CHLORPHENIRAMINE: 1,919 Adverse Event Reports & Safety Profile

Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension contains hydrocodone, an opioid agonist; and chlorpheniramine, a histamine-1 (H 1 ) receptor antagonist.

Each

5 mL of Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release (ER) Suspension contains hydrocodone polistirex equivalent to 10 mg of hydrocodone bitartrate and chlorpheniramine polistirex equivalent to 8 mg of chlorpheniramine maleate. Hydrocodone is a centrally-acting narcotic antitussive. Chlorpheniramine is an antihistamine.

Hydrocodone

Polistirex and Chlorpheniramine Polistirex ER Suspension is for oral use only.

Hydrocodone

Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension also contains the following inactive ingredients: Ascorbic acid, D&C Yellow No. 10, flavors, high fructose corn syrup, modified food starch, methylparaben, polysorbate 80, polyvinyl acetate, propylene glycol, propylparaben, purified water, sodium ascorbate, sodium metabisulfite, sodium polystyrene sulfonate, sucrose, triacetin, xanthan gum.

Hydrocodone Polistirex

The chemical name for hydrocodone, a centrally-acting narcotic antitussive, is 4,5α-epoxy-3-methoxy-17- methylmorphinan-6-one. Hydrocodone polistirex is a complex of sulfonated styrene-divinylbenzene copolymer. The molecular weight for hydrocodone and the polistirex resin is 298.364 g/mol and n x 315 g/mol- 1, respectively. The molecular formula for hydrocodone and the polistirex resin is C 18 H 21 NO 3 and (C 18 SO 3 H 19 )n, respectively. It has the following structural formula: Structure 1 Chlorpheniramine Polistirex The chemical name for chlorpheniramine, an antihistamine, is 2-[p-chloro-α-[2-(dimethylamino)ethyl]- benzyl]pyridine. Chlorpheniramine polistirex is a complex of sulfonated styrene-divinylbenzene copolymer. The molecular weight for chlorpheniramine and the polistirex resin is 274.79 g/mol and n x 315 g/mol-1, respectively. The molecular formula for chlorpheniramine and the polistirex resin is C 16 N 2 H 19 Cl and (C 18 SO 3 H 19 )n, respectively. It has the following structural formula: structure 2 Structure 1 structure 2

AND USAGE Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension is indicated for the temporary relief of cough and upper respiratory symptoms associated with allergy or the common cold in patients 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 ) ].
• Contraindicated in pediatric patients less than 6 years of age [ see Contraindications (4) ].
• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [ see Warnings and Precautions (5.1) ], reserve Hydrocodone Polistirex and Chlorpheniramine Polistirex for use in adult patients for whomthe benefits of cough suppression are expected to outweigh the risks, and in whom an adequateassessment of the etiology of the cough has been made.

Hydrocodone

Polistirex and Chlorpheniramine Polistirex is a combination of hydrocodone, an opioid agonist; and chlorpheniramine, a histamine-1 (H1) receptor antagonist, indicated for the temporary relief of cough and upper respiratory symptoms associated with allergy or the common cold in patients 18 years of age and older. ( 1 )

Important

Limitations of Use ( 1 ) Not indicated for pediatric patients under 18 years of age. Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Hydrocodone Polistirex and Chlorpheniramine Polistirex for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made.

AND ADMINISTRATION Adults 18 years of age and older : 5 mL every 12 hours as needed, not to exceed 2 doses (10 mL) in 24 hours. ( 2.2 )

Measure Hydrocodone

Polistirex and Chlorpheniramine Polistirex with an accurate milliliter measuring device. ( 2.1 , 5.5 ) Do not increase the dose or dosing frequency. ( 2.1 ) Prescribe for the shortest duration consistent with treatment goals. (2.3 ) Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology. ( 2.3 ) Reevaluate patient prior to refilling. ( 2.3 )

2.1 Important Dosage and Administration Instructions Administer Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension by the oral route only.

Hydrocodone

Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension can be taken with or without food. Shake well before using. Do not mix Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension with other liquids or medicines. Mixing may change how Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension works. Always use an accurate milliliter measuring device when administering Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension to ensure that the dose is measured and administered accurately. A household teaspoon is not an accurate measuring device and could lead to overdosage [ see Warnings and Precautions (5.5) ]. The dosing cup is provided with the 3 oz (70 mL) and 4 oz (115 mL) packaged product. The dosing cup fills for 2.5 mL dose and for 5 mL dose. Instruct the patient to fill to the line that the dose has been prescribed. Do not fill over the dose prescribed. Rinse the measuring cup with water after each use. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate measuring device and can provide instructions for measuring the correct dose. Do not overfill. Rinse the measuring device with water after each use. Advise patients not to increase the dose or dosing frequency of Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension because serious adverse events such as respiratory depression may occur with overdosage [ see Warnings and Precautions (5.2 ) and Overdosage (10 ) ]. The dosage of Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension should not be increased if cough fails to respond; an unresponsive cough should be reevaluated for possible underlying pathology [ see Dosage and Administration (2.3 ) and Warnings and Precautions (5.4) ] .

2.2 Recommended Dosage Adults 18 years of age and older : 5 mL every 12 hours as needed, not to exceed 2 doses (10 mL) in 24 hours

2.3 Monitoring, Maintenance, and Discontinuation of Therapy Prescribe Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension for the shortest duration that is consistent with individual patient treatment goals [ see Warnings and Precautions (5.1) ]. Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy [ see Warnings and Precautions (5.2 ) ]. Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [ see Warnings and Precautions (5.4) ]. If a patient requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse [ see Warnings and Precautions (5.1) ]. Do not abruptly discontinue Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension in a physically-dependent patient [ see Drug Abuse and Dependence (9.3 ) ]. When a patient who has been taking Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension regularly and may bephysically dependent no longer requires therapy with Hydrocodone Polistirex and Chlorpheniramine Polistirex Extended-Release Suspension, taper the dose gradually, by25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patientdevelops these signs or symptoms, raise the dose to the previous level and taper more slowly, either byincreasing the interval between decreases, decreasing the amount of change in dose, or both.

TUXARIN ER is contraindicated for: All children younger than 12 years of age [ see Warnings and Precautions (5.2 , 5.3 , 5.4) , Use in Specific Populations (8.4) ]. Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Warnings and Precautions (5.2 , 5.3) ]. TUXARIN ER is also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.2) ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [ see Warnings and Precautions (5.5) ]. Known or suspected gastrointestinal obstruction, including paralytic ileus [ see Warnings and Precautions (5.10) ]. Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within 14 days [ see Warnings and Precautions (5.13) , Drug Interactions (7.7) ]. Hypersensitivity to codeine, chlorpheniramine, or any of the inactive ingredients in TUXARIN ER [ see Adverse Reactions (6) ]. Persons known to be hypersensitive to certain other opioids may exhibit cross-reactivity to codeine. Children younger than 12 years of age ( 4 ) Significant respiratory depression. ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Concurrent use of monoamine oxidase inhibitor (MAOI) therapy or within the last 14 days. ( 4 ) Hypersensitivity to codeine or other opiates, chlorpheniramine, or any of the inactive ingredients in TUXARIN ER. ( 4 )

REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, abuse, and misuse [ see Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.3) ] Life-threatening respiratory depression [ see Warnings and Precautions (5.2 , 5.3 , 5.4 , 5.5 , 5.9) , Overdosage (10) ] Ultra-rapid metabolism of codeine and other risk factors for life-threatening respiratory depression in children [ see Warnings and Precautions (5.3) ] Accidental overdose and death due to medication errors [ see Warnings and Precautions (5.6) ] Decreased mental alertness with impaired mental and/or physical abilities [ see Warnings and Precautions (5.7) ] Interactions with benzodiazepines and other CNS depressants [ see Warnings and Precautions (5.9) ] Paralytic ileus, gastrointestinal adverse reactions [ see Warnings and Precautions (5.10) ] Increased intracranial pressure [ see Warnings and Precautions (5.11) ] Obscured clinical course in patients with head injuries [ see Warnings and Precautions (5.11) ] Seizures [ see Warnings and Precautions (5.12) ] Interactions with MAOI [ see Warnings and Precautions (5.13) ] Severe hypotension [ see Warnings and Precautions (5.14) ]

Neonatal Opioid Withdrawal

Syndrome [ see Warnings and Precautions (5.15) ] Adrenal insufficiency [ see Warnings and Precautions (5.16) ] The following adverse reactions have been identified during clinical studies, or during post-approval use of codeine and/or chlorpheniramine. 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. The most common adverse reactions to TUXARIN ER include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, constipation, shortness of breath, and sweating. Other reactions include: Anaphylaxis : Anaphylaxis has been reported with codeine, one of the ingredients in TUXARIN ER. Body as a whole : Coma, death, fatigue, falling injuries, lethargy. Cardiovascular : Peripheral edema, increased blood pressure, decreased blood pressure, tachycardia, chest pain, palpitation, syncope, orthostatic hypotension, prolonged QT interval, hot flush.

Central Nervous

System : Ataxia, facial dyskinesia, insomnia, increased intracranial pressure, migraine, seizure, tremor, tinnitus, vertigo. Dermatologic : Flushing, hyperhidrosis, pruritus, rash. Endocrine/Metabolic : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Cases of androgen deficiency have occurred with chronic use of opioids [ see Clinical Pharmacology (12.2) ]. Gastrointestinal : Abdominal pain, bowel obstruction, decreased appetite, diarrhea, difficulty swallowing, GERD, indigestion, pancreatitis, paralytic ileus, biliary tract spasm (spasm of the sphincter of Oddi). Genitourinary : Urinary tract infection, ureteral spasm, spasm of vesicle sphincters, urinary retention. Hematologic : Agranulocytosis, aplastic anemia, and thrombocytopenia have been reported. Laboratory: Increases in serum amylase. Musculoskeletal : Arthralgia, backache, muscle spasm. Ophthalmic : Blurred vision, diplopia, miosis (constricted pupils), visual disturbances. Psychiatric : Agitation, anxiety, confusion, fear, dysphoria, depression, hallucinations. Reproductive : Hypogonadism, infertility. Respiratory : Bronchitis, cough, dry nose, dry throat, dyspnea, nasal congestion, nasopharyngitis, respiratory depression, sinusitis, thickening of bronchial secretions, tightness of chest and wheezing, upper respiratory tract infection. Other : Drug abuse, drug dependence, opioid withdrawal syndrome. Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Common adverse reactions of TUXARIN ER include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, constipation, shortness of breath, and sweating. ( 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 or www.fda.gov/medwatch.

AND PRECAUTIONS See Boxed WARNINGS Life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients: Monitor closely, particularly during initiation of therapy. ( 5.5 ) Activities requiring mental alertness: Avoid engaging in hazardous tasks requiring mental alertness such as driving or operating machinery. ( 5.7 ) Risks of use in patients with head injury, impaired consciousness, increased intracranial pressure, or brain tumors: Avoid use. May increase intracranial pressure and obscure the clinical course of head injuries. ( 5.11 ) Seizures in patients with seizure disorders: Monitor during therapy. ( 5.12 ) Severe hypotension: Monitor during initiation of therapy. Avoid use in patients with circulatory shock. ( 5.14 ) Adrenal insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.16 )

5.1 Addiction, Abuse, and Misuse TUXARIN ER contains codeine, a Schedule III controlled substance. As an opioid, TUXARIN ER exposes users to the risks of addiction, abuse, and misuse [ see Drug Abuse and Dependence (9) ] , which can lead to overdose and death [ see Overdosage (10) ] . Reserve TUXARIN ER for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each patient's risk prior to prescribing TUXARIN ER, prescribe TUXARIN ER for the shortest duration that is consistent with individual patient treatment goals , monitor all patients regularly for the development of addiction or abuse, and refill only after reevaluation of the need for continued treatment. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed TUXARIN ER. Addiction can occur at recommended dosages and if the drug is misused or abused. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing TUXARIN ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [ see Patient Counseling Information (17) ]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including codeine, one of the active ingredients in TUXARIN ER. Codeine produces dose-related respiratory depression by directly acting on the brain stem respiratory center that controls respiratory rhythm and may produce irregular and periodic breathing. Codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to the active metabolite morphine [ see Warnings and Precautions (5.3) ]. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression includes discontinuation of TUXARIN ER, close observation, supportive measures, and use of opioid antagonists (e.g. naloxone), depending on the patient&apos;s clinical status [ see Overdosage (10) ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of TUXARIN ER, the risk is greatest during the initiation of therapy, when TUXARIN ER is used concomitantly with other drugs that may cause respiratory depression [ see Warnings and Precautions (5.9) ], in patients with chronic pulmonary disease or decreased respiratory reserve, and in patients with altered pharmacokinetics or altered clearance (e.g. elderly, cachectic, or debilitated patients) [ see Warnings and Precautions (5.5) ]. To reduce the risk of respiratory depression, proper dosing of TUXARIN ER is essential <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) , Warnings and Precautions (5.6) ]</span>. Monitor patients closely, especially within the first 24- 72 hours of initiating therapy or when used in patients at higher risk. Overdose of codeine in adults has been associated with fatal respiratory depression, and the use of codeine in children younger than 12 years of age has been associated with fatal respiratory depression when used as recommended [ see Warnings and Precautions (5.3) ]. Accidental ingestion of even one dose of TUXARIN ER, especially by children, can result in respiratory depression and death.

5.3 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. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. 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 (5.9) , Use in Specific Populations (8.4) ] Healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [ see Warnings and Precautions (5.1) , Overdosage (10) ]. Lactation At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with TUXARIN ER [ see Use in Specific Populations (8.2) ]. CYP2D6 Genetic Variability: Ultra-Rapid Metabolizers Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1×N or *1/*2×N). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain /ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [ see Overdosage (10) ]. Therefore, individuals who are ultra-rapid metabolizers should not use TUXARIN ER.

5.4 Risks with Use in Pediatric Populations Children are particularly sensitive to the respiratory depressant effects of codeine [ see Warnings and Precautions (5.2 , 5.3) ]. Because of the risk of life-threatening respiratory depression and death, TUXARIN ER is contraindicated in children less than 12 years of age, and in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Contraindications (4) ]. Use of TUXARIN ER in children also exposes them to the risks of addiction, abuse, and misuse [ see Drug Abuse and Dependence (9) ] , which can lead to overdose and death [ see Warnings and Precautions (5.1) , Overdosage (10) ] . Because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks of use of codeine in pediatric patients, TUXARIN ER is not indicated for use in patients younger than 18 years of age [ see Indications (1) , Use in Specific Populations (8.4) ].

5.5 Risks with Use in Other At-Risk Populations Unresponsive Cough The dosage of TUXARIN ER should not be increased if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [ see Dosage and Administration (2.3) ]. Asthma and Other Pulmonary Disease The use of TUXARIN ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [ see Contraindications (4) ]. Opioid analgesics and antitussives, including codeine, one of the active ingredients in TUXARIN ER, should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient&apos;s respiratory function. TUXARIN ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of TUXARIN ER [ see Warnings and Precautions (5.2) ] . Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [ see Warnings and Precautions (5.2) ]. Because of the risk of respiratory depression, avoid the use of opioid antitussives, including TUXARIN ER in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients. If TUXARIN ER is prescribed, monitor such patients closely, particularly when initiating TUXARIN ER and when TUXARIN ER is given concomitantly with other drugs that depress respiration [ see Warnings and Precautions (5.9) ].

5.6 Risk of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of TUXARIN ER is communicated clearly and dispensed accurately [ see Dosage and Administration (2.1) ].

5.7 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery Codeine and chlorpheniramine, the active ingredients in 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. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of TUXARIN ER. Avoid concurrent use of TUXARIN ER with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur [ See Warnings and Precautions (5.9) ].

5.8 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with TUXARIN ER requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Cytochrome P450 3A4 Interaction The concomitant use of TUXARIN ER with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. The concomitant use of TUXARIN ER with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Avoid the use of TUXARIN ER in patients who are taking a CYP3A4 inhibitor or CYP3A4 inducer. If concomitant use of TUXARIN ER with inhibitors and inducers of CYP3A4 is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [ see Drug Interactions (7.1 , 7.2) ]. Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of TUXARIN ER with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. Avoid the use of TUXARIN ER in patients who are taking a CYP2D6 inhibitor. If concomitant use of TUXARIN ER with inhibitors of CYP2D6 is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [ see Drug Interactions (7.4) ].

5.9 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants Concomitant use of opioids, including TUXARIN ER, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol [ see Drug Interactions (7.5) ]. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol. Advise both patients and caregivers about the risks of respiratory depression and sedation if TUXARIN ER is used with benzodiazepines, alcohol, or other CNS depressants [ see Patient Counseling Information (17) ].

5.10 Risks of Use in Patients with Gastrointestinal Conditions TUXARIN ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [ see Contraindications (4) ]. The use of codeine in TUXARIN ER may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of anticholinergics with TUXARIN ER may produce paralytic ileus [ see Drug Interactions (7.10) ]. The codeine in TUXARIN ER may result in constipation or obstructive bowel disease, especially in patients with underlying intestinal motility disorders. Use with caution in patients with underlying intestinal motility disorders. The codeine in TUXARIN ER may cause spasm of the sphincter of Oddi, resulting in an increase in biliary tract pressure. Opioids may cause increases in serum amylase [ see Warnings and Precautions (5.17) ]. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

5.11 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors Avoid the use of TUXARIN ER in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), TUXARIN ER may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.

5.12 Increased Risk of Seizures in Patients with Seizure Disorders The codeine and chlorpheniramine in TUXARIN ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during TUXARIN ER therapy.

5.13 Co-administration with Monoamine Oxidase Inhibitors (MAOIs) Concurrent use of TUXARIN ER is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping such therapy [ see Contraindications (4) ]. MAOIs may potentiate the effects of morphine, codeine&apos;s active metabolite, including respiratory depression, coma, and confusion MAOIs [ see Drug Interactions (7.7) ].

5.14 Severe Hypotension TUXARIN ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [ see Drug Interactions (7.5) ] . Monitor these patients for signs of hypotension after initiating TUXARIN ER. In patients with circulatory shock, TUXARIN ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of TUXARIN ER in patients with circulatory shock.

5.15 Neonatal Opioid Withdrawal Syndrome TUXARIN ER is not recommended for use in pregnant women. Prolonged use of TUXARIN ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. [ see Use in Specific Populations (8.1) , Patient Counseling Information (17) ]

5.16 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.17 Drug/Laboratory Test Interactions Because opioid agonists may increase biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after administration of a dose of TUXARIN ER.

INTERACTIONS No specific drug interaction studies have been conducted with Hydrocodone Polistirex and Chlorpheniramine Polistirex. Phenytoin : Avoid concomitant use; may increase phenytoin levels. ( 7.4 ) Serotonergic drugs : Concomitant use may result in serotonin syndrome. Discontinue if serotonin syndrome is suspected. ( 7.6 )

Monoamine Oxidase

Inhibitors (MAOIs): Can potentiate the effects of hydrocodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping an MAOI. ( 7.7 ) Muscle relaxants : Avoid concomitant use. ( 7.8 ) Diuretics : Hydrocodone may reduce the efficacy of diuretics. Monitor for reduced effect. ( 7.9 ) Anticholinergic drugs : Concomitant use may cause paralytic ileus. ( 5.9 , 7.10 )

7.1 Alcohol Concomitant use of alcohol with Hydrocodone Polistirex and Chlorpheniramine Polistirex can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on Hydrocodone Polistirex and Chlorpheniramine Polistirex therapy [ see Warnings and Precautions (5.8) , Clinical Pharmacology (12.3) ].

7.2 Inhibitors of CYP3A4 and CYP2D6 The concomitant use of Hydrocodone Polistirex and Chlorpheniramine Polistirex and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Hydrocodone Polistirex and Chlorpheniramine Polistirex and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Hydrocodone Polistirex and Chlorpheniramine Polistirex is achieved [ see Warnings and Precautions (5.7 ) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [ see Clinical Pharmacology (12.3 ) ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone. Avoid the use of Hydrocodone Polistirex and Chlorpheniramine Polistirex while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

7.3 CYP3A4 Inducers The concomitant use of Hydrocodone Polistirex and Chlorpheniramine Polistirex and CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin, can decrease the plasma concentration of hydrocodone [ see Clinical Pharmacology (12.3) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [ see Warnings and Precautions (5.7) ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [ see Clinical Pharmacology (12.3) ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Avoid the use of Hydrocodone Polistirex and Chlorpheniramine Polistirex in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

7.4 Phenytoin 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. Avoid the use of Hydrocodone Polistirex and Chlorpheniramine Polistirex in patients who are taking phenytoin.

7.5 Benzodiazepines, and Other CNS Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of Hydrocodone Polistirex and Chlorpheniramine Polistirex in patients who are taking benzodiazepines or other CNS depressants [ see Warnings and Precautions (5.8) ], and instruct patients to avoid consumption of alcohol while on Hydrocodone Polistirex and Chlorpheniramine Polistirex [ see Drug Interactions (7.1 ) , Patient Counseling Information (17) ].

7.6 Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation.

Discontinue Hydrocodone

Polistirex and Chlorpheniramine Polistirex if serotonin syndrome is suspected.

7.7 Monoamine Oxidase Inhibitors (MAOIs) Avoid the use of Hydrocodone Polistirex and Chlorpheniramine Polistirex in patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken MAOIs within 14 days. The use of MAOIs or tricyclic antidepressants with hydrocodone, one of the active ingredients in Hydrocodone Polistirex and Chlorpheniramine Polistirex, may increase the effect of either the antidepressant or hydrocodone. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

7.8 Muscle Relaxants Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of Hydrocodone Polistirex and Chlorpheniramine Polistirex in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

7.9 Diuretics Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

7.10 Anticholinergic Drugs The concomitant use of anticholinergic drugs with Hydrocodone Polistirex and Chlorpheniramine Polistirex may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [ see Warnings and Precautions (5.9) ].Monitor patients for signs of urinary retention or reduced gastric motility when Hydrocodone Polistirex and Chlorpheniramine Polistirex is used concomitantly with anticholinergic drugs. Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with chlorpheniramine.

Active ingredients Active ingredients (in each 10 m)

Purposes

Chlorpheniramine maleate, USP 4 mg -------------------------------Antihistamine Dextromethorphan HBr, USP 20 mg -----------------------------------Cough supressant Phenylephrine HCl, USP 10 mg -----------------------------------------Nasal descongestant Active ingredients

INACTIVE INGREDIENTS calcium sulfate, carnauba wax, colloidal silicon dioxide, confectioner’s sugar, D&C yellow No. 10 aluminum lake, FD&C blue No. 2/indigo carmine aluminum lake, FD&C yellow No. 6, gelatin, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, methyl parahydroxybenzoate, microcrystalline cellulose, pharmaceutical ink, polysorbate 80, povidone, propyl parahydroxybenzoate, propylene glycol, sodium benzoate, sodium lauryl sulphate, sucrose, talc, titanium dioxide, triethyl citrate