Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action 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 psychological dependence. Chlorpheniramine is a propylamine derivative antihistamine drug (H1 receptor antagonist) that also possesses anticholinergic and sedative activity. It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa. Pharmacokinetics Absorption Pharmacokinetic (PK) parameters (Mean ± SD) for TUZISTRA XR (codeine polistirex and chlorpheniramine polistirex) extended-release oral suspension in fasting, healthy volunteers are shown in the table below. PK Parameter Single-dose Multiple-dose (BID for 7 days) Codeine Mean (± SD) Chlorpheniramine Mean (± SD) Codeine Mean (± SD) Chlorpheniramine Mean (± SD) Tmax (h) (Range) 2.19 (1-4.05) 6.52 (5-9) 1.86 (0.5-3) 5.77 (2.5-9.5) Cmax (ng/mL) 51.4 (± 13.8) 7.84 (± 1.84) 64.6 (± 21.9) 38.7 (± 15.2) AUCinf (ng•h/mL) for single-dose OR AUC0-12 (ng•h/mL) for multiple-dose 348.5 (± 94) 304.3 (± 104) 384.8 (± 128) 392.4 (± 147) Half-life (h) 5 (± 1.07) 21.45 (± 5.87) Not determined Not determined Food Effect The presence of a high-fat, high calorie meal did not significantly impact TUZISTRA XR pharmacokinetics. Distribution Codeine has been reported to have an apparent volume of distribution of approximately 3 to 6 L/kg, indicating extensive distribution of the drug into tissues. About 7 to 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-6glucuronide (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 glucuronidination of codeine to C6G. CYP2D6 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 CYP2D6. 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 5 hours with TUZISTRA XR. 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 TUZISTRA XR. Clinical Studies The efficacy of TUZISTRA XR is based on previously established findings of effectiveness of codeine and chlorpheniramine at the proposed doses.

Find Lowest Prices on TUZISTRA® XR (codeine polistirex and chlorpheniramine polistirex) Extended-Release Oral Suspension WARNING ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism [see WARNINGS AND PRECAUTIONS]. Tuzistra XR is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS]. Avoid the use of TUZISTRA XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine [see WARNINGS AND PRECAUTIONS]. RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol. DESCRIPTION TUZISTRA® XR (codeine polistirex and chlorpheniramine polistirex) extended-release oral suspension is a pink to reddish pink, cherry-flavored liquid suspension that contains an opiate agonist antitussive codeine and a histamine-1 (H1) receptor antagonist (antihistamine) chlorpheniramine. Each 5 mL of TUZISTRA XR contains 14.7 mg of codeine (equivalent to 20 mg of codeine phosphate) and 2.8 mg of chlorpheniramine (equivalent to 4 mg of chlorpheniramine maleate) bound to sulfonated styrenedivinylbenzene copolymer (polistirex). TUZISTRA XR contains the following inactive ingredients: cherry flavor, citric acid, D&C Red No. 30, ethyl maltol, glycerin, methylparaben, polysorbate 80, polyvinyl acetate, povidone, propyl gallate, propylparaben, purified water, sodium citrate, sodium polystyrene sulfonate, starch, sucrose, triacetin, xanthan gum. Codeine is (5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol, has the following molecular formula, C18H21NO3, and a molecular weight of 299.36. Codeine polistirex is a complex of codeine with sulfonated styrene-divinylbenzene copolymer, having the following structural formula: Chlorpheniramine is γ-(4-chlorophenyl)-N, N-dimethyl-2-pyridinepropanamine, has the following molecular formula, C16H19ClN2, and a molecular weight of 274.80. Chlorpheniramine polistirex is a complex of chlorpheniramine with sulfonated styrene-divinylbenzene copolymer, having the following structural formula:

INDICATIONS Cough And Upper Respiratory Allergy Symptoms TUZISTRA XR is indicated for the relief of cough and symptoms associated with upper respiratory allergies or a common cold in adults 18 years of age and older. Important Limitations Of Use Not indicated for pediatric patients under 18 years of age [see Use In Specific Populations]. DOSAGE AND ADMINISTRATION Adults 18 Years Of Age And Older TUZISTRA XR should be orally administered in a dose of 10 mL every 12 hours, not to exceed 2 doses (20 mL) in 24 hours. Administration Information Administer TUZISTRA XR by the oral route only, with or without food. Shake well before use. Measure with an accurate milliliter measuring device. Do not use a household teaspoon to measure the dose [see WARNINGS AND PRECAUTIONS]. HOW SUPPLIED Dosage Forms And Strengths TUZISTRA XR is a pink to reddish pink, cherry-flavored liquid oral suspension. Extended-release oral suspension contains: codeine polistirex, which contains 14.7 mg of codeine (equivalent to 20 mg codeine phosphate), and chlorpheniramine polistirex, which contains 2.8 mg of chlorpheniramine (equivalent to 4 mg chlorpheniramine maleate) per 5 mL [see DESCRIPTION and Storage and Handling]. TUZISTRA XR is supplied as a pink to reddish pink, cherry-flavored liquid oral suspension containing codeine polistirex, providing 14.7 mg of codeine (equivalent to 20 mg codeine phosphate), and chlorpheniramine polistirex, providing 2.8 mg chlorpheniramine (equivalent to 4 mg chlorpheniramine maleate) per 5 mL. It is available in bottles of 16 fluid oz. (473 mL) NDC 69442-480-01. Storage And Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Shake well. Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure. Ensure that patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed. Manufactured by: n/a. Revised: Aug 2017

PATIENT INFORMATION TUZISTRA® XR (two-zis-tra) (codeine polistirex and chlorpheniramine polistirex) Extended-Release Oral Suspension What is the most important information I should know about TUZISTRA XR? TUZISTRA XR can cause children to stop breathing (respiratory depression) and cause death. Do not give TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR. Ask your healthcare provider for a list of these medicines if you are not sure. TUZISTRA XR can cause breathing problems (respiratory depression) and drowsiness Take TUZISTRA XR exactly as prescribed by your healthcare provider. If you take the wrong dose of TUZISTRA XR, you could overdose and die. See the Medication Guide section called “How should I take TUZISTRA XR?” for important information about how to take TUZISTRA XR correctly. Avoid driving a car or operating machinery during treatment with TUZISTRA XR. Call your healthcare provider or get emergency medical help right away if anyone taking TUZISTRA XR, or your breastfeeding baby has any of the symptoms listed below: increased sleepiness shallow breathing confusion limpness difficulty breathing your baby has difficulty breastfeeding Keep TUZISTRA XR 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 TUZISTRA XR, get emergency help right away. What is TUZISTRA XR? TUZISTRA XR is a prescription medicine used to treat cough and upper respiratory symptoms that you can have with allergies or a common cold. TUZISTRA XR is for adults 18 years and older only. TUZISTRA XR contains 2 medicines, codeine and chlorpheniramine. Codeine is a narcotic cough suppressant. Chlorpheniramine is an antihistamine. TUZISTRA XR is a federal controlled substance (C-III) because it contains codeine that can be abused or lead to dependence. Keep TUZISTRA XR in a safe place to prevent misuse and abuse. Selling or giving away TUZISTRA XR may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. TUZISTRA XR is not for children under 18 years of age. It is not known if TUZISTRA XR is safe and effective in children under 18 years of age. Who should not take TUZISTRA XR? Do not give TUZISTRA XR to any children younger than 12 years of age. Do not give TUZISTRA XR to children younger than 18 years of age after tonsillectomy or adenoidectomy surgery. Do not take TUZISTRA XR if you are allergic to any of the ingredients in TUZISTRA XR. See the end of this Medication Guide for a complete list of ingredients in TUZISTRA XR. You may have an increased risk of having an allergic reaction to TUZISTRA XR if you are allergic to certain other opioid medicines. Before you take TUZISTRA XR, tell your healthcare provider about all your medical conditions, including if you: have a drug dependence have problems with your urinary tract (urethral stricture) have lung or breathing problems plan to have surgery have had a head injury drink alcohol have pain in your stomach-area (abdomen) have kidney or liver problems have a history of severe or persistent cough have diabetes have prostate problems have thyroid problems, such as hypothyroidism are pregnant or plan to become pregnant. It is not known if TUZISTRA XR will harm your unborn baby. You and your healthcare provider should decide if you should take TUZISTRA XR while you are pregnant. are breastfeeding or plan to breastfeed. Codeine and chlorpheniramine pass into your breast milk and may harm your baby. You should not breastfeed during treatment with TUZISTRA XR. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking TUZISTRA XR with certain other medicines can cause side effects or affect how well TUZISTRA XR or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. 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 including monoamine oxidase inhibitors (MAOIs) 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 TUZISTRA XR? Take TUZISTRA XR exactly as your healthcare provider tells you. Your healthcare provider will tell you how much TUZISTRA XR to take and when to take it. Do not change your dose without talking to your healthcare provider. TUZISTRA XR is usually taken every 12 hours. Do not take more than 20 mL of TUZISTRA XR in 24 hours. Take TUZISTRA XR by mouth only. Shake the TUZISTRA XR bottle well before you use it. TUZISTRA XR can be taken with or without food. Do not mix TUZISTRA XR with other fluids or medicines. TUZISTRA XR should be taken using an accurate milliliter measuring device. Ask your pharmacist to give you a measuring device to help you measure the correct amount of TUZISTRA XR. Do not use a household teaspoon to measure your medicine. You may accidently take too much. If you take too much TUZISTRA XR, call your healthcare provider or go to the nearest hospital emergency room right away. What should I avoid doing while taking TUZISTRA XR? TUZISTRA XR can cause you to be drowsy. Avoid driving a car or using machinery during treatment with TUZISTRA XR. Avoid drinking alcohol during treatment with TUZISTRA XR. Drinking alcohol can increase your chances of having serious side effects. What are the possible side effects of TUZISTRA XR? TUZISTRA XR may cause serious side effects, including: See “What is the most important information I should know about TUZISTRA XR?” 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 TUZISTRA XR exactly as your healthcare provider tells you to take it. Stopping TUZISTRA XR suddenly could cause withdrawal symptoms. Increased intracranial pressure. Bowel problems including constipation or stomach pain. The most common side effects of TUZISTRA XR include: nausea and vomiting dizziness general feeling of discomfort or illness constipation swelling or bloating of your stomach-area depression drowsiness unable to control muscle movements excitability, nervousness stomach-area pain headache agitation, restlessness, irritability vision problems, including blurred vision and double-vision feel high (euphoria) feeling faint sleepiness difficulty sleeping (insomnia) confusion lightheadedness tremor These are not all the possible side effects of TUZISTRA XR. 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 TUZISTRA XR? Store TUZISTRA XR in a safe place at room temperature between 68°F to 77°F (20°C to 25°C). Keep TUZISTRA XR 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 TUZISTRA XR and all medicines out of the reach of children. General information about the safe and effective use of TUZISTRA XR: Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TUZISTRA XR for a condition for which it was not prescribed. Do not give TUZISTRA XR 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 TUZISTRA XR that is written for health professionals. What are the ingredients in TUZISTRA XR? Active ingredients: codeine and chlorpheniramine. Inactive ingredients: cherry flavor, citric acid, D&C Red No. 30, ethyl maltol, glycerin, methylparaben, polysorbate 80, polyvinyl acetate, povidone, propyl gallate, propylparaben, purified water, sodium citrate, sodium polystyrene sulfonate, starch, sucrose, triacetin, xanthan gum This Medication Guide has been approved by the U.S. Food and Drug Administration.

SIDE EFFECTS Use of codeine, a semisynthetic opioid, may result in the following: Respiratory depression [see WARNINGS AND PRECAUTIONS and OVERDOSAGE] Drug dependence [see WARNINGS AND PRECAUTIONS] Increased intracranial pressure [see WARNINGS AND PRECAUTIONS and OVERDOSAGE] Decreased mental alertness with impaired mental and/or physical abilities [see WARNINGS AND PRECAUTIONS] Paralytic ileus [see WARNINGS AND PRECAUTIONS] Use of chlorpheniramine, an antihistamine, may result in: Decreased mental alertness with impaired mental and/or physical abilities [see WARNINGS AND PRECAUTIONS] Adverse reactions listed below have been reported in the literature for codeine and chlorpheniramine and may be expected to occur with TUZISTRA XR. Also included are events that occurred during clinical pharmacokinetic studies (in a total of 66 healthy adult volunteers with either single or multiple dose exposure) with TUZISTRA XR and judged by the investigator to be related to study treatment. Because these reactions may be reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic Allergic laryngospasm, nasal stuffiness, bronchospastic allergic reaction, hives, itching, swelling of face. Body As A Whole Asthenia, feeling of relaxation, redness or flushing of the face, unusual tiredness, weakness. Cardiovascular Fast, or slow heartbeat, hypertension, hypotension, orthostatic hypotension, palpitations, shock-like state, syncope. Dermatological System Skin rash, pruritus, erythema, urticaria, excessive perspiration, dermatitis. Endocrine System Changes in glucose utilization, decreased lactation, early menses, glycosuria, gynecomastia, hypoglycemia, increased appetite, increased libido, pheochromocytoma stimulation. Gastrointestinal System Nausea and vomiting, constipation, abdominal distension, abdominal pain, acute pancreatitis, dry mouth, dyspepsia, epigastric distress, loss of appetite, diarrhea, gastro-esophageal reflux, gastrointestinal hypomotility. Genitourinary System Ureteral spasm, urinary retention, dysuria, urinary frequency, urinary hesitancy, irritative bladder symptom. Nervous System Blurred vision, diplopia, visual disturbances, confusion, dizziness, depression, drowsiness, sedation, headache, euphoria, facial dyskinesia, false sense of well-being, feeling faint, lightheadedness, general feeling of discomfort or illness, excitability, nervousness, agitation, restlessness, somnolence, insomnia, dyskinesia, irritability, tremor. Respiratory Dryness of the pharynx and respiratory passages, laryngismus, atelectasis, wheezing, troubled breathing, respiratory depression, hiccups. Special Senses labyrinthitis, tinnitus, vertigo, hypermetropia, lacrimation increased, mydriasis, photophobia. DRUG INTERACTIONS Drug interaction studies have not been conducted with TUZISTRA XR. Benzodiazepines, Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, Or Other CNS Depressants (Including Alcohol) The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with TUZISTRA XR may cause an additive CNS depressant effect, profound sedation, respiratory depression, coma, and death and should be avoided [see WARNINGS AND PRECAUTIONS]. Monoamine Oxidase Inhibitors And Tricyclic Antidepressants Do not prescribe TUZISTRA XR if the patient is taking a monoamine oxidase inhibitor (MAOI) (i.e., certain drugs used for depression, psychiatric or emotional conditions, or Parkinson's disease), or for 2 weeks after stopping a MAOI drug. The use of MAOIs or tricyclic antidepressants with codeine preparations may increase the effect of either the antidepressant or codeine. 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. Inhibitors Or Inducers Of Metabolic Enzymes Codeine is metabolized by the CYP2D6 and CYP3A4 isoenzymes [see CLINICAL PHARMACOLOGY]. 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. Drug Abuse And Dependence Controlled Substance TUZISTRA XR is a Schedule III controlled prescription product containing codeine and should be prescribed and administered with caution. 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 TUZISTRA XR, and it should be prescribed and administered with the same degree of caution appropriate to the use of other opioid drugs. Dependence Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, TUZISTRA XR 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.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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: TUZISTRA XR is contraindicated in all children younger than 12 years of age [see CONTRAINDICATIONS]. TUZISTRA XR is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS]. Avoid the use of TUZISTRA XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. When prescribing codeine for adolescents, 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 OVERDOSAGE]. Nursing Mothers 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 TUZISTRA XR [see Use In Specific Populations]. CYP2D6 Genetic Variability: Ultra-Rapid Metabolizer Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). 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 of signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [see OVERDOSAGE]. Therefore, individuals who are ultra-rapid metabolizers should not use TUZISTRA XR. Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids, including TUZISTRA XR, with benzodiazepines, or other CNS depressants, including alcohol, may results 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]. 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 TUZISTRA XR is used with benzodiazepines, alcohol, or other CNS depressants [see PATIENT INFORMATION]. Respiratory Depression Codeine, one of the active ingredients in TUZISTRA XR, produces dose-related respiratory depression by directly acting on brain stem respiratory centers. Codeine affects the center that controls respiratory rhythm and may produce irregular and periodic breathing. Caution should be exercised when TUZISTRA XR is used postoperatively, in patients with pulmonary disease or shortness of breath, or whenever ventilator function is depressed. Overdose of codeine in adults has been associated with fatal respiratory depression, and the use of codeine in children has been associated with fatal respiratory depression. Exercise caution when administering TUZISTRA XR because of the potential for respiratory depression. If respiratory depression occurs, discontinue TUZISTRA XR and use naloxone hydrochloride when indicated to antagonize the effect and other supportive measures as necessary [see OVERDOSAGE]. Drug Dependence 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 TUZISTRA XR. Prescribe and administer TUZISTRA XR with the same degree of caution appropriate to the use of other opioid drugs [see Drug Abuse and Dependence]. Head Injury And Increased Intracranial Pressure The respiratory depression effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries. The use of TUZISTRA XR should be avoided in these patients. Activities Requiring Mental Alertness Codeine and chlorpheniramine, the active ingredients in TUZISTRA XR, 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 TUZISTRA XR. Concurrent use of TUZISTRA XR with alcohol or other central nervous system depressants should be avoided because additional impairment of central nervous system performance may occur. Obstructive Bowel Disease Chronic use of opioids, including codeine, 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. Acute Abdominal Conditions TUZISTRA XR should be used with caution in patients with acute abdominal conditions since the administration of codeine may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of other anticholinergics with codeine may produce paralytic ileus [see DRUG INTERACTIONS] Dosing Patients should be advised to measure TUZISTRA XR with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions [see OVERDOSAGE]. Patients should be advised to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose. Special Risk Patients As with other opioids, TUZISTRA XR should be used with caution in elderly or debilitated patients and those with asthma, persistent or chronic cough, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed, and the possibility of respiratory depression should be kept in mind. 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 TUZISTRA XR in children younger than 18 years of age. Advise patients that TUZISTRA XR 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]. Overdosage Advise patients not to increase the dose or dosing frequency of TUZISTRA XR because serious adverse events such as respiratory depression may occur with overdosage [see WARNINGS AND PRECAUTIONS; OVERDOSAGE]. Dosing Administer TUZISTRA XR by the oral route only. Pharmacists and prescribers should ensure patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed [see WARNINGS AND PRECAUTIONS]. TUZISTRA XR should not be diluted with fluids or mixed together with other drugs. Interactions With Benzodiazepines And Other Central Nervous System Depressants Inform patients and caregivers that potentially fatal additive effects may occur if TUZISTRA XR is used with benzodiazepines or other CNS depressants, including, alcohol. Because of this risk, patients should avoid concomitant use of TUZISTRA XR with benzodiazepines or other CNS depressants, including alcohol [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]. Activities Requiring Mental Alertness Caution patients that TUZISTRA XR 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] Controlled Substance Status/Potential For Abuse And Dependence Caution patients that TUZISTRA XR contains codeine and can produce drug dependence [see Abuse and Dependence]. Lactation Advise women that breastfeeding is not recommended during treatment with TUZISTRA XR [see Use In Specific Populations]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity, mutagenicity, and reproductive studies have not been conducted with TUZISTRA XR; however, published information is available for the individual active ingredients or related active ingredients. Codeine Carcinogenicity studies were conducted with 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 10 and 30 times, respectively, the MRHDD 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 the MRHDD on a mg/m² basis, respectively. Use In Specific Populations Pregnancy Pregnancy Category C. Teratogenic Effects There are no adequate and well-controlled studies of TUZISTRA XR in pregnant women. Reproductive toxicity studies have not been conducted with TUZISTRA XR; however, studies are available with individual active ingredients or related active ingredients. Because animal reproduction studies are not always predictive of human response, TUZISTRA XR should be used during pregnancy only if the benefit justifies the potential risk to the fetus. Codeine Codeine has embryolethal and fetotoxic effects in rats. In a study in which pregnant rats were dosed throughout organogenesis, a dose approximately 20 times the maximum recommended human daily dose (MRHDD; on a mg/m² basis at an oral maternal dose of 120 mg/kg/day) increased resorptions and decreased fetal weight; however, these effects occurred in the presence of maternal toxicity. In studies in which rabbits and mice were dosed throughout organogenesis, codeine at doses approximately 9 and 45 times the MRHDD (on a mg/m² basis at 30 and 600 mg/kg/day, respectively) produced no adverse developmental effects. Chlorpheniramine A retrospective study found a small, but statistically significant, association between maternal use of chlorpheniramine and inguinal hernia and eye or ear anomalies in children. Other retrospective studies have found that the frequency of congenital anomalies, in general, was not increased among offspring of women who took chlorpheniramine during pregnancy. The significance of these findings to the therapeutic use of chlorpheniramine in human pregnancy is not known. In studies with chlorpheniramine in which pregnant rats and rabbits were dosed throughout organogenesis, oral doses up to approximately 25 and 30 times the MRHDD on a mg/m² basis, respectively, produced no adverse developmental effects. However, when mice were dosed throughout pregnancy, a dose approximately 9 times the MRHDD (on a mg/m² basis at an oral maternal dose of 20 mg/kg/day) was embryolethal, and postnatal survival was decreased when dosing was continued after parturition. Embryolethality was also observed when male and female rats were dosed with approximately 9 times the MRHDD (on a mg/m² basis at an oral parental dose of 10 mg/kg/day) prior to mating. Nonteratogenic Effects Codeine Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. Labor And Delivery As with all opioids, administration of TUZISTRA XR to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used. Nursing Mothers Risk Summary Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. There is no information on the effects of the codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with TUZISTRA XR [see WARNINGS AND PRECAUTIONS]. Clinical Considerations If infants are exposed to TUZISTRA XR through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Chlorpheniramine is excreted in human milk. The clinical significance is unknown; however, the anticholinergic action of chlorpheniramine may suppress lactation if taken prior to nursing. Pediatric Use Safety and effectiveness of TUZISTRA XR in pediatric patients under 18 years of age have not been established. Life-threatening respiratory depression and death have occurred in children who received codeine [see WARNINGS AND PRECAUTIONS]. In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine. Because of the risk of life-threatening respiratory depression and death: TUZISTRA XR is contraindicated in all children younger than 12 years of age [see CONTRAINDICATIONS]. TUZISTRA XR is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS]. Avoid the use of TUZISTRA XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression [see WARNINGS AND PRECAUTIONS]. Geriatric Use Clinical efficacy and safety studies have not been conducted with TUZISTRA XR. Other reported clinical experience with the individual active ingredients of TUZISTRA XR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be made with caution, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment Pharmacokinetics of TUZISTRA XR has not been characterized in renal impairment subjects. Both codeine and chlorpheniramine are cleared substantially by the kidney. As such, impaired renal function could potentially lead to the risk of decreased clearance and thereby increased retention or systemic levels of both these drugs. TUZISTRA XR should be used with caution in patients with severe renal impairment. Hepatic Impairment Pharmacokinetics of TUZISTRA XR has not been characterized in hepatic impairment subjects. Both codeine and chlorpheniramine are extensively metabolized by the liver before elimination from the body. As such, impaired hepatic function could potentially lead to the risk of decreased metabolism and thereby increased systemic levels of both these drugs. TUZISTRA XR should be used with caution in patients with severe hepatic impairment.