upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well. seizure risk seizures have been reported in patients receiving tramadol within the recommended dosage range. spontaneous postmarketing 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 reuptake inhibitors (ssri antidepressants or anorectics), • tricyclic antidepressants (tcas), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or • other opioids. administration of tramadol may enhance the seizure risk in patients taking: • mao inhibitors (see also warnings, use with mao inhibitors and serotonin re-uptake inhibitors), • neuroleptics, or • other drugs that reduce the seizure threshold. risk of convulsions 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, or cns infections). in tramadol overdose, naloxone administration may increase the risk of seizure. suicide risk • do not prescribe tramadol hydrochloride and acetaminophen tablets for patients who are suicidal or addiction-prone. • prescribe tramadol hydrochloride and acetaminophen tablets with caution for patients taking tranquilizers or antidepressant drugs 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 non-narcotic 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 and acetaminophen tablets, 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). hypersensitivity/ anaphylaxis serious and rarely fatal anaphylactic 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 hydrochloride and acetaminophen tablets (see contraindications ). there have been postmarketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. clinical signs include swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritis, and vomiting. there were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. instruct patients to discontinue tramadol hydrochloride and acetaminophen tablets immediately and seek medical care if they experience these symptoms. do not prescribe tramadol hydrochloride and acetaminophen tablets for patients with acetaminophen allergy. respiratory depression administer tramadol hydrochloride and acetaminophen tablets cautiously in patients at risk for respiratory depression. in these patients, alternative non-opioid analgesics should be considered. when large doses of tramadol 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 and acetaminophen tablets 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 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 and acetaminophen tablets 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 reactions when evaluating altered mental status in these patients if they are receiving tramadol hydrochloride and acetaminophen tablets (see warnings, respiratory depression ). use in ambulatory patients tramadol 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 and acetaminophen tablets with great caution in patients taking monoamine oxidase inhibitors. animal studies have shown increased deaths with combined administration of mao inhibitors and tramadol. concomitant use of tramadol with mao inhibitors or ssri’s increases the risk of adverse events, including seizure and serotonin syndrome. use with alcohol tramadol hydrochloride and acetaminophen tablets should not be used concomitantly with alcohol consumption. the use of tramadol hydrochloride and acetaminophen tabletsin patients with liver disease is not recommended. use with other acetaminophen-containing products due to the potential for acetaminophen hepatotoxicity at doses higher than the recommended dose, tramadol hydrochloride and acetaminophen tablets should not be used concomitantly with other acetaminophen-containing products. misuse, abuse and diversion tramadol has mu-opioid agonist activity. tramadol hydrochloride and acetaminophen tablets, a tramadol-containing product, 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 and acetaminophen tablets 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, tricyclic 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 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 ). a serious potential consequence of overdosage with acetaminophen is hepatic (centrilobular) necrosis, leading to hepatic failure and death. emergency help should be sought immediately and treatment initiated immediately if overdose is suspected, even if symptoms are not apparent. withdrawal withdrawal symptoms may occur if tramadol hydrochloride and acetaminophen tablets are 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 hydrochloride and acetaminophen tabletdiscontinuation include: panic attacks, severe anxiety, and paresthesias. clinical experience suggests that withdrawal symptoms may be avoided by tapering tramadol hydrochloride and acetaminophen tablets at the time of discontinuation.

gue, hot flushes central and peripheral nervous system – dizziness, headache, tremor gastrointestinal system – abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting psychiatric disorders – anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence skin and appendages – pruritus, rash, increased sweating. selected adverse events occurring at less than 1% : the following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in tramadol hydrochloride and acetaminophen tablets clinical trials. body as a whole – chest pain, rigors, syncope, withdrawal syndrome cardiovascular disorders – hypertension, aggravated hypertension, hypotension central and peripheral nervous system – ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo gastrointestinal system – dysphagia, melena, tongue edema hearing and vestibular disorders – tinnitus heart rate and rhythm disorders – arrhythmia, palpitation, tachycardia liver and biliary system – hepatic function abnormal metabolic and nutritional disorders – weight decrease psychiatric disorders – amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, abnormal thinking red blood cell disorders – anemia respiratory system – dyspnea urinary system – albuminuria, micturition disorder, oliguria, urinary retention vision disorders – abnormal vision other clinically significant adverse experiences previously reported with tramadol hydrochloride: other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, stevens-johnson syndrome/tens), cognitive dysfunction, difficulty concentrating, depression, suicidal tendency, hepatitis, liver failure and gastrointestinal bleeding. reported laboratory abnormalities included elevated creatinine and liver function tests. serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as ssris and maois. other clinically significant adverse experiences previously reported with acetaminophen: allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to acetaminophen are rare and generally controlled by discontinuation of the drug and, when necessary, symptomatic treatment.

ative contribution of both tramadol and m1 to human analgesia is dependent upon the plasma concentrations of each compound (see clinical pharmacology, pharmacokinetics) . tramadol has been 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. apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. acetaminophen is a non-opiate, non-salicylate analgesic. pharmacokinetics tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and m1 are detected in the circulation. the pharmacokinetics of plasma tramadol and acetaminophen following oral administration of one tramadol hydrochloride and acetaminophen tablet are shown in table 1. tramadol has a slower absorption and longer half-life when compared to acetaminophen. table 1: summary of mean (±sd) pharmacokinetic parameters of the (+)- and (-) enantiomers of tramadol and m1 and acetaminophen following a single oral dose of one tramadol hydrochloride and acetaminophen combination tablet (37.5 mg/325 mg) in volunteers. parameter a (+)-tramadol (-)-tramadol (+)-m1 (-)-m1 acetaminophen c max (ng/ml) 64.3 (9.3) 55.5 (8.1) 10.9 (5.7) 12.8 (4.2) 4.2 (0.8) t max (h) 1.8 (0.6) 1.8 (0.7) 2.1 (0.7) 2.2 (0.7) 0.9 (0.7) cl/f (ml/min) 588 (226) 736 (244) - - - - 365 (84) t ½ (h) 5.1 (1.4) 4.7 (1.2) 7.8 (3) 6.2 (1.6) 2.5 (0.6) a for acetaminophen, c max was measured as mcg/ml. a single dose pharmacokinetic study of tramadol hydrochloride and acetaminophen tablets in volunteers showed no drug interactions between tramadol and acetaminophen. upon multiple oral dosing to steady-state, however, the bioavailability of tramadol and metabolite m1 was lower for the combination tablets compared to tramadol administered alone. the decrease in auc was 14% for (+)-tramadol, 10.4% for (-)-tramadol, 11.9% for (+)-m1 and 24.2% for (-)-m1. the cause of this reduced bioavailability is not clear. following single- or multiple-dose administration of tramadol hydrochloride and acetaminophen tablets, no significant change in acetaminophen pharmacokinetics was observed when compared to acetaminophen given alone. absorption the absolute bioavailability of tramadol from tramadol hydrochloride and acetaminophen tablets has not been determined. tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of tramadol hydrochloride tablets. the mean peak plasma concentration of racemic tramadol and m1 after administration of two tramadol hydrochloride and acetaminophen tablets occurs at approximately two and three hours, respectively, post-dose. peak plasma concentrations of acetaminophen occur within one hour and are not affected by co-administration with tramadol. oral absorption of acetaminophen following administration of tramadol hydrochloride and acetaminophen tablets occurs primarily in the small intestine. food effects when tramadol hydrochloride and acetaminophen tablets were administered with food, the time to peak plasma concentration was delayed for approximately 35 minutes for tramadol and almost one hour for acetaminophen. however, peak plasma concentrations, and the extents of absorption, of tramadol and acetaminophen were not affected. the clinical significance of this difference is unknown. distribution the volume of distribution of tramadol was 2.6 and 2.9 l/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. acetaminophen appears to be widely distributed throughout most body tissues except fat. its apparent volume of distribution is about 0.9 l/kg. a relative small portion (~20%) of acetaminophen is bound to plasma protein. metabolism following oral administration, tramadol is extensively metabolized 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 major metabolic pathways appear to be n - and o - demethylation and glucuronidation or sulfation in the liver. metabolite m1 ( o -desmethyltramadol) 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 p450. these individuals are “poor metabolizers” of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. based on a population pk analysis of phase 1 studies in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers”, while m1 concentrations were 40% lower. in vitro drug interaction studies in human liver microsomes indicates that inhibitors of cyp2d6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees. 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. acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: a) conjugation with glucuronide; b) conjugation with sulfate; and c) oxidation via the cytochrome, p450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. the principal cytochrome p450 isoenzyme involved appears to be cyp2e1, with cyp1a2 and cyp3a4 as additional pathways. in adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. these glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity. in premature infants, newborns, and young infants, the sulfate conjugate predominates. elimination tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. the plasma elimination half-lives of racemic tramadol and m1 are approximately 5 to 6 and 7 hours, respectively, after administration of tramadol hydrochloride and acetaminophen tablets. the apparent plasma elimination half-life of racemic tramadol increased to 7 to 9 hours upon multiple dosing of tramadol hydrochloride and acetaminophen tablets. the half-life of acetaminophen is about 2 to 3 hours in adults. it is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. less than 9% of acetaminophen is excreted unchanged in the urine. special populations renal the pharmacokinetics of tramadol hydrochloride and acetaminophen in patients with renal impairment has not been studied. based on studies using tramadol alone, excretion of tramadol and metabolite m1 is reduced in patients with creatinine clearance of less than 30 ml/min. adjustment of dosing regimen in this patient population 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 based on studies using tramadol alone. hepatic the pharmacokinetics and tolerability of tramadol hydrochloride and acetaminophen in patients with impaired hepatic function has not been studied. since tramadol and acetaminophen are both extensively metabolized by the liver, the use of tramadol hydrochloride and acetaminophen in patients with hepatic impairment is not recommended (see precautions and dosage and administration ). geriatric a population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain treated with tramadol hydrochloride and acetaminophen, which included 55 patients between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes in pharmacokinetics of tramadol and acetaminophen in elderly patients with normal renal and hepatic function (see precautions, geriatric use ). gender tramadol clearance was 20% higher in female subjects compared to males on four phase i studies of tramadol hydrochloride and acetaminophen in 50 male and 34 female healthy subjects. the clinical significance of this difference is unknown. pediatric the pharmacokinetics of tramadol hydrochloride and acetaminophen tablets has not been studied in pediatric patients below 16 years of age. clinical studies single-dose studies for treatment of acute pain in pivotal single-dose studies in acute pain, two tablets of tramadol hydrochloride and acetaminophen administered to patients with pain following oral surgical procedures provided greater relief than placebo or either of the individual components given at the same dose. the onset of pain relief after tramadol hydrochloride and acetaminophen was faster than tramadol alone. onset of analgesia occurred in less than one hour. the duration of pain relief after tramadol hydrochloride and acetaminophen tablets was longer than acetaminophen alone. analgesia was generally comparable to that of the comparator, ibuprofen.