Phosphate Tablets, USP
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
DRUG ABUSE AND DEPENDENCE
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
Acetaminophen and codeine 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, 5-epoxy-3-methoxy-17-methylmorphinan-6-ol phosphate
(1:1) (salt)
hemihydrate, a white crystalline powder, is a narcotic analgesic and antitussive. It has the
following structural
formula:
Each tablet contains:
300 mg/30 mg Acetaminophen ..................................300 mg
Codeine Phosphate* ..............................30 mg
*WARNING: May be habit forming.
300 mg/60 mg Acetaminophen ..................................300 mg
Codeine Phosphate* ..............................60 mg
*WARNING: May be habit forming.
In addition each tablet contains the following inactive ingredients:
300 mg/30 mg — Corn starch, stearic acid and may also contain
colloidal silicon dioxide croscarmellose sodium,
lactose monohydrate, magnesium stearate,
microcrystalline cellulose, pregelatinized
starch, sodium lauryl sulfate.
300 mg/60 mg — Corn starch, colloidal silicon dioxide,
pregelatinized starch, and stearic acid.
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: 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: Acetaminophen is rapidly absorbed from the gastrointestinal tract and is
distributed
throughout most body tissues. The plasma haif-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 tablets are indicated for the relief of mild to moderately
severe pain.
This product should not be administered to patients who have previously exhibited
hypersensitivity to codeine
or acetaminophen.
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.
General: 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.
Information for Patients: 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.
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
organogeneses 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 and codeine are excreted in breast milk in small amounts, but
the significance
of their effects on nursing infants is not known. Because of the potential for serious adverse
reactions in
nursing infants from acetaminophen and codeine, a decision should be made whether to
discontinue nursing or
to discontinue the drug, taking into account the importance of the drug to the mother.
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 nonambulatory 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.
Controlled Substance: Acetaminophen and Codeine Phosphate tablets are classified as a
Schedule III 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.
Following an acute overdosage, toxicity may result from codeine or acetaminophen.
Signs and Symptoms:
Codeine: Toxicity from codeine poisoning includes the opioid triad of: pinpoint pupils, depression
of respiration,
and loss of consciousness. Convulsions may occur.
Acetaminophen: in acetaminophen overdosage: dose-dependent, potentially fatal hepatic
necrosis is the most
serious adverse effect. Renal tubular necrosis, hypoglycemic coma and thrombocytopenia 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.
In adults hepatic toxicity has rarely been reported with acute overdoses of less than 10 grams,
or fatalities
with less than 15 grams.
Treatment: A single or multiple 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.
Vomiting should be induced mechanically, or with syrup of ipecac, if the patient is alert
(adequate pharyngeal
and laryngeal reflexes). Oral activated charcoal (1 g/kg) should follow gastric emptying. The first
dose should
be accompanied by an appropriate cathartic. If repeated doses are used, the cathartic might be
included with
alternate doses as required. Hypotension is usually hypovolemic and should respond to fluids.
Vasopressors
and other supportive measures should be employed as indicated. A cuffed endo-tracheal tube
should be inserted
before gastric lavage of the unconscious patient and, when necessary, to provide assisted
respiration.
Meticulous attention should be given to maintaining adequate pulmonary ventilation. In severe
cases of
intoxication, peritoneal dialysis, or preferably hemodialysis may be considered. If
hypoprothrombinemia occurs
due to acetaminophen overdose, vitamin K should be administered intravenously.
Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with
opioid overdose. Naloxone hydrochloride 0.4 mg to 2 mg is given parenterally. Since the
duration of action of codeine may
exceed that of the naloxone, the patient should be kept under continuous surveillance and
repeated doses of
the antagonist should be administered as needed to maintain adequate respiration. A narcotic
antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular
depression.
If the dose of acetaminophen may have exceeded 140 mg/kg. acetylcysteine should be
administered as early
as possible. Serum acetaminophen levels should be obtained, since levels four or more hours
following
ingestion help predict acetaminophen toxicity. Do not await acetaminophen assay results before
initiating treatment. Hepatic enzymes should be obtained initially, and repeated at 24-hour
intervals.
Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous
administration.
Toxic Doses (for adults):
Dosage should be adjusted according to severity of pain and response of the patient.
The usual adult dosage is:
Single Doses (Range) Maximum 24 Hour Doses Codeine Phosphate 15 mg to 60 mg 360 mg Acetaminophen 300 mg to 1000 mg 4000 mg
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.
300 mg/30 mg -- Each white, round, scored tablet imprinted R001/3
contains 300 mg of Acetaminophen and 30 mg of
Codeine Phosphate. Tablets are supplied in bottles
of 100 (NDC 0228-2001-10) and 1000 (NDC 0228-2001-96).
300 mg/60 mg -- Each white, round, scored tablet imprinted R001/4
contains 300 mg of Acetaminophen and 60 mg of
Codeine Phosphate. Tablets are supplied in bottles
of 100 (NDC 0228-2003-10) and 500 (NDC 0228-2003-50).
Store at controlled room temperature 15°- 30°C (59°- 86°F).
Protectfrom moisture.
Dispense in a tight, light-resistant container as defined in the USP.
CAUTION: Federal law prohibits dispensing without prescription.
Manufactured by:
PUREPAC PHARMACEUTICAL CO.
Elizabeth, NJ 07207 USA
40-8751
Revised—November 1994