Fioricet With Codeine (butalbital/acetaminophen/caffeine/codeine phosphate)

It isessential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

To minimize risk of overdosage, recommended age-appropriate daily dosages of acetaminophen should not be exceeded.

Dosage of codeine sulfate and codeine phosphate is expressed in terms of the salt.

Some clinicians suggest that when used as a mild CNS stimulant to overcome fatigue, oral doses of 100-200 mg of anhydrous caffeine are required. The manufacturers state that adults and children 12 years of age or older may receive a dosage of 100-200 mg no more frequently than every 3-4 hours.

For the treatment of apnea of prematurity, commercially available caffeine citrate injection in a loading dose of 20 mg/kg (10 mg/kg when expressed in terms of anhydrous caffeine) is administered by slow IV infusion (i.e., over 30 minutes) using a syringe infusion pump. Beginning 24 hours after the loading dose, maintenance doses of caffeine citrate of 5 mg/kg (2.5 mg/kg when expressed as anhydrous caffeine) may be administered every 24 hours, either orally or via slow IV infusion (i.e., over 10 minutes) using a syringe infusion pump. The manufacturer states that the safety and efficacy of dosing periods exceeding 10-12 days have not been established. Other dosing regimens+ for the treatment of apnea of prematurity have used caffeine doses (in terms of anhydrous caffeine) of 5-10 mg/kg, given IV, IM, or orally as a loading dose, and followed by 2.5-5 mg/kg, given IV, IM, or orally once daily. Maintenance dosage has been adjusted according to the patient's response and tolerance and plasma caffeine concentrations.

When caffeine citrate is used for the treatment of apnea of prematurity in infants with hepatic or renal impairment, serum concentrations of caffeine should be monitored and dosage adjusted to avoid toxicity.

Analeptic use of caffeine is strongly discouraged by most clinicians. However, the manufacturers of caffeine and sodium benzoate injection recommend IM, or in emergency respiratory failure, IV injection of 500 mg of the drug (about 250 mg of anhydrous caffeine) or a maximum single dose of 1 g (about 500 mg of anhydrous caffeine) for the treatment of respiratory depression associated with overdosage of CNS depressants, including opiate analgesics and alcohol, and with electric shock.

Some clinicians recommend that when caffeine and sodium benzoate injection is used in children for CNS stimulation+, an IM, IV, or subcutaneous dose of 8 mg/kg (about 4 mg of anhydrous caffeine per kg) (not to exceed 500 mg) or 250 mg/m2 (about 125 mg of anhydrous caffeine per m2) be given up to every 4 hours if necessary.

In general, the smallest effective dose should be used. Dosage must be individualized for each patient. Dosage should be reduced in geriatric or debilitated patients and in patients with impaired hepatic function. Because of their higher metabolic rate, children may tolerate comparatively larger doses than adults. Barbiturates should be withdrawn slowly to avoid the possibility of precipitating withdrawal symptoms.

In the treatment of insomnia, consideration should be given to intermittent rather than to daily administration; with daily administration, duration of therapy should be limited to 2 weeks. To prevent rebound in rapid eye movement (REM) sleep, withdrawal of a single therapeutic dose over 5 or 6 days (e.g., decreasing dosage from 3 to 2 doses daily for 1 week) has been recommended when barbiturates are discontinued following prolonged use.

*Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

*Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse.

*Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with butalbital/acetaminophen/caffeine/codeine. Consider prescribing naloxone based on the patient's risk factors for overdose.

*Initiate treatment with 1 or 2 capsules every 4 hours as needed for pain. Total daily dosage should not exceed 6 capsules.

*Do not abruptly discontinue butalbital/acetaminophen/caffeine/codeine in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.

Acetaminophen injection is administered by IV infusion over 15 minutes.

Acetaminophen is also commercially available in fixed-combination with ibuprofen (Combogesic(R)IV) for IV administration. See the full prescribing information for administration of this combination product.

Several commercially available fixed-combination prescription preparations containing acetaminophen are also available for oral use. See the full prescribing information for administration of these combination products.

Acetaminophen is commercially available in various oral and rectal over-the-counter (OTC) preparations as a single ingredient or in combination with other analgesics (e.g., ibuprofen), antihistamines, or decongestants. See the FDA Orange Book and the manufacturer's Drug Facts for further information.

Codeine-containing preparations are administered orally.

Codeine sulfate is commercially available as a single-entity tablet preparation. Codeine phosphate is commercially available in the following fixed-combination preparations for oral use: codeine/acetaminophen, promethazine/codeine, promethazine/phenylephrine/codeine, butalbital/acetaminophen/caffeine/codeine, and butalbital/aspirin/caffeine/codeine. See the full prescribing information for additional information on these combination preparations. Codeine also may be commercially available in over-the-counter (OTC) preparations in combination with antihistamines, expectorants, or decongestants. See the FDA Orange Book and the manufacturer's Drug Facts for additional information.

Codeine sulfate tablets should be stored at 20-25degreesC (excursions permitted between 15-30degreesC) in a secure location; protect from moisture.

Caffeine may be administered orally. Caffeine citrate is administered orally or by slow IV infusion using a syringe infusion pump. Caffeine and sodium benzoate injection may be administered by IM or slow IV injection; the drug has also been administered subcutaneously.

The preservative-free commercially available injection is for single use only, and any unused portion should be discarded. It is important that such oral solution be measured accurately (e.g., using a 1-mL or other appropriate syringe).

Although most of the barbiturates are administered orally, some barbiturates may be administered rectally, subcutaneously, IM, and/or IV.

No dosing information is available for this tab.

No dosing information is available for this tab.

Codeine is metabolized by cytochrome P-450 (CYP) 2D6 to its active metabolite, morphine. Codeine is also metabolized by CYP3A4 to an inactive metabolite.

Concurrent administration of numerous drugs with barbiturates has been reported to affect either the patient's response to the barbiturates or to the other drugs. Most of the reported drug interactions relate to phenobarbital, but the possibility of similar interaction with other barbiturates should be considered.

In addition to the interactions listed, many other drugs have been reported to alter the response to barbiturates and/or have their responses altered by barbiturates; however, in most instances the clinical importance of these interactions has not been established. Since documentation for these interactions may be forthcoming and additional clinically important interactions may be established, caution should be observed when any drug is added to or deleted from any therapeutic regimen which contains a barbiturate, giving consideration to the possible need for dosage adjustment.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*Children younger than 12 years of age.

*Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

*Significant respiratory depression.

*Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment.

*Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.

*Known or suspected GI obstruction, including paralytic ileus.

*Intolerance or hypersensitivity to acetaminophen, caffeine, butalbital or codeine, or components of the preparation.

*Porphyria.

*Known hypersensitivity to acetaminophen or any ingredient in the formulation.

*Severe hepatic impairment or severe active liver disease.

*Children younger than 12 years of age.

*Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

*Significant respiratory depression.

*Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment.

*Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.

*Known or suspected GI obstruction, including paralytic ileus.

*Hypersensitivity to codeine or any components of the formulation.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

Frequently reported adverse reactions are drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, abdominal pain, and intoxicated feeling.

The most common adverse effects reported in clinical trials in >=5% of patients receiving IV acetaminophen were nausea, vomiting, headache, and insomnia in adults and nausea, vomiting, constipation, and pruritus in pediatric patients.

Common adverse effects associated with oral or rectal administration of acetaminophen include skin rash, hypersensitivity reactions, nephrotoxicity, and hematologic abnormalities (e.g., anemia, leukopenia, neutropenia, and pancytopenia).

The most common adverse reactions reported with codeine sulfate tablets include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, and sweating.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

The safety and effectiveness of butalbital/acetaminophen/caffeine/codeine in pediatric patients have not been established.

Life-threatening respiratory depression and deaths have occurred in children who received codeine. In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children 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). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life-threatening respiratory depression and death:

Butalbital/acetaminophen/caffeine/codeine is contraindicated for all children younger than 12 years of age.

Butalbital/acetaminophen/caffeine/codeine is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

Avoid the use of butalbital/acetaminophen/caffeine/codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.

Use of IV acetaminophen for analgesia in pediatric patients >=2 years of age is supported by evidence from adequate and well-controlled studies of IV acetaminophen in adults and additional safety and pharmacokinetic data from 483 pediatric patients ranging in age from neonates to adolescents. Efficacy of IV acetaminophen for analgesia has not been established in pediatric patients <2 years of age.

Use of IV acetaminophen for fever in pediatric patients <2 years of age, including premature neonates (postmenstrual age of at least 32 weeks) is supported by evidence from adequate and well-controlled studies of IV acetaminophen in adults, clinical data in pediatric patients >=2 years of age, and additional safety and pharmacokinetic data from 239 patients <2 years of age, including neonates with a postmenstrual age of at least 32 weeks.

Safety and effectiveness of codeine have not been established in pediatric patients. Pediatric patients receiving codeine for the management of pain, especially those who are obese, have obstructive sleep apnea or severe lung disease, or have evidence of ultrarapid metabolism of CYP2D6 substrates, are at increased risk of respiratory depression. Serious adverse events, including deaths, have been reported during postmarketing experience in pediatric patients receiving codeine. Between January 1969 and May 2015, the FDA Adverse Event Reporting System (FAERS) received 64 reports of respiratory depression, including 24 reports of death, worldwide that were associated with codeine use in pediatric patients younger than 18 years of age. Ten of the 64 reports provided information about CYP2D6 metabolizer status. Seven of these patients were ultrarapid or extensive metabolizers of CYP2D6 substrates; 5 of which reported death. Most of the cases of respiratory depression, including most of the deaths, occurred in children younger than 12 years of age. Respiratory depression may occur despite therapeutic serum concentrations of codeine or morphine; 1 patient who had concentrations within the therapeutic range died following use of codeine for management of pain after tonsillectomy and adenoidectomy.

Codeine-containing preparations are contraindicated in children younger than 12 years of age and contraindicated for postoperative pain management following tonsillectomy and/or adenoidectomy in pediatric patients younger than 18 years of age. Avoid the use of codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of the drug unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with butalbital/acetaminophen/caffeine/codeine in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Animal reproduction studies have not been conducted with the combination of butalbital/acetaminophen/caffeine/codeine or with butalbital alone. In animal reproduction studies, codeine administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 2.8 times the maximum recommended human dose (MRHD) of 180 mg/day, embryolethal and fetotoxic effects in the offspring of rats and hamsters at approximately 4 to 6 times the MRHD, and cranial malformations/cranioschisis in the offspring of hamsters between 2 and 8 times the MRHD. Reproductive and developmental studies in rats and mice from the published literature identified adverse events at clinically relevant doses with acetaminophen. Treatment of pregnant rats with doses of acetaminophen approximately 2 times the maximum human daily dose (MHDD) showed evidence of fetotoxicity and increases in bone variations in the fetuses. In another study, necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses approximately 2 times the MHDD. In mice treated with acetaminophen at doses within the clinical dosing range, cumulative adverse effects on reproduction were seen in a continuous breeding study. A reduction in number of litters of the parental mating pair was observed as well as retarded growth and abnormal sperm in their offspring and reduced birth weight in the next generation.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Prolonged use of opioid analgesics during pregnancy for medical or non-medical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Use of codeine during labor may lead to respiratory depression in the neonate.

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Butalbital/acetaminophen/caffeine/codeine is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including butalbital/acetaminophen/caffeine/codeine, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Published data from a large population-based prospective cohort study and a population-based, case-control study do not clearly report an association with oral acetaminophen and major birth defects, miscarriage, or adverse maternal or fetal outcomes when acetaminophen is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including recall bias.

Withdrawal seizures were reported in a 2-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.

Epidemiologic data regarding oral acetaminophen use in pregnant females have shown no increased risk of major congenital malformations in infants exposed in utero to the medication. In a large population-based prospective cohort study involving more than 26,000 females with live-born singleton infants who were exposed to oral acetaminophen during the first trimester of pregnancy, no increase in the risk of congenital malformations was observed in exposed children compared with a control group of unexposed children; rate of congenital malformations (4.3%) was similar to the rate in the general population. A population-based, case-control study from the National Birth Defects Prevention Study also found no increase in the risk of major birth defects in a group of 11,610 children who had been exposed to acetaminophen during the first trimester of pregnancy compared with a control group of 4,500 children.

Animal reproduction studies in pregnant rats given oral acetaminophen during organogenesis at dosages up to 0.85 times the maximum recommended human daily dosage (4 g daily, based on body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes); the offspring showed no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at a dosage of 1.2 times the maximum recommended human daily dosage, areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses; these effects did not occur in animals given acetaminophen at dosages of 0.3 times the maximum recommended human dosage.

In a continuous breeding study in which pregnant mice were given acetaminophen at dosages approximately equivalent to 0.43, 0.87, or 1.7 times the maximum recommended human daily dosage (based on body surface area comparison), a dose-related reduction in body weight of the fourth and fifth litter offspring of the treated mating pair occurred during lactation and following weaning at all dosages studied. Animals receiving the highest dosage had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next-generation pups.

The manufacturer states that there are no animal reproductive studies with IV acetaminophen.

A correlation between acetaminophen use during pregnancy and neurodevelopmental disorders in children, including autism and attention-deficit/hyperactivity disorder (ADHD), has been observed in studies; however, inconsistent findings have been reported in the literature and a causal relationship has not been established. Results of 2 high-quality studies with sibling controls indicate prenatal exposure to acetaminophen was not associated with an increased risk of a neurodevelopmental diagnosis. There are unmeasured familial confounding factors that may explain the apparent association observed in some studies. Acetaminophen is considered the preferred analgesic/antipyretic for use during pregnancy because of its relatively favorable safety profile compared with other common analgesics. The American College of Obstetricians and Gynecologists (ACOG) supports use of acetaminophen during pregnancy when taken as needed in moderation and after consultation with a doctor. There is no evidence to support any risk associated with appropriate use of acetaminophen during pregnancy. However, untreated maternal fever and pain pose risks such as neural tube defects and preterm birth, necessitating a balanced approach.

Available data with codeine are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In animal studies, embryolethal and fetotoxic effects were observed in animals administered codeine during the period of organogenesis.

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Codeine is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including codeine, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excessive sedation and respiratory depression.

Use of opioid analgesics for an extended period during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.

There are no adequate and well-controlled studies in pregnant women. In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained-release pellets at 50 mg/kg (less than the maximum IV loading dose for neonates on a mg/m2 basis) during the period of organogenesis caused a low incidence of cleft palate and exencephaly in fetuses. Based on data from a large retrospective epidemiologic study and from a large retrospective case-control study in humans, it appears that use of caffeine during pregnancy has little, if any, effect on the outcome of pregnancy. Although caffeine use during pregnancy does not appear to be associated with substantial risk, most clinicians recommend that pregnant women avoid or limit their consumption of foods, beverages, and drugs containing caffeine, since caffeine crosses the placenta.

Barbiturates can cause fetal harm when administered to pregnant women. Retrospective, case-controlled studies have suggested an association between maternal ingestion of barbiturates and a higher than expected incidence of fetal abnormalities. If a barbiturate is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.

Based on animal data, repeated or prolonged use of general anesthetics and sedation drugs during the third trimester of pregnancy may result in adverse neurodevelopmental effects in the fetus. The clinical relevance of these animal findings to humans is not known; the potential risk of adverse neurodevelopmental effects should be considered and discussed with pregnant women undergoing procedures requiring general anesthetics and sedation drugs. (See Cautions: Pediatric Precautions.)

Barbiturates have caused postpartum hemorrhage and hemorrhagic disease in neonates. The drug-induced hemorrhagic disease of the neonate is similar to that resulting from vitamin K deficiency and is readily reversible with vitamin K therapy. Neonates born to women who receive barbiturates throughout the last trimester of pregnancy may show withdrawal symptoms. (See Chronic Toxicity: Manifestations.) Neonates whose mothers have received barbiturates during labor should be closely observed for signs of respiratory depression, and treatment for barbiturate overdosage should be instituted if necessary. (See Acute Toxicity: Treatment.) Premature neonates are particularly susceptible to the depressant effects of barbiturates, and the drugs should be administered with caution when delivery of a premature neonate is anticipated.

Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent.

There is no information on the effects of the codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with butalbital/acetaminophen/caffeine/codeine.

Acetaminophen is present in human milk in small quantities after oral administration. Based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 to 2% of the maternal dose. There is one well-documented report of a rash in a breastfed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use.

Barbiturates and caffeine are also excreted in breast milk in small amounts. Because of potential for serious adverse reactions in nursing infants from butalbital/acetaminophen/caffeine/codeine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

If infants are exposed to butalbital/acetaminophen/caffeine/codeine through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

It is not known if IV acetaminophen is excreted into human milk; however, data suggest following oral administration of acetaminophen, infant exposure is approximately 1-2% of the weight-adjusted maternal daily dosage. Limited published studies report acetaminophen passes rapidly into human milk with similar levels noted in milk and plasma. A case of rash in a breast-fed infant has been reported; the rash resolved when the mother discontinued acetaminophen use and recurred when she resumed acetaminophen therapy. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for acetaminophen and any potential adverse effects on the breast-fed infant from exposure to the medication or to the underlying maternal condition.

Breastfeeding is not recommended during treatment with codeine, especially in patients who have evidence of ultrarapid metabolism of CYP2D6 substrates. Serious adverse events (e.g., excessive sedation, difficulty nursing, respiratory depression), including death, have been reported in nursing infants exposed to codeine. At least one case of opioid toxicity resulting in neonatal death has been reported in the nursing infant of a woman receiving codeine; genetic testing of the woman indicated that she was an ultrarapid metabolizer of codeine. Higher than expected concentrations of morphine were found in breast milk and in the blood of the infant. Somnolence has been reported more frequently in nursing infants whose mothers received codeine in combination with acetaminophen compared with those whose mothers received acetaminophen alone; evidence of ultrarapid metabolism of CYP2D6 substrates was identified in some of these women. Concentrations of morphine in breast milk are low and dose-dependent in women who are normal metabolizers of codeine. FDA-approved tests (e.g., AmpliChip(R) CYP450 Test) are available to identify an individual's CYP2D6 genotype. Infants exposed to codeine through breast milk should be monitored closely for clinical manifestations of opioid toxicity (e.g., sedation, difficulty breastfeeding or breathing, hypotonia). Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic or breastfeeding is stopped.

Caffeine is distributed into the milk of nursing women. Milk-to-plasma ratios of 0.5-0.76 have been reported. The amount of caffeine ingested from usual quantities of caffeinated beverages is considered compatible with breast-feeding; however, caffeine may accumulate in nursing infants following moderate to heavy maternal consumption of caffeine, resulting in irritability and poor sleeping patterns.

Because barbiturates are distributed into the milk of nursing women, nursing should be discontinued if nursing infants of barbiturate-treated women exhibit signs of toxicity.

The manufacturer makes no specific dosage recommendations for geriatric patients. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to IV acetaminophen cannot be ruled out.

In general, select dosage with caution in geriatric patients, 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. Titrate dosage of codeine slowly in geriatric patients and frequently re-evaluate the patient for CNS and respiratory depression.

Clinical studies of butalbital/acetaminophen/caffeine/codeine did not include sufficient numbers of subjects 65 years of age 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.

Elderly patients (aged 65 years or older) may have increased sensitivity to butalbital/acetaminophen/caffeine/codeine. In general, use caution when selecting a dosage for an elderly patient, 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.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of butalbital/acetaminophen/caffeine/codeine slowly in geriatric patients and monitor closely for signs of respiratory depression.

Components of this product are known to be substantially excreted by the kidney, and the risk of adverse 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.

When the total number of patients studied in clinical trials of IV acetaminophen is considered, 15% were >=65 years of age, while 5% were >=75 years of age. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility some older patients may exhibit increased sensitivity to acetaminophen cannot be ruled out.

Geriatric patients may have increased sensitivity to codeine. In general, use caution when selecting a dosage for an elderly patient, 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. Respiratory depression is the main risk for geriatric patients treated with opioids and has occurred after large initial doses in patients who were not opioid-tolerant or when opioids were co-administered with other drugs that depress respiration. Titrate the dosage of codeine slowly in geriatric patients and frequently re-evaluate for signs of CNS and respiratory depression.

Codeine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased renal function; dosing should be selected with care and renal function should be regularly evaluated.