Data from FDA - Curated by EPG Health - Last updated 29 September 2017

Indication(s)

1 INDICATIONS AND USAGE TUZISTRA XR is a combination of codeine, an opiate agonist antitussive, and chlorpheniramine, a histamine-1 (H1) receptor antagonist indicated for relief of cough and symptoms associated with upper respiratory allergies or a common cold. (1.1) Limitation of Use: Not indicated for pediatric patients under 18 years of age. (1.1) 1.1 Cough and Upper Respiratory Allergy Symptoms TUZISTRA XR 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 Specific Populations (8.4)].

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Advisory information

contraindications
4 CONTRAINDICATIONS TUZISTRA XR is contraindicated for: • All children younger than 12 years of age [see Warnings and Precautions (5.1)]. • Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.1)]. •Patients with known hypersensitivity to codeine, chlorpheniramine or any of the inactive ingredients of TUZISTRA XR. Persons known to be hypersensitive to certain other opioids may exhibit cross-sensitivity to codeine. •Children less than 12 years of age (4) •Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. (4) •Patients with known hypersensitivity to codeine, chlorpheniramine, or any of the product components of TUZISTRA XR. (4)
Adverse reactions
6 ADVERSE REACTIONS Use of codeine, a semisynthetic opioid, may result in the following: •Respiratory depression [see Warnings and Precautions (5.1) , (5.3) and Overdosage (10)] •Drug dependence [see Warnings and Precautions (5.4)] •Increased intracranial pressure [see Warnings and Precautions (5.5) and Overdosage (10)] •Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and Precautions (5.6)] •Paralytic ileus [see Warnings and Precautions (5.8)] 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 TUZISTRA XR. 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 TUZISTRA XR 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 TUZISTRA XR 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 Vernalis Therapeutics, Inc. 1-855-705-9546 and www.vernalistherapeutics.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •Adults 18 years of age and older: 10 mL every 12 hours. Not to exceed 2 doses (20 mL) in 24 hours. (2.1) •For Oral Use Only, with or without food. (2.2) 2.1 Adults 18 Years of Age and Older TUZISTRA XR should be orally administered in a dose of 10 mL every 12 hours, not to exceed 2 doses (20 mL) in 24 hours. 2.2 Administration Information Administer TUZISTRA XR by the oral route only, with or without food. Shake well before use. Measure with an accurate milliliter measuring device. Do not use a household teaspoon to measure the dose [see Warnings and Precautions (5.9)].
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) •Lactation: Breastfeeding not recommended. (8.3) •Pediatric patients: Safety and effectiveness of this drug product has not been established for patients under 18 years of age. (8.4) 8.1 Pregnancy Pregnancy Category C Teratogenic Effects There are no adequate and well-controlled studies of TUZISTRA XR in pregnant women. Reproductive toxicity studies have not been conducted with TUZISTRA XR; however, studies are available with individual active ingredients or related active ingredients. Because animal reproduction studies are not always predictive of human response, TUZISTRA XR 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 20 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 9 and 45 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 30 times the MRHDD on a mg/m2 basis, respectively, produced no adverse developmental effects. However, when mice were dosed throughout pregnancy, a dose approximately 9 times 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 9 times 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 Labor and Delivery As with all opioids, administration of TUZISTRA XR 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 Nursing Mothers Risk Summary Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. There is no information on the effects of the codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with TUZISTRA XR [see Warnings and Precautions (5.1)]. Clinical Considerations If infants are exposed to TUZISTRA XR through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 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 TUZISTRA XR in pediatric patients under 18 years of age have not been established. Life-threatening respiratory depression and death have occurred in children who received codeine [see Warnings and Precautions (5.1)]. In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life-threatening respiratory depression and death: •TUZISTRA XR is contraindicated in all children younger than 12 years of age [see Contraindications (4)]. •TUZISTRA XR is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. •Avoid the use of TUZISTRA XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression [see Warnings and Precautions (5.1)]. 8.5 Geriatric Use Clinical efficacy and safety studies have not been conducted with TUZISTRA XR. Other reported clinical experience with the individual active ingredients of TUZISTRA XR 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 TUZISTRA XR has not been characterized in renal impairment subjects. Both codeine and chlorpheniramine 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. TUZISTRA XR should be used with caution in patients with severe renal impairment. 8.7 Hepatic Impairment Pharmacokinetics of TUZISTRA XR has not been characterized in hepatic impairment subjects. Both codeine and chlorpheniramine are extensively metabolized by the 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. TUZISTRA XR should be used with caution in patients with severe hepatic impairment.
Pregnancy and lactation
8.3 Nursing Mothers Risk Summary Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. There is no information on the effects of the codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with TUZISTRA XR [see Warnings and Precautions (5.1)]. Clinical Considerations If infants are exposed to TUZISTRA XR through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 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 Drug interaction studies have not been conducted with TUZISTRA XR. •Benzodiazepines, 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 TUZISTRA XR 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 TUZISTRA XR 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 Clinical Pharmacology (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 NDA207768
Agency product number V1Q0O9OJ9Z
Orphan designation No
Product NDC 69442-480
Date Last Revised 29-08-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1652093
Marketing authorisation holder Vernalis Therapeutics, Inc.
Warnings WARNING WARNING ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning. • Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy and many of the children had evidence of being an ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism. (5.1) TUZISTRA XR is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (4). Avoid the use of TUZISTRA XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. (5.1) • 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. ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism [see Warnings and Precautions (5.1)]. TUZISTRA XR is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of TUZISTRA XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine [see Warnings and Precautions (5.1)]. 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 and Precautions (5.2), Drug Interactions (7.1)]. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.