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CLINICAL PHARMACOLOGY:
Pharmacodynamics: Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood. 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. 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. 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: Tramadol is well absorbed orally with an absolute bioavailability of 75%. Tramadol has a volume of distribution of approximately 2.7L/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. 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.
Absorption: The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic Tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. Steady-state plasma concentrations of both Tramadol and M1 are achieved within two days with q.i.d. dosing.
Food Effects: Oral administration of Tramadol with food does not significantly affect its rate or extent of absorption.
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.
Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. These individuals are "poor metabolizers". Concentrations of Tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 40% lower.
Elimination: Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys.
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.
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.
Geriatric: Adjustment of the daily dose is recommended for patients older than 75 years.
Clinical Studies: Tramadol has been given in single oral doses of 50 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars). A dose of 100 mg Tramadol tended to provide analgesia superior to codeine sulfate 60 mg. Average daily doses of approximately 250 mg 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.
WARNINGS:
Seizure Risk: Seizures have been reported in patients receiving Tramadol within the recommended dosage range. Concomitant use of Tramadol increases the seizure risk in patients taking:
- Selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics),
- Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or
- Other opioids.
- MAO inhibitors
- Neuroleptics, or Other drugs that reduce the seizure threshold.
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In Tramadol 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. When these events do occur it is often following the first dose. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Tramadol.
Respiratory Depression: Administer Tramadol cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered.
Increased Intracranial Pressure or Head Trauma: Tramadol should be used with caution in patients with increased intracranial pressure or head injury.
Use in Ambulatory Patients: Tramadol may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
Withdrawal: These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication.
Physical Dependence and Abuse: Tramadol should not be used in opioid-dependent patients.
PRECAUTIONS:
Acute Abdominal Conditions: The administration of Tramadol may complicate the clinical assessment of patients with acute abdominal conditions.
Use in Renal and Hepatic Disease: In patients with creatinine clearances of less than 30 mL/min, dosing reduction is recommended.In cirrhotic patients, dosing reduction is recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tramadol does not pose a genotoxic risk to humans. No effects on fertility were observed for Tramadol.
Pregnancy: Pregnancy Category C, 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 should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks.
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.
Pediatric Use: The use of Tramadol in the pediatric population is not recommended.
Geriatric Use: In patients over 75 years of age, daily doses in excess of 300 mg are not recommended.
Drug Interactions:
Carbamazepine: carbamazepine increases Tramadol metabolism and because of the seizure risk associated with Tramadol, concomitant administration of Tramadol and carbamazepine is not recommended.
Quinidine: Concomitant administration of quinidine and Tramadol results in increased concentrations of Tramadol and reduced concentrations of M1.
Inhibitors of CYP2D6: Concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of Tramadol.
MAO Inhibitors: Due to interference with detoxification mechanisms, have been reported for some centrally acting drugs.
Digoxin and Warfarin: Rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
Interaction with Central Nervous System (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, narcotics, phenothiazines, tranquilizers or sedative hypnotics.
Use with MAO Inhibitors and Serotonin Re-uptake Inhibitors: Concomitant use of Tramadol with MAO inhibitors or SSRI's increases the risk of adverse events, including seizure and serotonin syndrome.
SIDE EFFECTS:
Incidence 1% to less than 5%, possibly causally related: the following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with Tramadol 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.
DRUG ABUSE AND DEPENDENCE: Tramadol may induce psychic and physical dependence of the morphine-type (µ-opioid). 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.
OVERDOSAGE:
Serious potential consequences of overdosage are respiratory depression, lethargy, coma, seizure, cardiac arrest and death. 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. Naloxone will reverse some but not all, symptoms. 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.
DOSAGE AND ADMINISTRATION:
Adults (17 years of age and over): For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect; Tramadol should be started at 25 mg/day qAM and titrated in 25 mg increments as separate doses every 3 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 3 days to reach 200 mg/day (50 mg q.i.d.). After titration, Tramadol 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 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.
- In all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of Tramadol 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. For elderly patients over 75 years old, total dose should not exceed 300 mg/day.
How Supplied: Each Pack of Ruz-Tramadol tablets or capsules contain 100 film coated tablets or 100 capsules in 10 blisters.
stotage: Dispense in a tight container. Store at 15-30°C.
Reference: PDR 2000, page 2218-20
USPDI Vol for Professional Health Care, 2004, Page 2722-2725