FDA Label for Promethazine Hydrochloride And Codeine Phosphate
View Indications, Usage & Precautions
- WARNING: RESPIRATORY DEPRESSION IN CHILDREN; DEATH RELATED TO ULTRA RAPID METABOLISM OF CODEINE TO MORPHINE AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
- DESCRIPTION
- CODEINE
- PROMETHAZINE
- INDICATIONS AND USAGE
- CONTRAINDICATIONS
- WARNINGS
- RESPIRATORY DEPRESSION IN CHILDREN
- USE IN PEDIATRIC PATIENTS
- OTHER CONSIDERATIONS
- GENERAL
- INFORMATION FOR PATIENTS
- DRUG INTERACTIONS
- DRUG/LABORATORY TEST INTERACTIONS
- CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
- PREGNANCY
- NONTERATOGENIC EFFECTS
- LABOR AND DELIVERY
- NURSING MOTHERS
- PEDIATRIC USE
- GERIATRIC USE
- ADVERSE REACTIONS
- CONTROLLED SUBSTANCE
- ABUSE
- DEPENDENCE
- TREATMENT
- DOSAGE AND ADMINISTRATION
- HOW SUPPLIED
- MEDICATION GUIDE
- PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
Promethazine Hydrochloride And Codeine Phosphate Product Label
The following document was submitted to the FDA by the labeler of this product Akorn. The document includes published materials associated whith this product with the essential scientific information about this product as well as other prescribing information. Product labels may durg indications and usage, generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, warnings, inactive ingredients, etc.
Warning: Respiratory Depression In Children; Death Related To Ultra Rapid Metabolism Of Codeine To Morphine And Risks From Concomitant Use With Benzodiazepines Or Other Cns Depressants
Respiratory Depression in Children
The combination of promethazine 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.
Death Related to Ultra-Rapid Metabolism of Codeine to Morphine
Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism.
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see WARNINGS, PRECAUTIONS - Drug Interactions). Avoid use of
opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.
Description
Each 5 mL (one teaspoonful), for oral administration contains:
Promethazine hydrochloride 6.25 mg; codeine phosphate 10 mg in a flavored syrup base with a pH between 4.8 and 5.4. Alcohol 7%.
Inactive ingredients: Artificial boysenberry flavor, ascorbic acid, citric acid, D&C Red No. 33, FD&C Blue No. 1, FD&C Yellow No. 6, methylparaben, propylene glycol, propylparaben, purified water, saccharin sodium, sodium benzoate, sodium citrate, and sucrose syrup.
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 designated as 7,8-Didehydro-4, 5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate.
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. It has a molecular weight of 406.37, a molecular formula of C18H21NO3•H3PO4 • ½ H2O, and the following structural formula:
Promethazine hydrochloride, a phenothiazine derivative, is chemically designated as (±)-10-[2-(Dimethylamino)propyl] phenothiazine monohydrochloride.
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. It has a molecular weight of 320.88, a molecular formula of C17H20N2S•HCl, and the following structural formula:
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 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.
• Death Related to Ultra-Rapid Metabolism of Codeine to Morphine• Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants• 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.• Administration of codeine may be accomplished by histamine release and should be used with caution in atopic children.• Head Injury and Increased Intracranial PressureThe 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 ConditionsNarcotic 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 EffectCodeine may produce orthostatic hypotension in ambulatory patients.
Central 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.
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 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.
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 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.
• CNS DepressionPromethazine 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 avoid use of promethazine HCl and codeine phosphate syrup in patients on these medications. (See PRECAUTIONS – Information for PatientsandDrug Interactions).
• Respiratory DepressionPromethazine 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 ThresholdPromethazine 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 DepressionPromethazine 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 SyndromeA 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).
Central Nervous System: Drowsiness is the most prominent CNS effect of this drug. Sedation, somnolence, blurred vision, dizziness, confusion, disorientation and extrapyramidal symptoms such as oculogyric crisis, torticollis, and tongue protrusion; lassitude, tinnitus, incoordination, fatigue, euphoria, nervousness, diplopia, insomnia, tremors, convulsive seizures, excitation, catatonic-like states, hysteria. Hallucinations have also been reported.
Cardiovascular: Increased or decreased blood pressure, tachycardia, bradycardia, faintness.
Dermatologic: Dermatitis, photosensitivity, urticaria.
Hematologic: Leukopenia, thrombocytopenia, thrombocytopenic purpura, agranulocytosis.
Gastrointestinal: Dry mouth, nausea, vomiting, jaundice.
Respiratory: Asthma, nasal stuffiness, respiratory depression (potentially fatal) and apnea (potentially fatal) (see WARNINGS – Promethazine; Respiratory Depression).
Other: Angioneurotic edema. Neuroleptic malignant syndrome (potentially fatal) has also been reported (see WARNINGS – Promethazine; Neuroleptic Malignant Syndrome).
Paradoxical Reactions: Hyperexcitability and abnormal movements have been reported in patients following a single administration of promethazine HCl. Consideration should be given to the discontinuation of promethazine HCl and to the use of other drugs if these reactions occur.
Respiratory depression, nightmares, delirium and agitated behavior have also been reported in some of these patients.
Signs and symptoms of overdosage with promethazine 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.
Indications And Usage
Promethazine hydrochloride and codeine phosphate syrup is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold.
Contraindications
The combination of promethazine 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.
Codeine sulfate is contraindicated for post-operative pain management in children who have undergone tonsillectomy and/or adenoidectomy. (See WARNINGS - Death Related to Ultra- Rapid Metabolism of Codeine to Morphine). Codeine is contraindicated in patients with a known hypersensitivity to the drug.
Promethazine hydrochloride 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.
Antihistamines and codeine are both contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma.
Warnings
(see Boxed Warnings)
Respiratory Depression In Children
The combination of promethazine 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.
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.
Use In Pediatric Patients
The combination of promethazine 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. The association does not directly relate to individualized weight-based dosing, which might otherwise permit safe administration.
Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in these patients. (See WARNINGS - Death Related to Ultra-Rapid Metabolism of Codeine to MorphineandCONTRAINDICATIONS).
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.
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.
Information For Patients
Patients should be advised to measure promethazine HCl and codeine phosphate 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 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. Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities.
Inform patients and caregivers that potentially fatal additive effects may occur if promethazine HCl and codeine phosphate syrup is used with benzodiazepines or other CNS depressants, including alcohol. Because of this risk, patients should avoid concomitant use of promethazine HCl and codeine phosphate syrup with benzodiazepines or other CNS depressants, including alcohol. (See WARNINGS - Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants).
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.
Advise patients that some people have a genetic variation that results in codeine changing into morphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid codeine metabolizer or not. These higher-than-normal levels of morphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this population due to respiratory depression. As a result, codeine is contraindicated in children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving codeine for other reasons to monitor for signs of respiratory depression. (See WARNINGS - Death Related to Ultra-Rapid Metabolism of Codeine to Morphine).
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).
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.
The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with promethazine HCl and codeine phosphate syrup may cause an additive CNS depressant effect, profound sedation, respiratory depression, coma, and death and should be avoided. (See WARNINGS - Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants).
Promethazine
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.
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 HCl and codeine phosphate syrup should be given to a pregnant woman only if clearly needed.
Promethazine HCl and codeine phosphate syrup 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 the 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 of need 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 excreted 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 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 WARNINGS – Death Related to Ultra-Rapid Metabolism of Codeine to Morphine.)
Pediatric Use
The combination of promethazine 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 – Boxed WarningandUse in Pediatric Patients).
Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy. (See WARNINGS - Death Related to Ultra-Rapid Metabolism of Codeine to MorphineandCONTRAINDICATIONS).
Geriatric Use
Clinical studies of promethazine HCl 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.
Adverse Reactions
To report SUSPECTED ADVERSE REACTIONS, contact Hi-Tech Pharmacal Co.,m Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Controlled Substance
Promethazine HCl and codeine phosphate syrup is a Schedule V Controlled Substance.
Abuse
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.
Dependence
Psychological dependence, physical dependence, and tolerance are known to occur with codeine.
Treatment
Treatment of overdosage with promethazine 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 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 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.
Dosage And Administration
It is important that Promethazine HCl and Codeine Phosphate Syrup is measured with an accurate measuring device (see PRECAUTIONS-Information for Patients). A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is to be measured. It is strongly recommended that an accurate measuring device be used. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.
The combination of promethazine 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.
The average effective dose is given in the following table:
Adults (12 years of age and over) | 5 mL (1 teaspoonful) every 4 to 6 hours, not to exceed 30.0 mL in 24 hours. |
Children 6 years to under 12 years | 2.5 mL to 5 mL (½ to 1 teaspoonful) every 4 to 6 hours, not to exceed 30.0 mL in 24 hours. |
How Supplied
Promethazine Hydrochloride and Codeine Phosphate Syrup contains promethazine hydrochloride 6.25 mg/5 mL, codeine phosphate 10 mg/5 mL and alcohol 7 percent, and is available in a 4 fl oz and 16 fl oz containers.
Store at 20°-25° C (68°-77° F) [see USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP.
DEA Order Form Required
Manufactured by
Hi-Tech Pharmacal Co., Inc.
Amityville, NY 11701
Rev. 804:10 01/17
Medication Guide
MEDICATION GUIDE Promethazine Hydrochloride and Codeine Phosphate Syrup (proe meth’ a zeen hye” droe klor’ ide and koe’ deen fos’ fate) |
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Before you take Promethazine Hydrochloride and Codeine Phosphate Syrup, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking Promethazine Hydrochloride and Codeine Phosphate Syrup with certain other medicines can cause side effects or affect how well Promethazine Hydrochloride and Codeine Phosphate Syrup or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. Especially tell your healthcare provider if you: Ask your healthcare provider if you are not sure if you take one of these medicines. |
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What should I avoid while taking Promethazine Hydrochloride and Codeine Phosphate Syrup?
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What are the possible side effects of Promethazine Hydrochloride and Codeine Phosphate Syrup? Promethazine Hydrochloride and Codeine Phosphate Syrup may cause serious side effects, including:
The most common side effects of Promethazine Hydrochloride and Codeine Phosphate Syrup include: These are not all the possible side effects of Promethazine Hydrochloride and Codeine Phosphate Syrup. Call your doctor for medical advice about side effects. You may report side effects to Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088. |
How should I store Promethazine Hydrochloride and Codeine Phosphate Syrup?
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General information about the safe and effective use of Promethazine Hydrochloride and Codeine Phosphate Syrup. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Promethazine Hydrochloride and Codeine Phosphate Syrup for a condition for which it was not prescribed. Do not give Promethazine Hydrochloride and Codeine Phosphate Syrup to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Promethazine Hydrochloride and Codeine Phosphate Syrup that is written for health professionals. |
What are the ingredients in Promethazine Hydrochloride and Codeine Phosphate Syrup? Active ingredients: promethazine hydrochloride and codeine phosphate Inactive ingredients: Alcohol 7%, artificial boysenberry flavor, ascorbic acid, citric acid, D&C Red No. 33, FD&C Blue No. 1, FD&C Yellow No. 6, methylparaben, propylene glycol, propylparaben, purified water, saccharin sodium, sodium benzoate, sodium citrate, and sucrose syrup. Manufactured by: Hi-Tech Pharmacal Co., Inc. Amityville, NY 1170 |
This Medication Guide has been approved by the U.S. Food and Drug Administration
Issued: January 2017
Package/Label Principal Display Panel
AKORN
PROMETHAZINE HYDROCHLORIDE AND CODEINE PHOSPHATE SYRUP
6.25 mg/10 mg per 5 mL
Dispense the accompanying Medication Guide to each patient.
This container is not intended for household use.
Each 5 mL contains:
Promethazine hydrochloride ……………………… 6.25 mg
Codeine Phosphate …………………………………..10 mg
Alcohol ………………………………………………….7%
Contains FD&C Yellow No.6
USUAL DOSAGE: See attached insert for full prescribing information.
Keep tightly closed. Store at room temperature between 20° and 25°C (68° to 77°F). [See USPControlled Room Temperature]. Protect from light. Dispense in a tight, light-resistant container, as defined in the USP.
16 fl oz (473 mL)
Hi-Tech Pharmacal Co., Inc.
Amityville, NY 11701
* Please review the disclaimer below.