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warnings and cautions
5 WARNINGS 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 TUZISTRA XR contains codeine, a Schedule III controlled substance. As an opioid, TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR, prescribe TUZISTRA XR 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 TUZISTRA XR. 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 TUZISTRA XR. 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 TUZISTRA XR. 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 TUZISTRA XR, close observation, supportive measures, and use of opioid antagonists (e.g. naloxone), depending on the patient’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 TUZISTRA XR, the risk is greatest during the initiation of therapy, when TUZISTRA XR 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 TUZISTRA XR is essential [ see Dosage and Administration (2.1) , Warnings and Precautions (5.6) ]. 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 TUZISTRA XR, 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: TUZISTRA XR is contraindicated in all children younger than 12 years of age [ see Contraindications (4) ]. TUZISTRA XR is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [ see Contraindications (4) ]. Avoid the use of TUZISTRA XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. [ see Warnings and Precautions (5.9), 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 TUZISTRA XR [ 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/*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 signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [ see Overdosage (10) ]. Therefore, individuals who are ultra-rapid metabolizers should not use TUZISTRA XR. 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, TUZISTRA XR 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 TUZISTRA XR 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, TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR, 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’s respiratory function. TUZISTRA XR-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 TUZISTRA XR [ 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 TUZISTRA XR in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients. If TUZISTRA XR is prescribed, monitor such patients closely, particularly when initiating TUZISTRA XR and when TUZISTRA XR 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 TUZISTRA XR is communicated clearly and dispensed accurately [ see Dosage and Administration (2.1) ]. Advise patients to always use an accurate milliliter measuring device when measuring and administering TUZISTRA XR. Inform patients that household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [ ]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose. Advise patients to always use an accurate milliliter measuring device when measuring and administering TUZISTRA XR. Inform patients that household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [ see Overdosage (10) ]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose. 5.7 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery 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. Avoid concurrent use of TUZISTRA XR 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 TUZISTRA XR requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine. Cytochrome P450 3A4 Interaction The concomitant use of TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR in patients who are taking a CYP3A4 inhibitor or CYP3A4 inducer. If concomitant use of TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR in patients who are taking a CYP2D6 inhibitor. If concomitant use of TUZISTRA XR 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 TUZISTRA XR, 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 TUZISTRA XR is used with benzodiazepines, alcohol, or other CNS depressants [ see Patient Counseling Information (17) ] . 5.10 Risks of Use in Patients with Gastrointestinal Conditions TUZISTRA XR is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [ see Contraindications (4) ]. The use of codeine in TUZISTRA XR may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of anticholinergics with TUZISTRA XR may produce paralytic ileus [ see Drug Interactions (7.10) ]. The codeine in TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR 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), TUZISTRA XR 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 TUZISTRA XR 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 TUZISTRA XR therapy. 5.13 Co-administration with Monoamine Oxidase Inhibitors (MAOIs) Concurrent use of TUZISTRA XR 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’s active metabolite, including respiratory depression, coma, and confusion MAOIs [ see Drug Interactions (7.7) ]. 5.14 Severe Hypotension TUZISTRA XR 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 TUZISTRA XR. In patients with circulatory shock, TUZISTRA XR may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of TUZISTRA XR in patients with circulatory shock. 5.15 Neonatal Opioid Withdrawal Syndrome TUZISTRA XR is not recommended for use in pregnant women. Prolonged use of TUZISTRA XR 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 TUZISTRA XR.