Acetaminophen and Codeine Phosphate

Hi-Tech Pharmacal Co., Inc.

ACETAMINOPHEN AND CODEINE PHOSPHATE ORAL SOLUTION, USP120 mg/12 mg per 5 mL

FULL PRESCRIBING INFORMATION: CONTENTS*

• ACETAMINOPHEN AND CODEINE PHOSPHATE DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Pharmacokinetics
• ACETAMINOPHEN AND CODEINE PHOSPHATE INDICATIONS AND USAGE
• ACETAMINOPHEN AND CODEINE PHOSPHATE CONTRAINDICATIONS
• WARNINGS
  • Hepatotoxicity
  • Hypersensitivity/anaphylaxis
• PRECAUTIONS
  • General
  • Information for Patients/Caregivers
  • Laboratory tests
  • Drug interactions
  • Drug/laboratory test interactions
  • Carcinogenesis, mutagenesis, impairment of fertility
  • Pregnancy
  • Labor and delivery
  • Nursing mothers
  • Pediatric use
• ACETAMINOPHEN AND CODEINE PHOSPHATE ADVERSE REACTIONS
• DRUG ABUSE AND DEPENDENCE
  • Controlled Substance
  • Abuse and Dependence
• OVERDOSAGE
  • Signs and Symptoms
  • Treatment
• ACETAMINOPHEN AND CODEINE PHOSPHATE DOSAGE AND ADMINISTRATION
  • Children:
  • Adults:
• HOW SUPPLIED
• PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

ACETAMINOPHEN AND CODEINE PHOSPHATE DESCRIPTION

Acetaminophen and codeine phosphate oral solution is pharmacologically classified as an analgesic.

Acetaminophen, 4’-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, nonsalicylate 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 5 mL, for oral administration, contains:

Acetaminophen 120 mg

Codeine Phosphate 12 mg

(Warning: May be habit forming)

Alcohol 7%

In addition the following inactive ingredients are present: artificial cherry flavor, citric acid, FD&C Yellow No. 6, propylene glycol, purified water, saccharin sodium, sodium benzoate, and sucrose.

CLINICAL PHARMACOLOGY

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

Pharmacokinetics

The behavior of the individual components is described below.

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 is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.

See OVERDOSAGE for toxicity information.

ACETAMINOPHEN AND CODEINE PHOSPHATE INDICATIONS AND USAGE

Acetaminophen and codeine phosphate oral solution is indicated for the relief of mild to moderate pain.

ACETAMINOPHEN AND CODEINE PHOSPHATE CONTRAINDICATIONS

Codeine-containing products are contraindicated for postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy.

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

WARNINGS

In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS depressant effects, such as drowsiness, that may further obscure the clinical course of the patients with head injuries.

Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions.

Codeine is habit-forming and potentially abusable. Consequently, the extended use of this product is not recommended.

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.

Serious Skin Reactions

Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Death Related to Ultra-Rapid Metabolism of Codeine to Morphine

Respiratory depression and death have occurred in children who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine [see Precautions, Nursing Mothers ].

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). [See Overdosage ].

Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine-containing products are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy. [See Contraindications ].

When prescribing codeine-containing drugs, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose. [see Overdosage ].

Hypersensitivity/anaphylaxis

There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, uricaria, rash, pruritis, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Acetaminophen and Codeine Phosphate Oral Solution, USP immediately and seek medical care if they experience these symptoms. Do not prescribe Acetaminophen and Codeine Phosphate Oral Solution, USP for patients with acetaminophen allergy.

PRECAUTIONS

General

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

Information for Patients/Caregivers

• Do not take Acetaminophen and Codeine Phosphate Oral Solution, 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 Oral Solution, 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 may be 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.

Advise patients that some people have a genetic variation that results in codeine changing into morphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid codeine metabolizer or not. These higher-than-normal levels of morphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this population due to respiratory depression. Codeine-containing products are contraindicated in all children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving codeine-containing products for other reasons to monitor for signs of respiratory depression.

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).

Laboratory tests

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

Drug interactions

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.

Drug/laboratory test interactions

Codeine may increase serum amylase levels.

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

Carcinogenesis, mutagenesis, impairment of fertility

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.

Pregnancy

Teratogenic effects

Pregnancy Category C

Codeine

A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120 mg/kg level, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In another study a single 100 mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring. There are no adequate and well-controlled studies in pregnant women. Acetaminophen and codeine phosphate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic effects

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.

Labor and delivery

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.

Nursing mothers

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 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-thanexpected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

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

Pediatric use

Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine-containing products are contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS and WARNINGS ).

Safe dosage of acetaminophen and codeine phosphate oral solution has not been established in pediatric patients below the age of 3 years.

ACETAMINOPHEN AND CODEINE PHOSPHATE ADVERSE REACTIONS

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.

To report SUSPECTED ADVERSE REACTIONS, contact Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Acetaminophen and codeine phosphate oral solution is classified as a Schedule V controlled substance.

Abuse and Dependence

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

OVERDOSAGE

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

Signs and Symptoms

Toxicity from codeine poisoning includes the opioid triad of: pinpoint pupils, depression of respiration, and loss of consciousness. Convulsions may occur.

In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

Treatment

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.

ACETAMINOPHEN AND CODEINE PHOSPHATE DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to severity of pain and response of the patient. However, it should be kept in mind 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 appreciable increased incidence of undesirable side effects. Equivalently high doses in children would have similar effects.

Acetaminophen and codeine phosphate oral solution contains 120 mg of acetaminophen and 12 mg of codeine phosphate per 5 mL (teaspoonful) and is given orally.

The recommended dose of codeine phosphate in children is 0.5 mg/kg of body weight.

The usual doses are:

Children:

(7 to 12 years):

10 mL (2 teaspoonfuls) 3 or 4 times daily.

(3 to 6 years):

5 mL (1 teaspoonful) 3 or 4 times daily.

(under 3 years):

safe dosage has not been established.

Adults:

15 mL (1 tablespoonful) every 4 hours as needed.

HOW SUPPLIED

Acetaminophen and Codeine Phosphate Oral Solution, USP is an amber colored, cherry flavored solution containing 120 mg acetaminophen and 12 mg codeine phosphate/5 mL supplied in 16 fl oz bottles.

Store at controlled room temperature 15° to 30°C (59° to 86°F). Do not refrigerate.

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

Rx only

Manufactured by

HI-TECH PHARMACAL CO., INC.

Amityville, NY 11701

Rev. 079:06 2/13

PRINCIPAL DISPLAY PANEL

NDC 50383-079-16

ACETAMINOPHEN AND CODEINE PHOSPHATE ORAL SOLUTION, USP

120 mg/12 mg per 5 mL

Rx only

This is a bulk container. Not intended for household use.

Each 5 mL (teaspoonful) contains:

Acetaminophen.........................120 mg

Codeine* Phosphate....................12 mg

Alcohol............................................7 %

*WARNING: May be habit-forming.

Protect from light.

Inactive Ingredients: artificial cherry flavor, citric acid, FD&C Yellow No. 6, propylene glycol, purified water, saccharin sodium, sodium benzoate, and sucrose.

Usual Dosage:
Adults: One tablespoonful (15 mL) every four hours as needed.

Children (7-12 years): Two teaspoonfuls (10 mL) three or four times daily.

Children (3-6 years): One teaspoonful (5 mL) three or four times daily.

Children (under 3 years): Safe dosage has not been established. For prescribing information, see accompanying literature.

Store at controlled room temperature 15° to 30°C (59° to 86°F). Do not refrigerate.

Dispense in a tight, light-resistant container as defined in the official compendium.

CAP SEALED WITH BREAKAWAY BAND. DO NOT ACCEPT IF BROKEN OR MISSING.

16 fl oz (473 mL)