  
  Evaluate patients receiving BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE and any CYP3A4 inhibitor or inducer at frequent intervals for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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 until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation.
  
  
  
  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 dosage until stable drug effects are achieved. Evaluate patients at frequent intervals 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 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.
  
  
  
  Evaluate patients receiving BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE and any CYP2D6 inhibitor at frequent intervals for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE are used in conjunction with inhibitors of CYP2D6.
  
  
  
  If concomitant use with a CYP2D6 inhibitor is necessary, evaluate patients at frequent intervals for signs of reduced efficacy or opioid withdrawal and consider increasing the BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE dosage and evaluate patients at frequent intervals for signs and symptoms of respiratory depression or sedation. [see Drug Interactions (7)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)].

Do not rapidly reduce or abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt 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, there are a variety of factors that should be considered, including the total daily dose of opioid (including BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE) 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 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, evaluate 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 an extended period of time, 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 (5.16), Drug Abuse and Dependence (9.3)].

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE

See full prescribing information for complete boxed warning.

• BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE exposes users to the risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor regularly for these behaviors and conditions. (5.1)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. (5.2)
• Accidental ingestion of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, especially by children, can result in fatal overdose. (5.2)
• 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 for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.3, 5.9, 7)
• Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (5.4)
• 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 (5.5)
• Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. (5.6) BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (4). Avoid the use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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.
• 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 requires careful consideration of the effects on codeine, and the active metabolite, morphine. (5.7, 5.9, 7)

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 is contraindicated for all children younger than 12 years of age [see Contraindications (4)].
• BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is 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 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 for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [see Use in Specific Populations (8.4), Overdosage (10)].

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 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.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients with impaired consciousness or coma.

The use of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE 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 -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 [see Warnings and Precautions (5.9)].

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 (5.9)].

Regularly evaluate patients, particularly when initiating and titrating BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE and when BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. Alternatively, consider the use of non-opioid analgesics in these patients.