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Tramadol
Tramadol hydrochloride is a centrally acting analgesic. The chemical name for tramadol hydrochloride is (±)cis-2- [(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. The molecular weight of tramadol hydrochloride is 299.8. 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 water/n-octanol partition coefficient is 1.35 at pH 7. Ultram tablets contain 50 mg of tramadol hydrochloride and are white in color. Inactive ingredients in the tablet are corn starch, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and wax.
Pharmacodynamics Tramadol is a centrally acting synthetic analgesic compound. 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 mc-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 mc-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mc-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 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 HCl. 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 an opioid. However, tramadol causes less respiratory depression than morphine at recommended doses (see OVERDOSAGE). 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. Pharmacokinetics The analgesic activity of tramadol HCl is due to both parent drug and the M1 metabolite (see 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 only 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 Cytochrome P-450(2D6) and as such is subject to both metabolic induction and inhibition which may affect the therapeutic response (see 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. Absorption: 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 TABLE 1).
Food Effect on Absorption: Oral administration of tramadol HCl with food does not significantly affect its rate or extent of absorption, therefore, tramadol HCl can be administered without regard to food. 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. Although not confirmed in humans, tramadol has been shown in rats to cross the blood-brain barrier. Metabolism: 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. Production of M1 is dependent on the CYP2D6 isoenzyme of cytochrome P-450 and as such is subject to both metabolic induction and inhibition which may affect the therapeutic response (see DRUG INTERACTIONS). Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. After a single oral dose of tramadol, concentrations of tramadol were only slightly higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 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 pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Elimination: 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. Special Populations Renal: Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 ml/min, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose. Hepatic: Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hrs for tramadol and 19 hrs for M1). In cirrhotic patients adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION). Age: 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 slightly elevated (208 vs. 162 ng/ml) and the elimination half-life is slightly prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (see DOSAGE AND ADMINISTRATION). Gender: The absolute bioavailability of tramadol was 73% in males and 79% in females. The plasma clearance was 6.4 ml/min/kg in males and 5.7 ml/min/kg in females following a 100 mg IV dose of tramadol. Following a single oral dose, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown. CLINICAL STUDIESTramadol hydrochloride has been given in single oral doses of 50, 75, 100, 150 and 200 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 tramadol tended to provide analgesia superior to codeine sulfate 60 mg, but it was not effective as the combination of aspirin 650 mg with codeine phosphate 60 mg. In single-dose models of pain following surgical procedures, 150 mg provided analgesia generally comparable to the combination of acetaminophen 650 mg with propoxyphene napsylate 100 mg, with a tendency toward later peak effect. Tramadol hydrochloride has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving 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 tramadol in divided doses were generally comparable with five doses of acetaminophen 300 mg with codeine phosphate 30 mg (Tylenol with Codeine #3) daily, five doses of aspirin 325 mg with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (Tylox) daily.
Tramadol is indicated for the management of moderate to moderately severe pain.
For the treatment of painful conditions tramadol 50 mg to 100 mg can be administered as needed for relief every four to six hours, not to exceed 400 mg per day. For moderate pain tramadol 50 mg may be adequate as the initial dose, and for more severe pain, tramadol 100 mg is usually more effective as the initial dose. Individualization of Dose: Available data do not suggest that a dosage adjustment is necessary in elderly patients 65 to 75 years of age unless they also have renal or hepatic impairment. For elderly patients over 75 years old, not more than 300 mg/day in divided doses as above is recommended. In all patients with creatine clearance less than 30 ml/min, it is recommended that the dosing interval of tramadol HCl 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 patients with cirrhosis is 50 mg every 12 hours. Patients receiving chronic carbamazepine doses up to 800 mg daily may require up to twice the recommended dose of tramadol HCl. HOW SUPPLIED Ultram 50 mg (white, film-coated capsule-shaped tablet) is engraved "McNeil" on one side and "659" on the other side. Dispense in a tight container. Store at controlled room temperature (up to 25°C, 77°F). PRODUCT LISTING
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 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. (TABLE 2)
Body as a Whole: Malaise. Incidence Less Than 1%, Possible 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: Allergic reaction, Accidental injury,
Weight loss, Anaphylaxis. 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. Body as a whole: Suicidal tendency. DRUG ABUSE AND DEPENDENCETramadol HCl has a potential to cause psychic and physical dependence of the morphone-type (mc-opioid). The drug has been associated with craving, drug-seeking behavior and tolerance development. Cases of abuse and dependence on tramadol HCl have been reported. Tramadol HCl should not be used in opioid-dependent patients. Tramadol HCl can reinitiate physical dependence in patients that have been previously dependent or chronically using other opioids. In patients with a tendency to drug abuse, a history of drug dependence, or are chronically using opioids, treatment with tramadol HCl is not recommended.
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. Use with Carbamazepine: Concomitant administration of tramadol hydrochloride with carbamazepine causes a significant increase in tramadol metabolism, presumably through metabolic induction by carbamazepine. Patients receiving chronic carbamazepine doses of up to 800 mg daily may require up to twice the recommended dose of tramadol. Use with Quinidine: Tramadol is metabolized to M1 by the CYP2D6 P-450 isoenzyme.Quinidine is a selective inhibitor of that isoenzyme; so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of this effect have not been fully investigated, and the effect on quinidine concentrations is unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. Use with Inhibitors of CYP2D6: 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. Use with Cimetidine: Concomitant administration of tramadol with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the tramadol dosage regimen is recommended. Use with MAO Inhibitors: Interactions with MAO Inhibitors due to interference with detoxification mechanisms, have been reported for some centrally acting drugs (see WARNINGS, Use with MAO Inhibitors). Use with Digoxin and Warfarin: Post-marketing surveillance has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
Seizure Risk: Seizures have been reported in patients receiving tramadol HCl within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol HCl above the recommended range. Concomitant use of tramadol HCl increases the seizure risk in patients taking:
Administration of tramadol HCl may enhance the seizure risk in patients taking:
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, CNS infections). In tramadol HCl overdose, naloxone administration may increase the risk of seizure. Anaphylactoid Reactions: Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol HCl. These reactions often occur following the first dose. Other reported reactions include pruritus, hives, bronchospasm, and angioedema. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive tramadol HCl (see CONTRAINDICATIONS). Use in Opioid-dependent Patients: Tramadol HCl should not be used in opioid-dependent patients. Tramadol HCl has been shown to reinitiate physical dependence in some patients that have been previously dependent on other opioids. Consequently, in patients with a tendency to opioid abuse or opioid dependence, treatment with tramadol HCl is not recommended. Use with CNS Depressants: Tramadol should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, phenothiazines, tranquilizers or sedative hypnotics. Use with MAO Inhibitors: Tramadol should be used with great caution in patients taking monoamine oxidase inhibitors, because animal studies have shown increased deaths with combined administration.
Respiratory Depression: Administer tramadol HCl cautiously
in patients at risk for respiratory
depression. When large doses of tramadol HCl are administered with anesthetic
medications or alcohol, respiratory depression may result. Treat such
cases as an overdose. If naloxone is to be administered, use cautiously
because it may precipitate
seizures (see Increased Intracranial Pressure or Head Trauma: Tramadol should be used with caution in patients with increased intracranial pressure or head injury. 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. Acute Abdominal Conditions: The administration of tramadol may complicate the clinical assessment of patients with acute abdominal conditions. Withdrawal: Withdrawal symptoms may occur if tramadol HCl is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhoea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication. Patients Physically Dependent on Opioids: Tramadol is not recommended for patients who are dependent on opioids. Patients who have recently taken substantial amounts of opioids may experience withdrawal symptoms. Because of the difficulty in assessing dependence in patients who have previously received substantial amounts of opioid medication, administer tramadol cautiously to such patients. Use in Renal and Hepatic Disease: 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. Information for the Patient
Carcinogenesis, Mutagenesis, and Impairment of Fertility: 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. 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 (dosing orally up to 30 mg/kg 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. No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats. Pregnancy, Teratogenic Effects, Pregnancy Category C: 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. Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats and rabbits at maternally toxic doses 3 to 15 times the maximum human dose or higher (120 mg/kg in mice, 25 mg/kg or higher in rats and 75 mg/kg or higher in rabbits), but was not teratogenic at these dose levels. No harm to the fetus due to tramadol was seen at doses that were not maternally toxic. No drug-related teratogenic effects were observed in progeny of mice, rats or rabbits treated with tramadol by various routes (up to 140 mg/kg for mice, 80 mg/kg for rats or 300 mg/kg for rabbits). 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, a dose that would cause extreme maternal toxicity in the rabbit. In peri- and post-natal studies in rats, progeny of dams receiving oral (gavage) dose levels of 50 mg/kg or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (6 to 10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe. Labor and Delivery: Tramadol 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 dependance and post-partum withdrawl symptoms in the newborn. 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 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 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1. Pediatric Use: The pediatric use of tramadol is not recommended because safety and efficacy in patients under 16 years of age have not been established. Geriatric Use: In subjects over the age of 75 years, serum concentrations are slightly elevated and the elimination half-life is slightly prolonged. The aged also can be expected to vary more widely in their ability to tolerate adverse drug effects. Daily doses in excess of 300 mg are not recommended in patients over 75 (see DOSAGE AND ADMINISTRATION).
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