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Glaxo Wellcome
Acetaminophen - Codeine Phosphate
Analgesic - Antipyretic - Antitussive
Action And Clinical Pharmacology: Acetaminophen is in the category of an analgesic and antipyretic, codeine is in the category of analgesic and antitussive. Codeine retains at least one-half of its analgesic activity when administered orally. tag_IndicationsIndications

Indications And Clinical Uses: Empract-30: For relief of mild to moderate pain.

Empract-60: For relief of moderate to severe pain.

Contra-Indications: Hypersensitivity to acetaminophen or codeine. tag_WarningWarnings

Manufacturers' Warnings In Clinical States: Drug dependence: Codeine can produce drug dependence of the morphine type, and therefore, has the potential for being abused. Psychic and 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-containing medications.

Occupational Hazards: Acetaminophen with codeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Patients using this drug should be cautioned accordingly.

Interaction with other CNS depressants: Patients receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics, or other CNS depressants (including alcohol) concomitantly with acetaminophen and codeine may exhibit an additive CNS depression. If such combined therapy is contemplated, the dose of 1 or both agents should be reduced. The concurrent use of anticholinergic with codeine may produce paralytic ileus.

Pregnancy: Safety in pregnancy has not been established relative to the possible adverse effects on fetal development. Therefore, acetaminophen with codeine should not be used unless, in the judgment of the physician, the potential benefits outweigh the possible hazards.

Lactation: It is not known whether the components of this drug are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when acetaminophen and codeine is administered to a nursing woman.

Precautions: Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury or intracranial lesions or pre-existing increase in intracranial pressure. Furthermore, the narcotics produce adverse reactions which may obscure the clinical course of a patient with head injuries.

Acute Abdominal Conditions: The administration of acetaminophen with codeine or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Special-Risk Patients: Acetaminophen with codeine should be given with caution to certain patients such as the elderly or debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture. Overdose can cause severe liver toxicity (see Overdose).

Adverse Reactions: Being a combination of codeine and acetaminophen, certain problems can be presented due to a large overdose as these compounds produce different types of toxicity.

The adverse effects attributable to therapeutic doses of codeine are seldom serious. These include nausea, vomiting, constipation with repeated doses, epigastric pain, dizziness and occasionally sedation. Allergic reactions may occur but are rare. Overdose of codeine 100 to 500 mg may cause a slow pulse, flush facies, kinetosis and lassitude or excitement. Doses of 800 mg or more have caused prolonged miosis, muscular weakness, semiconsciousness, delirium, convulsions, rapid pulse, and finally circulatory collapse or respiratory paralysis. The human lethal dose for codeine is not known with certainty. Mortalities due to codeine appear to be quite unusual.

Most frequently observed adverse effects referable to acetaminophen include lightheadedness, dizziness, sedation, 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 euphoria, dysphoria, constipation and pruritus. Rare hypersensitivity reactions may occur that require discontinuation of the drug. Hypersensitivity is manifested by rash or urticaria. Regular use of acetaminophen has shown to produce a slight increase in prothrombin time in patients receiving oral anticoagulants, but the clinical significance of this effect is not clear. The incidence of gastrointestinal upset is less than after salicylate administration.

Symptoms And Treatment Of Overdose: Acetaminophen: Serious hepatotoxicity may occur in adults after ingestion of a single dose of 10 g (150 mg/kg or greater) and fatalities have usually been reported after ingestion of a single dose of 15 g or more of acetaminophen.Symptoms: Patients suffering from an overdose of acetaminophen will progress through 3 stages if untreated. During the first stage, which lasts from 12 to 24 hours, there may be anorexia, nausea, vomiting, diaphoresis and pallor. After 24 hours, earlier symptoms tend to abate and the patient may even feel well for one or a few days. Unfortunately, during this second phase, hepatic enzymes, serum bilirubin and prothrombin time begin to rise as hepatic necrosis progresses and tenderness may develop in the right upper quadrant. Three to 5 days after drug ingestion, the third phase sets in for those patients who develop significant hepatic necrosis. This phase is marked by the sequelae of hepatic necrosis which include jaundice, coagulation effects, hypoglycemia, encephalopathy as well as renal failure and myocardiopathy. Death occurs as a result of hepatic failure. tag_Treatment

Treatment: Large overdoses of acetaminophen are potentially fatal, unless an appropriate antidote such as N-acetylcysteine (NAC) is administered early after drug ingestion, usually within 12 to 16 hours. There is some evidence to suggest that NAC may offer some protection even when given up to 24 hours after drug ingestion. The hepatotoxicity of acetaminophen is related to a secondary, reactive metabolite which is detoxified by conjugation with hepatic glutathione. A large overdosage of acetaminophen will result in an increased formation of the reactive metabolite which in turn may deplete stores of glutathione in the liver. Antidotes such as NAC probably act by restoring glutathione levels.

Emergency Procedure: The stomach should be emptied promptly.

Specific Therapy: A careful estimate should be made of the quantity of acetaminophen ingested. Regardless of the quantity ingested, and particularly if it is estimated to be 7.5 g or more, an immediate loading dose of NAC should be administered if 24 hours or less have elapsed since drug ingestion. NAC is available as Mucomyst which contains a 20% solution of N-acetylcysteine in sterile vials of 10 and 30 mL. The 20% solution NAC in Mucomyst should be diluted to a 5% solution for oral administration, by using water, cola, grapefruit juice or orange juice. The diluted mixture should be consumed within 1 hour of preparation. The loading dose of NAC is 140 mg/kg of bodyweight. This should be followed by maintenance doses of 70 mg of NAC/kg of bodyweight, every 4 hours, for 17 doses. If the patient vomits within 1 hour of administration, the NAC dose should be repeated. If the patient is unable to tolerate oral administration, NAC should be administered i.v. (see the monographs for Mucomyst and Parvolex for detailed instructions). If activated charcoal has been used, lavage must be performed before initiating treatment with NAC.

Cysteamine has also been used previously as an antidote with some success. It must, however, be given i.v., initially as a 2 g loading dose over 10 minutes followed immediately by continuous infusion of 800 mg in 500 mL of dextrose 5% in water over 4 hours, then 800 mg given over 16 hours for a total of 3.6 g in 20 hours. Solutions of cysteamine are unstable and should be prepared immediately before use.

Acetaminophen Plasma Assay: Acetaminophen plasma levels 4 hours post-ingestion of an overdose provide a fairly reliable prognostic indication of potential hepatotoxicity. Values of 200 µg/mL or more at 4 hours postingestion, or 50 µg/mL or more at 12 hours after ingestion, are associated with the possibility of hepatic toxicity. If the plasma levels of acetaminophen are more than 25% below these values, the risk of toxicity is much reduced.

Follow-Up and Supportive Therapy: Monitoring of hepatic and renal function, and supportive measures, should be used as indicated. Hemodialysis or peritoneal dialysis have not been found helpful. Experience indicates that children under 5 years of age are more resistant than adults to the hepatic effects of acetaminophen overdose.

Codeine: Symptoms: The primary symptoms due to overdosage of codeine include euphoria, dysphoria, visual disturbances, hypotension and coma or death due to respiratory depression.

Treatment: Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The narcotic antagonists naloxone, nalorphine or levallorphan are specific antidotes against respiratory depression which may result from overdose or unusual sensitivity to narcotics. Therefore, an appropriate dose of one of these antagonists should be administered, preferably by the i.v. route, simultaneously with efforts at respiratory resuscitation. Since the duration of action of acetaminophen with codeine may exceed that of the antagonist, patients should be kept under continued surveillance and repeated doses of antagonists should be administered as needed to maintain adequate respiration. An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Oxygen, i.v. fluids, vasopressors and other supportive measures should be employed as indicated.

Dosage And Administration: Empracet-30 Adults: 1 to 2 tablets every 4 to 6 hours as required.

Empracet-60: Adults: 1 tablet every 4 to 6 hours as required.

Both strengths of Empracet should not be used in children. Dosage should be adjusted according to the severity of pain and the response of the patient. Acetaminophen with codeine is given orally. 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. This product is inappropriate even in high doses for severe or intractable pain. 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.

Availability And Storage: Empracet-30: Each round, peach-colored tablet, imprinted EMPRACET 30 K9B and scored on the reverse side, contains: acetaminophen 300 mg and codeine phosphate 30 mg. Nonmedicinal ingredients: cornstarch, FD&C yellow No. 6, lactose, magnesium stearate, povidone and stearic acid. Bottles of 500. Store between 15 to 30°C.

Empracet-60: Each round, peach-colored tablet, imprinted EMPRACET 60 L9B, contains: acetaminophen 300 mg and codeine phosphate 60 mg. Nonmedicinal ingredients: cornstarch, FD&C yellow No. 6, lactose, magnesium stearate, povidone and stearic acid. Bottles of 50. Store between 15 to 30°C. (Shown in Product Recognition Section)