1 INDICATIONS AND USAGE Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when non-opioid analgesic and alternative treatments are inadequate.

Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [ see Warnings and Precautions (5.1) ], reserve opioid analgesics, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is a combination of butalbital, a barbiturate, aspirin, a nonsteroidal anti-inflammatory drug, caffeine, a methylxanthine, and codeine phosphate, an opioid agonist, and is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when other non-opioid analgesics and alternative treatments are inadequate.

Limitations of Use : Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

( 1 , 5.1 )

6 ADVERSE REACTIONS 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 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [ see Warnings and Precautions ( 5.6 ) ] 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 ) ] Risk of Use in Patients with Gastrointestinal Conditions Including Peptic Ulcer Disease [see Warnings and Precautions ( 5.14 )] Increase 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 ) ] Most common adverse reactions (incidence > 1%) are nausea and/or abdominal pain, drowsiness, and dizziness.

( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact LGM Pharma Solutions, LLC at 1-877-288-1495 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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.

Incidence in Controlled Clinical Trials : The following table summarizes the incidence rates of the adverse events reported by at least 1% of the Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules treated patients in controlled clinical trials comparing Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules to placebo, and provides a comparison to the incidence rates reported by the placebo-treated patients.

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials.

Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.

Adverse Events Reported by at Least 1% of Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules Treated Patients During Placebo Controlled Clinical Trials Incidence Rate of Adverse Events Body System/Adverse Event Butalbital, Aspirin, Caffeine, and Placebo Codeine Phosphate, USP (N =377) Capsules (N=382) Central Nervous Drowsiness 2.4% 0.5% Dizziness/Lightheadedness 2.6% 0.5% Intoxicated Feeling 1.0% 0% Gastrointestinal Nausea/Abdominal Pain 3.7% 0.8% Other Adverse Events Reported During Controlled Clinical Trials The listing that follows represents the proportion of the 382 patients exposed to Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules while participating in the controlled clinical trials who reported, on at least one occasion, an adverse event of the type cited.

All reported adverse events, except those already presented in the previous table, are included.

It is important to emphasize that, although the adverse events reported did occur while the patient was receiving Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules, the adverse events were not necessarily caused by Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules.

Adverse events are classified by body system and frequency.

“Frequent” is defined as an adverse event which occurred in at least 1/100 (1%) of the patients; all adverse events listed in the previous table are frequent.

“Infrequent” is defined as an adverse event that occurred in less than 1/100 patients but at least 1/1000 patients.

All adverse events tabulated below are classified as infrequent.

Central Nervous : headache, shaky feeling, tingling, agitation, fainting, fatigue, heavy eyelids, high energy, hot spells, numbness, and sluggishness.

Autonomic Nervous : dry mouth and hyperhidrosis.

Gastrointestinal : vomiting, difficulty swallowing, and heartburn.

Cardiovascular : tachycardia.

Musculoskeletal : leg pain and muscle fatigue.

Genitourinary : diuresis.

Miscellaneous : pruritus, fever, earache, nasal congestion, and tinnitus.

The following adverse drug reactions have been reported with the components of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP.

Potential effects of high dosage are listed in the [see Overdosage ( 10 ) ] section of this insert.

Aspirin : occult blood loss, hemolytic anemia, iron deficiency anemia, gastric distress, heartburn, nausea, peptic ulcer, prolonged bleeding time, acute airway obstruction, renal toxicity when taken in high doses for prolonged periods, impaired urate excretion, hepatitis.

Caffeine : cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia.

Codeine : nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules.

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 Capsules, USP.

Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time.

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

Hyp o glycemia : 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 interview-based 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.