Tramadol Hydrochloride orally disintegrating tablets is a centrally acting analgesic in an orally disintegrating formulation using a tablet formulation base. The chemical name for tramadol hydrochloride is (±) cis -2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

Tramadol Hydrochloride is supplied as orally disintegrating tablets containing 50 mg of tramadol hydrochloride for oral administration.

Tramadol hydrochloride is a white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7.

The tablets are white in color and contain the inactive ingredients aspartame, copovidone, crospovidone, ethylcellulose, magnesium stearate, mannitol, mint flavor, and silicon dioxide.

Tramadol Hydrochloride is indicated for the management of moderate to moderately severe pain in adults.

Do NOT chew, break, or split the tablet.

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 a titration regimen. The total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg q.i.d.). After titration, Tramadol Hydrochloride 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 50 mg to 100 mg can be administered as needed for pain relief every 4 to 6 hours, not to exceed 400 mg per day.

Place Tramadol Hydrochloride tablet on the tongue until it completely disintegrates and then swallow it. It may take approximately one minute for the tablet to disintegrate on the tongue. Tablet may be taken with or without water.

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.

In all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of Tramadol Hydrochloride 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.

Tramadol Hydrochloride (tramadol hydrochloride orally disintegrating tablets) - 50 mg (white, tablet) debossed with "B" on one side and "50" on the other side.

30 tablets, 5 cards of 6 single dose units in child resistant blister packs.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-89°F).

An orally swallowed immediate release tablet of 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, 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.

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 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 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, Speech disorders.

Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.

Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.

Sensory: Cataracts, Deafness, Tinnitus.

Tramadol Hydrochloride may induce psychic and physical dependence of the morphine-type (µ-opioid). (See WARNINGS .) Dependence and abuse, including drug-seeking behavior and taking illicit actions to obtain the drug are not limited to those patients with prior history of opioid dependence. The risk in patients with substance abuse has been observed to be higher. Tramadol is associated with craving and tolerance development. Withdrawal symptoms may occur if Tramadol Hydrochloride is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Other symptoms that have been seen less frequently with reference listed drug discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.

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. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.

Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of Tramadol Hydrochloride and carbamazepine is not recommended.

Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of the isoenzyme, so that concomitant administration of quinidine and tramadol 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.

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.

Concomitant administration with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the Tramadol Hydrochloride dosage regimen is recommended.

Interactions with MAO Inhibitors , due to interference with detoxification mechanisms, have been reported for some centrally acting drugs (see WARNINGS , Use With MAO Inhibitors).

Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.

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 Hydrochloride 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 Opioid drugs.

· MAO inhibitors (see also WARNINGS - Use with MAO Inhibitors),

· Neuroleptics, or

· Other drugs that reduce the seizure threshold.

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 Hydrochloride (see CONTRAINDICATIONS ).

Administer Tramadol Hydrochloride 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 ).

Tramadol Hydrochloride should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, other opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol increases the risk of CNS and respiratory depression in these patients.

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 Respiratory Depression .)

Patients with a history of sensitivity to phenylketones may be at increased risk and therefore should not receive Tramadol Hydrochloride .

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 Tramadol Hydrochloride with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of tramadol with MAO inhibitors or SSRI's increases the risk of adverse events, including seizure and serotonin syndrome.

Withdrawal symptoms may occur if Tramadol Hydrochloride is discontinued abruptly. (See DRUG ABUSE AND DEPENDENCE .) These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Other symptoms that have been seen less frequently with tramadol discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication.

Tramadol Hydrochloride may induce psychic and physical dependence of the morphine-type (µ-opioid) (see DRUG ABUSE AND DEPENDENCE ). Tramadol Hydrochloride should not be used in opioid-dependent patients. Tramadol has been shown to reinitiate physical dependence in some patients who have been previously dependent on other opioids. Dependence and abuse, including drug-seeking behavior and taking illicit actions to obtain the drug, are not limited to those patients with prior history of opioid dependence.

Serious potential consequences of overdosage with tramadol hydrochloride tablets are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE ).

The administration of Tramadol Hydrochloride may complicate the clinical assessment of patients with acute abdominal conditions.

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, 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in a 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/m ² ) 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 a 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 a 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 C .

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 a 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/m ² ), a 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/m ² 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 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 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 a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 µg of tramadol (0.1% of the maternal dose) and 27 µg 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 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.

Serious potential consequences of overdosage are respiratory depression, lethargy, coma, seizure, cardiac arrest and death. (See WARNINGS .) Fatalities have been reported in post marketing in association with both intentional and unintentional overdose with tramadol. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals convulsions following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.

Tramadol Hydrochloride should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or other opioids. Tramadol Hydrochloride is contraindicated in any situation where other opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol Hydrochloride may worsen central nervous system and respiratory depression in these patients.

Tramadol Hydrochloride is a centrally acting synthetic opioid analgesic in an orally disintegrating tablet form. 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 µ-opioid receptors and weak inhibition of reuptake 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 µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-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. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

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. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.

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. Tramadol is well absorbed orally with an absolute bioavailability of 75%. Tramadol has a volume of distribution of approximately 2.7 L/kg and is 20% bound to plasma proteins. Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. One metabolite, M1, is pharmacologically active in animal models. The formation of M1 is dependent upon CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see PRECAUTIONS , Drug Interactions ). Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

No difference has been identified in systemic exposure (AUC), peak exposure (C_max), time to peak exposure (T_max), and apparent elimination half-life (t_½) of tramadol and metabolites M1 and M5 between administration of Tramadol Hydrochloride with and without water and Ultram®.

Racemic tramadol is rapidly and almost completely absorbed after oral administration. 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 q.i.d. 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 q.i.d.

Food Effects: Oral administration of Tramadol Hydrochloride with food does not significantly affect its extent of absorption, however, food does delay t_max by about 30 minutes compared to fasting conditions. The clinical significance of this delay is not known.

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 µg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.

Tramadol is extensively metabolized after oral administration. 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.

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.

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.

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 ).

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 ).

Following a single oral dose of Tramadol Hydrochloride to healthy volunteers, no gender effect was observed. The AUC and C_max values for Tramadol Hydrochloride were similar in males and females. Dosage adjustment based on gender is not recommended.

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 dose of tramadol.

Tramadol Hydrochloride is an orally disintegrating tablet, but there are no studies that indicate that its onset of action is faster than tramadol tablets.

An orally swallowed immediate release tablet of tramadol has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).

In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg of orally swallowed immediate release tablet of tramadol tended to provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin 650 mg with codeine phosphate 60 mg.

An orally swallowed immediate release tablet of tramadol has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving an orally swallowed immediate release tablet of tramadol. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250 mg of an orally swallowed immediate release tablet of tramadol in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg 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 daily.

In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily orally swallowed immediate release tablet of tramadol dose of 200 mg (50 mg q.i.d.), 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.

Figure 2: Protocol CAPSS 047 Time to Discontinuation Due to Nausea/Vomiting

· Tramadol Hydrochloride may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.

· Tramadol Hydrochloride should not be taken with alcohol containing beverages.

· Tramadol Hydrochloride should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.

· Female patients 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 ).

· The 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.

· To open the blister pack, peel back the foil on the blister. Do not push tablet through the foil. Remove the tablet and place it in the mouth, where it will dissolve in seconds and then be swallowed with the saliva.

· Tablet may be taken with or without water.

· Do NOT chew, break, or split the tablet.

· Phenylketonurics: Tramadol Hydrochloride contains phenylalanine.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

TRAMADOL - ORAL

(TRAH-muh-dall)

COMMON BRAND NAME(S): Ultram

USES: This medication is used to relieve moderate pain. It is similar to narcotic pain medications. It works on certain nerves in the brain that control how you experience pain.

HOW TO USE: Take this medication by mouth with or without food as directed by your doctor. If you have nausea, you may take this drug with food. Consult your doctor or pharmacist about other ways to decrease nausea (e.g., antihistamines, lying down for 1 to 2 hours with as little head movement as possible).

The dosage is based on your medical condition and response to treatment. To reduce the risk of side effects, your doctor may tell you to gradually increase your dose when starting tramadol.

The maximum recommended dose is 400 milligrams a day. If you have serious kidney disease (e.g., if you are on dialysis), the maximum recommended dose is 100 milligrams every 12 hours. If you have serious liver disease (e.g., cirrhosis), the maximum recommended dose is 50 milligrams every 12 hours. If you are older than 75 years, the maximum recommended dose is 300 milligrams a day.

Pain medications work best if they are used as the first signs of pain (or migraine) occur. If you wait until the pain has worsened, the medication may not work as well.

Follow your doctor's or pharmacist's instruction for the safe use of non-narcotic pain relievers (e.g., acetaminophen, ibuprofen). Ask your doctor or pharmacist for more details regarding your treatment.

This medication may cause dependence, especially if it has been used regularly for an extended time or if it has been used in high doses. In such cases, withdrawal reactions (e.g., anxiety, sweating, sleeplessness, shaking, diarrhea, rapid breathing) may occur if you suddenly stop this drug. To prevent withdrawal reactions when stopping extended, regular treatment with this drug, gradually reduce the dosage as directed. Also, if you are taking regular doses of narcotic medications for ongoing pain (e.g., cancer pain), starting tramadol may cause a withdrawal reaction. Consult your doctor or pharmacist for more details, and report any withdrawal reactions immediately.

Rarely, abnormal drug-seeking behavior (addiction) is possible with this medication. Do not increase your dose, take it more frequently, or use it for a longer time than prescribed. Properly stop the medication when so directed.

When used for an extended period, this medication may not work as well and may require different dosing. Talk with your doctor if this medication stops working well.

Tell your doctor if your pain persists or worsens.

SIDE EFFECTS: Nausea, vomiting, constipation, lightheadedness, dizziness, drowsiness, headache, or weakness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

To prevent constipation, maintain a diet adequate in fiber, drink plenty of water, and exercise. If you are taking tramadol regularly, it may be useful to start using a laxative right away instead of waiting until you become constipated. Consult your pharmacist for details regarding the correct use of laxatives (e.g., stimulant-type with stool softener).

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual or extreme stiffness in the muscles, shaking (tremor), severe stomach/abdominal pain, change in the amount of urine, vision changes.

This medication may rarely cause a very serious condition called serotonin syndrome. The risk increases when this medication is used with certain other drugs (see Drug Interactions section). Seek immediate medical attention if you develop some of the following symptoms: mental/mood changes (such as agitation, hallucinations), unusual restlessness, loss of coordination, fast heartbeat, severe dizziness, unexplained fever, severe nausea/vomiting/diarrhea, twitchy muscles.

Tell your doctor immediately if any of these rare but very serious side effects occur: slow/shallow breathing, seizures, fever/flu-like symptoms.

A very serious allergic reaction to this drug (which may occur as early as the first dose) is rare. However, seek immediate medical attention if you notice any of the following symptoms: rash, itching, swelling (especially of the lips, tongue, or throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking tramadol, tell your doctor or pharmacist if you are allergic to it; or to other narcotics (e.g., codeine); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe breathing problems (e.g., respiratory depression, hypercapnia), intoxication with drugs that depress the nervous system or your breathing (CNS/respiratory depressants such as alcohol or tranquilizers/sedatives).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: certain bowel diseases (paralytic ileus), brain disorders (e.g., seizures, increased intracranial pressure), conditions that increase the risk of seizures (e.g., head injury, brain tumors, meningitis, metabolic disorders, alcohol/drug withdrawal), adrenal gland problem (e.g., Addison's disease), difficulty urinating (e.g., enlarged prostate, urethral narrowing), heart problems (e.g., irregular heartbeat), personal or family history of regular use/abuse of drugs/alcohol, kidney disease, liver disease, lung diseases (e.g., chronic obstructive pulmonary disease-COPD, hypoxia), disease of the pancreas (e.g., pancreatitis), mental/mood conditions (e.g., major depression, toxic psychosis), a certain spinal problem (kyphoscoliosis), stomach/intestinal problems (e.g., gallbladder disease), underactive thyroid (hypothyroidism).

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or doing any activity that requires alertness. Avoid alcoholic beverages because they may increase the risk of this drug's side effects.

To reduce dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Caution is advised when using this drug in the elderly because they may be more sensitive to its effects, especially slow/shallow breathing and drowsiness.

During pregnancy, this medication should be used only when clearly needed. It is not recommended for use for long periods or in high doses late in pregnancy because of possible serious harm to your baby. Discuss the risks and benefits with your doctor. Infants born to mothers who have been using this medication for an extended time may have seizures or withdrawal symptoms such as irritability, abnormal/persistent crying, or diarrhea. Tell your doctor immediately if you notice any of these symptoms in your newborn.

This drug passes into breast milk. While there have been no reports of harm to nursing infants, consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious (possibly fatal) interactions may occur: MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine).

Avoid taking MAO inhibitors within 2 weeks before, during, and after treatment with tramadol.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting tramadol.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other narcotic medications.

Before using tramadol, report the use of other drugs that increase serotonin, such as dextromethorphan, lithium, St. John's wort, sibutramine, street drugs such as MDMA/"ecstasy", tryptophan, certain antidepressants including SSRIs (such as citalopram, paroxetine) and SNRIs (such as duloxetine, venlafaxine), "triptans" used to treat migraine headaches (such as eletriptan, sumatriptan), among others. The risk of serotonin syndrome may be more likely when you start or increase the dose of these medications.

Also report the use of drugs that might increase seizure risk when combined with tramadol such as isoniazid (INH), phenothiazines (e.g., thioridazine, chlorpromazine, promethazine), theophylline, or tricyclic antidepressants (e.g., amitriptyline), among others. Consult your doctor or pharmacist for details.

Other medications can affect the removal of tramadol from your body, which may affect how tramadol works or increase the risk of side effects. These drugs include quinidine, azole antifungals (such as ketoconazole), macrolide antibiotics (such as erythromycin), rifamycins (such as rifabutin), drugs used to treat seizures (such as carbamazepine, phenytoin), and St. John's wort. This is not a complete list.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as certain antihistamines (e.g., diphenhydramine), anti-anxiety drugs (e.g., diazepam), anti-seizure drugs (e.g., phenytoin), medicine for sleep (e.g., zolpidem), muscle relaxants (e.g., cyclobenzaprine).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: slow/shallow breathing, very slow/irregular heartbeat, loss of consciousness, heart attack.

NOTES: Do not share this medication with others. It is against the law.

This medication has been prescribed for your current condition only. Do not use it later for another condition unless told to do so by your doctor. A different medication may be necessary in that case.

MISSED DOSE: Not applicable.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.