but use in such patients necessitates intensive counseling about the risks and proper use of tramadol along with intensive monitoring for signs of addiction, abuse, and misuse. 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. 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. 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 (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 tramadol, 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. to reduce the risk of respiratory depression, proper dosing and titration of tramadol are essential (see dosage and administration ). overestimating the tramadol 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, especially by children, can result in respiratory depression and death due to an overdose of tramadol. neonatal opioid withdrawal syndrome prolonged use of tramadol 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 are complex. use of cytochrome p450 3a4 inducers, 3a4 inhibitors, or 2d6 inhibitors with tramadol requires 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 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 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 is used in conjunction with inhibitors of cyp2d6 (see precautions; drug interactions ). cytochrome p450 3a4 interaction the concomitant use of tramadol 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 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 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 is used in conjunction with inhibitors and inducers of cyp3a4 (see precautions; drug interactions ). risks from concomitant use with benzodiazepines or other cns depressants profound sedation, respiratory depression, coma, and death may result from the concomitant use of tramadol 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. advise both patients and caregivers about the risks of respiratory depression and sedation when tramadol is 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; drug interactions, information for patients/caregivers ). serotonin syndrome risk cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, particularly during concomitant use 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), 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 if serotonin syndrome is suspected. increased risk of seizure seizures have been reported in patients receiving tramadol within the recommended dosage range. spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. concomitant use of tramadol increases the seizure risk in patients taking: • selective serotonin re-uptake inhibitors (ssri antidepressants or anorectics), • tricyclic antidepressants (tcas), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or • other opioids, • mao inhibitors (see also warnings, serotonin syndrome risk ), • neuroleptics, or • other drugs that reduce the seizure threshold. risk of seizure 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, metabolic disorders, alcohol and drug withdrawal, cns infections). in tramadol overdose, naloxone administration may increase the risk of seizure. suicide risk • do not prescribe tramadol 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 tablets with caution for patients with a history of misuse and/or are currently taking cns-active drugs including tranquilizers or antidepressant drugs, alcohol in excess, and patients who suffer from emotional disturbance or depression (see precautions; drug interactions ). • inform patients not to exceed the recommended dose and to limit their intake of alcohol (see dosage and administration ). 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. life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients the use of tramadol 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 -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 tramadol (see warnings ). 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 ). monitor such patients closely, particularly when initiating and titrating tramadol and when tramadol is given concomitantly with other drugs that depress respiration (see warnings ). alternatively, consider the use of non-opioid analgesics in these patients. severe hypotension tramadol 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 precautions; drug interactions ). monitor these patients for signs of hypotension after initiating or titrating the dosage of tramadol. in patients with circulatory shock, tramadol may cause vasodilation that can further reduce cardiac output and blood pressure. avoid the use of tramadol in patients 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 co 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), tramadol may reduce respiratory drive, and the resultant co 2 retention can further increase intracranial pressure. monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with tramadol. opioids may also obscure the clinical course in a patient with a head injury. avoid the use of tramadol in patients with impaired consciousness or coma. risks of use in patients with gastrointestinal conditions tramadol is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus (see contraindications ). the tramadol in tramadol hydrochloride 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 anaphylactoid reactions have been reported in patients receiving therapy with tramadol. when these events do occur it is often following the first dose. other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and stevens-johnson syndrome. patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive tramadol (see contraindications ). if anaphylaxis or other hypersensitivity occurs, stop administration of tramadol immediately, discontinue tramadol 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 , precautions; information for patients ). withdrawal 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. in these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. when discontinuing tramadol in a physically-dependent patient, gradually taper the dosage (see dosage and administration ). do not abruptly discontinue tramadol in these patients (see drug abuse and dependence ). risks of driving and operating machinery tramadol 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 and know how they will react to the medication.

50 mg as tolerated every 3 days to reach 200 mg/day (50 mg four times a day). after titration, tramadol hydrochloride tablets usp 50 to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day . for the subset of patients for whom rapid onset of analgesic effect is required and for whom the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses, tramadol hydrochloride tablets usp 50 mg to 100 mg can be administered as needed for pain relief every four to six hours, not to exceed 400 mg per day . conversion from tramadol to extended-release tramadol the relative bioavailability of tramadol compared to extended-release tramadol is unknown, so conversion to extended-release formulations must be accompanied by close observation for signs of excessive sedation and respiratory depression. dosage modification in patients with hepatic impairment the recommended dose for adult patients with cirrhosis is 50 mg every 12 hours. dosage modification in patients with renal impairment in all patients with creatinine clearance less than 30 ml/min, it is recommended that the dosing interval of tramadol be increased to 12 hours, with a maximum daily dose of 200 mg. since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis. dosage modification in geriatric patients in general, dose selection for an elderly patient over 65 years old should be cautious, 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. for elderly patients over 75 years old, total dose should not exceed 300 mg/day. titration and maintenance of therapy individually titrate tramadol to a dose that provides adequate analgesia and minimizes adverse reactions. continually reevaluate patients receiving tramadol 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. if the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the tramadol 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. discontinuation of tramadol when a patient who has been taking tramadol hydrochloride tablets regularly and may be physically dependent no longer requires therapy with tramadol, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. if the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. do not abruptly discontinue tramadol in a physically-dependent patient (see warnings , drug abuse and dependence ).

ice. tramadol was administered to 550 patients during the double-blind or open-label extension periods in u.s. studies of chronic nonmalignant pain. of these patients, 375 were 65 years old or older. table 2 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). the most frequently reported events were in the central nervous system and gastrointestinal system. although the reactions listed in the table are felt to be probably related to tramadol administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication. the overall incidence rates of adverse experiences in these trials were similar for tramadol and the active control groups, tylenol with codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the tramadol groups. table 2: cumulative incidence of adverse reactions for tramadol in chronic trials of nonmalignant pain (n=427) up to 7 days up to 30 days up to 90 days dizziness/vertigo 26% 31% 33% nausea 24% 34% 40% constipation 24% 38% 46% headache 18% 26% 32% somnolence 16% 23% 25% vomiting 9% 13% 17% pruritus 8% 10% 11% “cns stimulation” “cns stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations 7% 11% 14% asthenia 6% 11% 12% sweating 6% 7% 9% dyspepsia 5% 9% 13% dry mouth 5% 9% 10% diarrhea 5% 6% 10% incidence 1% to less than 5% possibly causally related: the following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with tramadol exists. body as a whole: malaise. cardiovascular: vasodilation. central nervous system: anxiety, confusion, coordination disturbance, euphoria, miosis, nervousness, sleep disorder. gastrointestinal: abdominal pain, anorexia, flatulence. musculoskeletal: hypertonia. skin: rash. special senses: visual disturbance. urogenital: menopausal symptoms, urinary frequency, urinary retention. incidence less than 1%, possibly causally related: the following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials of tramadol and/or reported in post-marketing experience with tramadol-containing products. body as a whole: accidental injury, allergic reaction, anaphylaxis, death, suicidal tendency, weight loss, serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma). cardiovascular: orthostatic hypotension, syncope, tachycardia. central nervous system: abnormal gait, amnesia, cognitive dysfunction, delirium, depression, difficulty in concentration, hallucinations, movement disorder, paresthesia, seizure, speech disorder, tremor. metabolism and nutrition disorders: cases of hypoglycemia have been reported very rarely in patients taking tramadol. most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients. respiratory: dyspnea. skin: stevens-johnson syndrome/toxic epidermal necrolysis, urticaria, vesicles. special senses: dysgeusia, mydriasis. urogenital: dysuria, menstrual disorder. other adverse experiences, causal relationship unknown: a variety of other adverse events were reported infrequently in patients taking tramadol during clinical trials and/or reported in post-marketing experience. a causal relationship between tramadol and these events has not been determined. however, the most significant events are listed below as alerting information to the physician. cardiovascular: abnormal ecg, hypertension, hypotension, myocardial ischemia, palpitations, pulmonary edema, pulmonary embolism. central nervous system: migraine. gastrointestinal: gastrointestinal bleeding, hepatitis, stomatitis, liver failure. laboratory abnormalities: creatinine increase, elevated liver enzymes, hemoglobin decrease, proteinuria. sensory: cataracts, deafness, tinnitus. postmarketing experience 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. androgen deficiency : cases of androgen deficiency have occurred with chronic use of opioids (see clinical pharmacology ).

shown to 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. analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours. 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 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. they also stimulate prolactin, growth hormone (gh) secretion, and pancreatic secretion of insulin and glucagon (see warnings , adverse reactions ). 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 in in vitro and animal models. 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 the analgesic activity of tramadol is due to both parent drug and the m1 metabolite (see clinical pharmacology; pharmacodynamics ). tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and m1 are detected in the circulation. linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state. absorption the mean absolute bioavailability of a 100 mg oral dose is approximately 75%. the mean peak plasma concentration of racemic tramadol and m1 occurs at two and three hours, respectively, after administration in healthy adults. in general, both enantiomers of tramadol and m1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present. steady-state plasma concentrations of both tramadol and m1 are achieved within two days with four times per day dosing. there is no evidence of self-induction (see figure 1 and table 1 below). figure 1: mean tramadol and m1 plasma concentration profiles after a single 100 mg oral dose and after twenty-nine 100 mg oral doses of tramadol hcl given four times per day. table 1: mean (%cv) pharmacokinetic parameters for racemic tramadol and m1 metabolite population/ dosage regimen sd = single dose, md = multiple dose, p.o.= oral administration, i.v.= intravenous administration, q.i.d. = four times daily parent drug/ metabolite peak conc. (ng/ml) time to peak (hrs) clearance/f f represents the oral bioavailability of tramadol (ml/min/kg) t 1/2 (hrs) healthy adults, 100 mg qid, md p.o. tramadol 592 (30) 2.3 (61) 5.90 (25) not applicable 6.7 (15) m1 110 (29) 2.4 (46) 7.0 (14) healthy adults, 100 mg sd p.o. tramadol 308 (25) 1.6 (63) 8.50 (31) 5.6 (20) m1 55.0 (36) 3.0 (51) 6.7 (16) geriatric, (>75 yrs) 50 mg sd p.o. tramadol m1 208 (31) not measured 2.1 (19) 6.89 (25) 7.0 (23) hepatic impaired, 50 mg sd p.o. tramadol 217 (11) 1.9 (16) 4.23 (56) 13.3 (11) m1 19.4 (12) 9.8 (20) 18.5 (15) renal impaired, clcr 10 to 30 ml/min 100 mg sd i.v. tramadol 4.23 (54) 10.6 (31) m1 11.5 (40) renal impaired, clcr < 5ml/min 100 mg sd i.v. tramadol 3.73 (17) 11.0 (29) m1 16.9 (18) food effects oral administration of tramadol with food does not significantly affect its rate or extent of absorption, therefore, tramadol can be administered without regard to food. figure 1 distribution the volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100 mg intravenous dose. the binding of tramadol to human plasma proteins is approximately 20% and 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 tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. the mean (%cv) apparent total clearance of tramadol after a single 100 mg oral dose is 8.50 (31) ml/min/kg. the mean terminal plasma elimination half-lives of racemic tramadol and racemic m1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. the plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing. metabolism tramadol is extensively metabolized after oral administration by a number of pathways, including cyp2d6 and cyp3a4, as well as by conjugation of parent and metabolites. 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. the major metabolic pathways appear to be n - and o- demethylation and glucuronidation or sulfation in the liver. 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, which may affect the therapeutic response (see precautions; drug interactions ). approximately 7% of the population has reduced activity of the cyp2d6 isoenzyme of cytochrome p-450. these individuals are “poor metabolizers” of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. based on a population pk analysis of phase i studies in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers”, while m1 concentrations were 40% lower. concomitant therapy with inhibitors of cyp2d6 such as fluoxetine, paroxetine and quinidine could result in significant drug interactions. in vitro drug interaction studies in human liver microsomes indicate that inhibitors of cyp2d6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of m1. the full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. concomitant use of serotonin re-uptake inhibitors and mao inhibitors may enhance the risk of adverse events, including seizure and serotonin syndrome (see warnings ). excretion tramadol metabolites are eliminated primarily by the kidneys. special populations hepatic impairment 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 for tramadol and longer tramadol and m1 elimination half-lives (13 hrs. for tramadol and 19 hrs. for m1). in cirrhotic patients, adjustment of the dosing regimen is recommended (see 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 with creatinine clearances of less than 30 ml/min, adjustment of the dosing regimen is recommended (see 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. age: geriatric healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. in subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/ml) and the 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 the absolute bioavailability of tramadol was 73% in males and 79% in females. the plasma clearance was 6.4 ml/min/kg in males and 5.7 ml/min/kg in females following a 100 mg iv dose of tramadol. following a single oral dose, 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. poor / extensive metabolizers, cyp2d6 the formation of the active metabolite, m1, is mediated by cyp2d6, a polymorphic enzyme. approximately 7% of the population has reduced activity of the cyp2d6 isoenzyme of cytochrome p450 metabolizing enzyme system. these individuals are “poor metabolizers” of debrisoquine, dextromethorphan and tricyclic antidepressants, among other drugs. based on a population pk analysis of phase 1 studies with ir tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers,” while m1 concentrations were 40% lower. 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. 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 (see precautions; drug interactions ). quinidine tramadol is metabolized to active metabolite m1 by cyp2d6. coadministration of quinidine, a selective inhibitor of cyp2d6, with tramadol extended-release tablets resulted in a 50 to 60% increase in tramadol exposure and a 50 to 60% decrease in m1 exposure. the clinical consequences of these findings are unknown. to evaluate the effect of tramadol, a cyp2d6 substrate on quinidine, an in vitro drug interaction study in human liver microsomes was conducted. the results from this study indicate that tramadol has no effect on quinidine metabolism (see warnings , precautions; drug interactions ). cyp3a4 inhibitors and inducers since tramadol is also metabolized by cyp3a4, administration of cyp3a4 inhibitors, such as ketoconazole and erythromycin, or cyp3a4 inducers, such as rifampin and st. john’s wort, with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure (see warnings , precautions; drug interactions ). cimetidine concomitant administration of tramadol ir tablets with cimetidine, a weak cyp3a4 inhibitor, does not result in clinically significant changes in tramadol pharmacokinetics. no alteration of the tramadol 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 and carbamazepine is not recommended.

with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (tylox) daily. titration trials in a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily tramadol dose of 200 mg (50 mg four times per day), attained in 50 mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration. in a second study with 54 to 59 patients per group, patients who had nausea or vomiting when titrated over 4 days were randomized to re-initiate tramadol therapy using slower titration rates. figure 2: protocol capss-047 figure 2