Data from FDA - Curated by EPG Health - Last updated 22 August 2017

Indication(s)

1 INDICATIONS AND USAGE CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE is indicated for the relief of cough and symptoms associated with upper respiratory allergies or a common cold in adults 18 years of age and older. Important Limitations of Use Not indicated for pediatric patients under 18 years of age [see Use in Special Population (8.4)] CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE is a combination of codeine phosphate, an opiate agonist antitussive, and chlorpheniramine maleate, a histamine-1 (H1) receptor antagonist indicated for the relief of cough and symptoms associated with upper respiratory allergies or a common cold. ( 1 ) Important Limitations of Use Not indicated for pediatric patients under 18 years of age (8.4))

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Advisory information

contraindications
4 CONTRAINDICATIONS CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE is contraindicated in: Postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.1)]. Patients with known hypersensitivity to codeine, chlorpheniramine or any of the inactive ingredients of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE. Persons known to be hypersensitive to certain other opioids may exhibit cross-sensitivity to codeine. •Post-operative pain management in children undergoing tonsillectomy and/or adenoidectomy. ( 4 ) •Patients with known hypersensitivity to codeine, chlorpheniramine, or any of the product components of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE. ( 4 )
Adverse reactions
6 ADVERSE REACTIONS Use of codeine, an opioid, may result in the following: •Respiratory depression [see Warnings and Precautions (5.3) and Overdosage (10)] •Drug dependence [see Warnings and Precautions (5.4)] •Increased intracranial pressure [see Warnings and Precautions (5.5)] •Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and Precautions (5.6)] •Paralytic ileus [see Warnings and Precautions (5.7)] Use of chlorpheniramine, an antihistamine, may result in: •Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and Precautions (5.6)] Adverse reactions listed below have been reported in the literature for codeine and chlorpheniramine and may be expected to occur with CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE. Also included are events that occurred during clinical pharmacokinetic studies (in a total of 66 healthy adult volunteers with either single or multiple dose exposure) with CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE and judged by the investigator to be related to study treatment. Because these reactions may be reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic: Allergic laryngospasm, nasal stuffiness, bronchospastic allergic reaction, hives, itching, swelling of face. Body as a whole: Asthenia, feeling of relaxation, redness or flushing of the face, unusual tiredness, weakness. Cardiovascular: Fast, or slow heartbeat, hypertension, hypotension, orthostatic hypotension, palpitations, shock-like state, syncope. Dermatological System: Skin rash, pruritus, erythema, urticaria, excessive perspiration, dermatitis. Endocrine System: Changes in glucose utilization, decreased lactation, early menses, glycosuria, gynecomastia, hypoglycemia, increased appetite, increased libido, pheochromocytoma stimulation. Gastrointestinal System: Nausea and vomiting,, constipation, abdominal distension, abdominal pain, acute pancreatitis, dry mouth, dyspepsia, epigastric distress, loss of appetite, diarrhea, gastro-esophageal reflux, gastrointestinal hypomotility. Genitourinary System: Ureteral spasm, urinary retention, dysuria, urinary frequency, urinary hesitancy, irritative bladder symptom. Nervous System: Blurred vision, diplopia, visual disturbances, confusion, dizziness, depression, drowsiness, sedation, headache, euphoria, facial dyskinesia, false sense of well-being, feeling faint, lightheadedness, general feeling of discomfort or illness, excitability nervousness, agitation, restlessness, somnolence, insomnia, dyskinesia, irritability, tremor. Respiratory: Dryness of the pharynx and respiratory passages, laryngismus, atelectasis, wheezing, troubled breathing, respiratory depression, hiccups. Special Senses: labyrinthitis, tinnitus, vertigo, hypermetropia, lacrimation increased, mydriasis, photophobia. Common adverse reactions of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE include: Nausea and vomiting, constipation, abdominal distension, abdominal pain, blurred vision, diplopia, visual disturbances, confusion, dizziness, depression, drowsiness, sedation, headache, euphoria, facial dyskinesia, feeling faint, light-headedness, general feeling of discomfort or illness, excitability, nervousness, agitation, restlessness, somnolence, insomnia, dyskinesia, irritability, tremor. (6) To report SUSPECTED ADVERSE REACTIONS, contact Nexgen Pharma, Inc. at 888-710-0006 or go to www.nexgenpharma.com or FDA at 1-800-FDA-1088

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Adults and children 18 years of age and older: 1 tablet every 12 hours, not to exceed 2 doses in 24 hours. ( 2.1) 2.1 Adults 18 Years of Age and Older CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE should be administered orally at a dosage of one tablet every 12 hours, not to exceed 2 tablets in 24 hours.
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Pregnancy: Based on animal data, may cause fetal harm. (8.1) •Labor: Use of codeine during labor can produce respiratory depression in the neonate. (8.2) •Nursing mothers: 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 the baby. (8.3) •Pediatric patients: Safety and effectiveness of this drug product has not been established for patients under 18. (8.4) 8.1 Pregnancy Teratogenic Effects Pregnancy Category C There are no adequate and well-controlled studies of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE in pregnant women. Reproductive toxicity studies have not been conducted with CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE; however, studies are available with individual active ingredients or related active ingredients. Because animal reproduction studies are not always predictive of human response, CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE should be used during pregnancy only if the benefit justifies the potential risk to the fetus. Codeine: Codeine has embryolethal and fetotoxic effects in rats. In a study in which pregnant rats were dosed throughout organogenesis, a dose approximately 15 times the maximum recommended human daily dose (MRHDD; on a mg/m2 basis at an oral maternal dose of 120 mg/kg/day) 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, codeine at doses approximately 7 and 35 times the MRHDD (on a mg/m2 basis at 30 and 600 mg/kg/day, respectively) produced no adverse developmental effects. Chlorpheniramine: 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. In studies with chlorpheniramine in which pregnant rats and rabbits were dosed throughout organogenesis, oral doses up to approximately 25 and 30times the MRHDD on a mg/m2 basis, respectively, produced no adverse developmental effects. However, when mice were dosed throughout pregnancy, a dose approximately 9times the MRHDD (on a mg/m2 basis at an oral maternal dose of 20 mg/kg/day) was embryolethal, and postnatal survival was decreased when dosing was continued after parturition. Embryolethality was also observed when male and female rats were dosed with approximately 9times the MRHDD (on a mg/m2 basis at an oral parental dose of 10 mg/kg/day) prior to mating. Nonteratogenic Effects Codeine: Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. 8.2 Lactation As with all opioids, administration of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used. 8.3 Females and Males of Reproductive Potential Caution should be exercised when CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE is administered to 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. 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 the 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 breast-feeding [see Warnings and Precautions (5.1)]. Chlorpheniramine is excreted in human milk. The clinical significance is unknown; however, the anticholinergic action of chlorpheniramine may suppress lactation if taken prior to nursing. 8.4 Pediatric Use Safety and effectiveness of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE in patients under 18 years of age have not been established. The use of codeine in children has been associated with fatal respiratory depression. [see Warnings and Precautions (5.1)]. 8.5 Geriatric Use Clinical efficacy and safety studies have not been conducted with CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE. Other reported clinical experience with the individual active ingredients of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be made with caution, 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. 8.6 Renal Impairment Pharmacokinetics of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE has not been characterized in renal impairment subjects. Both codeine phosphate and chlorpheniramine maleate are cleared substantially by the kidney. As such, impaired renal function could potentially lead to the risk of decreased clearance and thereby increased retention or systemic levels of both these drugs. CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE should be used with caution in patients with severe renal impairment. 8.7 Hepatic Impairment Pharmacokinetics of CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE has not been characterized in hepatic impairment subjects. Both codeine and chlorpheniramine maleate are extensively metabolized by liver before elimination from the body. As such, impaired hepatic function could potentially lead to the risk of decreased metabolism and thereby increased systemic levels of both these drugs. CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE should be used with caution in patients with severe hepatic impairment.
Pregnancy and lactation
8.3 Females and Males of Reproductive Potential Caution should be exercised when CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE is administered to 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. 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 the 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 breast-feeding [see Warnings and Precautions (5.1)]. Chlorpheniramine is excreted in human milk. The clinical significance is unknown; however, the anticholinergic action of chlorpheniramine may suppress lactation if taken prior to nursing.

Interactions

7 DRUG INTERACTIONS •Opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants: may cause additive CNS depression. (7.1) •MAOIs or tricyclic antidepressants: may increase the effect of either the antidepressant or codeine. (7.2) •Anticholinergic drugs: Use with caution. Additive adverse effects resulting from cholinergic blockage (e.g., xerostomia, blurred vision, or constipation) may occur. (7.3) •Inhibitors or inducers of metabolic enzymes: Concomitant use of cytochrome P450 2D6 and 3A4 enzyme inhibitors or inducers may result in an altered response to codeine, monitor antitussive activity. Chlorpheniramine may inhibit the hepatic metabolism of phenytoin, monitor phenytoin toxicity. (7.4) 7.1 Benzodiazepines, Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol) The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE may cause an additive CNS depressant effect, profound sedation, respiratory depression, coma, and death and should be avoided. [see Warnings and Precautions (5.2)]. 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Do not prescribe CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE if the patient is taking a monoamine oxidase inhibitor (MAOI) (i.e., certain drugs used for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping a MAOI drug. The use of MAOIs or tricyclic antidepressants with codeine preparations may increase the effect of either the antidepressant or codeine. 7.3 Anticholinergic Drugs Codeine and chlorpheniramine should be administered cautiously to persons receiving other anticholinergic drugs in order to avoid paralytic ileus and excessive anticholinergic effects. Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with chlorpheniramine. 7.4 Inhibitors or Inducers of Metabolic Enzymes Codeine is metabolized by the CYP2D6 and CYP3A4 isoenzymes [see Pharmacokinetics (12.3)]. The concurrent use of drugs that preferentially induce codeine N-demethylation (via CYP3A4) may increase the plasma concentrations of codeine’s inactive metabolite norcodeine. Drugs that inhibit codeine O-demethylation (via CYP2D6), 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. Adverse event reports in the literature suggest a possible drug interaction involving increased serum phenytoin levels and phenytoin toxicity when chlorpheniramine and phenytoin are co-administered. The exact mechanism for this interaction is not known, however it is believed that chlorpheniramine may inhibit the hepatic metabolism of phenytoin. Patients should be monitored for evidence of phenytoin toxicity such as ataxia, hyperreflexia, nystagmus and tremor when these two drugs are co-administered.

More information

Category Value
Authorisation number NDA206323
Agency product number GSL05Y1MN6
Orphan designation No
Product NDC 0722-7184
Date Last Revised 20-01-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1664543
Marketing authorisation holder Nexgen Pharma, Inc.
Warnings WARNING DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Ultra-Rapid Metabolism 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. ( 5.1) Concomitant Use with Benzodiazepines, 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 Warning and Precautions ( 5.2) Drug Interactions (7.1). Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol. WARNING DEATH RELATED TO ULTRA-RAPID METABOLISM OF CODEINE TO MORPHINE and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Ultra-Rapid Metabolism 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. (5.1) Concomitant Use with Benzodiazepines, 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 Warning and Precautions ( 5.2) Drug Interactions (7.1). Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.