BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE (Page 5 of 11)

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 Codeine Phosphate, USP Capsules (N=382)	Placebo (N =377)
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 ASCOMP with Codeine.

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, hives, rash, toxic epidermal necrolysis.

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 ASCOMP with Codeine.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

7 DRUG INTERACTIONS

Table 1 includes clinically significant drug interactions with ASCOMP with Codeine.

Table 1: Clinically Significant Drug Interactions with ASCOMP with Codeine

Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of ASCOMP with Codeine with CYP3A4 inhibitors may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of ASCOMP with Codeine is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology (12.3)] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine.
Intervention:	If concomitant use with CYP3A4 inhibitor is necessary, consider dosage reduction of ASCOMP with Codeine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the ASCOMP with Codeine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Example:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of ASCOMP with Codeine and CYP3A4 inducers can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [see Warnings and Precautions (5.15)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the codeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see Clinical Pharmacology (12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the ASCOMP with Codeine dosage as needed. If a CYP3A4 inducer is discontinued, consider ASCOMP with Codeine dosage reduction, and monitor for signs of respiratory depression and sedation at frequent intervals.
Examples:	Rifampin, carbamazepine, phenytoin
Inhibitors of CYP2D6
Clinical Impact:	Codeine in ASCOMP with Codeine is metabolized by CYP2D6 to form morphine. The concomitant use of ASCOMP with Codeine and CYP2D6 inhibitors can increase the plasma concentration of codeine, but can decrease the plasma concentrations of active metabolite morphine which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of ASCOMP with Codeine is achieved [see Clinical Pharmacology (12.3)]. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:	If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of ASCOMP with Codeine and monitor patients closely at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the ASCOMP with Codeine as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the ASCOMP with Codeine and monitor the patient for signs and symptoms of respiratory depression or sedation.
Examples:	paroxetine, fluoxetine, bupropion, quinidine
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ASCOMP with Codeine if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.9)].
Intervention:	Do not use ASCOMP with Codeine in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of ASCOMP with Codeine and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact:	Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of ASCOMP with Codeine and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when ASCOMP with Codeine is used concomitantly with anticholinergic drugs.
Anticoagulants
Clinical Impact:	Aspirin may enhance the effects of anticoagulants. Concurrent use may increase the risk of bleeding. Aspirin can also displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time.
Intervention:	Monitor patients for signs of bleeding.
Examples:	Warfarin, heparin, enoxaparin, clopidogrel, prasugrel, rivaroxaban, apixaban
Uricosuric Agents
Clinical Impact:	Aspirin inhibits the uricosuric effects of uricosuric agents.
Intervention:	Avoid concomitant use.
Examples:	Probenecid
Carbonic Anhydrase Inhibitors
Clinical Impact:	Concurrent use with aspirin can lead to high serum concentrations of the carbonic anhydrase inhibitor and cause toxicity due to competition at the renal tubule for secretion.
Intervention:	Consider reducing the dose of the carbonic anhydrase inhibitor and monitor patient for any adverse effects from the carbonic anhydrase inhibitor.
Examples:	Acetazolamide, methazolamide
Methotrexate
Clinical Impact:	Aspirin may enhance the toxicity of methotrexate by displacing it from its plasma protein binding sites and/or reducing its renal clearance.
Intervention:	Use caution if using concomitantly, especially in elderly patients or patients with renal impairment. Monitor patients for methotrexate toxicity.
Nephrotoxic Agents
Clinical Impact:	Concomitant use with aspirin may lead to additive nephrotoxicity due to the inhibition of renal prostaglandins by aspirin. Also, the plasma concentration of aspirin is increased by conditions that reduce the glomerular filtration rate or tubular secretion.
Intervention:	Use ASCOMP with Codeine with caution if used concomitantly with nephrotoxic agents. Closely monitor the renal function of patients
Examples:	Aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, cyclosporine, foscarnet, or parenteral vancomycin
Angiotensin Converting Enzyme (ACE) Inhibitors
Clinical Impact:	The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway.
Intervention:	Use caution if using concomitantly. Monitor the blood pressure and renal function of patients.
Examples:	Ramipril, captopril
Beta Blockers
Clinical Impact:	The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention.
Intervention:	Use caution if using concomitantly. Monitor the blood pressure and renal function of patients
Examples:	Metoprolol, propranolol
Hypoglycemic Agents
Clinical Impact:	Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia.
Intervention:	Patients should be advised to consult a physician if any signs or symptoms of hypoglycemia occur.
Examples:	Insulin, glimepiride, glipizide
Anticonvulsants
Clinical Impact:	Aspirin can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels.
Intervention:	Use caution if using concomitantly.
Examples:	Phenytoin, valproic acid
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Clinical Impact:	Concurrent use with aspirin may increase the risk of bleeding or lead to decreased renal function. Aspirin may enhance serious side effects and toxicity of ketorolac by displacing it from its plasma protein binding sites and/or reducing its renal clearance.
Intervention:	Avoid concomitant use.
Examples:	Ketorolac, ibuprofen, naproxen, diclofenac
Corticosteroids
Clinical Impact:	In patients receiving concomitant corticosteroids and chronic use of aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance.
Intervention:	Avoid concomitant use