PRECAUTIONS General Selection of patients for treatment with TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules should be governed by the same principles that apply to the use of similar opioid/non-opioid fixed combination analgesics. As with any such opioid analgesic, the dosing regimen should be adjusted for each patient [see DOSAGE AND ADMINISTRATION]. This combination product should be used with caution in elderly or debilitated patients or those with any of the following conditions: acute alcoholism; adrenocortical insufficiency (e.g., Addison's disease); asthma; central nervous system depression or coma; chronic obstructive pulmonary disease; decreased respiratory reserve (including emphysema, severe obesity, cor pulmonale, or kyphoscoliosis); delirium tremens; head injury; hypotension; increased intracranial pressure; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and toxic psychosis. The benefits and risks of using opioids in patients taking monoamine oxidase inhibitors and in those with a history of drug abuse should be carefully considered. The administration of an analgesic containing an opioid may obscure the diagnosis or clinical course in patients with acute abdominal conditions. This combination product may aggravate convulsions in patients with convulsive disorders and, like all opioids, may induce or aggravate seizures in some clinical settings. Acetaminophen is relatively non-toxic at therapeutic doses, but should be used with caution in patients with severe renal or hepatic disease. Care should be observed when using large doses of acetaminophen in malnourished patients or those with a history of chronic alcohol abuse because they may be more susceptible to hepatic damage similar to that observed with toxic overdosage. Caffeine in high doses may produce central nervous system and cardiovascular stimulation and gastrointestinal irritation. Information for Patients/Caregivers Addiction, Abuse, and Misuse Inform patients that the use of TREZIX™ even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS]. Instruct patients not to share TREZIX™ with others and to take steps to protect TREZIX™ from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting TREZIX™ or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS]. Instruct patients to take steps to store TREZIX™ securely and to dispose of unused TREZIX™. Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children Advise patients that TREZIX™ is contraindicated in all in children younger than 12 years of age and in children younger than 18 years following tonsillectomy and/or adenoidectomy. Advise caregivers of children ages 12 to 18 years of age receiving TREZIX™ to monitor for signs of respiratory depression [see WARNINGS]. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if TREZIX™ is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider [see WARNINGS and PRECAUTIONS; Drug Interactions]. Serotonin Syndrome Inform patients that TREZIX™ could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions]. Adrenal Insufficiency Inform patients that TREZIX™ could cause adrenal insufficiency, a potentially life threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS]. Important Administration Instructions Instruct patients how to properly take TREZIX™ [see DOSAGE AND ADMINISTRATION]. • Advise patients not to adjust the dose of TREZIX™ without consulting a physician or other healthcare professional. • If patients have been receiving treatment with TREZIX™ for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal symptoms. Provide a dose schedule to accomplish a gradual discontinuation of the medication [see Warnings]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of TREZIX™ during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS, PRECAUTIONS; Pregnancy] Embryo-Fetal Toxicity Inform female patients of reproductive potential that TREZIX™ can cause fetal harm and to inform the prescriber of a known or suspected pregnancy [see PRECAUTIONS; Pregnancy]. Lactation Advise woment that breastfeeding is not recommended during treatment with TREZIXTM [see PRECAUTIONS; Nursing Mothers]. Disposal of Unused TREZIX™ Advise patients to properly dispose of unused TREZIX™. Advise patients to throw the drug in the household trash following these steps. Remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag, or to dispose of in accordance with the local state guidelines and/or regulations. Patients receiving TREZIX™ capsules should be given the following information: Do not take TREZIX™ if you are allergic to any of its ingredients. If you develop signs of allergy such as a rash or difficulty breathing stop taking TREZIX™ and contact your healthcare provider immediately. Do not take more than 4000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose. Patients should be advised that TREZIX™ capsules may impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Patients should be advised to report adverse experiences occurring during therapy. Patients should be advised not to adjust the dose of TREZIX™ capsules without consulting the prescribing professional. Patients should be advised that TREZIX™ capsules are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed. Advise patients that some people have a genetic variation that results in dihydrocodeine changing into dihydromorphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid dihydrocodeine metabolizer or not. These higher-than-normal levels of dihydromorphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this population due to respiratory depression. Dihydrocodeine-containing products are contraindicated in all children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving dihydrocodeine-containing products for other reasons to monitor for signs of respiratory depression. Drug Interactions CYP2D6 InhibitorsDihydrocodeine in TREZIX™ is metabolized by CYP2D6 to form dihydromorphine . The concomitant use of TREZIX™ and CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine, fluoxetine, bupropion, quinidine) can increase the plasma concentration of dihydrocodeine, but can decrease the plasma concentration of active metabolite dihydromorphine which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of TREZIX™ is achieved. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the dihydrocodeine plasma concentration will decrease but the active metabolite dihydromorphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. If concomitant use with a CYP2D6 inhibitor is necessary or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of TREZIX™ and monitor patients closely at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the TREZIX™ as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the TREZIX™ and monitor the patient for signs and symptoms of respiratory depression or sedation CYP3A4 Inhibitors The concomitant use of TREZIX™ with CYP3A4 inhibitors such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g., ritonavir), may result in an increase in dihydrocodeine plasma concentration with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater dihydromorphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of TREZIX™ is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower dihydrocodeine plasma levels, greater dihydronorcodeine levels, and less metabolism via 2D6 with resultant lower dihyromorphine levels, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to dihydrocodeine. If concomitant use with CYP3A4 inhibitor is necessary, consider dosage reduction of TREZIX™ until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the TREZIX™ dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. CYP3A4 Inducers The concomitant use of TREZIX™ and CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin), can result in lower dihydrocodeine levels, greater dihydronorcodeine levels, and less metabolism via 2D6 with resultant lower dihyromorphine levels, resulting in decreased efficacy or a withdrawal syndrome in patients who had developed physical dependence to dihydrocodeine. After stopping a CYP3A4 inducer, as the effects of the inhibitor decline, the dihydrocodeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater dihyromorphine levels, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. If concomitant use with CYP3A4 inducer is necessary, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the TREZIX™ dosage as needed. If a CYP3A4 inducer is discontinued, consider TREZIX™ dosage reduction and monitor for signs of respiratory depression and sedation at frequent intervals. Benzodiazepines and Other Central Nervous System (CNS) Depressants Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, and 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. . Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see WARNINGS]. Serotonergic Drugs The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (used to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see PRECAUTIONS; Information for Patients]. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue TREZIX™ immediately if serotonin syndrome is suspected. Dihydrocodeine with Monoamine Oxidase Inhibitors Dihydrocodeine, like all opioid analgesics, interacts with monoamine oxidase inhibitors causing central nervous system excitation and hypertension. Dihydrocodeine with Mixed Agonist/Antagonist Opioid Analgesics Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) may reduce the analgesic effect of this combination product. Acetaminophen Drug Interactions Chronic and excessive consumption of alcohol may increase the hepatotoxic risk of acetaminophen. The potential for hepatotoxicity with acetaminophen also may be increased in patients receiving anticonvulsants that induce hepatic microsomal enzymes (including phenytoin, barbiturates, and carbamazepine) or isoniazide. Chronic ingestion of large doses of acetaminophen may slightly potentiate the effects of warfarin-and indandione-derivative anticoagulants. Severe hypothermia is possible in patients receiving acetaminophen concomitantly with phenothiazines. Caffeine Drug Interactions Caffeine may enhance the cardiac inotropic effects of beta-adrenergic stimulating agents. Co-administration of caffeine and disulfiram may lead to a substantial decrease in caffeine clearance. Caffeine may increase the metabolism of other drugs such as phenobarbital and aspirin. Caffeine accumulation may occur when products or foods containing caffeine are consumed concomitantly with quinolones such as ciprofloxacin. Carcinogenesis, Mutagenesis, Impairment of Fertility Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS]. Pregnancy Teratogenic Effects – Pregnancy Category C. Animal reproduction studies have not been conducted with TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules. It is also not known whether this combination product can cause fetal harm when administered to pregnant women or can affect reproduction capacity in males and females. This combination product should be given to pregnant women only if clearly needed, especially during the first trimester. Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS]. Labor and Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. TREZIX™ is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including TREZIX™, and can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Nursing Mothers Dihydrocodeine bitartrate 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 dihydrocodeine 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 dihydrocodeine metabolism (normal CYP2D6 activity), the amount of dihydrocodeine secreted into human milk is low and dose-dependent. There is no information on the effects of the dihydrocodeine 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 TREZIX™ [see WARNINGS]. Clinical Considerations If Infants are exposed to TREZIXTM 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. Acetaminophen and caffeine are also excreted in breast milk in small amounts. Because of the potential for serious adverse reactions in nursing infants from this combination product, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of TREZIX™ in pediatric patients have not been established. Life-threatening respiratory depression and death have occurred in children who received codeine [see WARNINGS]. 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: TREZIXTM is contraindicated for all children younger than 12 years of age [see CONTRAINDICATIONS]. TREZIXTM is contraindicated for post-operative pain management in pediatric patients of any age undergoing tonsillectomy and/or adenoidectomy [see CONTRAINDICATIONS]. Avoid the use of TREZIX™ 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 unless the benefits outweigh the risks. 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]. Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to TREZIX™. In general, use caution when selecting a dosage for an elderly patient, 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. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of TREZIX™ slowly in geriatric patients and monitor closely for signs of central nervous system and central nervous system depression [see WARNINGS]. Hepatic Impairment TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules should be given with caution to patients with hepatic insufficiency. Since dihydrocodeine is metabolized by the liver and since acetaminophen potentially causes hepatotoxicity, the effects of this combination product should be monitored closely in such patients. Renal Impairment TREZIX™ (acetaminophen, caffeine, and dihydrocodeine bitartrate) capsules should be used with caution and at reduced dosage in the presence of impaired renal function. Pancreatic/Biliary Tract Disease Opioids may cause spasms of the sphincter of Oddi and should be used with caution in patients with biliary tract disease including pancreatitis.