disorders, alcohol and drug withdrawal, cns infections). in tramadol hydrochloride overdose, naloxone administration may increase the risk of seizure. suicide risk do not prescribe tramadol hydrochloride for patients who are suicidal or addiction-prone. prescribe tramadol hydrochloride tablets with caution for patients who are taking tranquilizers or antidepressant drug and patients who use alcohol in excess and who suffer from emotional disturbance or depression. the judicious prescribing of tramadol is essential to the safe use of this drug. with patients who are depressed or suicidal, consideration should be given to the use of nonnarcotic analgesics. tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other cns-active drugs (see warnings, risk of overdosage ). serotonin syndrome risk the development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including tramadol hydrochloride, particularly with concomitant use of serotonergic drugs such as ssris, snris, tcas, maois, and triptans, with drugs which impair metabolism of serotonin (including maois), and with drugs which impair metabolism of tramadol (cyp2d6 and cyp3a4 inhibitors). this may occur within the recommended dose (see clinical pharmacology, pharmacokinetics ). serotonin syndrome 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) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). anaphylactoid reactions serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol hydrochloride. 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 hydrochloride (see contraindications ). respiratory depression administer tramadol hydrochoride cautiously in patients at risk for respiratory depression. in these patients alternative non-opioid analgesics should be considered. when large doses of tramadol hydrochloride are administered with anesthetic medications or alcohol, respiratory depression may result. respiratory depression should be treated as an overdose. if naloxone is to be administered, use cautiously because it may precipitate seizures (see warnings, seizure risk and overdosage ). interaction with central nervous system (cns) depressants tramadol hydrochloride should be used with caution and in reduced dosages when administered to patients receiving cns depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. tramadol hydrochloride increases the risk of cns and respiratory depression in these patients. interactions with alcohol and drugs of abuse tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. increased intracranial pressure or head trauma tramadol hydrochloride should be used with caution in patients with increased intracranial pressure or head injury. the respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol hydrochloride (see warnings, respiratory depression ). use in ambulatory patients tramadol hydrochloride may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. the patient using this drug should be cautioned accordingly. use with mao inhibitors and serotonin re-uptake inhibitors use tramadol hydrochloride with great caution in patients taking monoamine oxidase inhibitors. animal studies have shown increased deaths with combined administration. concomitant use of tramadol hydrochloride with mao inhibitors or ssri’s increases the risk of adverse events, including seizure and serotonin syndrome. misuse, abuse and diversion tramadol has mu-opioid agonist activity. tramadol hydrochloride® can be sought by drug abusers and people with addiction disorders and may be subject to criminal diversion. the possibility of illegal or illicit use should be considered when prescribing or dispensing tramadol hydrochloride® in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. misuse or abuse poses a significant risk to the abuser that could result in overdose and death (see drug abuse and dependence and overdosage ). concerns about abuse, addiction, and diversion should not prevent the proper management of pain. the development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. however, data are not available to establish the true incidence of addiction in chronic pain patients. risk of overdosage patients taking tramadol should be warned not to exceed the dose recommended by their physician. tramadol products in excessive doses, either alone or in combination with other cns depressants, including alcohol, are a cause of drug-related deaths. patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious cns additive effects of these agents. because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other cns depressant drugs. patients should be advised of the additive depressant effects of these combinations. serious potential consequences of overdosage with tramadol hydrochloride (tramadol hydrochloride) tablets are central nervous system depression, respiratory depression and death. some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. in treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see overdosage ). withdrawal withdrawal symptoms may occur if tramadol hydrochloride is discontinued abruptly (see also drug abuse and dependence). reported symptoms have included anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. other symptoms that have been reported less frequently with tramadol hydrchloride discontinuation include panic attacks, severe anxiety, and paresthesias. clinical experience suggests that withdrawal symptoms may be avoided by tapering tramadol hydrochloride at the time of discontinuation.

alized according to patient need using the lowest beneficial dose. studies with tramadol in adults have shown that starting at the lowest possible dose and titrating upward will result in fewer discontinuations and increased tolerability. in all patients with creatinine clearance less than 30 ml/min , it is recommended that the dosing interval of tramadol hydrochloride tablets 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. the recommended dose for adult patients with cirrhosis is 50 mg every 12 hours. 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.

awals due to adverse events appeared to be higher in the tramadol hydrochloride groups. table 2: cumulative incidence of adverse reactions for tramadol hydrochloride 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’ 1 7% 11% 14% asthenia 6% 11% 12% sweating 6% 7% 9% dyspepsia 5% 9% 13% dry mouth 5% 9% 10% diarrhea 5% 9% 10% 1 “cns stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations 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 hydrochloride 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 and/or reported in post-marketing experience. 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, depression, difficulty in concentration, hallucinations, paresthesia, seizure (see warnings ). tremor. respiratory: dyspnea. skin: stevens-johnson syndrome/toxic epidermal necrolysis, urticaria, vesicles. special senses: dysgeusia. urogenital: dysuria, menstrual disorder. other adverse experiences, causal relationship unknown: a variety of other adverse events were reported infrequently in patients taking tramadol hydrochloride during clinical trials and/or reported in post-marketing experience. a causal relationship between tramadol hydrochloride 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, speech disorders. gastrointestinal: gastrointestinal bleeding, hepatitis, stomatitis, liver failure. laboratory abnormalities: creatinine increase, elevated liver enzymes, hemoglobin decrease, proteinuria. sensory: cataracts, deafness, tinnitus.

en 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 hydrochloride. analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours. apart from analgesia, tramadol hydrochloride administration may produce a constellation of 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 hydrochloride has no effect on heart rate, left-ventricular function or cardiac index. orthostatic hypotension has been observed. pharmacokinetics the analgesic activity of tramadol hydrochloride 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 a parent drug/ metabolite peakconc. (ng/ml) time to peak (hrs) clearence/f b (ml/min/kg) t 1/2 (hrs) healthy adults, 100 mg qid, md p.o. tramadol m1 592 (30) 110 (29) 2.3 (61) 2.4 (46) 5.90 (25) c 6.7 (15) 7.0 (14) healthy adults, 100 mg sd p.o. tramadol m1 308 (25) 55.0 (36) 1.6 (63) 3.0 (51) 8.50 (31) c 5.6 (20) 6.7 (16) geriatric, (>75 yrs) 50 mg sd p.o. tramadol m1 208 (31) d 2.1 (19) d 6.89 (25) c 7.0 (23) d hepatic impaired, 50 mg sd p.o. tramadol m1 217 (11) 19.4 (12) 1.9 (16) 9.8 (20) 4.23 (56) c 13.3 (11) 18.5 (15) renal impaired, cl cr 10-30 ml/min 100 mg sd i.v tramadol m1 c c c c 4.23 (54) c 10.6 (31) 11.5 (40) renal impaired, cl cr <5ml/min 100 mg sd i.v tramadol m1 c c c c 3.73 (17) c 11.0 (29) 16.9 (18) a sd = single dose, md = multiple dose, p.o.= oral administration, i.v.= intravenous administration, q.i.d. = four times daily b f represents the oral bioavailability of tramadol c not applicable d not measured food effects oral administration of tramadol hydrochloride with food does not significantly affect its rate or extent of absorption, therefore, tramadol hydrochloride can be administered without regard to food. 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. 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 interaction ). 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 (see warnings ) and serotonin syndrome. elimination tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. 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. 7bb9a2e6-figure-02 special populations renal 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. hepatic 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 ). 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 ). gender 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.

e 30 mg (tylenol® with codeine #3) daily, five doses of aspirin 325 mg 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 hydrochloride 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. 7bb9a2e6-figure-03