Kenya - Tiếng Anh - Pharmacy and Poisons Board

macarthy laboratories ltd t/a martindale pharma bamptom road harold hill romford essex rm3 8ug - caffeine citrate - solution for injection - 10mg/ml - caffeine

Kenya - Tiếng Anh - Pharmacy and Poisons Board

caffeine citrate - oral drops - 20mg/ml - caffeine

Malta - Tiếng Anh - Medicines Authority

chefaro ireland dac the sharp building, hogan place, dublin 2,, ireland - codeine phosphate, hemihydrate, caffeine, paracetamol - effervescent tablet - codeine phosphate hemihydrate 8 mg caffeine 30 mg paracetamol 500 mg - analgesics

Úc - Tiếng Anh - Department of Health (Therapeutic Goods Administration)

fit-bioceuticals limited - caffeine,ribose,ubidecarenone -

Hoa Kỳ - Tiếng Anh - NLM (National Library of Medicine)

sohm inc. - caffeine (unii: 3g6a5w338e) (caffeine - unii:3g6a5w338e) - caffeine 200 mg - alertness aid - helps restore mental alertness or wakefulness when experiencing fatigue or drowsiness

Hoa Kỳ - Tiếng Anh - NLM (National Library of Medicine)

mikart, inc. - acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d), caffeine (unii: 3g6a5w338e) (caffeine - unii:3g6a5w338e), dihydrocodeine bitartrate (unii: 8lxs95bsa9) (codeine - unii:q830pw7520) - tablet - 712.8 mg - acetaminophen, caffeine and dihydrocodeine bitartrate tablets are indicated for the relief of moderate to moderately severe pain. this combination product is contraindicated in patients with hypersensitivity to dihydrocodeine, codeine, acetaminophen, caffeine, or any of the inactive components listed above, or in any situation where opioids are contraindicated including significant respiratory depression (in unmonitored settings or in the absence of resuscitative equipment), acute or severe bronchial asthma or hypercapnia, and paralytic ileus. this combination product is subject to the provisions of the controlled substance act, and has been placed in schedule iii. dihydrocodeine can produce drug dependence of the codeine type and therefore has the potential of being abused. like other opioid analgesics, dihydrocodeine may produce subjective effects other than analgesia (e.g., euphoria, relaxation), which may contribute to abuse by some patients. psychological dependence, physical dependence, and tolerance ma

Hoa Kỳ - Tiếng Anh - NLM (National Library of Medicine)

par pharmaceutical, inc. - butalbital (unii: khs0az4jvk) (butalbital - unii:khs0az4jvk), acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d), caffeine (unii: 3g6a5w338e) (caffeine - unii:3g6a5w338e), codeine phosphate (unii: gsl05y1mn6) (codeine anhydrous - unii:ux6owy2v7j) - butalbital 50 mg - butalbital, acetaminophen, caffeine, and codeine phosphate capsules are indicated for the management of the symptom complex of tension (or muscle contraction) headache when non-opioid analgesic and alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse with opioids and butalbital, even at recommended doses [see warnings and precautions (5.1)], reserve butalbital, acetaminophen, caffeine, and codeine phosphate capsules for use in patients for whom alternative treatment options [e.g., non-opioid, non-barbiturate analgesics]: - have not been tolerated, or are not expected to be tolerated, - have not provided adequate analgesia, or are not expected to provide adequate analgesia. butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated for: - all children younger than 12 years of age [see warnings and precautions (5.5)]. - post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoide

Hoa Kỳ - Tiếng Anh - NLM (National Library of Medicine)

actavis pharma, inc. - codeine phosphate (unii: gsl05y1mn6) (codeine anhydrous - unii:ux6owy2v7j), butalbital (unii: khs0az4jvk) (butalbital - unii:khs0az4jvk), caffeine (unii: 3g6a5w338e) (caffeine - unii:3g6a5w338e), acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d) - butalbital 50 mg - butalbital, acetaminophen, caffeine, and codeine phosphate capsules are indicated for the management of the symptom complex of tension (or muscle contraction) headache when non-opioid analgesic and alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse with opioids and butalbital, which can occur at any dosage or duration [see warnings and precautions (5.1)], reserve butalbital, acetaminophen, caffeine, and codeine phosphate capsules for use in patients for whom alternative treatment options [e.g., non-opioid, non-barbiturate analgesics]: - have not been tolerated or are not expected to be tolerated, - have not provided adequate analgesia or are not expected to provide adequate analgesia. butalbital, acetaminophen, caffeine, and codeine phosphate capsules should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated for: - all children younger than 12 years of age [see warnings and precautions (5.6 )] - post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see warnings and precautions (5.6 )] butalbital, acetaminophen, caffeine, and codeine phosphate capsules are also contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.2)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.10)] - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days [see warnings and precautions (5.11), drug interactions (7)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.15)] - known intolerance or hypersensitivity to acetaminophen, caffeine, butalbital, or codeine or to the components of butalbital, acetaminophen, caffeine, and codeine phosphate capsules - porphyria risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.4)] . available data with butalbital, acetaminophen, caffeine, and codeine phosphate capsules in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. there are risks to the mother and infant associated with use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules for an extended period of time during pregnancy (see clinical considerations). animal reproduction studies have not been conducted with the combination of butalbital, acetaminophen, caffeine, and codeine phosphate capsules 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 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 [see data ]. 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 to 4% and 15 to20%, respectively. clinical considerations fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time 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. 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 [see warnings and precautions (5.4)] . labor or delivery 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, and codeine phosphate capsules are 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, and codeine phosphate capsules, 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. data human data 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 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. animal data animal reproduction studies have not been conducted with butalbital, acetaminophen, caffeine, and codeine phosphate capsules or with butalbital alone. the following data are based on findings from studies performed with either codeine or acetaminophen alone. codeine in a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 14 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. in an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on gestation day 8 (oral; approximately 4 to 16 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis), reportedly produced cranioschisis in all of the fetuses examined. in studies in rats, doses at the 120 mg/kg level (oral; approximately 6 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. in pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 2.8 times the recommended daily dose of 180 mg/day for adults on a mg/mg2 basis) administered between gestation day 7 and 12 reportedly resulted in delayed ossification in the offspring. no teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) of codeine during organogenesis. codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. this dose is 1.6 times the maximum recommended human dose of 180 mg/day on a body surface area comparison. acetaminophen studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 1.7 the maximum human daily dose (mhdd) of 1950 mg/day based on a 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). offspring had no evidence of external, visceral, or skeletal malformations. when pregnant rats received oral acetaminophen throughout gestation at doses of 2.4 times the mhdd (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. these effects did not occur in animals that received oral acetaminophen at doses 0.6 times the mhdd, based on a body surface area comparison. in a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). these doses are approximately 0.86, 1.7, and 3.4 times the mhdd, respectively, based on a body surface area comparison. a dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. animals in the high dose group 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. caffeine 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 recommended daily dose on a mg/m2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. risk summary 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, and codeine phosphate capsules [see warnings and precautions (5.6) ]. 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, and codeine phosphate capsules, 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. clinical considerations if infants are exposed to butalbital, acetaminophen, caffeine, and codeine phosphate capsules 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 breastfeeding is stopped. infertility use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6), clinical pharmacology (12.2), nonclinical pharmacology (13.1)]. published literature indicates that acetaminophen affects sperm development in mice with consequent reduction in litter size in a multigeneration study [see nonclinical toxicology (13.1)] . the safety and effectiveness of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in pediatric patients have not been established. life-threatening respiratory depression and deaths have occurred in children who received codeine [see warnings and precautions (5.6)] . 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, and codeine phosphate capsules are contraindicated for all children younger than 12 years of age [see contraindications (4)] . - butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see contraindications (4)] . - avoid the use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules 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 [see warnings and precautions (5.6)]. clinical studies of butalbital, acetaminophen, caffeine, and codeine phosphate capsules 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. elderly patients (aged 65 years or older) may have increased sensitivity to butalbital, acetaminophen, caffeine, and codeine phosphate capsules. 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, and codeine phosphate capsules slowly in geriatric patients and frequently reevaluate the patient for signs of respiratory depression [see warnings and precautions (5.10)]. 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 regularly evaluate renal function. no formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of butalbital, codeine, and acetaminophen in this patient population are unknown. start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while regularly evaluating for side effects. codeine pharmacokinetics may be altered in patients with renal failure. clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully regularly evaluating for side effects. in patients with renal disease, regularly evaluate effects of therapy with serial renal function tests. butalbital, acetaminophen, caffeine, and codeine phosphate capsules contain codeine. codeine in combination with butalbital, acetaminophen, and caffeine is a schedule iii controlled substance. butalbital, acetaminophen, caffeine, and codeine phosphate capsules contains codeine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings and precautions (5.1)]. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. misuse and abuse of butalbital, acetaminophen, caffeine, and codeine phosphate capsules increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of butalbital, acetaminophen, caffeine, and codeine phosphate capsules with alcohol and/or other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of butalbital, acetaminophen, caffeine, and codeine phosphate capsules abuse include those with a history of prolonged use of any opioid, including products containing codeine, those with a history of drug or alcohol abuse, or those who use butalbital, acetaminophen, caffeine, and codeine phosphate capsules in combination with other abused drugs. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. butalbital, acetaminophen, caffeine, and codeine phosphate capsules, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. careful record keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of butalbital, acetaminophen, caffeine, and codeine phosphate capsules abuse of butalbital, acetaminophen, caffeine, and codeine phosphate capsules poses a risk of overdose and death. the risk is increased with concurrent use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules with alcohol and/or other cns depressants. butalbital, acetaminophen, caffeine, and codeine phosphate capsules are approved for oral use only. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. 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. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. do not abruptly discontinue butalbital, acetaminophen, caffeine, and codeine phosphate capsules in a patient physically dependent on opioids. rapid tapering of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing butalbital, acetaminophen, caffeine, and codeine phosphate capsules gradually taper the dosage using a patient-specific plan that considers the following: the dose of butalbital, acetaminophen, caffeine, and codeine phosphate capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see dosage and administration (2.5), warnings and precautions (5.18)]. infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations (8.1)].

Hoa Kỳ - Tiếng Anh - NLM (National Library of Medicine)

breckenridge pharmaceutical, inc. - butalbital (unii: khs0az4jvk) (butalbital - unii:khs0az4jvk), acetaminophen (unii: 362o9itl9d) (acetaminophen - unii:362o9itl9d), caffeine (unii: 3g6a5w338e) (caffeine - unii:3g6a5w338e), codeine phosphate (unii: gsl05y1mn6) (codeine anhydrous - unii:ux6owy2v7j) - butalbital 50 mg - butalbital, acetaminophen, caffeine, and codeine phosphate capsules are indicated for the management of the symptom complex of tension (or muscle contraction) headache when non-opioid analgesic and alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse with opioids and butalbital, even at recommended doses [see warnings and precautions (5.1)], reserve butalbital, acetaminophen, caffeine, and codeine phosphate capsules for use in patients for whom alternative treatment options [e.g., non-opioid, non-barbiturate analgesics]: - have not been tolerated, or are not expected to be tolerated, - have not provided adequate analgesia or are not expected to provide adequate analgesia. butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated for: - all children younger than 12 years of age [see warnings and precautions (5.5)] . - post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see warnings and precautions (5.5)] . butalbital, acetaminophen, caffeine, and codeine phosphate capsules are also contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.3)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see warnings and precautions (5.9)] - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days [see warnings and precautions (5.10), drug interactions (7)] - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.14)] - known intolerance or hypersensitivity to acetaminophen, caffeine, butalbital, or codeine or to the components of butalbital, acetaminophen, caffeine, and codeine phosphate capsules - porphyria risk summary prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see warnings and precautions (5.6)] . available data with butalbital, acetaminophen, caffeine, and codeine phosphate capsules 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, and codeine phosphate capsules 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 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 [see data ]. 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. clinical considerations fetal/neonatal adverse reactions 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 [see warnings and precautions (5.6)] . labor or delivery 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, and codeine phosphate capsules are 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, and codeine phosphate capsules, 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. data human data 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 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. animal data animal reproduction studies have not been conducted with butalbital, acetaminophen, caffeine, and codeine phosphate capsules or with butalbital alone. the following data are based on findings from studies performed with either codeine or acetaminophen alone. codeine in a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 14 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. in an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on gestation day 8 (oral; approximately 4 to 16 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis), reportedly produced cranioschisis in all of the fetuses examined. in studies in rats, doses at the 120 mg/kg level (oral; approximately 6 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. in pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 2.8 times the recommended daily dose of 180 mg/day for adults on a mg/m2 basis) administered between gestation day 7 and 12 reportedly resulted in delayed ossification in the offspring. no teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) of codeine during organogenesis. codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. this dose is 1.6 times the maximum recommended human dose of 180 mg/day on a body surface area comparison. acetaminophen studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 1.7 the maximum human daily dose (mhdd) of 1950 mg/day based on a 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). offspring had no evidence of external, visceral, or skeletal malformations. when pregnant rats received oral acetaminophen throughout gestation at doses of 2.4 times the mhdd (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. these effects did not occur in animals that received oral acetaminophen at doses 0.6 times the mhdd, based on a body surface area comparison. in a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). these doses are approximately 0.86, 1.7, and 3.4 times the mhdd, respectively, based on a body surface area comparison. a dose-related reduction in body weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and post-weaning at all doses. animals in the high dose group 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. caffeine 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 recommended daily dose on a mg/m2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. risk summary 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, and codeine phosphate capsules [see warnings and precautions (5.5)] . 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, and codeine phosphate capsules, 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. clinical considerations if infants are exposed to butalbital, acetaminophen, caffeine, and codeine phosphate capsules 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 breastfeeding is stopped. infertility chronic use of opioids may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6), clinical pharmacology (12.2), nonclinical pharmacology (13.1)]. published literature indicates that acetaminophen affects sperm development in mice with consequent reduction in litter size in a multigeneration study [see nonclinical toxicology (13.1)] . the safety and effectiveness of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in pediatric patients have not been established. life-threatening respiratory depression and deaths have occurred in children who received codeine [see warnings and precautions (5.5)] . 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, and codeine phosphate capsules are contraindicated for all children younger than 12 years of age [see contraindications (4)] . - butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see contraindications (4)] . - avoid the use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules 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 [see warnings and precautions (5.5)]. clinical studies of butalbital, acetaminophen, caffeine, and codeine phosphate capsules 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. elderly patients (aged 65 years or older) may have increased sensitivity to butalbital, acetaminophen, caffeine, and codeine phosphate capsules. 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, and codeine phosphate capsules slowly in geriatric patients and monitor closely for signs of respiratory depression [see warnings and precautions (5.9)]. 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. no formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of butalbital, codeine, and acetaminophen in this patient population are unknown. start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. codeine pharmacokinetics may be altered in patients with renal failure. clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. start these patients cautiously with lower doses of codeine sulfate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. in patients with renal disease, monitor effects of therapy with serial renal function tests. butalbital, acetaminophen, caffeine, and codeine phosphate capsules contain codeine. codeine in combination with butalbital, acetaminophen, and caffeine is a schedule iii controlled substance. butalbital, acetaminophen, caffeine, and codeine phosphate capsules contains codeine, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. butalbital, acetaminophen, caffeine, and codeine phosphate capsules can be abused and is subject to misuse, addiction, and criminal diversion [see warnings and precautions (5.1)]. all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. "drug-seeking" behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. abuse and addiction are separate and distinct from physical dependence and tolerance. healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. in addition, abuse of opioids can occur in the absence of true addiction. butalbital, acetaminophen, caffeine, and codeine phosphate capsules, like other opioids, can be diverted for non-medical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of butalbital, acetaminophen, caffeine, and codeine phosphate capsules butalbital, acetaminophen, caffeine, and codeine phosphate capsules are for oral use only. abuse of butalbital, acetaminophen, caffeine, and codeine phosphate capsules poses a risk of overdose and death. the risk is increased with concurrent use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules with alcohol and other central nervous system depressants. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. 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. both tolerance and physical dependence can develop during chronic opioid therapy. tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. do not abruptly discontinue butalbital, acetaminophen, caffeine, and codeine phosphate capsules in a patient physically dependent on opioids. rapid tapering of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing butalbital, acetaminophen, caffeine, and codeine phosphate capsules, gradually taper the dosage using a patient-specific plan that considers the following: the dose of butalbital, acetaminophen, caffeine, and codeine phosphate capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see dosage and administration (2.4), warnings and precautions (5.16)] . infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations (8.1)] .

Hoa Kỳ - Tiếng Anh - NLM (National Library of Medicine)

amneal pharmaceuticals of new york, llc - butalbital (unii: khs0az4jvk) (butalbital - unii:khs0az4jvk), aspirin (unii: r16co5y76e) (aspirin - unii:r16co5y76e), caffeine (unii: 3g6a5w338e) (caffeine - unii:3g6a5w338e), codeine phosphate (unii: gsl05y1mn6) (codeine anhydrous - unii:ux6owy2v7j) - butalbital, aspirin, caffeine and codeine phosphate is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when non-opioid analgesic and alternative treatments are inadequate. limitations of use because of the risks of addiction, abuse, and misuse with opioids and butalbital, which can occur at any dosage or duration [see warnings and precautions (5.1)], reserve butalbital, aspirin, caffeine and codeine phosphate for use in patients for whom alternative treatment options (e.g., non-opioid, non-barbiturate analgesics): - have not been tolerated or are not expected to be tolerated, - have not provided adequate analgesia or are not expected to provide adequate analgesia butalbital, aspirin, caffeine and codeine phosphate should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. butalbital, aspirin, caffeine and codeine phosphate is contraindicated for: - all children younger than 12 years of age [see warnings and precautions (5.6)] - postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy[see warnings and precautions (5.6)]. butalbital, aspirin, caffeine and codeine phosphate is also contraindicated in patients with: - significant respiratory depression [see warnings and precautions (5.9)] - acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment[see warnings and precautions (5.9)] - concurrent use of monoamine oxidase inhibitors (maois) or use of maois within the last 14 days [see warnings and precautions (5.10)/drug interactions (7)]. - known or suspected gastrointestinal obstruction, including paralytic ileus [see warnings and precautions (5.14)] - hypersensitivity or intolerance to aspirin, caffeine, butalbital, or codeine. - hemophilia [see warnings and precautions (5.19)] - reye's syndrome [see warnings and precautions (5.20)] - known allergy to nonsteroidal anti-inflammatory drugs (nsaids) [see warnings and precautions (5.22)] - syndrome of asthma, rhinitis, and nasal polyps [see warnings and precautions (5.22)] risk summary use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome. [see warnings and precautions (5.4) ]. use of nsaids, including aspirincan cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. because of these risks, limit dose and duration of butalbital, aspirin, caffeine and codeine phosphate use between about 20 and 30 weeks of gestation, and avoid butalbital, aspirin, caffeine and codeine phosphate use at about 30 weeks of gestation and later in pregnancy [see clinical considerations, data ]. premature closure of fetal ductus arteriosus use of nsaids, including aspirin, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment use of nsaids at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. animal reproduction studies have not been conducted with the combination of butalbital, aspirin, caffeine, and codeine phosphate capsules 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 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 [see data ]. based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as aspirin, resulted in increased pre-and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. the estimated background risk of major birth defects and miscarriage for the indicated population(s) 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. clinical considerations fetal/neonatal adverse reactions use of opioid analgesics for an extended period of time 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. 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 [see warnings and precautions (5.4) ]. premature closure of fetal ductus arteriosus: avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including butalbital, aspirin, caffeine and codeine phosphate, can cause premature closure of the fetal ductus arteriosus [see data ]. oligohydramnios/neonatal renal impairment: if an nsaid is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if butalbital, aspirin, caffeine and codeine phosphate treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue butalbital, aspirin, caffeine and codeine phosphate and follow up according to clinical practice [see data ]. labor or delivery there are no studies on the effects of butalbital, aspirin, caffeine and codeine phosphate during labor or delivery. in animal studies, nsaids, including aspirin, inhibit prostaglandin synthesis, caused delayed parturition, and increase the incidence of stillbirth. opioids such as codeine 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, aspirin, caffeine and codeine phosphate 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, aspirin, caffeine and codeine phosphate, 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. aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported. data human data premature closure of fetal ductus arteriosus: published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment: published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain. animal data animal reproduction studies have not been conducted with the combination of butalbital, aspirin, caffeine, and codeine phosphate capsules or with butalbital alone. codeine: in a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 14 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. in an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on gestation day 8 (oral; approximately 4 to 16 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis), reportedly produced cranioschisis in all of the fetuses examined. in studies in rats, doses at the 120 mg/kg level (oral; approximately 6 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. in pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 2.8 times the recommended daily dose of 180 mg/day for adults on a mg/mg2 basis) administered between gestation day 7 and 12 reportedly resulted in delayed ossification in the offspring. no teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) of codeine during organogenesis. codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. this dose is 1.6 times the maximum recommended human dose of 180 mg/day on a body surface area comparison. caffeine: 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 recommended daily dose on a mg/m2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. risk summary 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, aspirin, caffeine and codeine phosphate (see warnings and precautions, (5.7) ). the aspirin and caffeine in butalbital, aspirin, caffeine and codeine phosphate, are also excreted in breast milk in small amounts. adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. furthermore, nursing women are advised against aspirin use because of the possible development of reye's syndrome in their babies. barbiturates and caffeine are also excreted in breast milk in small amounts. because of potential for serious adverse reactions in nursing infants from butalbital, aspirin, caffeine, and codeine phosphate capsules, 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. clinical considerations if infants are exposed to butalbital, aspirin, caffeine and codeine phosphate, 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. infertility use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. it is not known whether these effects on fertility are reversible [see adverse reactions (6.2), clinical pharmacology (12.2) ], nonclinical toxicology (13.1) ]. females based on the mechanism of action, the use of prostaglandin-mediated nsaids, including aspirin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. small studies in women treated with nsaids have also shown a reversible delay in ovulation. consider withdrawal of nsaids, including aspirin, in women who have difficulties conceiving or who are undergoing investigation of infertility. preparations containing aspirin should be kept out of the reach of children. reye's syndrome is a rare condition that affects the brain and liver and is most often observed in children given aspirin during a viral illness. safety and effectiveness in pediatric patients have not been established. the safety and effectiveness of butalbital, aspirin, caffeine and codeine phosphate in pediatric patients have not been established. life-threatening respiratory depression and death have occurred in children who received codeine [see warnings and precautions (5.6) ]. 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, aspirin, caffeine and codeine phosphate is contraindicated for all children younger than 12 years of age [see contraindications (4) ]. - butalbital, aspirin, caffeine and codeine phosphate is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see contraindications (4) ]. - avoid the use of butalbital, aspirin, caffeine and codeine phosphate 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 postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. [see warnings and precautions (5.6) ]. clinical studies of butalbital, aspirin, 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 regularly evaluate renal function. elderly patients (aged 65 years or older) may have increased sensitivity to butalbital, aspirin, caffeine and codeine phosphate. 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, aspirin, caffeine and codeine phosphate slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see warnings and precautions (5.9) ]. 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. elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. if the anticipated benefit for the elderly patient outweighs these potential risks, dose selection should start at the low end of the dosing range, and monitor patients for adverse effects [see warnings and precautions(5) ]. no formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of aspirin, codeine and butalbital in this patient population are unknown. start these patients cautiously with lower doses of butalbital, aspirin, caffeine and codeine phosphate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. in patients with severe hepatic disease, monitor effects of therapy with serial liver function tests. butalbital, aspirin, caffeine and codeine phosphate contains aspirin, which should be avoided in patients with severe renal failure (glomerular filtration rate less than 10 ml/minute). codeine pharmacokinetics may be altered in patients with renal failure. clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. start these patients cautiously with lower doses of butalbital, aspirin, caffeine and codeine phosphate or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. in patients with renal disease, monitor effects of therapy with serial renal function tests. butalbital, aspirin, caffeine and codeine phosphate contains codeine. codeine in combination with butalbital, aspirin, and caffeine is a schedule iii controlled substance. butalbital, aspirin, caffeine and codeine phosphate contains aspirin, butalbital, caffeine, and codeine phosphate, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see warnings and precautions (5.1) ]. misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. misuse and abuse of butalbital, aspirin, caffeine and codeine phosphate increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. the risk is increased with concurrent abuse of butalbital, aspirin, caffeine and codeine phosphate with alcohol and other cns depressants. abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. in addition, abuse of opioids can occur in the absence of addiction. all patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. patients at high risk of butalbital, aspirin, caffeine and codeine phosphate abuse include those with a history of prolonged use of any opioid, including products containing aspirin, butalbital, caffeine, and codeine phosphate, those with a history of drug or alcohol abuse, or those who use butalbital, aspirin, caffeine and codeine phosphate in combination with other abused drugs. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. butalbital, aspirin, caffeine and codeine phosphate, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of butalbital, aspirin, caffeine and codeine phosphate abuse of butalbital, aspirin, caffeine and codeine phosphate poses a risk of overdose and death. the risk is increased with concurrent use of butalbital, aspirin, caffeine and codeine phosphate with alcohol and/or other cns depressants. butalbital, aspirin, caffeine and codeine phosphate is approved for oral use only. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. 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. both tolerance and physical dependence can develop during use of opioid therapy. tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. do not abruptly discontinue butalbital, aspirin, caffeine and codeine phosphate in a patient physically dependent on opioids. rapid tapering of butalbital, aspirin, caffeine and codeine phosphate in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing butalbital, aspirin, caffeine and codeine phosphate, gradually taper the dosage using a patient-specific plan that considers the following: the dose of butalbital, aspirin, caffeine and codeine phosphate the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see dosage and administration (0), warnings and precautions (5.16) ]. infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see use in specific populations (8.1, 8.2) ].