ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS Tramadol hydrochloride 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 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 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 hydrochloride 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 hydrochloride and the active control groups, TYLENOL(R) with Codeine (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 hydrochloride groups.Table 2: Cumulative Incidence of Adverse Reactions for Tramadol Hydrochloride in Chronic Trials of Nonmalignant Pain (N=427) Up to Days Up to 30 Days Up to 90 DaysDizziness/Vertigo26%31%33%Nausea24%34%40%Constipation24%38%46%Headache18%26%32%Somnolence16%23%25%Vomiting9%13%17%Pruritus8%10%11%CNS Stimulation1 7%11%14%Asthenia6%11%12%Sweating6%7%9%Dyspepsia5%9%13%Dry Mouth5%9%10%Diarrhea5%9%10%1 CNS Stimulation is composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinationsIncidence 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 causal relationship with tramadol hydrochloride exists.Body as 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 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: variety of other adverse events were reported infrequently in patients taking tramadol hydrochloride during clinical trials and/or reported in post-marketing experience. 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.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY PHARMACODYNAMICS Tramadol Hydrochloride contains tramadol, centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to u-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin.Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to u-opioid receptors. In animal models, M1 is up to times more potent than tramadol in producing analgesia and 200 times more potent in u-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative 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 hydrochloride. Analgesia in humans begins approximately within one hour after administration and reaches peak in approximately two to three hours.Apart from analgesia, tramadol hydrochloride administration may produce 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 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.AbsorptionThe mean absolute bioavailability of 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 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 and Table below).Figure 1: Mean Tramadol and M1 Plasma Concentration Profiles after Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given four times per yearTable Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite Population/Dosage Regimena Parent Drug/Metabolite PeakConc.(ng/mL) Time to Peak (hrs) Clearence/Fb (mL/min/Kg) t1/2 (hrs)Healthy Adults,100 mg qid, MD p.o.TramadolM1592 (30)110 (29)2.3 (61)2.4 (46)5.90 (25)c6.7 (15)7.0 (14)Healthy Adults,100 mg SD p.o.TramadolM1308 (25)55.0 (36)1.6 (63)3.0 (51)8.50 (31)c5.6 (20)6.7 (16)Geriatric, (>75 yrs)50 mg SD p.o.TramadolM1208 (31)d2.1 (19)d6.89 (25)c7.0 (23)dHepatic Impaired,50 mg SD p.o.TramadolM1217 (11)19.4 (12)1.9 (16)9.8 (20)4.23 (56)c13.3 (11)18.5 (15)Renal Impaired,CLcr10-30 mL/min100 mg SD i.vTramadolM1cccc4.23 (54)c10.6 (31)11.5 (40)Renal Impaired,CLcr<5mL/min100 mg SD i.vTramadolM1cccc3.73 (17)c11.0 (29)16.9 (18)a SD Single dose, MD Multiple dose, p.o.= Oral administration, i.v.= Intravenous administration, q.i.d. Four times dailyb represents the oral bioavailability of tramadolc Not applicabled Not measuredFood EffectsOral 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.DistributionThe volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following 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 ug/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.MetabolismTramadol is extensively metabolized after oral administration by 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 population PK analysis of Phase 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.EliminationTramadol 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.. Figure 1. Special Populations RenalImpaired renal function results in 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 4-hour dialysis period is less than 7% of the administered dose.HepaticMetabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both 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).GeriatricHealthy 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. 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).GenderThe 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 100 mg IV dose of tramadol. Following single oral dose, and after adjusting for body weight, females had 12% higher peak tramadol concentration and 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE ADMINISTRATION Adults (17 years of age and over) For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the tolerability of tramadol hydrochloride tablets can be improved by initiating therapy with the following titration regimen: tramadol hydrochloride tablets should be started at 25 mg/day qAM and titrated in 25 mg increments as separate doses every days to reach 100 mg/day (25 mg q.i.d.). Thereafter the total daily dose may be increased by 50 mg as tolerated every days to reach 200 mg/day (50 mg q.i.d.). After titration, tramdol hydrochloride tablets 50 to 100 mg can be administered as needed for pain relief every to 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, tramdol hydrochloride tablets 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. Individualization of Dose Good pain management practice dictates that the dose be individualized 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.oIn 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 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.oThe recommended dose for adult patients with cirrhosis is 50 mg every 12 hours.oIn 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.. oIn 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 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.. oThe recommended dose for adult patients with cirrhosis is 50 mg every 12 hours.. oIn 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.

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE Abuse Tramadol has mu-opioid agonist activity. Tramadol hydrochloride tablets can be abused and may be subject to criminal diversion.Addiction is primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. Drug addiction is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm, and craving. Drug addiction is treatable disease, utilizing multidisciplinary approach, but relapse is common.Drug-seeking behavior is very common in addicts and drug abusers. 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 physician(s). Doctor shopping to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of ULTRAM(R) can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances.Concerns about abuse and addiction should not prevent the proper management of pain. However all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.Proper assessment of the patient and periodic re-evaluation of therapy are appropriate measures that help to limit the potential abuse of this product.Tramadol hydrochloride tablets is intended for oral use only.Dependence Tolerance is the need for increasing doses of drugs to maintain defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of drug or upon administration of an antagonist (see also WARNINGS, Withdrawal).The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other 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.Generally, tolerance and/or withdrawal are more likely to occur the longer patient is on continuous therapy with tramadol hydrochloride tablets.

PHARMACOKINETICS SECTION.

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 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.AbsorptionThe mean absolute bioavailability of 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 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 and Table below).Figure 1: Mean Tramadol and M1 Plasma Concentration Profiles after Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given four times per yearTable Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite Population/Dosage Regimena Parent Drug/Metabolite PeakConc.(ng/mL) Time to Peak (hrs) Clearence/Fb (mL/min/Kg) t1/2 (hrs)Healthy Adults,100 mg qid, MD p.o.TramadolM1592 (30)110 (29)2.3 (61)2.4 (46)5.90 (25)c6.7 (15)7.0 (14)Healthy Adults,100 mg SD p.o.TramadolM1308 (25)55.0 (36)1.6 (63)3.0 (51)8.50 (31)c5.6 (20)6.7 (16)Geriatric, (>75 yrs)50 mg SD p.o.TramadolM1208 (31)d2.1 (19)d6.89 (25)c7.0 (23)dHepatic Impaired,50 mg SD p.o.TramadolM1217 (11)19.4 (12)1.9 (16)9.8 (20)4.23 (56)c13.3 (11)18.5 (15)Renal Impaired,CLcr10-30 mL/min100 mg SD i.vTramadolM1cccc4.23 (54)c10.6 (31)11.5 (40)Renal Impaired,CLcr<5mL/min100 mg SD i.vTramadolM1cccc3.73 (17)c11.0 (29)16.9 (18)a SD Single dose, MD Multiple dose, p.o.= Oral administration, i.v.= Intravenous administration, q.i.d. Four times dailyb represents the oral bioavailability of tramadolc Not applicabled Not measuredFood EffectsOral 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.DistributionThe volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following 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 ug/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.MetabolismTramadol is extensively metabolized after oral administration by 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 population PK analysis of Phase 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.EliminationTramadol 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.. Figure 1.

PRECAUTIONS SECTION.

PRECAUTIONS Acute Abdominal Conditions The administration of tramadol hydrochloride may complicate the clinical assessment of patients with acute abdominal conditions.. Use in Renal and Hepatic Disease Impaired renal function results in decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION).With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.. Information for Patients oPatients should be informed that tramadol hydrochloride may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol.omay impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving car or operating machinery.oTramadol hydrochloride should not be taken with alcohol containing beverages.oTramadol hydrochloride should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.oThe patient should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (see PRECAUTIONS, Labor and Delivery).oThe patient should understand the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures and death.. oPatients should be informed that tramadol hydrochloride may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol.. omay impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving car or operating machinery.. oTramadol hydrochloride should not be taken with alcohol containing beverages.. oTramadol hydrochloride should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.. oThe patient should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (see PRECAUTIONS, Labor and Delivery).. oThe patient should understand the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures and death.. Drug Interactions CYP2D6 and CYP3A4 InhibitorsConcomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Pharmacokinetics), such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome.Serotonergic DrugsThere have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and 2-adrenergic blockers. Caution is advised when tramadol hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is reversible non-selective MAOI), lithium, or St. Johns Wort. If concomitant treatment of tramadol hydrochloride with drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).TriptansBased on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when tramadol hydrochloride is coadministered with triptan. If concomitant treatment of tramadol hydrochloride with triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).Use With CarbamazepinePatients taking carbamazepine may have significantly reduced analgesic effect of tramadol hydrochloride. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride and carbamazepine is not recommended.Use With QuinidineTramadol is metabolized to M1 by CYP2D6. Quinidine is selective inhibitor of that isoenzyme, so that concomitant administration of quinidine and tramadol hydrochloride results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.Potential for Other Drugs to Affect TramadolIn 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. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. Johns Wort, with tramadol hydrochloride may affect the metabolism of tramadol leading to alteted tramadol exposure.Potential for Tramadol to Affect Other DrugsIn 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. Tramadol is mild inducer of selected drug metabolism pathways measured in animals.Use With CimetidineConcomitant administration of tramadol hydrochloride(R) with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the tramadol hydrochloride dosage regimen is recommended.Use with Digoxin and WarfarinPost-marketing surveillance has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.. Carcinogenesis, Mutagenesis, Impairment of Fertility A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m2 or 0.36 times the maximum daily human dosage of 246 mg/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m2, or 0.73 times the maximum daily human dosage).Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose genotoxic risk to humans.No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (300 mg/m2) in male rats and 75 mg/kg (450 mg/m2) in female rats. These dosages are 1.2 and 1.8 times the maximum daily human dosage of 246 mg/m2, respectively.. Pregnancy, Teratogenic Effects: Pregnancy Category . Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m2), rats (>=25 mg/kg or 150 mg/m2) and rabbits (>=75 mg/kg or 900 mg/m2) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on mg/m2 basis are 1.4, >=0.6, and >=3.6 times the maximum daily human dosage (246 mg/m2) for mouse, rat and rabbit, respectively.No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg or 420 mg/m2), rats (up to 80 mg/kg or 480 mg/m2) or rabbits (up to 300 mg/kg or 3600 mg/m2) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg (3600 mg/m2), dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the maximum daily human dosage (246 mg/m2), respectively.. Non-teratogenic Effects Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m2 or 1.2 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 1.9 and higher the maximum daily human dose).There are no adequate and well-controlled studies in pregnant women. Tramadol Hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing.. Labor and Delivery Tramadol hydrochloride should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn (see DRUG ABUSE AND DEPENDENCE). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.The effect of tramadol hydrochloride, if any, on the later growth, development, and functional maturation of the child is unknown.. Nursing Mothers Tramadol hydrochloride is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 ug of tramadol (0.1% of the maternal dose) and 27 ug of M1.. Pediatric Use The safety and efficacy of tramadol hydrochloride in patients under 16 years of age have not been established. The use of tramadol hydrochloride in the pediatric population is not recommended.. Geriatric Use In general, dose selection for an elderly patient 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. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride in controlled clinical trials. Of those, 145 subjects were 75 years of age and older.In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.

WARNINGS SECTION.

WARNINGS Seizure Risk Seizures have been reported in patients receiving Tramadol hydrochloride within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol hydrochloride above the recommended range. Concomitant use of tramadol hydrochloride increases the seizure risk in patients taking: oSelective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics), oTricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine promethazine, etc.), or oOther opioids. Administration of tramadol hydrochloride may enhance the seizure risk in patients taking: oMAO inhibitors (see alsoWARNINGS, Use with MAO Inhibitors and Serotonin Re-Uptake Inhibitors), oNeuroleptics, or oOther drugs that reduce the seizure threshold. Risk of convulsions may also increase in patients with epilepsy, those with history of seizures, or in patients with recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol hydrochloride overdose, naloxone administration may increase the risk of seizure. oSelective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics), oTricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine promethazine, etc.), or oOther opioids. oMAO inhibitors (see alsoWARNINGS, Use with MAO Inhibitors and Serotonin Re-Uptake Inhibitors), oNeuroleptics, or oOther drugs that reduce the seizure threshold. Suicide Risk oDo not prescribe tramadol hydrochloride for patients who are suicidal or addiction-prone. oPrescribe 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).. oDo not prescribe tramadol hydrochloride for patients who are suicidal or addiction-prone. oPrescribe 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. Serotonin Syndrome Risk The development of 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 (seeCLINICAL 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 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 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 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 SSRIs increases the risk of adverse events, including seizure and serotonin syndrome.. Misuse, Abuse and Diversion Tramadol has mu-opioid agonist activity. Tramadol hydrochloride(R) 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(R) in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Misuse or abuse poses 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 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 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.