Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate
Nexgen Pharma, Inc.
Nexgen Pharma, Inc.
FULL PRESCRIBING INFORMATION: CONTENTS*
- WARNING: HEPATOTOXICITY AND DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE
- BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE DESCRIPTION
- CLINICAL PHARMACOLOGY
- INDICATIONS
- BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE ADVERSE REACTIONS
- DRUG ABUSE AND DEPENDENCE
- OVERDOSAGE
- BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE DOSAGE AND ADMINISTRATION
- HOW SUPPLIED
- PRINCIPAL DISPLAY PANEL
FULL PRESCRIBING INFORMATION
WARNING: HEPATOTOXICITY AND DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE
• Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product.
• Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism.
BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE DESCRIPTION
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate is supplied in capsule form for oral administration.
Each capsule contains:
butalbital, USP…………..........50 mg
acetaminophen, USP………...325 mg
caffeine, USP……………........40 mg
codeine phosphate, USP….......30 mg
Butalbital (5allyl5isobutylbarbituric acid), is a short-to intermediate-acting barbiturate. It has the following structural formula:
C11H16N2O3 MW 224.26
Acetaminophen (4'hydroxyacetanilide), is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:
C8H9NO2 MW 151.16
Caffeine (1,3,7trimethylxanthine), is a central nervous system stimulant. It has the following structural formula:
C8H10N4O2 MW 194.19
Codeine phosphate [morphine3methyl ether phosphate (1:1) (salt) hemihydrate], is a narcotic analgesic and antitussive. It has the following structural formula:
C18H24NO7P anhydrous MW 397.37
Active Ingredients: butalbital, USP, caffeine, USP, acetaminophen, USP, and codeine phosphate, USP.
Inactive Ingredients: FD&C blue #1, FD&C yellow #6, D&C yellow #10, FD&C red #40, gelatin, microcrystalline cellulose, stearic acid, sodium lauryl sulfate, talc, and titanium dioxide.
CLINICAL PHARMACOLOGY
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules is a combination drug product intended as a treatment for tension headache. It consists of a fixed combination of butalbital 50 mg, acetaminophen 325 mg, caffeine 40 mg, and codeine phosphate 30 mg. The role each component plays in the relief of the complex of symptoms known as tension headache is incompletely understood.
Pharmacokinetics
The behavior of the individual components is described below
Butalbital
Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most tissues in the body. Barbiturates in general may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility.
Elimination of butalbital is primarily via the kidney (59% to 88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products include parent drug (about 3.6% of the dose), 5isobutyl5(2,3dihydroxypropyl) barbituric acid (about 24% of the dose), 5allyl5(3-hydroxy2methyl1propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% is conjugated.
The in vitro plasma protein binding of butalbital is 45% over the concentration range of 0.5 to 20 mcg/mL. This falls within the range of plasma protein binding (20% to 45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells.
See OVERDOSAGE for toxicity information.
Acetaminophen
Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.
See OVERDOSAGE for toxicity information.
Caffeine
Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk.
Caffeine is cleared through metabolism and excretion in the urine. The plasma half-life is about 3 hours. Hepatic biotransformation prior to excretion results in about equal amounts of 1methylxanthine and 1methyluric acid. Of the 70% of the dose that is recovered in the urine, only 3% is unchanged drug.
See OVERDOSAGE for toxicity information.
Codeine
Codeine is readily absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain; however, codeine is not bound to plasma proteins and does not accumulate in body tissues.
The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.
At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours.
See OVERDOSAGE for toxicity information.
INDICATIONS
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate capsules are indicated for the relief of the symptom complex of tension (or muscle contraction) headache.
Evidence supporting the efficacy and safety of Butalbital, Acetaminophen, 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, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE CONTRAINDICATIONS
This combination product is contraindicated under the following conditions:
Post-operative pain management in children who have undergone tonsillectomy and/or adenoidectomy.
Hypersensitivity or intolerance to acetaminophen, caffeine, butalbital, or codeine.
Patients with porphyria.
WARNINGS
Hepatotoxicity
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.
The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.
Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.
Serious skin reactions
Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Death Related to Ultra-Rapid Metabolism of Codeine to Morphine
Respiratory depression and death have occurred in children who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and 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). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine.
Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing).
Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see Contraindications ].
When prescribing Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules, 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.
Hypersensitivity/ anaphylaxis
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth. and throat. respiratory distress, urticaria, rash, pruritus. and vomiting, There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Butalbital, Acetaminophen Caffeine, and Codeine Phosphate Capsules immediately and seek medical care if they experience these symptoms. Do not prescribe Butalbital, Acetaminophen Caffeine, and Codeine Phosphate Capsules for patients with acetaminophen allergy.
In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS depressant effects, such as drowsiness, that may further obscure the clinical course of the patients with head injuries.
Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions.
Butalbital and codeine are both habit-forming and potentially abusable. Consequently, the extended use of this combination product is not recommended.
PRECAUTIONS
General
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate should be prescribed with caution in certain special risk patients such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison's disease, or prostatic hypertrophy.
Information for patients
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In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.
Drug interactions
The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors.
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate may enhance the effects of:
- Other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative hypnotics, or other CNS depressants, causing increased CNS depression.
Drug/laboratory test interactions
Codeine may increase serum amylase levels.
Acetaminophen may produce false positive test results for urinary 5hydroxyindoleacetic acid.
Carcinogenesis, mutagenesis, impairment of fertility
No adequate studies have been conducted in animals to determine whether acetaminophen, codeine and butalbital have a potential for carcinogenesis or mutagenesis. No adequate studies have been conducted in animals to determine whether acetaminophen and butalbital have a potential for impairment of fertility.
Pregnancy
Teratogenic effects
Pregnancy Category C: Animal reproduction studies have not been conducted with Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate. It is also not known whether this combination product can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. This combination product should be given to a pregnant woman only when clearly needed.
Nonteratogenic effects
Withdrawal seizures were reported in a two-day-old male infant whose mother had taken a butalbital containing drug during the last 2 months of pregnancy. Butalbital was found in the infant's serum. The infant was given phenobarbital 5 mg/kg, which was tapered without further seizure or other withdrawal symptoms.
Labor and delivery
Use of codeine during labor may lead to respiratory depression in the neonate.
Nursing Mothers
Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants,
The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. (See WARNINGS — Death Related to Ultra-Rapid Metabolism of Codeine to Morphine) .
Pediatric use
Safety and effectiveness in pediatric patients have not been established.
Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and 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). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules with Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy [see Contraindications].
Geriatric use
Clinical studies of Butalbital, Acetaminophen, 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 monitor renal function.
BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE ADVERSE REACTIONS
Frequently Observed
The most frequently reported adverse reactions are drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, abdominal pain, and intoxicated feeling.
Infrequently Observed
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, sluggishness, seizure. Mental confusion, excitement or depression can also occur due to intolerance, particularly in elderly or debilitated patients, or due to overdosage of butalbital.
Autonomic Nervous: dry mouth, hyperhidrosis.
Gastrointestinal: difficulty swallowing, heartburn, flatulence, constipation.
Cardiovascular: tachycardia.
Musculoskeletal: leg pain, muscle fatigue.
Genitourinary: diuresis.
Miscellaneous: pruritus, fever, earache, nasal congestion, tinnitus, euphoria, allergic reactions.
The following adverse reactions have been voluntarily reported as temporally associated with Fiorinal® with Codeine, a related product containing aspirin, butalbital, caffeine, and codeine phosphate.
Central Nervous: abuse, addiction, anxiety, disorientation, hallucination, hyperactivity, insomnia, libido decrease, nervousness, neuropathy, psychosis, sexual activity increase, slurred speech, twitching, unconsciousness, vertigo.
Autonomic Nervous: epistaxis, flushing, miosis, salivation.
Gastrointestinal: anorexia, appetite increased, diarrhea, esophagitis, gastroenteritis, gastrointestinal spasms, 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.
The following adverse drug events may be borne in mind as potential effects of the components of Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate. Potential effects of high dosage are listed in the OVERDOSAGE section.
Acetaminophen: allergic reactions, rash, thrombocytopenia, agranulocytosis.
Caffeine: cardiac stimulation, irritability, tremor, dependence, nephrotoxicity, hyperglycemia.
Codeine: nausea, vomiting, drowsiness, lightheadedness, constipation, pruritus.
Several cases of dermatological reactions, including toxic epidermal necrolysis and erythema multiforme, have been reported for Fioricet® (Butalbital, Acetaminophen, and Caffeine Tablets, USP).
DRUG ABUSE AND DEPENDENCE
Controlled Substance
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate is controlled by the Drug Enforcement Administration and is classified under Schedule III.
Abuse and Dependence
Butalbital
Barbiturates may be habit-forming: Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high doses of barbiturates. The average daily dose for the barbiturate addict is usually about 1,500 mg. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than twofold. As this occurs, the margin between an intoxication dosage and fatal dosage becomes smaller. The lethal dose of a barbiturate is far less if alcohol is also ingested. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs. Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. One method involves initiating treatment at the patient's regular dosage level and gradually decreasing the daily dosage as tolerated by the patient.
Codeine
Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic medications.
OVERDOSAGE
Following an acute overdosage of butalbital, acetaminophen, caffeine, and codeine phosphate, toxicity may result from the barbiturate, the codeine, or the acetaminophen. Toxicity due to caffeine is less likely, due to the relatively small amounts in this formulation.
Signs and Symptoms
Toxicity from barbiturate poisoning includes drowsiness, confusion, and coma; respiratory depression; hypotension; and hypovolemic shock. Toxicity from codeine poisoning includes the opioid triad of: pinpoint pupils, depression of respiration, and loss of consciousness. Convulsions may occur. In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necroses, hypoglycemic coma, and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Acute caffeine poisoning may cause insomnia, restlessness, tremor, and delirium, tachycardia and extrasystoles.
Treatment
A single or multiple drug overdose with butalbital, acetaminophen, caffeine, and codeine phosphate is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to codeine, parenteral naloxone is a specific and effective antagonist.
Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.
Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.
BUTALBITAL, ACETAMINOPHEN, CAFFEINE, AND CODEINE PHOSPHATE DOSAGE AND ADMINISTRATION
One or 2 capsules every 4 hours. Total daily dosage should not exceed 6 capsules.
Extended and repeated use of this combination product is not recommended because of the potential for physical dependence.
HOW SUPPLIED
Butalbital, Acetaminophen, Caffeine, and Codeine Phosphate Capsules 50 mg/325 mg/ 40 mg/30 mg are blue, opaque cap with a gray, opaque body, and body is imprinted with “B073” in white ink.
Bottles of 100 (NDC 0722-6670-01)
Bottles of 500 (NDC 0722-6670-05)
Store and Dispense
Store at 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight container.
Manufactured by:
Nexgen Pharma, Inc.
Irvine, CA 92614
(Rev. 2/14)
PRINCIPAL DISPLAY PANEL
100 Count Container Label
Butalbital, Acetaminophen, Caffeine, and Codeine PhosphateButalbital, Acetaminophen, Caffeine, and Codeine Phosphate CAPSULE
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