BUTALBITAL, ASPIRIN, CAFFEINE AND CODEINE PHOSPHATE (Page 10 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of the combination of butalbital, aspirin, caffeine, and codeine or butalbital alone have not been conducted.

Administration of aspirin for 68 weeks at 0.5 percent in the feed of rats was not carcinogenic. Two-year carcinogenicity studies with codeine sulfate have been conducted in F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of codeine sulfate (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m² basis) for two years. Similarly there was no evidence of carcinogenicity activity in male and female mice at dietary doses up to 400 mg/kg/day of codeine sulfate (approximately 10 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m² basis) for two years.

In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 4 and 7 times, respectively, the maximum human daily dose on a mg/m² basis). In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses up to 55 mg/kg (equivalent to the MHDD on a mg/m² basis).

Mutagenesis

There are no genetic toxicology data for butalbital.

Codeine sulfate was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay.

Aspirin is not mutagenic in the Ames Salmonella assay; however, aspirin did induce chromosome aberrations in cultured human fibroblasts.

Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation (5-fold) in folate-deficient mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary cell (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/hypoxanthine guanine phosphoribosyltransferase (HGPRT) gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay. Caffeine was negative in the in vitro bacterial reverse mutation assay (Ames test).

Impairment of Fertility

No adequate studies have been conducted in animals to characterize the impact of the combinations of butalbital, aspirin, caffeine, and codeine on fertility. There are also no data on butalbital alone or codeine alone.

Aspirin inhibits ovulation in rats.

Caffeine (as caffeine base) administered to male rats at 50 mg/kg/day subcutaneously (2 times the MHDD on a mg/m² basis) for 4 days prior to mating with untreated females, caused decreased male reproductive performance in addition to causing embryotoxicity. In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration.

14 CLINICAL TRIALS

Evidence supporting the efficacy of Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules 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, USP Capsules, codeine, Butalbital, Aspirin, and 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, USP Capsules proved statistically significantly superior to each of its components (butalbital, aspirin, caffeine, and codeine) and to placebo on measures of pain relief.

Evidence supporting the efficacy and safety of Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP Capsules 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

NDC: 63629-2952-1: 30 Capsules in a BOTTLE

NDC: 63629-2952-2: 20 Capsules in a BOTTLE

NDC: 63629-2952-3: 90 Capsules in a BOTTLE

NDC: 63629-2952-4: 60 Capsules in a BOTTLE

NDC: 63629-2952-5: 40 Capsules in a BOTTLE

NDC: 63629-2952-6: 18 Capsules in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store ASCOMP with Codeine securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)]. Inform patients that leaving ASCOMP with Codeine unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that medicine take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take-back programs or DEA-registered collectors are available, instruct patients to dispose of ASCOMP with Codeine by following these four steps:

• Mix ASCOMP with Codeine (do not crush) with an unpalatable substance such as dirt, cat litter, or used coffee grounds;
• Place the mixture in a container such as a sealed plastic bag;
• Throw the container in the household trash;
• Delete all personal information on the prescription label of the empty bottle

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

Addiction, Abuse, and Misuse

Inform patients that the use of ASCOMP with Codeine, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share ASCOMP with Codeine with others and to take steps to protect ASCOMP with Codeine from theft or misuse.

Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting ASCOMP with Codeine or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death.

Risks from Concomitant Use with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if ASCOMP with Codeine is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.4), Drug Interactions (7)].

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

Advise caregivers that ASCOMP with Codeine is contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12-18 years of age receiving ASCOMP with Codeine to monitor for signs of respiratory depression [see Warnings and Precautions (5.5)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications. [see Drug Interactions (7)].

MAOI Interaction

Inform patients not to take ASCOMP with Codeine while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking ASCOMP with Codeine [see Drug Interactions (7) ].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.10)].

Important Administration Instructions

Instruct patients how to properly take ASCOMP with Codeine. [see Dosage and Administration (2.2)]. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue ASCOMP with Codeine without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.3)].

Hypotension

Inform patients that ASCOMP with Codeine may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.11)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in ASCOMP with Codeine. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

Aspirin Allergy

Patients should be informed that ASCOMP with Codeine contains aspirin and should not be taken by patients with an aspirin or NSAIDs allergy [see Warnings and Precautions (5.19)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of ASCOMP with Codeine during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that ASCOMP with Codeine can (or may) cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women that breastfeeding is not recommended during treatment with ASCOMP with Codeine [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

Risk of Bleeding

Inform patients about the signs and symptoms of bleeding. Tell patients to notify their physician if they are prescribed any drug which may increase risk of bleeding.

Counsel patients who consume three or more alcoholic drinks daily about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin [see Warnings and Precautions (5.17)].

Driving or Operating Heavy Machinery

Inform patients that ASCOMP with Codeine may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.16)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6)].

Manufactured by:
LGM Pharma Solutions, LLC
Irvine, CA 92614

Distributed by:
Breckenridge Pharmaceutical, Inc.
Berlin, CT 06037

6094

Rev 10/2020