WARNINGS
Deaths Related to Ultra-Rapid Metabolism of Codeine to Morphine
Respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultrarapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine (see PRECAUTIONS-Nursing Mothers).
Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). 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 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. 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 regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) (see OVERDOSAGE).
Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain 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 CONTRAINDICATIONS).
When prescribing codeine-containing drugs, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose.
Triprolidine and pseudoephedrine hydrochlorides and codeine phosphate syrup should be used with considerable caution in patients with increased intraocular pressure (narrow angle glaucoma), stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy, bladder neck obstruction, hypertension, diabetes mellitus, ischemic heart disease, and hyperthyroidism.
In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure.
Narcotics also produce other CNS depressant effects, such as drowsiness, that may further obscure the clinical course of patients with head injuries.
Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions.
PRECAUTIONS
General: Triprolidine and pseudoephedrine hydrochlorides and codeine phosphate syrup should be prescribed with caution for certain special-risk patients, such as the elderly or debilitated, and for those with severe impairment of renal or hepatic function, gallbladder disease or gallstones, respiratory impairment, cardiac arrhythmias, history of bronchial asthma, prostatic hypertrophy or urethral stricture, and in patients known to be taking other antitussive, antihistamine or decongestant medications. Patients’ self-medication habits should be investigated to determine their use of such medications. Triprolidine and pseudoephedrine hydrochlorides and codeine phosphate syrup is intended for short-term use only.
Information For Patients:
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 all 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 Releated to Ultra-Rapid metabolism of Codeine to Morphine).
- Patients should be warned about engaging in activities requiring mental alertness such as driving a car, operating dangerous machinery or hazardous appliances.
- Patients with a history of glaucoma, peptic ulcer, urinary retention or pregnancy should be cautioned before starting this product.
- Patients should be told not to take alcohol, sleeping pills, sedatives or tranquilizers while taking triprolidine and pseudoephedrine hydrochlorides and codeine phosphate syrup.
- Antihistamines may cause dizziness, drowsiness, dry mouth, blurred vision, weakness, nausea, headache or nervousness in some patients.
- Patients should be told to store this medicine in a tightly closed container in a dry, cool place away from heat or direct sunlight and out of the reach of children.
- Nursing Mothers – refer to following section titled “Nursing Mothers.” (see WARNINGS – Death Related to Ultra-Rapid Metabolism of Codeine to Morphine).
This product should not be used by persons intolerant to sympathomimetics used for the relief of nasal or sinus congestion. Such drugs include ephedrine, epinephrine, phenylephrine and phenylpropanolamine. Symptoms of intolerance include drowsiness, dizziness, weakness, difficulty in breathing, tenseness, muscle tremors or palpitations.
Codeine may be habit-forming when used over long periods or in high doses. Patients should take the drug only for as long, in the amounts, and as frequently as prescribed.
Drug Interactions: Triprolidine and pseudoephedrine hydrochlorides and codeine phosphate syrup may enhance the effects of:
- Monoamine oxidase (MAO) inhibitors;
- other narcotic analgesics, alcohol, general anesthetics, tranquilizers, sedative-hypnotics, surgical skeletal muscle relaxants, or other CNS depressants, by causing increased CNS depression.
This product may diminish the antihypertensive effects of guanethidine, bethanidine, methyldopa and reserpine.
Drug/Laboratory Test Interactions: Codeine: Narcotic administration may increase serum amylase levels.
Carcinogenesis, Mutagenesis, Impairment Of Fertility: No adequate studies have been conducted in animals to determine whether the components of triprolidine and pseudoephedrine hydrochlorides and codeine phosphate syrup have a potential for carcinogenesis, mutagenesis or impairment of fertility.
Pregnancy: Teratogenic Effects –
Pregnancy category C. Animal reproduction studies have not been conducted with triprolidine and pseudoephedrine hydrochlorides and codeine phosphate syrup. It is also not known whether this product can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. This product should be given to a pregnant woman only if clearly needed.
Teratology studies have been conducted with the three ingredients of triprolidine and pseudoephedrine hydrochlorides and codeine phosphate syrup. Pseudoephedrine studies were conducted in rats at doses up to 150 times the human dose; triprolidine was studied in rats and rabbits at doses up to 125 times the human dose, and codeine studies were conducted in rats and rabbits at doses up to 150 times the human dose. No evidence of teratogenic harm to the fetus was revealed in any of these studies. However, overt signs of toxicity were observed in the dams which received pseudoephedrine. This was reflected in reduced average weight and length and rate of skeletal ossification in their fetuses.
Nursing Mothers
The components of triprolidine and pseudoephedrine hydrochlorides and codeine phosphate syrup are excreted in breast milk in small amounts, but the significance of their effects on nursing infants is not known. Because of the potential for serious adverse reactions in nursing infants from maternal ingestion of this product, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (see WARNINGS - Death Related to Ultra-Rapid Metabolism of Codeine to Morphine).
Pediatric Use
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 cytochrome P450 isoenzyme 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 Morphine and CONTRAINDICATIONS)
As in adults, the combination of an antihistamine, sympathomimetic amine and codeine can elicit either mild stimulation or mild sedation in pediatric patients. In pediatric patients particularly, the ingredients in this drug product in overdosage may produce hallucinations, convulsions and death. Symptoms of toxicity in pediatric patients may include fixed dilated pupils, flushed face, dry mouth, fever, excitation, hallucinations, ataxia, incoordination, athetosis, tonic clonic convulsions and postictal depression, (see CONTRAINDICATIONS and OVERDOSAGE sections).
Use In Elderly (Approximately 60 Years Or Older)
The ingredients in triprolidine and pseudoephedrine hydrochlorides and codeine phosphate syrup are more likely to cause adverse reactions in elderly patients.
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