Tuxarin

6 ADVERSE REACTIONS Use of codeine, an 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) ] 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 TUXARIN ER. 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 TUXARIN ER 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 TUXARIN ER 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 MainPointe Pharmaceuticals, LLC at 502-709-7544 or go to mainpointepharmaceuticals.com or FDA at 1-800-FDA-1088

4 CONTRAINDICATIONS TUXARIN ER 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 TUXARIN ER. Persons known to be hypersensitive to certain other opioids may exhibit cross-sensitivity to codeine. All children younger than 12 years of age ( 4 ) Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. ( 4 ) Hypersensitivity to codeine, chlorpheniramine, or any of the product components of TUXARIN ER. ( 4 )

11 DESCRIPTION TUXARIN ER are extended release tablets that contain 54.3 mg of codeine phosphate (equivalent to 40 mg of codeine) and 8 mg of chlorpheniramine maleate (equivalent to 5.6 mg of chlorpheniramine). Codeine phosphate [morphine3methyl ether phosphate (1:1) (salt)] hemihydrate, is a narcotic analgesic and antitussive. It has the following structural formula: H 3 PO 4 ∙ 1/2 H 2 O Codeine Phosphate Hemihydrate C 18 H 21 NO 3 ∙ H 3 PO 4 ∙ ½H 2 O MW 406.37 Chlorpheniramine maleate is 2-pyridinepropanamine, γ-(4-chlorophenyl)- N,N -dimethyl-, ( Z )-2-butenedioate (1:1) and has the following chemical structure: Chlorpheniramine Maleate C 16 H 19 ClN 2 ∙ C 4 H 4 O 4 Molecular weight = 390.86 TUXARIN ER are white to off-white, uncoated, standard round extended release matrix tablets. Other ingredients: hypromellose, lactose monohydrate, cellulose microcrystalline, polysorbate 80, magnesium stearate, and colloidal silicon dioxide. Chemical Structure Chemical Structure

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 ) 2.1 Adults 18 Years of Age and Older TUXARIN ER should be administered orally at a dosage of one tablet every 12 hours, not to exceed 2 tablets in 24 hours.

1 INDICATIONS AND USAGE TUXARIN ER 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. TUXARIN ER 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 )) Important Limitations of Use Not indicated for pediatric patients under 18 years of age [see Use in Special Population (8.4) ]

9.2 Abuse Codeine can produce drug dependence of the morphine type and therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of TUXARIN ER, and it should be prescribed and administered with the same degree of caution appropriate to the use of other opioid drugs.

9.1 Controlled Substance TUXARIN ER is a Schedule III controlled prescription product containing codeine and should be prescribed and administered with caution.

9.3 Dependence Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, TUXARIN ER should be prescribed and administered with caution. Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued oral opioid use, although some mild degree of physical dependence may develop after a few days of opioid therapy.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance TUXARIN ER is a Schedule III controlled prescription product containing codeine and should be prescribed and administered with caution. 9.2 Abuse Codeine can produce drug dependence of the morphine type and therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of TUXARIN ER, and it should be prescribed and administered with the same degree of caution appropriate to the use of other opioid drugs. 9.3 Dependence Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, TUXARIN ER should be prescribed and administered with caution. Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued oral opioid use, although some mild degree of physical dependence may develop after a few days of opioid therapy.

10 OVERDOSAGE No human overdosage data are available for TUXARIN ER. Codeine Overdosage 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. In severe overdosage, apnea, circulatory collapse, cardiac arrest, and death may occur. Codeine may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Chlorpheniramine Manifestations of chlorpheniramine overdosage may vary from central nervous system depression to stimulation. Central toxic effects are characterized by agitation, anxiety, delirium, disorientation, hallucinations, hyperactivity, sedation, and seizures. Severe overdosage may produce coma, medullary paralysis, and death. Peripheral toxicity includes hypertension, tachycardia, dysrhythmias, vasodilation, hyperpyrexia, mydriasis, urinary retention, and diminished gastrointestinal motility. Dry mouth, pharynx, bronchi, and nasal passages may be observed. Impaired secretion from sweat glands following toxic doses of drugs with anticholinergic side effects may predispose to hyperthermia. An adult ingested 400 mg chlorpheniramine with no reported serious adverse effects. Toxic psychosis, a possible class effect from overdose of sedating antihistamines, has been reported with accidental overdose of chlorpheniramine. Treatment of overdosage consists of discontinuation of TUXARIN ER together with institution of appropriate therapy. Give primary attention to re-establishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The opioid antagonist naloxone hydrochloride is a specific antidote for respiratory depression that may result from overdosage or unusual sensitivity to opioids including codeine. Therefore, an appropriate dose of naloxone hydrochloride should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. For further information, see full prescribing information for naloxone hydrochloride. An antagonist should not be administered in the absence of clinically significant respiratory or circulatory depression. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Gastric emptying may be useful in removing unabsorbed drug. Hemodialysis is not routinely used to enhance the elimination of codeine or chlorpheniramine from the body. Urinary excretion of chlorpheniramine is increased when the pH of the urine is acidic; however, acid diuresis is NOT recommended to enhance elimination in overdose, as the risks of acidemia and acute tubular necrosis in patients with rhabdomyolysis far outweigh any potential benefits.

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 TUXARIN ER 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 TUXARIN ER 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Codeine : Codeine is a semisynthetic narcotic antitussive and analgesic with multiple actions qualitatively similar to those of morphine. The precise mechanism of action of codeine and other opiates is not known; however, codeine is believed to act centrally on the cough center. In excessive doses, codeine will depress respiration. Codeine can produce miosis, euphoria, and physical and physiological dependence. Chlorpheniramine : Chlorpheniramine is a propylamine derivative antihistamine (H 1 -receptor antagonist) of the alkylamine class that also possesses anticholinergic and sedative activity. It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa. 12.3 Pharmacokinetics Absorption Pharmacokinetic (PK) parameters (Mean ± SD) for TUXARIN ER in fasting, healthy volunteers are shown in the table below. PK Parameter Single-dose Multiple-dose (BID for 6.5 days) Codeine Mean (±SD) Chlorpheniramine Maleate Mean (± SD) Codeine Mean (± SD) Chlorpheniramine Maleate Mean (± SD) Tmax (h) (Range) 3 (2-12) 6 (4-12) 3 (2-5) 5 (3-7) Cmax (ng/mL) 46 (11) 9 (3) AUCinf (ng.h/mL) for single-dose OR AUC12 (ng.h/mL) for multiple-dose 383 (99) 312 (137) Half life (h) 4 (1) 21 (7) Not determined Not determined Food Effect The presence of a high-fat, high-calorie meal did not significantly impact the PK parameters of TUXARIN ER. Distribution Codeine has been reported to have an apparent volume of distribution of approximately 3-6 L/kg, indicating extensive distribution of the drug into tissues. About 7-25% of codeine, reportedly, is bound to plasma proteins. Codeine passes the blood brain barrier and the placental barrier. Small amounts of codeine and its metabolite, morphine, are transferred to human breast milk. Chlorpheniramine is widely distributed throughout the tissues of the body, including the central nervous system. It reportedly has an apparent steady-state volume of distribution of approximately 3.2 L/kg in adults and children and is about 70% bound to plasma proteins. Chlorpheniramine and its metabolites likely cross the placental barrier and are excreted into human breast milk. Metabolism About 70-80% of the administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G) and via O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucurodination of codeine to C6G. Cytochrome P-450 (CYP) 2D6 and CYP3A4 are the major enzymes mediating O-demethylation and N-demethylation of codeine respectively. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. Morphine and its M6 glucuronide conjugate are pharmacologically active. Whether C6G has pharmacological activity is unknown. Norcodeine and M3 glucuronide conjugate of morphine are generally not considered to be pharmacologically active. Chlorpheniramine is rapidly and extensively metabolized via demethylation in the liver, forming mono- and didesmethyl derivatives. Oxidative metabolism of chlorpheniramine is catalyzed by cytochrome P-450 2D6. Elimination Approximately 90% of the total dose of codeine is excreted through the kidneys, of which approximately 10% is unchanged codeine. Plasma half-life of codeine was observed to be about 4 hours with TUXARIN ER. Chlorpheniramine and its metabolites are primarily excreted through the kidneys, with large individual variation. Urinary excretion depends on urine pH and flow rate. Plasma half-life of chlorpheniramine was observed to be about 21 hours with TUXARIN ER.

12.1 Mechanism of Action Codeine : Codeine is a semisynthetic narcotic antitussive and analgesic with multiple actions qualitatively similar to those of morphine. The precise mechanism of action of codeine and other opiates is not known; however, codeine is believed to act centrally on the cough center. In excessive doses, codeine will depress respiration. Codeine can produce miosis, euphoria, and physical and physiological dependence. Chlorpheniramine : Chlorpheniramine is a propylamine derivative antihistamine (H 1 -receptor antagonist) of the alkylamine class that also possesses anticholinergic and sedative activity. It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa.

12.3 Pharmacokinetics Absorption Pharmacokinetic (PK) parameters (Mean ± SD) for TUXARIN ER in fasting, healthy volunteers are shown in the table below. PK Parameter Single-dose Multiple-dose (BID for 6.5 days) Codeine Mean (±SD) Chlorpheniramine Maleate Mean (± SD) Codeine Mean (± SD) Chlorpheniramine Maleate Mean (± SD) Tmax (h) (Range) 3 (2-12) 6 (4-12) 3 (2-5) 5 (3-7) Cmax (ng/mL) 46 (11) 9 (3) AUCinf (ng.h/mL) for single-dose OR AUC12 (ng.h/mL) for multiple-dose 383 (99) 312 (137) Half life (h) 4 (1) 21 (7) Not determined Not determined Food Effect The presence of a high-fat, high-calorie meal did not significantly impact the PK parameters of TUXARIN ER. Distribution Codeine has been reported to have an apparent volume of distribution of approximately 3-6 L/kg, indicating extensive distribution of the drug into tissues. About 7-25% of codeine, reportedly, is bound to plasma proteins. Codeine passes the blood brain barrier and the placental barrier. Small amounts of codeine and its metabolite, morphine, are transferred to human breast milk. Chlorpheniramine is widely distributed throughout the tissues of the body, including the central nervous system. It reportedly has an apparent steady-state volume of distribution of approximately 3.2 L/kg in adults and children and is about 70% bound to plasma proteins. Chlorpheniramine and its metabolites likely cross the placental barrier and are excreted into human breast milk. Metabolism About 70-80% of the administered dose of codeine is metabolized by conjugation with glucuronic acid to codeine-6-glucuronide (C6G) and via O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major enzymes mediating glucurodination of codeine to C6G. Cytochrome P-450 (CYP) 2D6 and CYP3A4 are the major enzymes mediating O-demethylation and N-demethylation of codeine respectively. Morphine and norcodeine are further metabolized by conjugation with glucuronic acid. Morphine and its M6 glucuronide conjugate are pharmacologically active. Whether C6G has pharmacological activity is unknown. Norcodeine and M3 glucuronide conjugate of morphine are generally not considered to be pharmacologically active. Chlorpheniramine is rapidly and extensively metabolized via demethylation in the liver, forming mono- and didesmethyl derivatives. Oxidative metabolism of chlorpheniramine is catalyzed by cytochrome P-450 2D6. Elimination Approximately 90% of the total dose of codeine is excreted through the kidneys, of which approximately 10% is unchanged codeine. Plasma half-life of codeine was observed to be about 4 hours with TUXARIN ER. Chlorpheniramine and its metabolites are primarily excreted through the kidneys, with large individual variation. Urinary excretion depends on urine pH and flow rate. Plasma half-life of chlorpheniramine was observed to be about 21 hours with TUXARIN ER.

20230622

5

3 DOSAGE FORMS AND STRENGTHS Extended release tablets: Each tablet contains 54.3 mg of codeine phosphate (equivalent to 40 mg of codeine) and 8 mg of chlorpheniramine maleate (equivalent to 5.6 mg of chlorpheniramine). Each tablet is white to off-white, uncoated, round, debossed with MP on one side and CC on the other side. Extended release (ER) tablet: contains 54.3 mg of codeine phosphate (equivalent to 40 mg of codeine) and 8 mg of chlorpheniramine maleate (equivalent to 5.6 mg of chlorpheniramine). ( 3 )

Tuxarin codeine phosphate and chlorpheniramine maleate CODEINE PHOSPHATE CODEINE ANHYDROUS CHLORPHENIRAMINE MALEATE CHLORPHENIRAMINE MP;CC

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and reproductive studies have not been conducted with TUXARIN ER however, published information is 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 9 and 25 times, respectively, the MRHDD 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 25 and 20 times, respectively, the MRHDD 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. Chlorpheniramine maleate had no effects on fertility in rats and rabbits at oral doses approximately 25 and 30 times, respectively, the MRHDD on a mg/m2 basis.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity, and reproductive studies have not been conducted with TUXARIN ER however, published information is 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 9 and 25 times, respectively, the MRHDD 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 25 and 20 times, respectively, the MRHDD 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. Chlorpheniramine maleate had no effects on fertility in rats and rabbits at oral doses approximately 25 and 30 times, respectively, the MRHDD on a mg/m2 basis.

NDA206323

Tuxarin

codeine phosphate and chlorpheniramine maleate

71269-040

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 100 Tablet Bottle Label NDC 71269-040-10 CIII Tuxarin ER™ (codeine phosphate and chlorpheniramine maleate extended-release tablets) 54.3 mg/ 8 mg Each Tablet Contains: Codeine Phosphate, USP 54.3 mg (Equivalent to 40 mg of Codeine) Chlorpheniramine Maleate, USP 8 mg (Equivalent to 5.6 mg of Chlorpheniramine) PHARMACIST: PLEASE DISPENSE WITH MEDICATION GUIDE R x only 100 Tablets PRINCIPAL DISPLAY PANEL - 100 Tablet Bottle Label

Boxed Warning 8/2017 Contraindications ( 4 ) 8/2017 Warnings and Precautions ( 5.1 ) 8/2017 Warnings and Precautions ( 5.2 ) 1/2017

Distributed By: MainPointe Pharmaceuticals, LLC Louisville, KY, 40202 NXG Rev 02/18

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children: Advise patients of the risks of respiratory depression and death with TUXARIN ER in children younger than 18 years of age. Advise patients that TUXARIN ER should not be used in children younger than 12 years of age or in a child younger than 18 years of age for treatment after tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.1) ] . Overdosage: Advise patients not to increase the dose or dosing frequency of TUXARIN ER because serious adverse events such as respiratory depression may occur with overdosage. [see Warnings and Precautions (5.2) ; Overdosage (10) ] Interactions with Benzodiazepines and Other Central Nervous System Depressants: Inform patients and caregivers that potentially fatal additive effects may occur if TUXARIN ER is used with benzodiazepines or other CNS depressants, including alcohol. Because of this risk, patients should avoid concomitant use of TUXARIN ER with benzodiazepines or other CNS depressants, including alcohol [see Warnings and Precautions (5.3) , Drug Interactions (7.1) ]. Activities Requiring Mental Alertness: Caution patients that TUXARIN ER 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. [see Warnings and Precautions (5.6) ] Controlled Substance Status/Potential for Abuse and Dependence: Caution patients that TUXARIN ER contains codeine and can produce drug dependence. [see Abuse and Dependence (9.2 , 9.3) ] . Lactation: Advise women that breastfeeding is not recommended during treatment with TUXARIN ER [ see Use in Specific Populations (8.3) ] .

MEDICATION GUIDE TUXARIN ER™ (tuks a ren) (codeine phosphate and chlorpheniramine maleate) extended release tablets, CIII This Medication Guide has been approved by the U.S. Food and Drug Administration Issued: August 2017 What is the most important information I should know about TUXARIN ER? TUXARIN ER can cause children to stop breathing (respiratory depression) and cause death. Do not give TUXARIN ER to children younger than 12 years of age, or to children younger than 18 years of age after tonsillectomy or adenoidectomy surgery. You should not give TUXARIN ER to children between 12 to 18 years of age who have certain risk factors for breathing problems, including: recent surgery obstructive sleep apnea are obese severe lung problems other medical conditions that can cause difficulty breathing, such as neuromuscular problems taking other medicines that cause breathing problems You should not breastfeed during treatment with TUXARIN ER because it may cause your child to stop breathing and cause death. Severe drowsiness, breathing problems (respiratory depression), coma, and death can happen in adults and children who take TUXARIN ER with benzodiazepines, or other central nervous system depressants, including alcohol. Avoid taking other medicines that can cause drowsiness or sleepiness, or drinking alcohol during treatment with TUXARIN ER. Ask your healthcare provider for a list of these medicines if you are not sure. TUXARIN ER can cause breathing problems (respiratory depression) and drowsiness. Take TUXARIN ER exactly as prescribed by your healthcare provider. If you take the wrong dose of TUXARIN ER, you could overdose and die. See the Medication Guide section called " How should I take TUXARIN ER? " for important information about how to take TUXARIN ER correctly. Avoid driving a car or operating machinery during treatment with TUXARIN ER. Call your healthcare provider or get emergency medical help right away if anyone taking TUXARIN ER, or your breastfeeding baby has any of the symptoms listed below: increased sleepiness difficulty breathing limpness confusion shallow breathing your baby has difficulty breastfeeding Keep TUXARIN ER in a safe place away from children. Accidental use by a child is a medical emergency and can cause death. If a child accidentally takes TUXARIN ER, get emergency help right away. What is TUXARIN ER? TUXARIN ER is a prescription medicine used to treat cough and upper respiratory symptoms that you can have with allergies or a common cold. TUXARIN ER is for adults 18 years and older. TUXARIN ER contains 2 medicines, codeine and chlorpheniramine. Codeine is a narcotic cough suppressant. Chlorpheniramine is an antihistamine. TUXARIN ER is a federal controlled substance (CIII) because it contains codeine that can be abused or lead to dependence. Keep TUXARIN ER in a safe place to prevent misuse and abuse. Selling or giving away TUXARIN ER may harm others and is against the law. TUXARIN ER is not for children under 18 years of age. It is not known if TUXARIN ER is safe and effective in children. Who should not take TUXARIN ER? Do not give TUXARIN ER to any children younger than 12 years of age. Do not give TUXARIN ER to children younger than 18 years of age following tonsillectomy or adenoidectomy surgery. Do not take TUXARIN ER if you are allergic to any of the ingredients in TUXARIN ER. See the end of this Medication Guide for a complete list of ingredients in TUXARIN ER. You may have an increased risk of having an allergic reaction to TUXARIN ER if you are allergic to certain other opioid medicines. Before taking TUXARIN ER, tell your healthcare provider about all of your medical conditions, including if you: have a drug dependence have lung or breathing problems have had a head injury have pain in your stomach (abdomen) have constipation or problems with your intestines have prostate problems have problems with your urinary tract (urethral stricture) plan to have surgery abuse alcohol have kidney or liver problems have thyroid problems, such as hypothyroidism have Addison's disease are pregnant or plan to become pregnant. It is not known if TUXARIN ER will harm your unborn baby. You and your healthcare provider should decide if you should take TUXARIN ER while you are pregnant. are breastfeeding or plan to breastfeed. Codeine and chlorpheniramine pass into your breast milk and may harm your baby. You and your healthcare provider should discuss whether you should take TUXARIN ER or breastfeed. You should not do both. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using TUXARIN ER with certain other medicines may affect each other. Using TUXARIN ER with other medicines can cause serious side effects. Especially tell your healthcare provider if you: take pain medicines such as narcotics take cold or allergy medicines that contain antihistamines or cough suppressants take medicines for mental illness (anti-psychotics, anti-anxiety) drink alcohol take medicines for depression, other mental health problems, or Parkinson's disease, including monoamine oxidase inhibitors (MAOIs), or if you have taken an MAOI in the last 14 days take medicines for stomach or intestine problems Ask your healthcare provider if you are not sure if you take one of these medicines. How should I take TUXARIN ER? Take TUXARIN ER exactly as your healthcare provider tells you. Do not take more than 2 TUXARIN ER tablets in 24 hours. If you take too much TUXARIN ER, call your healthcare provider or go to the nearest hospital emergency room right away. What should I avoid while taking TUXARIN ER? TUXARIN ER can cause you to be drowsy. Avoid driving a car or using machinery during treatment with TUXARIN ER. Do not drink alcohol during treatment with TUXARIN ER. Drinking alcohol can increase your chances of having serious side effects. What are the possible side effects of TUXARIN ER? TUXARIN ER may cause serious side effects, including: See " What is the most important information I should know about TUXARIN ER " Breathing problems (respiratory depression) which can lead to death. Call your healthcare provider or get emergency treatment right away if you have excessive sleepiness, shallow or slow breathing, or confusion. Physical dependence or abuse. Take TUXARIN ER exactly as your healthcare provider tells you to take it. Stopping TUXARIN ER suddenly could cause withdrawal symptoms . Increased intracranial pressure Bowel problems including constipation or stomach pain. The most common side effects of TUXARIN ER include: nausea and vomiting constipation swelling or bloating of your stomach-area stomach-area pain vision problems, including blurred vision and double vision confusion dizziness depression drowsiness headache feeling high (euphoria) feeling faint light-headedness excitability, nervousness agitation, restlessness, irritability sleepiness difficulty sleeping (insomnia) unable to control muscle movements tremor general feeling of discomfort or illness These are not all the possible side effects of TUXARIN ER. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store TUXARIN ER? Store TUXARIN ER in a safe place between 68°F to 77°F (20°C to 25°C). Keep TUXARIN ER in a tightly closed, child-resistant container and out of the light. Safely throw away medicine that is out of date or no longer needed. Keep TUXARIN ER and all medicines out of the reach of children. General information about the safe and effective use of TUXARIN ER. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TUXARIN ER for a condition for which it was not prescribed. Do not give TUXARIN ER 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 TUXARIN ER that is written for health professionals. What are the ingredients in TUXARIN ER? Active ingredients: codeine and chlorpheniramine Inactive ingredients: Hypromellose, lactose monohydrate, cellulose microcrystalline, polysorbate 80, magnesium stearate, and colloidal silicon dioxide. Distributed By: MainPointe Pharmaceuticals, LLC Louisville, KY, 40202 For more information go to mainpointepharmaceuticals.com or call 502-709-7544

14 CLINICAL STUDIES The efficacy of TUXARIN ER is based on previously established findings of effectiveness of codeine and chlorpheniramine at the proposed doses.

8.5 Geriatric Use Clinical efficacy and safety studies have not been conducted with TUXARIN ER. Other reported clinical experience with the individual active ingredients of TUXARIN ER 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.

8.2 Labor and Delivery As with all opioids, administration of TUXARIN ER 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 TUXARIN ER [see Warnings and Precautions (5.1) ] . Clinical Considerations If infants are exposed to TUXARIN ER 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 TUXARIN ER in 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: TUXARIN ER is contraindicated in all children younger than 12 years of age [see Contraindications (4) ] . TUXARIN ER 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 TUXARIN ER 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) ] .

8.1 Pregnancy Teratogenic Effects Pregnancy Category C There are no adequate and well-controlled studies of TUXARIN ER in pregnant women. Reproductive toxicity studies have not been conducted with TUXARIN ER; however, studies are available with individual active ingredients or related active ingredients. Because animal reproduction studies are not always predictive of human response, TUXARIN ER 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 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.

Teratogenic Effects Pregnancy Category C There are no adequate and well-controlled studies of TUXARIN ER in pregnant women. Reproductive toxicity studies have not been conducted with TUXARIN ER; however, studies are available with individual active ingredients or related active ingredients. Because animal reproduction studies are not always predictive of human response, TUXARIN ER 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 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.

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. ( 8.4 ) 8.1 Pregnancy Teratogenic Effects Pregnancy Category C There are no adequate and well-controlled studies of TUXARIN ER in pregnant women. Reproductive toxicity studies have not been conducted with TUXARIN ER; however, studies are available with individual active ingredients or related active ingredients. Because animal reproduction studies are not always predictive of human response, TUXARIN ER 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 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 TUXARIN ER 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 TUXARIN ER [see Warnings and Precautions (5.1) ] . Clinical Considerations If infants are exposed to TUXARIN ER 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 TUXARIN ER in 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: TUXARIN ER is contraindicated in all children younger than 12 years of age [see Contraindications (4) ] . TUXARIN ER 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 TUXARIN ER 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 TUXARIN ER. Other reported clinical experience with the individual active ingredients of TUXARIN ER 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 TUXARIN ER 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. TUXARIN ER should be used with caution in patients with severe renal impairment. 8.7 Hepatic Impairment Pharmacokinetics of TUXARIN ER 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. TUXARIN ER should be used with caution in patients with severe hepatic impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING TUXARIN ER is supplied as white to off-white, uncoated, standard round tablet, debossed with MP on one side and CC on the other side. Supplied in bottles of 100 tablets: NDC 71269-040-10. Store at 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure. Keep this and all medicine out of reach of children.

Store at 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure. Keep this and all medicine out of reach of children.

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 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 metabolizer of codeine due to a CYP2D6 polymorphism. [ See Warnings and Precautions (5.1) ]. TUXARIN ER 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 TUXARIN ER 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) ]. 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 cases followed 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) ]. TUXARIN ER 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 TUXARIN ER 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) ]. 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.