extended-release tablets for the development of these behaviors or conditions. 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). the potential for these risks should not, however, prevent the proper management of pain in any given patient. patients at increased risk may be prescribed opioids such as tramadol hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of tramadol hydrochloride extended-release tablets along with intensive monitoring for signs of addiction, abuse, and misuse. consider prescribing naloxone for the emergency treatment of opioid overdose [seewarnings; life-threatening respiratory depression, dosage and administration; patient access to naloxone for the emergency treatment of opioid overdose]. abuse or misuse of tramadol hydrochloride extended-release tablets by cutting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tramadol and can result in overdose and death [see overdosage]. opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. consider these risks when prescribing or dispensing tramadol hydrochloride extended-release tablets. 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 precautions; information for patients]. 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. opioid analgesic risk evaluation and mitigation strategy (rems) to ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the food and drug administration (fda) has required a risk evaluation and mitigation strategy (rems) for these products. under the requirements of the rems, drug companies with approved opioid analgesic products must make rems-compliant education programs available to healthcare providers. healthcare providers are strongly encouraged to do all of the following: • complete a rems-compliant education program offered by an accredited provider of continuing education (ce) or another education program that includes all the elements of the fda education blueprint for health care providers involved in the management or support of patients with pain. • discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. the patient counseling guide (pcg) can be obtained at this link: www.fda.gov/opioidanalgesicremspcg. • emphasize to patients and their caregivers the importance of reading the medication guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. • consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. to obtain further information on the opioid analgesic rems and for a list of accredited rems cme/ce, call 800-503-0784, or log on to www.opioidanalgesicrems.com. the fda blueprint can be found at www.fda.gov/opioidanalgesicremsblueprint. life-threatening respiratory depression serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see overdosage]. carbon dioxide (co2) 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 tramadol hydrochloride extended-release tablets, the risk is greatest during the initiation of therapy or following a dosage increase. monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with and following dosage increases of tramadol hydrochloride extended-release tablets. to reduce the risk of respiratory depression, proper dosing and titration of tramadol hydrochloride extended-release tablets are essential [see dosage and administration]. overestimating the tramadol hydrochloride extended-release tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. accidental ingestion of even one dose of tramadol hydrochloride extended-release tablets, especially by children, can result in respiratory depression and death due to an overdose of tramadol. educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [seeprecautions; information for patients]. opioids can cause sleep-related breathing disorders including central sleep apnea (csa) and sleep-related hypoxemia. opioid use increases the risk of csa in a dose-dependent fashion. in patients who present with csa, consider decreasing the opioid dosage using best practices for opioid taper [see dosage and administration]. patient access to naloxone for the emergency treatment of opioid overdose discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with tramadol hydrochloride extended-release tablets. inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [seeprecautions; information for patients]. consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of other cns depressants, a history of opioid use disorder, or prior opioid overdose. the presence of risk factors for overdose should not prevent the proper management of pain in any given patient. also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. if naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see warnings; addiction, abuse, and misuse, risks from concomitant use with benzodiazepines or other cns depressants, precautions; information for patients]. ultra-rapid metabolism of tramadol and other risk factors for life-threatening respiratory depression in children life-threatening respiratory depression and death have occurred in children who received tramadol. tramadol and codeine are subject to variability in metabolism based upon cyp2d6 genotype (described below), which can lead to increased exposure to an active metabolite. based upon postmarketing reports with tramadol or with codeine, children younger than 12 years of age may be more susceptible to the respiratory depressant effects of tramadol. furthermore, children with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. because of the risk of life-threatening respiratory depression and death: tramadol hydrochloride extended-release tablets are contraindicated for all children younger than 12 years of age [see contraindications]. tramadol hydrochloride extended-release tablets are 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 tramadol hydrochloride extended-release tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol 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. as with adults, when prescribing opioids 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 opioid overdose [see precautions/pediatric use, overdosage]. nursing mothers tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers of cyp2d6 substrates being potentially exposed to life-threatening levels of the active metabolite o-desmethyltramadol (m1). 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. a baby nursing from an ultra-rapid metabolizer mother taking tramadol hydrochloride extended-release tablets could potentially be exposed to high levels of m1, and experience life-threatening respiratory depression. for this reason, breastfeeding is not recommended during treatment with tramadol hydrochloride extended-release tablets (see precautions/nursing mothers). 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 racial/ethnic groups (i.e., oceanian, northern african, middle eastern, ashkenazi jews, puerto rican). these individuals convert tramadol into its active metabolite, o-desmethyltramadol (m1), more rapidly and completely than other people. this rapid conversion results in higher than expected serum m1 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]. therefore, individuals who are ultra-rapid metabolizers should not use tramadol hydrochloride extended-release tablets. neonatal opioid withdrawal syndrome prolonged use of tramadol hydrochloride extended-release tablets 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 precautions; information for patients, pregnancy]. 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 on levels of tramadol and m1 from tramadol hydrochloride extended-release tablets are complex. use of cytochrome p450 3a4 inducers, 3a4 inhibitors, or 2d6 inhibitors with tramadol hydrochloride extended-release tablets require careful consideration of the effects on the parent drug, tramadol which is a weak serotonin and norepinephrine reuptake inhibitor and μ-opioid agonist, and the active metabolite, m1, which is more potent than tramadol in μ-opioid receptor binding [see precautions; drug interactions]. risks of concomitant use or discontinuation of cytochrome p450 2d6 inhibitors the concomitant use of tramadol hydrochloride extended-release tablets with all cytochrome p450 2d6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels of the active metabolite, m1. a decrease in m1 exposure in patients who have developed physical dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced efficacy. the effect of increased tramadol levels may be an increased risk for serious adverse events including seizures and serotonin syndrome. discontinuation of a concomitantly used cytochrome p450 2d6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite m1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression. follow patients receiving tramadol hydrochloride extended-release tablets and any cyp2d6 inhibitor for the risk of serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and opioid withdrawal when tramadol hydrochloride extended-release tablets are used in conjunction with inhibitors of cyp2d6 [see precautions; drug interactions]. cytochrome p450 3a4 interaction the concomitant use of tramadol hydrochloride extended-release tablets with 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 tramadol plasma concentrations, which could increase or prolong adverse reactions, increase the risk for serious adverse events including seizures and serotonin syndrome, and may cause potentially fatal respiratory depression. the concomitant use of tramadol hydrochloride extended-release tablets with all cytochrome p450 3a4 inducers or discontinuation of a cytochrome p450 3a4 inhibitor may result in lower tramadol levels. this may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. follow patients receiving tramadol hydrochloride extended-release tablets and any cyp3a4 inhibitor or inducer for the risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when tramadol hydrochloride extended-release tablets are used in conjunction with inhibitors and inducers of cyp3a4 [see precautions; drug interactions]. risks of concomitant use with benzodiazepines or other cns depressants profound sedation, respiratory depression, coma, and death may result from the concomitant use of tramadol hydrochloride extended-release tablets with benzodiazepines or other cns depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other cns depressant drugs with opioid analgesics [see precautions; drug interactions]. if the decision is made to prescribe a benzodiazepine or other cns depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. in patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other cns depressant than indicated in the absence of an opioid, and titrate based on clinical response. if an opioid analgesic is initiated in a patient already taking a benzodiazepine or other cns depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. follow patients closely for signs and symptoms of respiratory depression and sedation. if concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see warnings; life-threatening respiratory depression, dosage and administration; patient access to naloxone for the emergency treatment of opioid overdose]. advise both patients and caregivers about the risks of respiratory depression and sedation when tramadol hydrochloride extended-release tablets are used with benzodiazepines or other cns depressants (including alcohol and illicit drugs). advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other cns depressant have been determined. screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional cns depressants including alcohol and illicit drugs [see precautions; information for patients, drug interactions]. serotonin syndrome with concomitant use of serotonergic drugs cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tramadol hydrochloride extended-release tablets with serotonergic drugs. serotonergic drugs include selective serotonin reuptake inhibitors (ssris), serotonin and norepinephrine reuptake inhibitors (snris), tricyclic antidepressants (tcas), triptans, 5-ht3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including mao inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see precautions; drug interactions]. this may occur within the recommended dosage range. serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). the onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected. increased risk of seizures seizures have been reported in patients receiving tramadol hydrochloride within the recommended dosage range. spontaneous postmarketing reports indicate that seizure risk is increased with doses above the recommended range. concomitant use of tramadol hydrochloride increases the seizure risk in patients taking [see precautions; drug interactions]: selective serotonin reuptake inhibitors (ssri antidepressants or anorectics), tricyclic antidepressants (tcas), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or other opioids. tramadol hydrochloride extended-release tablets monoamine oxidase (mao) inhibitors [see warnings; use with mao inhibitors and serotonin re-uptake inhibitors and precautions; drug interactions], neuroleptics, or other drugs that reduce the seizure threshold. risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, certain metabolic disorders, alcohol and drug withdrawal and cns infections). in tramadol overdose, naloxone administration may increase the risk of seizures. suicide risk do not prescribe tramadol hydrochloride extended-release tablets for patients who are suicidal or addiction-prone. consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed [see drug abuse and dependence]. prescribe tramadol hydrochloride extended-release tablets with caution for patients with history of misuse and/or are currently taking cns-active drugs including tranquilizers or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression [see precautions; drug interactions]. tell your patients not to exceed the recommended dose and to limit their intake of alcohol [see dosage and administration and warnings]. adrenal insufficiency cases of adrenal insufficiency have been reported with opioid use, more often following greater than one 1 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. life-threatening respiratory depression in patients with chronic pulmonary disease or elderly, cachectic, or debilitated patients the use of tramadol hydrochloride extended-release tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. patients with chronic pulmonary disease: tramadol hydrochloride extended-release tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of tramadol hydrochloride extended-release tablets [see warnings; respiratory depression]. 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, including clearance, compared to younger, healthier patients [see warnings; respiratory depression]. monitor such patients closely, particularly when initiating and titrating tramadol hydrochloride extended-release tablets and when tramadol hydrochloride extended-release tablets are given concomitantly with other drugs that depress respiration [see warnings; respiratory depression]. alternatively, consider the use of non-opioid analgesics in these patients. severe hypotension tramadol hydrochloride extended-release tablets may cause severe hypotension including 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 precautions; drug interactions]. monitor these patients for signs of hypotension after initiating or titrating the dosage of tramadol hydrochloride extended-release tablets. in patients with circulatory shock tramadol hydrochloride extended-release tablets may cause vasodilatation that can further reduce cardiac output and blood pressure. avoid the use of tramadol hydrochloride extended-release tablets with circulatory shock. risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness in patients who may be susceptible to the intracranial effects of co2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), tramadol hydrochloride extended-release tablets may reduce respiratory drive, and the resultant co2 retention can further increase intracranial pressure. monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with tramadol hydrochloride extended-release tablets. opioids may also obscure the clinical course in a patient with a head injury. avoid the use of tramadol hydrochloride extended-release tablets in patients with impaired consciousness or coma. risks of use in patients with gastrointestinal conditions tramadol hydrochloride extended-release tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. the tramadol in tramadol hydrochloride extended-release tablets may cause spasm of the sphincter of oddi. opioids may cause increases in serum amylase. monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. anaphylaxis and other hypersensitivity reactions serious and rarely fatal hypersensitive reactions have been reported in patients receiving therapy with tramadol. when these events do occur it is often following the first dose. other reported hypersensitivity reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and stevens-johnson syndrome. patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride extended-release tablets. if anaphylaxis or other hypersensitivity occurs, stop administration of tramadol hydrochloride extended-release tablets immediately, discontinue tramadol hydrochloride extended-release tablets permanently, and do not rechallenge with any formulation of tramadol. advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction [see contraindications and precautions; information forpatients]. withdrawal do not abruptly discontinue tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids. when discontinuing tramadol hydrochloride extended-release tablets in a physically dependent patient, gradually taper the dosage. rapid tapering of tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see dosage and administration, drug abuse and dependence]. additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including tramadol hydrochloride extended-release tablets. in these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see drug interactions]. risks of driving and operating machinery tramadol hydrochloride extended-release tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of tramadol hydrochloride extended-release tablets and know how they will react to the medication [see precautions; information for patients].

lowing dosage increases with tramadol hydrochloride extended-release tablets and adjust the dosage accordingly [see warnings]. instruct patients to swallow tramadol hydrochloride extended-release tablets whole [see precautions; information for patients], and to take it with liquid. crushing, chewing, splitting, or dissolving tramadol hydrochloride extended-release tablets will result in uncontrolled delivery of tramadol and can lead to overdose or death [see warnings]. tramadol hydrochloride extended-release tablets may be taken without regard to food, it is recommended that it be taken in a consistent manner [see clinical pharmacology]. patient access to naloxone for the emergency treatment of opioid overdose discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with tramadol hydrochloride extended-release tablets [see warnings, life-threatening respiratory depression; precautions, information for patients]. inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing regulations (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of cns depressants, a history of opioid use disorder, or prior opioid overdose. the presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see warnings, addiction, abuse, and misuse, life-threatening respiratory depression, risks from concomitant use with benzodiazepines or other cns depressants]. consider prescribing naloxone when the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. initial dosage patients not currently on a tramadol product the initial dose of tramadol hydrochloride extended-release tablets is 100 mg once daily. patients currently on tramadol ir products calculate the 24-hour tramadol ir dose and initiate a total daily dose of tramadol hydrochloride extended-release tablets rounded down to the next lower 100 mg increment. the dose may subsequently be individualized according to patient need. due to limitations in flexibility of dose selection with tramadol hydrochloride extended-release tablets, some patients maintained on tramadol ir products may not be able to convert to tramadol hydrochloride extended-release tablets. conversion from other opioids to tramadol hydrochloride extended-release tablets discontinue all other around-the-clock opioid drugs when tramadol hydrochloride extended-release tablets therapy is initiated. there are no established conversion ratios for conversion from other opioids to tramadol hydrochloride extended-release tablets defined by clinical trials. initiate dosing using tramadol hydrochloride extended-release tablets 100 mg once a day. titration and maintenance of therapy individually titrate tramadol hydrochloride extended-release tablets by 100 mg every five days to a dose that provides adequate analgesia and minimizes adverse reactions. the maximum daily dose of tramadol hydrochloride extended-release tablets is 300 mg per day. continually reevaluate patients receiving tramadol hydrochloride extended-release tablets to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see warnings]. frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. during chronic therapy, periodically reassess the continued need for the use of opioid analgesics. patients who experience breakthrough pain may require a dosage adjustment of tramadol hydrochloride extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. if the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the tramadol hydrochloride extended-release tablets dosage. if unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. safe reduction or discontinuation of tramadol hydrochloride extended-release tablets do not abruptly discontinue tramadol hydrochloride extended-release tablets in patients who may be physically dependent on opioids. rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. when a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking tramadol hydrochloride extended-release tablets, there are a variety of factors that should be considered, including the dose of tramadol hydrochloride extended-release tablets the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. it is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. when opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. there are no standard opioid tapering schedules that are suitable for all patients. good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. for patients on tramadol hydrochloride extended-release tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose lowering at an interval of every 2 to 4 weeks. patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. it may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. if withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. in addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. when managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. a multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see warnings/ withdrawal, drug abuse and dependence].

flect the rates observed in practice. tramadol hydrochloride extended-release tablets were administered to a total of 2707 subjects (2406 patients and 301 healthy volunteers) during clinical studies, including four randomized double-blind studies (treatment ≥ 12 weeks) and two open-label long-term studies (treatment up to 12 months) in patients with moderate to severe pain due to osteoarthritis of the knee. a total of 844 patients were exposed to tramadol hydrochloride extended-release tablets for 12 weeks, 493 patients for 6 months and 243 patients for 12 months. treatment emergent adverse events increased with dose from 100 mg to 300 mg in the three twelve-week, randomized, double-blind, placebo-controlled studies (table 2). table 2. percentage of patients with incidence of adverse events ≥ 2% from three 12-week placebo-controlled studies (mdt3-002, mdt3-003 and mdt3-005) adverse events (medra preferred terms) tramadol hydrochloride extended-release tablets placebo 100 mg 200 mg 300 mg total * n=216 n=311 n=530 n=1095 n=668 nausea 28 (13%) 42 (14%) 76 (14%) 179 (16%) 37 (6%) constipation 21 (10%) 36 (12%) 52 (10%) 140 (13%) 26 (4%) dizziness 16 (7%) 28 (9%) 52 (10%) 106 (10%) 18 (3%) somnolence 11 (5%) 22 (7%) 23 (4%) 77 (7%) 12 (2%) vomiting 7 (3%) 16 (5%) 31 (6%) 58 (5%) 4 (1%) pruritus 9 (4%) 15 (5%) 18 (3%) 51 (5%) 7 (1%) headache 10 (5%) 9 (3%) 15 (3%) 41 (4%) 21 (3%) sweating increased 1 (0%) 9 (3%) 14 (3%) 35 (3%) 5 (1%) dry mouth 7 (3%) 13 (4%) 6 (1%) 32 (3%) 8 (1%) fatigue 6 (3%) 7 (2%) 9 (2%) 26 (2%) 6 (1%) anorexia 4 (2%) 4 (1%) 10 (2%) 25 (2%) 2 (0%) vertigo 2 (1%) 3 (1%) 6 (1%) 21 (2%) 3 (0%) insomnia 2 (1%) 6 (2%) 9 (2%) 18 (2%) 8 (1%) * due to the difference in study design of mdt3-005, only the results of the double-blind phase of the study are presented and the dose specific results include maintenance period data only. the majority of patients who experienced the most common adverse events (≥5%) reported mild to moderate symptoms. less than 3% of adverse events were rated as severe. overall, onset of these adverse events usually occurred within the first two weeks of treatment. adverse reactions with an incidence of 1.0% to <5.0% ear and labyrinth disorders: vertigo gastrointestinal disorders: abdominal pain, diarrhea, dry mouth, dyspepsia, upper abdominal pain general disorders: fatigue, weakness investigations: weight decreased metabolism and nutrition disorders: anorexia musculoskeletal and connective tissue disorders: arthralgia nervous system disorders: headache, tremor psychiatric disorders: anxiety, insomnia skin and subcutaneous tissue disorders: pruritus, sweating increased vascular disorders: hot flushes adverse reactions with an incidence of <1.0% blood and lymphatic system disorders: anemia, thrombocytopenia cardiac disorders: bradycardia eye disorders: blurred vision, visual disturbance gastrointestinal disorders: abdominal discomfort, abdominal distension, abdominal tenderness, change in bowel habit, constipation aggravated, diverticulitis, diverticulum, dyspepsia aggravated, dysphagia, fecal impaction, gastric irritation, gastritis, gastrointestinal hemorrhage, gastrointestinal irritation, gastro-esophageal reflux disease, lower abdominal pain, pancreatitis aggravated, rectal hemorrhage, rectal prolapse, retching general disorders: asthenia, malaise hepatobiliary disorders: biliary tract disorder, cholelithiasis immune system disorders: hypersensitivity investigations: alanine aminotransferase decreased, alanine aminotransferase increased, aspartate aminotransferase decreased, aspartate aminotransferase increased, blood amylase increased, blood creatinine increased, blood in stool, blood potassium abnormal, blood pressure increased gamma glutamyltransferase increased metabolism and nutrition disorders: appetite decreased, dehydration nervous system disorders: ataxia, disturbance in attention, dysarthria, gait abnormal, headache aggravated, mental impairment, sedation, seizure, sleep apnea syndrome, syncope, tremor psychiatric disorders: abnormal behavior, agitation, anxiety, confusion, depression, emotional disturbance, euphoric mood, indifference, irritability, libido decreased, nervousness, sleep disorder renal and urinary disorders: difficulty in micturition, urinary hesitation, urinary retention reproductive system and breast disorders: erectile dysfunction, sexual dysfunction respiratory, thoracic and mediastinal disorders: dyspnea skin and subcutaneous tissue disorders: allergic dermatitis, cold sweat, dermatitis, night sweats, pallor, generalized pruritus, urticaria vascular disorders: flushing, hypertension, hypotension, orthostatic hypotension postmarketing experience the following adverse reactions have been identified during post approval use of tramadol. because these reactions are 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. serotonin syndrome: cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. adrenal insufficiency: cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. anaphylaxis: anaphylaxis has been reported with ingredients contained in tramadol hydrochloride extended-release tablets. androgen deficiency: cases of androgen deficiency have occurred with chronic use of opioids [see clinical pharmacology]. hyponatremia: cases of severe hyponatremia and/or siadh have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see precautions]. hypoglycemia: cases of hypoglycemia have been reported in patients taking tramadol. most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see precautions]. drug abuse and dependence controlled substance tramadol hydrochloride extended-release tablets contain tramadol, a schedule iv controlled substance. abuse tramadol hydrochloride extended-release tablets contain tramadol, a substance with a high potential for abuse similar to other opioids. tramadol hydrochloride extended-release tablets can be abused and is subject to misuse, addiction, and criminal diversion [see warnings]. all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects. drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “drug-seeking” behavior is very common in persons with substance use disorders. drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care providers. “doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. abuse and addiction are separate and distinct from physical dependence and tolerance. health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. in addition, abuse of opioids can occur in the absence of true addiction. tramadol hydrochloride extended-release tablets, can be diverted for non-medical use into illicit channels of distribution. careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. risks specific to abuse of tramadol hydrochloride extended-release tablets tramadol hydrochloride extended-release tablets are for oral use only. the abuse of tramadol hydrochloride extended-release tablets poses a risk of overdose and death the risk is increased with concurrent use of tramadol hydrochloride extended-release tablets with alcohol and other central nervous system depressants. with intravenous abuse the inactive ingredients in tramadol hydrochloride extended-release tablets can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, and increased risk of endocarditis and valvular heart injury. parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and hiv. dependence both tolerance and physical dependence can develop during chronic opioid therapy. tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. do not abruptly discontinue tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids. rapid tapering of tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. when discontinuing tramadol hydrochloride extended-release tablets, gradually taper the dosage using a patient specific plan that considers the following: the dose of tramadol hydrochloride extended-release tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. to improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. in patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see dosage and administration, warnings]. infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see precautions; pregnancy].

inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. these mechanisms may contribute independently to the overall analgesic profile of tramadol. apart from analgesia, tramadol hydrochloride administration may produce various symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. in contrast to morphine, tramadol has not been shown to cause histamine release. at therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. orthostatic hypotension has been observed. pharmacodynamics effects on the central nervous system tramadol produces respiratory depression by direct action on brain stem respiratory centers. the respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. tramadol causes miosis, even in total darkness. pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. effects on the gastrointestinal tract and other smooth muscle tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. digestion of food in the small intestine is delayed and propulsive contractions are decreased. propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of oddi, and transient elevations in serum amylase. effects on the cardiovascular system tramadol produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. effects on the endocrine system opioids inhibit the secretion of adrenocorticotropic hormone (acth), cortisol, and luteinizing hormone (lh) in humans [see adverse reactions]. they also stimulate prolactin, growth hormone (gh) secretion, and pancreatic secretion of insulin and glucagon. chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. the causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see adverse reactions]. effects on the immune system opioids have been shown to have a variety of effects on components of the immune system. the clinical significance of these findings is unknown. overall, the effects of opioids appear to be modestly immunosuppressive. concentration–efficacy relationships the minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent opioid agonists. the minimum effective analgesic concentration of tramadol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see dosage and administration]. concentration–adverse reaction relationships there is a relationship between increasing tramadol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, cns effects, and respiratory depression. in opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see dosage and administration]. pharmacokinetics tramadol hydrochloride extended-release tablets are formulated as a racemate and both tramadol and m1 are detected in the circulation. the pharmacokinetics of tramadol and m1 are dose-proportional over a 100 to 300 mg dose range in healthy subjects. absorption the median time to peak plasma concentrations of tramadol and m1 after multiple-dose administration of a tramadol hydrochloride extended-release tablet 200 mg to healthy subjects are attained at about 4 h and 5 h, respectively (table 1 and figure 1). the pharmacokinetic parameter values of a tramadol hydrochloride extended-release tablet 200 mg administered once daily and tramadol immediate-release 50 mg administered every six hours are provided in table 1. the relative bioavailability of a 200 mg tramadol hydrochloride extended-release tablet compared to a 50 mg immediate-release tablet dosed every six hours was approximately 95% in healthy subjects. table 1. mean (%cv) steady-state pharmacokinetic parameter values (n=26). pharmacokinetic parameter tramadol m1 metabolite tramadol hydrochloride extended-release 200 mg tablet once-daily immediate- release tramadol 50 mg tablet every 6 hours tramadol hydrochloride extended-release 200 mg tablet once-daily immediate- release tramadol 50 mg tablet every 6 hours auc0-24 (ng·h/ml) 5991 (22) 6399 (28) 1361 (27) 1438 (23) cmax (ng/ml) 345 (21) 423 (23) 71 (27) 79 (22) cmin (ng/ml) 157 (31) 190 (34) 41 (30) 50 (29) tmax (hr)* 4.0 (3.0 to 9.0) 1.0 (1.0 to 3.0) 5.0 (3.0 to 20) 1.5 (1.0 to 3.0) fluctuation (%) 77 (26) 91 (22) 53 (29) 49 (26) * tmax is presented as median (range) steady-state plasma concentrations are reached within approximately 48 hours. figure 1. mean tramadol plasma concentrations at steady state following five days of oral administration of a tramadol hydrochloride extended-release tablet 200 mg once daily and immediate-release tramadol 50 mg every 6 hours. figure 2. mean m1 plasma concentrations at steady state following five days of oral administration of a tramadol hydrochloride extended-release tablet 200 mg once daily and immediate-release tramadol 50 mg every 6 hours food effect coadministration with a high fat meal did not significantly affect auc (overall exposure to tramadol); however, cmax (peak plasma concentration) increased 67% following a single 300 mg tablet administration and 54% following a single 200 mg tablet administration. tramadol hydrochloride extended-release tablets were administered without regard to food in all clinical trials. distribution the volume of distribution of tramadol is 2.6 and 2.9 l/kg in males and females, respectively, following a 100 mg intravenous dose. the binding of tramadol to human plasma proteins is approximately 20%. protein binding also appears to be independent of concentration up to 10 mcg/ml. saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. elimination after single administration of tramadol hydrochloride extended-release tablets, the mean terminal plasma elimination half-lives of racemic tramadol and racemic m1 are 6.5 ± 1.5 and 7.5 ± 1.4 hours, respectively. metabolism tramadol is extensively metabolized after oral administration. the major metabolic pathways appear to be n- and o-demethylation and glucuronidation or sulfation in the liver. n-demethylation is mediated by cyp3a4 and cyp2b6. one metabolite (o-desmethyltramadol, denoted m1) is pharmacologically active in animal models. formation of m1 is dependent on cyp2d6 and as such is subject to inhibition and polymorphism, which may affect the therapeutic response [see precautions - drug interactions]. excretion approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. the remainder is excreted either as unidentified or as unextractable metabolites. special populations hepatic impairment the metabolism of tramadol and m1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve (auc) for tramadol and longer mean tramadol and m1 elimination half-lives (13 hours for tramadol and 19 hours for m1) after the administration of tramadol immediate-release tablets. tramadol hydrochloride extended-release tablets have not been studied in patients with hepatic impairment. the limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release tablets do not permit the dosing flexibility required for safe use in patients with hepatic impairment. therefore, tramadol hydrochloride extended-release tablets should not be used in patients with hepatic impairment [see warnings, use in renal and hepatic disease and dosage and administration]. renal impairment impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, m1 in patients taking an immediate-release formulation of tramadol. tramadol hydrochloride extended-release tablets have not been studied in patients with renal impairment. the limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release tablets do not permit the dosing flexibility required for safe use in patients with severe renal impairment. therefore, tramadol hydrochloride extended-release tablets should not be used in patients with severe renal impairment (creatinine clearance less than 30 ml/min) [see warnings, use in renal and hepatic disease and dosage and administration]. the total amount of tramadol and m1 removed during a 4-hour dialysis period is less than 7% of the administered dose. geriatric patients healthy elderly subjects aged 65 to 75 years administered an immediate-release formulation of tramadol, have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. in subjects over 75 years, mean maximum plasma concentrations are elevated (208 vs. 162 ng/ml) and the mean elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. adjustment of the daily dose is recommended for patients older than 75 years [see dosage and administration]. sex following a 100 mg iv dose of tramadol, plasma clearance was 6.4 ml/min/kg in males and 5.7 ml/min/kg in females. following a single oral dose of immediate-release tramadol, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. the clinical significance of this difference is unknown. drug interaction studies potential for tramadol to affect other drugs in vitro studies indicate that tramadol is unlikely to inhibit the cyp3a4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses. tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data. poor/extensive metabolizers, cyp2d6 the formation of the active metabolite of tramadol, m1, is mediated by cyp2d6, a polymorphic enzyme. approximately 7% of the population has reduced activity of cyp2d6. these individuals are "poor metabolizers" of debrisoquine, dextromethorphan and tricyclic antidepressants, among other drugs. in studies in healthy subjects administered immediate-release tramadol products, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus “extensive metabolizers”, while m1 concentrations were 40% lower. cyp2d6 inhibitors in vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of cyp2d6 such as (fluoxetine paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol. quinidine quinidine is a selective inhibitor of cyp2d6, so that concomitant administration of quinidine and tramadol hydrochloride extended-release tablets may result in increased concentrations of tramadol and reduced concentrations of m1. the clinical consequences of these findings are unknown [see precautions]. in vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. cyp3a4 inhibitors and inducers tramadol is also metabolized by cyp3a4. administration of cyp3a4 inhibitors such as ketoconazole and erythromycin, or inducers, such as rifampin and st. john’s wort, with tramadol hydrochloride extended-release tablets may affect the metabolism of tramadol leading to altered tramadol exposure [see precautions]. cimetidine concomitant administration of tramadol immediate-release tablets with cimetidine, a weak cyp3a4 inhibitor, does not result in clinically significant changes in tramadol pharmacokinetics. no alteration of the tramadol hydrochloride extended-release tablets dosage regimen with cimetidine is recommended. carbamazepine carbamazepine, a cyp3a4 inducer, increases tramadol metabolism. patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended [see precautions]. fig 1 fig 2

ing the randomized period of the study, with more patients discontinuing from the tramadol hydrochloride extended-release tablets arm than the placebo arm due to adverse events (10% vs. 5%, respectively) and more patients discontinuing from the placebo arm than the tramadol hydrochloride extended-release tablets arm due to lack of efficacy (10% vs. 8%, respectively). patients treated with tramadol hydrochloride extended-release tablets demonstrated a greater improvement in pain intensity, measured on an 11-point numerical rating scale, at the end of treatment compared to patients randomized to placebo. figure 3 shows the fraction of patients achieving various degree of improvement in pain from baseline to the end of treatment (week 12). the figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. patients who did not complete the study were assigned 0% improvement. figure 3. proportion of patients achieving various levels of pain relief as measured by 12-week pain intensity. fig 3