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MERSYNDOL® with CODEINE
Hoechst Marion Roussel
Acetaminophen - Codeine Phosphate - Doxylamine Succinate
Analgesic
 
Action And Clinical Pharmacology: Acetaminophen is the major metabolite of phenacetin and acetanilid. Acetaminophen is an effective and fast-acting analgesic which acts centrally to relieve mild to moderate pain. Animal and clinical studies have shown acetaminophen to have antipyretic and analgesic activity equal to that of ASA.

Unlike the salicylates, acetaminophen does not interfere with tubular secretion of uric acid, nor does it affect acid-base balance at normal therapeutic doses. Acetaminophen does not interfere with hemostasis and does not inhibit platelet aggregation.

Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract. Approximately 85% of a 1 g dose is recovered from the urine in 24 hours. About 3% is excreted unchanged, the balance being conjugated principally to the glucuronide or sulfate. Peak plasma concentrations of the free and conjugated drug are achieved 1/2 to 1 hour after oral administration. The plasma half-life of the unchanged drug is about 2 hours. Like the salicylates, acetaminophen reduces fever by a direct effect on the heat-regulating centres to increase dissipation of body heat.

Allergic reactions are rare with acetaminophen but have occurred. This drug may be useful in asthmatic patients sensitive to salicylates; however, patients with salicylate induced urticaria or angioedema can suffer cross-reactivity with acetaminophen.

Small amounts of acetaminophen are normally converted to a highly reactive metabolite by hepatic microsomal enzymes. At therapeutic doses, the small amounts of the active metabolite so formed are rapidly inactivated by hepatic glutathione and removed by renal excretion. However, where hepatic glutathione has been rapidly depleted by a large dose of acetaminophen, covalent binding of the metabolite to liver-cell macromolecules occurs and is presumed to be responsible for the hepatic cell necrosis. Prompt administration of acetylcysteine is indicated to prevent acetaminophen-induced hepatic necrosis (see Overdose).

Codeine phosphate and the other opiates cause a selective relief of pain by raising the threshold for pain. Codeine also exerts antitussive action by directly depressing the cough centre. Codeine phosphate is an effective oral analgesic which provides relief from mild to moderate pain. The abuse potential of codeine is lower than that of other opiates.

Doxylamine succinate belongs to the ethanolamine class of antihistamines which are associated with a tendency to induce sedation. Its sedative effect is useful in reducing the restlessness and allaying the anxiety which can perpetuate or increase pain. It has antinauseant and antiemetic activity. Its anticholinergic effects tend to lessen rhinorrhea.

Indications And Clinical Uses: For relief of headaches, cold symptoms, muscular aches and pains, and neuralgia.

Contra-Indications: Hypersensitivity to acetaminophen, codeine, or doxylamine. Pre-existing respiratory depression or embarrassment.

Precautions: Occupational Hazards: Patients should be cautioned not to operate vehicles or hazardous machinery until their response to the drug has been determined. Since the depressant effects of antihistamines are additive to those of other drugs affecting the CNS, patients should be cautioned against drinking alcoholic beverages or taking tranquilizers, hypnotics, sedatives, psychotherapeutic agents or other drugs with CNS depressant effects during antihistaminic therapy.

Products containing codeine should not be given for prolonged periods. Codeine phosphate may occasionally cause constipation. Codeine may be habit-forming.

In patients with asthma or pulmonary emphysema, indiscriminate use may precipitate respiratory insufficiency resulting from increased viscosity of bronchial secretions and suppression of the cough reflex.

Use with caution in sedated or debilitated patients, in patients who have undergone thoracotomies or laparotomies, since suppression of the cough reflex may lead to retention of secretions postoperatively in these patients.

Hepatic failure is known to occur occasionally with the long-term use of acetaminophen. Agranulocytosis, renal papillary necrosis and with higher doses, fatal liver damage and very rare complications of treatment with acetaminophen may occur.

Pregnancy and Lactation: Safe use in pregnancy has not been established in human studies, therefore, this medication should not be used during pregnancy unless, in the opinion of the prescribing doctor, the potential benefits outweigh the potential risks. There is epidemiological evidence of safety in pregnancy for acetaminophen and doxylamine succinate. There is inadequate evidence of safety of codeine in pregnancy but it has been in wide use for many years without apparent ill consequence. Since codeine phosphate crosses the placental barrier, its use in pregnancy is not recommended. No data are available on the use of Mersyndol during pregnancy and lactation.

Adverse Reactions: Acetaminophen: The incidence of gastrointestinal upset is less than after salicylate administration.

Hepatic toxicity has been associated with acetaminophen overdose. Phenobarbital increases the activity of microsomal enzymes which produce a toxic metabolite and therefore acetaminophen's hepatotoxicity may be enhanced. Thus, concomitant ingestion of phenobarbital may increase the likelihood of liver necrosis in acetaminophen overdose.

Nonfatal nepatic damage is usually reversible. There have been reports of kidney damage, disturbances in clotting mechanisms, metabolic acidosis, hypoglycemia, neutropenia, agranulocytosis, thrombocytopenia, methemoglobinemia and myocardial necrosis.

The chronic ingestion of alcohol may be implicated in the increasing potential for hepatic toxicity. Abnormal liver function has been associated with therapeutic doses ranging from 3 to 8 g/day. In patients with compromised liver function, acetaminophen could exacerbate liver insufficiency.

Renal papillary necrosis has been reported following prolonged acetaminophen administration of up to 19 g per day. There have been no authenticated reports of renal papillary necrosis with therapeutic doses of acetaminophen alone. Renal insufficiency may occur as an effect secondary to liver failure.

Anemia has been reported in patients with gastrointestinal bleeding who were often analgesic abusers, had chronic gastric ulcers or where gastrointestinal bleeding was already present.

Rarely, asthmatic attacks have been precipitated by acetaminophen.

Skin rashes and fixed dermatitis with pruritus have been rarely reported.

Codeine phosphate: Adverse reactions due to codeine phosphate may include drowsiness, nausea, vomiting and constipation. Infrequent adverse effects include palpitation, pruritus and, rarely, hyperhidrosis and agitation have been reported. Respiratory depression is seen with higher dosages. Habituation or true addiction should be guarded against.

Doxylamine succinate: Drowsiness, vertigo, nervousness, epigastric pain, headache, palpitation, diarrhea, disorientation, irritability, convulsions, urinary retention, or insomnia have been reported.

Other: Other infrequently observed side effects are anorexia, depression, dizziness and dry mouth.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acetaminophen: In adults, hepatotoxicity may occur after ingestion of a single dose of 10 to 15 g (200 to 250 mg/kg) of acetaminophen; a dose of 25 g or more is potentially fatal.

Reports have indicated hepatic necrosis with a single dose of 6 g and death occurring with a single dose of 13 g. Non-fatal overdoses of 12.5 to 31.5 g have also been reported. However, it is generally agreed that consumption of more than 50% of the toxic dose, e.g., 7.5 g in adults and 140 to 150 mg/kg in children could initiate liver damage.

The earliest symptoms of overdose with acetaminophen are nausea, vomiting, sweating and pallor. This initial period is frequently followed by an asymptomatic phase of 24 to 48 hours after which hepatic damage may become evident. Elevation in hepatic enzymes, AST, ALT are noted. BUN remains low. Hepatic function is altered as measured by bilirubin and prothrombin time. The liver enlarges with marked right upper quadrant pain and tenderness.

After 3 to 5 days, jaundice, hypoglycemia, encephalopathy, cardiomyopathy, renal failure, hepatic coma and death may occur.

Factors contributing to an accurate evaluation of toxicity include: the amount of drug ingested and more significantly, the serum acetaminophen concentration measured optimally, after 4 hours of ingestion.

When serum determinations of acetaminophen are above 150 µg/mL at 4 hours, or above 40 µg/mL at 12 hours following the estimated time of ingestion, the patient is at risk of liver damage and antidotal therapy should be instituted immediately.

An additional reliable indicator of possible hepatic injury is the serum half-life. The normal half-life of acetaminophen in a healthy adult is 2 hours. If the serum half-life exceeds 4 hours, it can be assumed that hepatic necrosis will occur; if the half-life exceeds 12 hours hepatic coma is a likely possibility.

Treatment of acetaminophen overdosage includes ipecac induced emesis or gastric lavage which should, when possible, commence within 4 hours of drug ingestion. Activated charcoal is effective only when given within 1 to 2 hours of the alleged overdose. Prior to antidotal treatment with acetylcysteine, residual activated charcoal must be removed by gastric lavage with water.

Acetylcysteine is effective orally. A loading dose of 140 mg/kg is given as a single dose. A maintenance dose of 70 mg/kg is then given every 4 hours for 17 doses. If nausea and vomiting occurs within 1 hour of the loading or maintenance dose, the entire dose should be repeated. Acetylcysteine 20% solution may be diluted to a 5% concentration with a soft drink or fruit juice to make it more palatable. This mixture should be consumed within 1 hour of preparation.

The use of i.v. acetylcysteine is recommended when oral therapy is not feasible or practical. A loading dose, 150 mg/kg of sterile acetylcysteine 20% is infused in 200 mL D5W over 15 minutes, followed by an infusion of 50 mg/kg in 500 mL D5W over 4 hours, and finally 100 mg/kg in 1 000 mL D5W during the next 16 hours. The total dose is 300 mg/kg administered over 20 hours.

Codeine phosphate: May result in euphoria, dysphoria, visual disturbances, hypotension and coma or death from respiratory depression.

In an evaluation of codeine intoxication in children, symptoms ranked by decreasing order of frequency included: sedation, rash, miosis, vomiting, itching, ataxia and swelling of the skin. Respiratory failure may occur. Blood concentrations of codeine ranged from 1.4 to 5.6 µg/mL in 8 adults whose deaths were attributed primarily to codeine overdosage.

Intubation measures aimed at supporting respiration, and the administration of a narcotic antagonist, e.g., naloxone, should be considered to counteract the effects of an overdose of codeine phosphate.

Doxylamine succinate: Dryness of mouth, dilated pupils, sleepiness, vertigo, mental confusion, restlessness or tachycardia. Reactions associated with doxylamine succinate overdosage may vary from CNS depression to stimulation. Stimulation is particularly likely in children. Atropine-like signs and symptoms (dry mouth, fixed, dilated pupils, flushing) and gastrointestinal symptoms may also occur.

Dosage: Adults and children over 12 years: 1 to 2 tablets every 4 hours as required. Do not exceed 12 tablets in a 24-hour period.

Availability And Storage: Each round, flat, white tablet with a stylized S contains: acetaminophen 325 mg, codeine phosphate 8 mg and doxylamine succinate 5 mg. Nonmedicinal ingredients: cellulose, cornstarch, magnesium stearate, povidone, silicon dioxide and sodium carboxymethylcellulose. Bisulfites-, gluten-, lactose-, parabens- and tartrazine-free. Bottles of 100. Blister packages of 24. (Shown in Product Recognition Section)