Fioricet with Codeine (Page 11 of 12)

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, acetaminophen, caffeine, and codeine or butalbital alone have not been conducted.

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.

Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 1.6 times the maximum human daily dose (MHDD) of 1950 mg/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats that received up to 1.4 times or mice at up to 2.4 to 2.8 times the MHDD, based on a body surface area comparison.

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.

In the published literature, acetaminophen has been reported to be clastogenic when administered at 1500 mg/kg/day to the rat model (7.2-times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (3.6-times the MHDD, based on a body surface area comparison), suggesting a threshold effect.

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, acetaminophen, caffeine, and codeine on fertility. There are also no data on butalbital alone or codeine alone.

In studies conducted by the National Toxicology Program, fertility assessments with acetaminophen have been completed in Swiss CD-1 mice via a continuous breeding study. There were no effects on fertility parameters in mice consuming up to 3.4 times the MHDD of acetaminophen, based on a body surface area comparison. Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 3.6 times the MHDD (based on a body surface comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing.

Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 2.4 times the MHDD and greater (based on a body surface comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. The clinical significance of these findings is not known.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

FIORICET with CODEINE (Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules) is a navy blue opaque cap with a gray opaque body. Cap is imprinted with “FIORICET” and “CODEINE” in blue and body is imprinted with four-head profile ” “

Bottles of 100 (NDC 52544-082-01)

Store and Dispense

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container. Store FIORICET with CODEINE securely and dispose of properly [see Patient Counseling Information (17)].

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 FIORICET 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, 5.3), Drug Abuse and Dependence (9.2)]. Inform patients that leaving FIORICET 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 FIORICET with CODEINE by following these four steps:

• Mix FIORICET 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 FIORICET 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 FIORICET with CODEINE with others and to take steps to protect FIORICET 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 FIORICET with CODEINE or when the dosage is increased, and that it can occur even at recommended dosages.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.3)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

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

If naloxone is prescribed, also advise patients and caregivers:

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

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

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

Accidental Ingestion

Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.3)].

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants (Including Alcohol)

Inform patients and caregivers that potentially fatal additive effects may occur if FIORICET with CODEINE is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare 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 FIORICET 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 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 physicians if they are taking, or plan to take serotonergic medications. [see Drug Interactions (7)].

MAOI Interaction

Inform patients not to take FIORICET with CODEINE while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking FIORICET 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 (5.11)].

Important Administration Instructions

Instruct patients how to properly take FIORICET with CODEINE, including the following:

• To take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed [see Dosage and Administration (2.1, 2.3)].

• Do not take more than 4000 milligrams of acetaminophen per day and to call their healthcare provider if they took more than the recommended dose.

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue FIORICET with CODEINE without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.4)].

Severe Hypotension

Inform patients that FIORICET 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 (5.12)].

Anaphylaxis

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

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of FIORICET 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 FIORICET with CODEINE can cause fetal harm and to inform their 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 FIORICET 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 Adverse Reactions (6)].

Risks of Driving and Operating Heavy Machinery

Inform patients that FIORICET 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 (5.17)].

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

Manufactured for:
Teva Pharmaceuticals USA, Inc.
Parsippany, NJ 07054

Rev. 03/2021