WARNINGS
THE COMBINATION OF PROMETHAZINE 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.
Codeine: 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 accomplished 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.
Hypotensive Effect: Codeine may produce orthostatic hypotension in ambulatory patients.
Promethazine: CNS Depression – Promethazine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of promethazine HCl (see PRECAUTIONS -Information for Patients and Drug Interactions).
Respiratory Depression – Promethazine may lead to potentially fatal respiratory depression.
Use of Promethazine in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided.
Lower Seizure Threshold – Promethazine may lower seizure threshold. It should be used with caution in persons with seizure disorder or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.
Bone-Marrow Depression – Promethazine should be used with caution in patients with bone-marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine HCl has been used in association with other known marrow-toxic agents.
Neuroleptic Malignant Syndrome – A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of promethazine HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine HCl should be carefully considered.
Use in Pediatric Patients
THE COMBINATION OF PROMETHAZINE 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. THE
ASSOCIATION DOES NOT DIRECTLY RELATE TO INDIVIDUALIZED
WEIGHT-BASED DOSING, WHICH MIGHT OTHERWISE PERMIT SAFE
ADMINISTRATION.
Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death (see Overdosage). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of promethazine hydrochloride in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine HCl.
Other Considerations
Administration of promethazine has been associated with reported cholestatic jaundice.
PRECAUTIONS
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. Promethazine hydrochloride and codeine phosphate syrup should be given to a pregnant woman only if clearly needed.
General
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.
Ultra-rapid Metabolizers of Codeine
Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regiments, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing.
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.
When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose. (See PRECAUTIONS -Nursing Mothers).
Information for patients
Promethazine 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 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 of 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).
Interactions
Drug interactions
Codeine: In patients receiving MAO inhibitors, an initial small test dose is advisable to allow observation of any excessive narcotic effects or MAOI interaction.
Promethazine:
CNS depressants – Promethazine may increase, prolong, or intensify the sedative action of other central-nervous-system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine HCl. When given concomitantly with promethazine, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of promethazine HCl relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain.
Epinephrine – Because of the potential for promethazine to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine overdose.
Anticholinergics – Concomitant use of other agents with anticholinergic properties should be undertaken with caution.
Monoamine oxidase inhibitors (MAOI) – Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly.
Drug/laboratory test interactions
Because narcotic analgesics may increase biliary tract pressure, with resultant increase 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.
Glucose Tolerance Test: An increase in blood glucose has been reported in patients receiving promethazine.
Carcinogenesis, mutagenesis, impairment of fertility
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.
Pregnancy
Teratogenic effects
Pregnancy Category C
Codeine: 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 HCl. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of promethazine for a 50-kg subject depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats.
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 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.
Promethazine and 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 administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.
Labor and delivery
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 suggests 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 for intervention in the newborn.
The effect of promethazine and/or codeine on later growth and development of the newborn is unknown.
Nursing mothers
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).
Caution should be exercised when promethazine hydrochloride and codeine phosphate syrup is administered to a nursing woman.
Pediatric use
THE COMBINATION OF PROMETHAZINE
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 (see WARNINGS – Black Box Warning and Use in
Pediatric Patients).
Geriatric use
Clinical studies of promethazine 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 and codeine phosphate syrup and observed closely.
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