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Each teaspoon (5 mL) of Phenergan with codeine contains 10 mg codeine phosphate (Warning--may be habit-forming) and 6.25 mg promethazine hydrochloride in a flavored syrup base with a pH between 4.8 to 5.4. Alcohol 7%. The inactive ingredients present are artificial and natural flavors, citric acid, D&C Red 33, FD&C Blue 1, FD&C Yellow 6, glycerine, saccharin sodium, sodium benzoate, sodium citrate, sodium propionate, water, and other ingredients.
Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy; it is classified pharmacologically as a narcotic analgesic. Codeine phosphate may be chemically named as (5(alpha),6(alpha))-7,8-didehydro-4, 5-epoxy-3-methoxy-17-methylmorphinan-6-ol phosphate (1:1) (salt) hemihydrate with the following structural formula:
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The phosphate salt of codeine occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohol, with a molecular weight of 406.37. The empirical formula is C 18 H 21 NO 3 ·H 3 PO 4 · 1 / 2 H 2 O, and the stereochemistry is 5(alpha), 6(alpha) isomer as indicated in the structure.
Promethazine hydrochloride is a racemic compound; the empirical formula is C 17 H 20 N 2 S·HCl and its molecular weight is 320.88.
Promethazine hydrochloride, a phenothiazine derivative, is designated chemically as 10 H -Phenothiazine-10-ethanamine, N,N, (alpha)-trimethyl-, monohydrochloride, (±)-. with the following structural formula:
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Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is soluble in water and freely soluble in alcohol.
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 2/3 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.
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 lack (1/10 that of chlorpromazine) of dopaminergic (CNS) action.
Promethazine is an H 1 receptor blocking agent. In addition to its antihistaminic action, it provides clinically useful sedative and antiemetic effects. In therapeutic dosages, promethazine produces no significant effects on the cardiovascular system.
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.
Phenergan with codeine is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold.
Codeine is contraindicated in patients with a known hypersensitivity to the drug.
Promethazine is contraindicated in individuals known to be hypersensitive or to have had an idiosyncratic reaction to promethazine or to other phenothiazines.
Antihistamines and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma.
Dosage of codeine SHOULD NOT BE INCREASED if cough fails to respond; an unresponsive cough should be reevaluated 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.
Head Injury and Increased Intracranial Pressure
The respiratory-depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions, or a preexisting increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries.
Asthma and Other Respiratory Conditions
Narcotic analgesics or cough suppressants, including codeine, should not be used in asthmatic patients (see " Contraindications "). Nor should they be used in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient's respiratory function.
Codeine may produce orthostatic hypotension in ambulatory patients.
Promethazine may cause marked drowsiness. Ambulatory patients should be cautioned against such activities as driving or operating dangerous machinery until it is known that they do not become drowsy or dizzy from promethazine therapy.
The sedative action of promethazine hydrochloride is additive to the sedative effects of central nervous system depressants; therefore, agents such as alcohol, narcotic analgesics, sedatives, hypnotics, and tranquilizers should either be eliminated or given in reduced dosage in the presence of promethazine hydrochloride. When given concomitantly with promethazine hydrochloride, the dose of barbiturates should be reduced by at least one-half, and the dose of analgesic depressants, such as morphine or meperidine, should be reduced by one-quarter to one-half.
Promethazine may lower seizure threshold. This should be taken into consideration when administering to persons with known seizure disorders or when giving in combination with narcotics or local anesthetics which may also affect seizure threshold.
Sedative drugs or CNS depressants should be avoided in patients with a history of sleep apnea.
Antihistamines should be used with caution in patients with narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, and urinary bladder obstruction due to symptomatic prostatic hypertrophy and narrowing of the bladder neck.
Administration of promethazine has been associated with reported cholestatic jaundice.
Animal reproduction studies have not been conducted with the drug combination--promethazine and codeine. It is not known whether this drug combination can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Phenergan with codeine should be given to a pregnant woman only if clearly needed.
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' disease, ulcerative colitis, prostatic hypertrophy, in patients with recent gastrointestinal or urinary tract surgery, and in the very young or elderly or debilitated patients.
Promethazine should be used cautiously in persons with cardiovascular disease or with impairment of liver function.
Phenergan with 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 Phenergan with codeine therapy. Children should be supervised to avoid potential harm in bike riding or in other hazardous activities.
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 or unusual sensitivity to sunlight.
Codeine, like other narcotic analgesics, may produce orthostatic hypotension in some ambulatory patients. Patients should be cautioned accordingly.
In patients receiving MAO inhibitors, an initial small test dose is advisable to allow observation of any excessive narcotic effects or MAOI interaction.
Promethazine
The sedative action of promethazine is additive to the effects of other central nervous system depressants, including alcohol, narcotic analgesics, sedatives, hypnotics, tricyclic antidepressants, and tranquilizers; therefore, these agents should be avoided or administered in reduced dosage to patients receiving promethazine.
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:
Pregnancy Tests
Diagnostic pregnancy tests based on immunological reactions between HCG and anti-HCG may result in false-negative or false-positive interpretations.
An increase in blood glucose has been reported in patients receiving promethazine.
Long-term animal studies have not been performed to assess the carcinogenic potential of codeine or of promethazine, nor are there other animal or human data concerning carcinogenicity, mutagenicity, or impairment of fertility with these agents. Codeine has been reported to show no evidence of carcinogenicity or mutagenicity in a variety of test systems, including the micronucleus and sperm abnormality assays and the Salmonella assay. Promethazine was nonmutagenic in the Salmonella test system of Ames.
Teratogenic Effects --Pregnancy Category C
A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis 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 studies in humans, and the significance of these findings to humans, if any, is not known.
Promethazine
Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of promethazine. These doses are 8.3 and 16.7 times the maximum recommended total daily dose of promethazine for a 50-kg subject. Specific studies to test the action of the drug on parturition, lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines, including promethazine, have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well-controlled studies of promethazine in pregnant women.
Phenergan® with codeine 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. Signs usually appear during the first few days of life.
Promethazine taken within two weeks of delivery may inhibit platelet aggregation in the newborn.
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.
See also " Nonteratogenic Effects ."
Some studies, but not others, have reported detectable amounts of codeine in breast milk. The levels are probably not clinically significant after usual therapeutic dosage. The possibility of clinically important amounts being excreted in breast milk in individuals abusing codeine should be considered.
It is not known whether promethazine is excreted in human milk.
Caution should be exercised when Phenergan with codeine is administered to a nursing woman.
This product should not be used in children under 2 years of age because safety for such use has not been established.
Nervous System --CNS depression, particularly respiratory depression, and to a lesser extent circulatory depression; light-headedness, dizziness, sedation, euphoria, dysphoria, headache, transient hallucination, disorientation, visual disturbances, and convulsions.
Cardiovascular --Tachycardia, bradycardia, palpitation, faintness, syncope, orthostatic hypotension (common to narcotic analgesics).
Gastrointestinal --Nausea, vomiting, constipation, and biliary tract spasm. Patients with chronic ulcerative colitis may experience increased colonic motility; in patients with acute ulcerative colitis, toxic dilation has been reported.
Genitourinary --Oliguria, urinary retention; antidiuretic effect has been reported (common to narcotic analgesics).
Allergic --Infrequent pruritus, giant urticaria, angioneurotic edema, and laryngeal edema.
Other --Flushing of the face, sweating and pruritus (due to opiate-induced histamine release); weakness.
Nervous System --Sedation, sleepiness, occasional blurred vision, dryness of mouth, dizziness; rarely confusion, disorientation, and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion (usually in association with parenteral injection or excessive dosage).
Cardiovascular --Increased or decreased blood pressure.
Dermatologic --Rash, rarely photosensitivity.
Hematologic --Rarely leukopenia, thrombocytopenia; agranulocytosis (1 case).
Gastrointestinal --Nausea and vomiting.
Phenergan with codeine 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 range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, and unconsciousness.
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.
The treatment of overdosage with Phenergan with 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 Phenergan with 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 losses should 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.
The average effective dose is given in the following table:
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Phenergan® with codeine is a clear, purple solution supplied as follows:
NDC 0008-0550-02, case of 24 bottles of 4 fl. oz. (118 mL).
NDC 0008-0550-03, bottle of 1 pint (473 mL).
Keep tightly closed--Store at room temperature, between 15° C and 25° C (59° F and 77° F).
Protect from light.
Dispense in light-resistant, glass, tight container.
Manufactured by:
Wyeth Laboratories
A Wyeth-Ayerst Company
Philadelphia, PA 19101
CI 4868-2 Revised July 22, 1998