Promethazine VC With 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 ⅔ 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.

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 H₁ receptor 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.

Phenylephrine is a potent postsynaptic-α-receptor agonist with little effect on β receptors of the heart. Phenylephrine has no effect on β-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.

WARNING:

The combination of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 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.

Dosage of codeine SHOULD NOT BE INCREASED if cough fails to respond; an unresponsive cough should be re-evaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease.

Codeine may cause or aggravate constipation.

Respiratory depression leading to arrest, coma and death has occurred with the use of codeine antitussives in young children, particularly in the under-one-year infants whose ability to deactivate the drug is not fully developed.

Administration of codeine may be accompanied by histamine release and should be used with caution in atopic children.

Narcotic analgesics, including codeine, should be administered with caution and the initial dose reduced in patients with acute abdominal conditions, convulsive disorders, significant hepatic or renal impairment, fever, hypothyroidism, Addison's disease, ulcerative colitis, prostatic hypertrophy, in patients with recent gastrointestinal or urinary tract surgery and in the very young or elderly or debilitated patients.

Drugs having anticholinergic properties should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, and bladder-neck obstruction.

Promethazine should be used cautiously in persons with cardiovascular disease or with impairment of liver function.

Phenylephrine should be used with caution in patients with cardiovascular disease.

Patients should be advised to measure promethazine, phenylephrine and codeine syrup with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when a half a teaspoon is measured. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.

Promethazine, phenylephrine and codeine may cause marked drowsiness or may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. Ambulatory patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy from promethazine, phenylephrine and codeine therapy. The concomitant use of alcohol or other central nervous system depressants, including narcotic analgesics, sedatives, hypnotics and tranquilizers, may have an additive effect and should be avoided or their dosage reduced.

Patients should be advised to report any involuntary muscle movements.

Avoid prolonged exposure to the sun.

Codeine, like other narcotic analgesics, may produce orthostatic hypotension in some ambulatory patients. Patients should be cautioned accordingly.

Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer.

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).

Because narcotic analgesics may increase biliary tract pressure, with resultant increases in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after a narcotic analgesic has been given.

The following laboratory tests may be affected in patients who are receiving therapy with promethazine hydrochloride.

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).

Limited data suggest that use of promethazine hydrochloride during labor and delivery does not have an appreciable effect on the duration of labor or delivery and does not increase the risk of need for intervention in the newborn.

The effect of promethazine and/or codeine on later growth and development of the newborn is unknown.

Administration of phenylephrine to patients in late pregnancy or labor may cause fetal anoxia or bradycardia by increasing contractility of the uterus and decreasing uterine blood flow.

See also "Nonteratogenic Effects".

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-than-expected 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 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, 1–10% in Caucasians, 3% in African Americans, and 16–28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

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 PRECAUTIONS – General - Ultra-Rapid Metabolizers of Codeine).

It is not known whether phenylephrine or promethazine are excreted in human milk.

Caution should be exercised when promethazine HCl, phenylephrine HCl and codeine phosphate syrup is administered to a nursing woman.

The combination of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population (see WARNINGS – Black Box Warning and Use In Pediatric Patients ).

Clinical studies of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate syrup did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of promethazine hydrochloride, phenylephrine hydrochloride and codeine phosphate syrup and observed closely.

Promethazine HCl, phenylephrine HCl and codeine phosphate syrup is a Schedule V Controlled Substance.

Codeine is known to be subject to abuse; however, the abuse potential of oral codeine appears to be quite low. Even parenteral codeine does not appear to offer the psychic effects sought by addicts to the same degree as heroin or morphine. However, codeine must be administered only under close supervision to patients with a history of drug abuse or dependence.

Psychological dependence, physical dependence and tolerance are known to occur with 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.

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.

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.

Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container with a child-resistant closure as defined in the USP.