Promethazine Hydrochloride, Phenylephrine Hydrochloride and Codeine Phosphate (Syrup)

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The combination of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 16 years of age, because the combination may cause fatal respiratory depression in this age population. The average effective dose for adults (16 years of age and over) is 1 teaspoonful (5 mL) every 4 to 6 hours, not to exceed 30 mL in 24 hours.

Codeine:: Narcotic analgesics, including codeine, exert their primary effects on the central nervous system and gastrointestinal tract. The analgesic effects of codeine are due to its central action; however, the precise sites of action have not been determined, and the mechanisms involved appear to be quite complex. Codeine resembles morphine both structurally and pharmacologically, but its actions at the doses of codeine used therapeutically are milder, with less sedation, respiratory depression and gastrointestinal, urinary and pupillary effects. Codeine produces an increase in biliary tract pressure, but less than morphine or meperidine. Codeine is less constipating than morphine. Codeine has good antitussive activity, although less than that of morphine at equal doses. It is used in preference to morphine, because side effects are infrequent at the usual antitussive dose of codeine. Codeine in oral therapeutic dosage does not usually exert major effects on the cardiovascular system. Narcotic analgesics may cause nausea and vomiting by stimulating the chemoreceptor trigger zone (CTZ); however, they also depress the vomiting center, so that subsequent doses are unlikely to produce vomiting. Nausea is minimal after usual oral doses of codeine. Narcotic analgesics cause histamine release, which appears to be responsible for wheals or urticaria sometimes seen at the site of injection on parenteral administration. Histamine release may also produce dilation of cutaneous blood vessels, with resultant flushing of the face and neck, pruritus and sweating. Codeine and its salts are well absorbed following both oral and parenteral administration. Codeine is about/3 as effective orally as parenterally. Codeine is metabolized primarily in the liver by enzymes of the endoplasmic reticulum, where it undergoes O-demethylation, N-demethylation and partial conjugation with glucuronic acid. The drug is excreted primarily in the urine, largely as inactive metabolites and small amounts of free and conjugated morphine. Negligible amounts of codeine and its metabolites are found in the feces. Following oral or subcutaneous administration of codeine, the onset of analgesia occurs within 15 to 30 minutes and lasts for four to six hours. The cough-depressing action, in animal studies, was observed to occur 15 minutes after oral administration of codeine, peak action at 45 to 60 minutes after ingestion. The duration of action, which is dose-dependent, usually did not exceed 3 hours.<br/>Promethazine:: Promethazine is a phenothiazine derivative which differs structurally from the antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution. It is thought that this configuration is responsible for its relative lack (1/10 that of chlorpromazine) of dopamine antagonist properties. Promethazine is an Hreceptor blocking agent. In addition to its antihistaminic action, it provides clinically useful sedative and antiemetic effects. Promethazine is well absorbed from the gastrointestinal tract. Clinical effects are apparent within 20 minutes after oral administration and generally last four to six hours, although they may persist as long as 12 hours. Promethazine is metabolized by the liver to a variety of compounds; the sulfoxides of promethazine and N-demethylpromethazine are the predominant metabolites appearing in the urine.<br/>Phenylephrine:: Phenylephrine is a potent postsynaptic-��-receptor agonist with little effect on��receptors of the heart. Phenylephrine has no effect on��-adrenergic receptors of the bronchi or peripheral blood vessels. A direct action at receptors accounts for the greater part of its effects, only a small part being due to its ability to release norepinephrine. Therapeutic doses of phenylephrine mainly cause vasoconstriction. Phenylephrine increases resistance and, to a lesser extent, decreases capacitance of blood vessels. Total peripheral resistance is increased, resulting in increased systolic and diastolic blood pressure. Pulmonary arterial pressure is usually increased, and renal blood flow is usually decreased. Local vasoconstriction and hemostasis occur following topical application or infiltration of phenylephrine into tissues. The main effect of phenylephrine on the heart is bradycardia; it produces a positive inotropic effect on the myocardium in doses greater than those usually used therapeutically. Rarely, the drug may increase the irritability of the heart, causing arrhythmias. Cardiac output is decreased slightly. Phenylephrine increases the work of the heart by increasing peripheral arterial resistance. Phenylephrine has a mild central stimulant effect. Following oral administration or topical application of phenylephrine to the mucosa, constriction of blood vessels in the nasal mucosa relieves nasal congestion associated with allergy or head colds. Following oral administration, nasal decongestion may occur within 15 or 20 minutes and may persist for up to 4 hours. Phenylephrine is irregularly absorbed from and readily metabolized in the gastrointestinal tract. Phenylephrine is metabolized in the liver and intestine by monoamine oxidase. The metabolites and their route and rate of excretion have not been identified. The pharmacologic action of phenylephrine is terminated at least partially by uptake of the drug into tissues.

Codeine is contraindicated in patients with a known hypersensitivity to the drug. Promethazine is contraindicated in comatose states, and in individuals known to be hypersensitive or to have had an idiosyncratic reaction to promethazine or to other phenothiazines. The combination of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 16 years of age, because the combination may cause fatal respiratory depression this age population. Antihistamines and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma. Phenylephrine is contraindicated in patients with hypertension or with peripheral vascular insufficiency (ischemia may result with risk of gangrene or thrombosis of compromised vascular beds). Phenylephrine should not be used in patients known to be hypersensitive to the drug or in those receiving a monoamine oxidase inhibitor (MAOI).

WARNING: THE COMBINATION OF PROMETHAZINE HYDROCHLORIDE, PHENYLEPHRINE HYDROCHLORIDE AND CODEINE PHOSPHATE IS CONTRAINDICATED IN PEDIATRIC PATIENTS LESS THAN 16 YEARS OF AGE. CONCOMITANT ADMINISTRATION OF PROMETHAZINE PRODUCTS WITH OTHER RESPIRATORY DEPRESSANTS HAS AN ASSOCIATION WITH RESPIRATORY DEPRESSION, AND SOMETIMES DEATH, IN PEDIATRIC PATIENTS. POSTMARKETING CASES OF RESPIRATORY DEPRESSION, INCLUDING FATALITIES, HAVE BEEN REPORTED WITH USE OF PROMETHAZINE HYDROCHLORIDE IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE. A WIDE RANGE OF WEIGHT-BASED DOSES OF PROMETHAZINE HYDROCHLORIDE HAVE RESULTED IN RESPIRATORY DEPRESSION IN THESE PATIENTS.

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Codeine:: Serious overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. The triad of coma, pinpoint pupils and respiratory depression is strongly suggestive of opiate poisoning. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest and death may occur. Promethazine is additive to the depressant effects of codeine. It is difficult to determine what constitutes a standard toxic or lethal dose. However, the lethal oral dose of codeine in an adult is reported to be in the range of 0.5 to 1.0 gram. Infants and children are believed to be relatively more sensitive to opiates on a body-weight basis. Elderly patients are also comparatively intolerant to opiates.<br/>Promethazine:: Signs and symptoms of overdosage with promethazine HCl range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness, and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes (Babinski reflex). Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares. Atropine-like signs and symptoms���dry mouth, fixed, dilated pupils, flushing, as well as gastrointestinal symptoms, may occur.<br/>Phenylephrine:: Signs and symptoms of overdosage with phenylephrine include hypertension, headache, convulsions, cerebral hemorrhage and vomiting. Ventricular premature beats and short paroxysms of ventricular tachycardia may also occur. Headache may be a symptom of hypertension. Bradycardia may also be seen early in phenylephrine overdosage through stimulation of baroreceptors. Treatment: The treatment of overdosage with promethazine, phenylephrine and codeine is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs including respiration, pulse, blood pressure, temperature and EKG need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. The narcotic antagonist, naloxone hydrochloride, may be administered when significant respiratory depression occurs with promethazine, phenylephrine and codeine; any depressant effects of promethazine are not reversed with naloxone. Diazepam may be used to control convulsions. Avoid analeptics, which may cause convulsions. Acidosis and electrolyte lossesshould be corrected. A rise in temperature or pulmonary complications may signal the need for institution of antibiotic therapy. Severe hypotension usually responds to the administration of norepinephrine or phenylephrine. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure. Limited experience with dialysis indicates that it is not helpful.

Promethazine Hydrochloride, Phenylephrine Hydrochloride and Codeine Phosphate (Syrup)

Promethazine HCl, phenylephrine HCl and codeine phosphate syrup is indicated for the temporary relief of coughs and upper respiratory symptoms, including nasal congestion, associated with allergy or the common cold.

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