WARNINGS
Respiratory Depression
Codeprex is not recommended for use in pediatric patients under 6 years of age. Pediatric patients under 2 years of age may be more susceptible to the respiratory depressant effects of codeine, including respiratory arrest, coma, and death (see PRECAUTIONS, Pediatric Use).
As with other opioids, codeine produces dose-related respiratory depression by directly acting on brain stem respiratory centers. Codeine affects the center that controls respiratory rhythm, and may produce irregular and periodic breathing. Caution should be exercised when Codeprex is used postoperatively, in patients with pulmonary disease or shortness of breath, or whenever ventilatory function is depressed. If respiratory depression occurs, it may be antagonized by the use of naloxone hydrochloride and other supportive measures when indicated (see OVERDOSAGE).
Head Injury and Increased Intracranial Pressure
Respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse reactions which may obscure the clinical course of patients with head injuries.
Acute Abdominal Conditions
Administration of opioids may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Obstructive Bowel Disease
Chronic use of opioids may result in obstructive bowel disease especially in patients with underlying intestinal motility disorder.
Respiratory Conditions
Codeprex should be used with caution in patients with persistent or chronic cough such as occurs with smoking, asthma, or emphysema, or with cough accompanied by excessive phlegm. In patients with asthma or pulmonary emphysema, the indiscriminate use of antitussives may precipitate respiratory insufficiency due to increased viscosity of bronchial secretions and suppression of the cough reflex. In addition, the anticholinergic activity of antihistamines might reduce the volume and cause thickening of bronchial secretions and thus result in obstruction of the respiratory passages. Benefit to risk ratio should be carefully considered especially in pediatric patients with respiratory embarrassment (e.g., croup). (See PRECAUTIONS.)
PRECAUTIONS
General
Caution is advised when prescribing this drug to patients with narrow-angle glaucoma, asthma or prostatic hypertrophy. Codeine may cause or aggravate constipation.
Special Risk Patients
As with other opioids, Codeprex should be used with caution in elderly or debilitated patients and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind.
Cough Reflex
Codeine suppresses the cough reflex; as with other opioids, caution should be exercised when Codeprex is used postoperatively, and in patients with pulmonary disease.
Information for Patients
Patients should be advised that Codeprex may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly.
Codeprex must not be diluted with fluids or mixed with other drugs as this may alter the resin-binding and change the absorption rate, possibly increasing the toxicity.
Antihistamines such as chlorpheniramine may also cause excitability, especially in children. Keep out of the reach of children. Careful parental education should be provided about the appropriate use and side effects of cough-cold medications, particularly in younger children. Patients should be advised that recommended dosages should not be exceeded.
Drug Interactions
Anticholinergics
Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, constipation) may occur when anticholinergic drugs are administered with chlorpheniramine. Codeine and chlorpheniramine should be administered cautiously to persons receiving other anticholinergic drugs in order to avoid paralytic ileus and excessive anticholinergic effects.
Antidepressants
Use of MAO inhibitors or tricyclic antidepressants with codeine may increase the effect of either the antidepressant or codeine. MAO inhibitors may prolong and intensify the anticholinergic and sedative effects of antihistamines such as chlorpheniramine. Codeine and chlorpheniramine should be administered cautiously and in reduced dosage to persons receiving MAO inhibitors or tricyclic antidepressants in order to avoid excessive sedation, acute hypotension and excessive anticholinergic effects.
CNS Depressants
Concurrent use of opioids, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with Codeprex may result in additive CNS depression. When combined therapy is contemplated, the dose of one or both agents should be reduced.
Metabolic Enzymes
Codeine is metabolized to pharmacologically active metabolites by the cytochrome P-450 2D6 and 3A4 isoenzymes (see CLINICAL PHARMACOLOGY). The concurrent use of drugs that preferentially induce codeine N-demethylation (cytochrome P-450 3A4) or drugs that are strong inhibitors of codeine O-demethylation (cytochrome P-450 2D6), may decrease the plasma concentration of codeine’s active metabolites, morphine and morphine-6-glucuronide. The contribution of these active metabolites to the overall antitussive effect of codeine is not known, but should be considered. Persons taking cytochrome P-450 enzyme inducers or inhibitors may demonstrate an altered response to codeine, therefore antitussive activity should be monitored.
Phenytoin
Chlorpheniramine may inhibit the hepatic metabolism of phenytoin. Reports in the literature suggest a possible association between the concurrent administration of chlorpheniramine and phenytoin with increased serum phenytoin levels and phenytoin toxicity. Monitoring patients for evidence of phenytoin toxicity such as ataxia, hyperreflexia, nystagmus and tremor is recommended. If the patient exhibits signs of toxicity, a serum phenytoin level should be considered and Codeprex should be discontinued immediately.
Drug-Laboratory Test Interactions
Codeprex may cause an elevation of plasma amylase and lipase due to the potential of codeine to produce spasm of the sphincter of Oddi. Determination of these enzyme levels may be unreliable for some time after an opiate agonist has been given.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Although studies with Codeprex to evaluate carcinogenic, mutagenic or impairment of fertility potential have not been conducted, published data are available for the active ingredients.
Codeine
In 2-year studies in F344/N rats and B6C3F1 mice, codeine showed no evidence of tumorigenicity at dietary doses up to 70 and 400 mg/kg/day, respectively (approximately 8 and 20 times, respectively, the maximum recommended daily dose for adults and children on a mg/m2 basis).
Codeine was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary (CHO) cell chromosomal aberration assay.
Fertility studies with codeine have not been conducted.
Chlorpheniramine
In 2-year studies in F344/N rats and B6C3F1 mice, chlorpheniramine maleate showed no evidence of tumorigenicity when administered 5 days/week at oral doses up to 30 and 50 mg/kg/day, respectively (approximately 15 times the maximum recommended dose for adults and children on a mg/m2 basis).
Chlorpheniramine maleate was not mutagenic in the in vitro bacterial reverse mutation assay or the in vitro mouse lymphoma forward mutation assay. Chlorpheniramine maleate was clastogenic in the in vitro CHO cell chromosomal aberration assay.
In rats and rabbits, oral doses of chlorpheniramine maleate up to approximately 20 and 25 times the human dose on a mg/m2 basis, respectively, did not impair fertility.
Pregnancy
Pregnancy Category C.
Teratogenic Effects
Although animal reproductive studies with Codeprex™ Pennkinetic® (codeine polistirex and chlorpheniramine polistirex) Extended-Release Suspension have not been conducted, published data are available which address reproductive toxicity of the active ingredients.
Codeine
In a study in which pregnant rats were dosed throughout organogenesis, an oral dose of 120 mg/kg/day (approximately 10 times the maximum recommended daily dose for adults on a mg/m2 basis) increased resorptions and decreased fetal weight; however, these effects occurred in the presence of maternal toxicity. In studies in which rabbits and mice were dosed throughout organogenesis, oral doses up to 30 and 600 mg/kg/day, respectively (approximately 6 and 30 times, respectively, the maximum recommended daily dose for adults on a mg/m2 basis), produced no adverse developmental effects.
Chlorpheniramine
In studies in which pregnant rats and rabbits were dosed throughout organogenesis, oral doses up to approximately 20 and 25 times the maximum recommended daily dose for adults on a mg/m2 basis, respectively, produced no adverse developmental effects. However, when mice were dosed throughout pregnancy, an oral dose of 20 mg/kg/day (approximately 5 times the maximum recommended daily dose for adults on a mg/m2 basis) was embryolethal, and postnatal survival was decreased when dosing was continued after parturition. Embryolethality was also observed when male and female rats were dosed prior to mating with 10 mg/kg/day (approximately 5 times the maximum recommended daily dose for adults on a mg/m2 basis).
A retrospective study found a small but statistically significant association between maternal use of chlorpheniramine and inguinal hernia and eye or ear anomalies in children. Other retrospective studies have found that the frequency of congenital anomalies, in general, was not increased among offspring of women who took chlorpheniramine during pregnancy. The significance of these findings to the therapeutic use of chlorpheniramine in human pregnancy is not known.
There are no adequate and well-controlled studies in pregnant women. Codeprex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Non-teratogenic Effects
Neonatal codeine withdrawal has occurred in infants born to addicted and non-addicted mothers who had been taking codeine-containing medications in the days prior to delivery. Typical symptoms of narcotic withdrawal include irritability, excessive crying, tremors, hyperreflexia, seizures, fever, vomiting, diarrhea, and poor feeding. These signs occur shortly after birth and may require specific treatment.
Labor and Delivery
As with other opioids, use of codeine during labor can produce respiratory depression in the neonate, especially if higher doses are used. If the mother receives opiates during labor, the newborn should be observed closely for signs of respiratory depression. Treatment of respiratory depression may require active resuscitation and the use of specific opioid-antagonists (e.g., naloxone).
Nursing Mothers
Caution should be exercised when Codeprex is administered to a nursing woman.
Codeine and its metabolite morphine, appear in human milk at low levels, although considerable variability exists. Low levels of free codeine and its metabolite morphine are present in neonatal plasma after exposure to breast milk containing these substances. Care should be taken to monitor the infant carefully for signs of central nervous system and respiratory depression.
Chlorpheniramine is excreted into human milk. The clinical significance is unknown, however, the anticholinergic action of chlorpheniramine may suppress lactation if taken prior to nursing.
Pediatric Use
Safety and effectiveness of Codeprex in patients under 6 years of age have not been established. Codeprex is not recommended for use in patients under 6 years of age. Patients under 2 years of age may be more susceptible to the respiratory depressant effects of codeine, including respiratory arrest, coma, and death (see WARNINGS). Additionally, antihistamines may cause excitability in pediatric patients.
Geriatric Use
Clinical studies of Codeprex did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, sedating drugs may cause confusion and over-sedation in the elderly. 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.
Codeprex is substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
|
