Acetaminophen And Codeine Phosphate Tablets Usp

WARNING



Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product.

Acetaminophen and codeine phosphate tablets are indicated for the relief of mild to moderately severe pain.

Dosage should be adjusted according to severity of pain and response of the patient.

The usual adult dosage for tablets is:

The usual dose of codeine phosphate in children is 0.5 mg/kg.

Doses may be repeated up to every 4 hours.

The prescriber must determine the number of tablets per dose, and the maximum number of tablets per 24 hours based upon the above dosage guidance. This information should be conveyed in the prescription.

It should be kept in mind, however, that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Adult doses of codeine higher than 60 mg fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of undesirable side effects. Equivalently high doses in children would have similar effects.

This product should not be administered to patients who have previously exhibited hypersensitivity to codeine or acetaminophen.

The most frequently reported adverse reactions are drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea and vomiting. These effects seem to be more prominent in ambulatory than in non-ambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include allergic reactions, euphoria, dysphoria, constipation, abdominal pain, pruritus, rash, thrombocytopenia, agranulocytosis.

At higher doses, codeine has most of the disadvantages of morphine including respiratory depression.

This drug may enhance the effects of other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS depressants, causing increased CNS depression.

Each Acetaminophen and Codeine Phosphate Tablet USP 300 mg/15 mg tablet contains acetaminophen 300 mg and codeine phosphate 15 mg. It is available as a round, white to off-white tablet debossed with "2" on one side and an M on the other side.

Each Acetaminophen and Codeine Phosphate Tablet USP 300 mg/30 mg tablet contains acetaminophen 300 mg and codeine phosphate 30 mg. It is available as a round, white to off-white tablet debossed with "3" on one side and an M on the other side.

49999-060-06

49999-060-15

49999-060-12

49999-060-10

49999-060-20

49999-060-24

49999-060-30

49999-060-50

49999-060-60

49999-060-90

49999-060-00

49999-060-01

Each Acetaminophen and Codeine Phosphate Tablet USP 300 mg/60 mg tablet contains acetaminophen 300 mg and codeine phosphate 60 mg. It is available as a round, white to off-white tablet debossed with "4" on one side and an M on the other side.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in tight, light-resistant container as defined in the USP.

Mallinckrodt Inc.

Hazelwood, MO 63042 USA

Rev 06/2011

Mallinckrodt



COVIDIEN™

Acetaminophen and codeine phosphate is supplied in tablet form for oral administration.

Acetaminophen, 4'-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

Codeine phosphate, 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate, a white crystalline powder, is a narcotic analgesic and antitussive. It has the following structural formula:

Each Acetaminophen and Codeine Phosphate Tablet USP (300 mg/30 mg) contains:

Acetaminophen USP . . . . . . . . . . . . . 300 mgCodeine Phosphate USP . . . . . . . . . . . . . 30 mg

Each Acetaminophen and Codeine Phosphate Tablet USP (300 mg/60 mg) contains:

Acetaminophen USP . . . . . . . . . . . . . 300 mgCodeine Phosphate USP . . . . . . . . . . . . . 60 mg

In addition, each Acetaminophen and Codeine Phosphate Tablet USP contains the following inactive ingredients: crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, stearic acid.

Codeine – Codeine is readily absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain; however, codeine is not bound to plasma proteins and does not accumulate in body tissues.

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.

At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours.

See OVERDOSAGE for toxicity information.

Acetaminophen and codeine phosphate tablets should be prescribed with caution in certain special risk patients, such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison's disease, or prostatic hypertrophy.

A single or multiple drug overdose with acetaminophen and codeine is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption.

Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to codeine, parenteral naloxone is a specific and effective antagonist.

Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.

Following an acute overdosage, toxicity may result from codeine or acetaminophen.

Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on nursing infants is not known. Because of the potential for serious adverse reactions in nursing infants from acetaminophen, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding (see PRECAUTIONS, General, Ultra-rapid Metabolizers of Codeine ).

In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.

The behavior of the individual components is described below.

Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see OVERDOSAGE). The effect of codeine, if any, on the later growth, development, and functional maturation of the child is unknown.

Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic medications.

Acetaminophen and codeine phosphate tablets are classified as a Schedule III controlled substance.

This product combines the analgesic effects of a centrally acting analgesic, codeine, with a peripherally acting analgesic, acetaminophen.

Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. These signs usually appear during the first few days of life.

Codeine may increase serum amylase levels.

Acetaminophen may produce false positive test results for urinary 5-hydroxyindoleacetic acid.

• Do not take acetaminophen and codeine phosphate tablets USP if you are allergic to any of its ingredients.
• If you develop signs of allergy such as a rash or difficulty breathing stop taking acetaminophen and codeine phosphate tablets USP and contact your healthcare provider immediately.
• Do not take more than 4000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose.

Codeine may impair mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking this product.

Alcohol and other CNS depressants may produce an additive CNS depression when taken with this combination product, and should be avoided.

Codeine is habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer.

Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).

No adequate studies have been conducted in animals to determine whether acetaminophen and codeine have a potential for carcinogenesis or mutagenesis. No adequate studies have been conducted in animals to determine whether acetaminophen has a potential for impairment of fertility.

Acetaminophen and codeine have been found to have no mutagenic potential using the Ames Salmonella-Microsomal Activation test, the Basc test on Drosophila germ cells, and the Micronucleus test on mouse bone marrow.

WARNING



Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product.

Codeine – Codeine is readily absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain; however, codeine is not bound to plasma proteins and does not accumulate in body tissues.

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.

At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours.

See OVERDOSAGE for toxicity information.

Acetaminophen and codeine phosphate tablets should be prescribed with caution in certain special risk patients, such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison's disease, or prostatic hypertrophy.

A single or multiple drug overdose with acetaminophen and codeine is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption.

Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to codeine, parenteral naloxone is a specific and effective antagonist.

Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.

Following an acute overdosage, toxicity may result from codeine or acetaminophen.

Acetaminophen and codeine phosphate is supplied in tablet form for oral administration.

Acetaminophen, 4'-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

Codeine phosphate, 7,8-didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate, a white crystalline powder, is a narcotic analgesic and antitussive. It has the following structural formula:

Each Acetaminophen and Codeine Phosphate Tablet USP (300 mg/30 mg) contains:

Acetaminophen USP . . . . . . . . . . . . . 300 mgCodeine Phosphate USP . . . . . . . . . . . . . 30 mg

Each Acetaminophen and Codeine Phosphate Tablet USP (300 mg/60 mg) contains:

Acetaminophen USP . . . . . . . . . . . . . 300 mgCodeine Phosphate USP . . . . . . . . . . . . . 60 mg

In addition, each Acetaminophen and Codeine Phosphate Tablet USP contains the following inactive ingredients: crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, stearic acid.

Each Acetaminophen and Codeine Phosphate Tablet USP 300 mg/15 mg tablet contains acetaminophen 300 mg and codeine phosphate 15 mg. It is available as a round, white to off-white tablet debossed with "2" on one side and an M on the other side.

Each Acetaminophen and Codeine Phosphate Tablet USP 300 mg/30 mg tablet contains acetaminophen 300 mg and codeine phosphate 30 mg. It is available as a round, white to off-white tablet debossed with "3" on one side and an M on the other side.

49999-060-06

49999-060-15

49999-060-12

49999-060-10

49999-060-20

49999-060-24

49999-060-30

49999-060-50

49999-060-60

49999-060-90

49999-060-00

49999-060-01

Each Acetaminophen and Codeine Phosphate Tablet USP 300 mg/60 mg tablet contains acetaminophen 300 mg and codeine phosphate 60 mg. It is available as a round, white to off-white tablet debossed with "4" on one side and an M on the other side.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in tight, light-resistant container as defined in the USP.

Mallinckrodt Inc.

Hazelwood, MO 63042 USA

Rev 06/2011

Mallinckrodt



COVIDIEN™

Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on nursing infants is not known. Because of the potential for serious adverse reactions in nursing infants from acetaminophen, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding (see PRECAUTIONS, General, Ultra-rapid Metabolizers of Codeine ).

In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.

The behavior of the individual components is described below.

The most frequently reported adverse reactions are drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea and vomiting. These effects seem to be more prominent in ambulatory than in non-ambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down. Other adverse reactions include allergic reactions, euphoria, dysphoria, constipation, abdominal pain, pruritus, rash, thrombocytopenia, agranulocytosis.

At higher doses, codeine has most of the disadvantages of morphine including respiratory depression.

This product should not be administered to patients who have previously exhibited hypersensitivity to codeine or acetaminophen.

This drug may enhance the effects of other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS depressants, causing increased CNS depression.

Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see OVERDOSAGE). The effect of codeine, if any, on the later growth, development, and functional maturation of the child is unknown.

Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic medications.

Acetaminophen and codeine phosphate tablets are classified as a Schedule III controlled substance.

This product combines the analgesic effects of a centrally acting analgesic, codeine, with a peripherally acting analgesic, acetaminophen.

Acetaminophen and codeine phosphate tablets are indicated for the relief of mild to moderately severe pain.

Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. These signs usually appear during the first few days of life.

Dosage should be adjusted according to severity of pain and response of the patient.

The usual adult dosage for tablets is:

The usual dose of codeine phosphate in children is 0.5 mg/kg.

Doses may be repeated up to every 4 hours.

The prescriber must determine the number of tablets per dose, and the maximum number of tablets per 24 hours based upon the above dosage guidance. This information should be conveyed in the prescription.

It should be kept in mind, however, that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Adult doses of codeine higher than 60 mg fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of undesirable side effects. Equivalently high doses in children would have similar effects.

Codeine may increase serum amylase levels.

Acetaminophen may produce false positive test results for urinary 5-hydroxyindoleacetic acid.

• Do not take acetaminophen and codeine phosphate tablets USP if you are allergic to any of its ingredients.
• If you develop signs of allergy such as a rash or difficulty breathing stop taking acetaminophen and codeine phosphate tablets USP and contact your healthcare provider immediately.
• Do not take more than 4000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose.

Codeine may impair mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking this product.

Alcohol and other CNS depressants may produce an additive CNS depression when taken with this combination product, and should be avoided.

Codeine is habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer.

Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).

No adequate studies have been conducted in animals to determine whether acetaminophen and codeine have a potential for carcinogenesis or mutagenesis. No adequate studies have been conducted in animals to determine whether acetaminophen has a potential for impairment of fertility.

Acetaminophen and codeine have been found to have no mutagenic potential using the Ames Salmonella-Microsomal Activation test, the Basc test on Drosophila germ cells, and the Micronucleus test on mouse bone marrow.