traMADol HCl 50 MG Oral Tablet
WARNINGS
Seizure Risk Seizures have been reported in patients receiving tramadol hydrochloride within the recommended dosage range. Spontaneous postmarketing 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: Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics), Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or Other opioids. Administration of tramadol hydrochloride may enhance the seizure risk in patients taking: MAO inhibitors (see also , Use with MAO Inhibitors and Serotonin Re-Uptake Inhibitors ), Neuroleptics, or Other drugs that reduce the seizure threshold. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol hydrochloride overdose, naloxone administration may increase the risk of seizure. Suicide Risk Do not prescribe tramadol hydrochloride for patients who are suicidal or addiction-prone. Prescribe 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 non narcotic analgesics Tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs (see , Risk of Overdosage ) Serotonin Syndrome Risk The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including tramadol hydrochloride, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and triptans, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose (see CLINICAL PHARMACOLOGY, Pharmacokinetics ). Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). 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 a 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 hydrochloride 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 , 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 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 ). 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 a car or operating machinery. The patient using this drug should be cautioned accordingly. Use With MAO Inhibitors and Serotonin Re-uptake Inhibitors Use tramadol hydrochloride 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 SSRI’s increases the risk of adverse events, including seizure and serotonin syndrome. Misuse, Abuse and Diversion Tramadol has mu-opioid agonist activity.Tramadol hydrochloride 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 in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Misuse or abuse poses a significant risk to the abuser that could result in overdose and death (see DRUG ABUSE AND DEPENDENCE and OVERDOSAGE ). Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Risk of Overdosage Patients taking tramadol should be warned not to exceed the dose recommended by their physician. Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a cause of drug-related deaths. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, 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 tablets are central nervous system depression, respiratory depression and death. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE ). 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 hydrochloride 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.
DRUG INTERACTIONS
Drug Interactions CYP2D6 and CYP3A4 Inhibitors Concomitant 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 Drugs There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-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 a reversible non-selective MAOI), lithium, or St. John’s Wort. If concomitant treatment of tramadol hydrochloride with a 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 ). Triptans Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when tramadol hydrochloride is coadministered with a triptan. If concomitant treatment of tramadol hydrochloride with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome ). Use With Carbamazepine Patients taking carbamazepine may have a 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 Quinidine Tramadol is metabolized to M1 by CYP2D6. Quinidine is a 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 Tramadol 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.Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John’s Wort, with tramadol hydrochloride may affect the metabolism of tramadol leading to altered tramadol exposure. Potential for Tramadol to Affect Other Drugs 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. Use With Cimetidine Concomitant administration of tramadol hydrochloride 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 Warfarin Postmarketing surveillance has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
OVERDOSAGE
Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death. Deaths due to overdose have been reported with abuse and misuse of tramadol (see WARNINGS,Misuse,Abuse,and Diversion ). Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids. In the treatment of tramadol overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. 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 hydrochloride 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.
DESCRIPTION
Tramadol hydrochloride is a centrally acting analgesic. The chemical name for tramadol hydrochloride is (±) cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is: The molecular weight of tramadol hydrochloride is 299.84. 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.Tramadol hydrochloride tablets USP contain 50 mg of tramadol hydrochloride and are white to off white in color. Inactive ingredients in the tablet are corn starch, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide. diagram
CLINICAL STUDIES
Tramadol hydrochloride 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 tramadol hydrochloride 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. Tramadol hydrochloride has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol hydrochloride. 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 hydrochloride in divided doses were generally comparable to 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. Titration Trials In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily tramadol hydrochloride dose of 200 mg (50 mg four times per day), 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 diagram
HOW SUPPLIED
Tramadol hydrochloride tablets USP 50 mg are white to off white, round, biconvex, film- coated tablets, debossed ‘‘50’’on one side and plain on other side. Bottles of 100 tablets: NDC 16729-167-01 Bottles of 500 tablets: NDC 16729-167-16 Bottles of 1000 tablets: NDC 16729-167-17 Dispense in a tight container. Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [See USP Controlled Room Temperature]. *Tylenol ® is a registered trademark of McNeil Cons. $Tylox ® is a registered trademark of Ortho McNeil Pharm.
GERIATRIC USE
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.
INDICATIONS AND USAGE
Tramadol hydrochloride tablets USP are indicated for the management of moderate to moderately severe pain in adults.
PEDIATRIC USE
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.
PREGNANCY
Pregnancy Teratogenic Effects: Pregnancy Category C Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m 2), rats (≥25 mg/kg or 150 mg/m 2) and rabbits (≥75 mg/kg or 900 mg/m 2) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on a mg/m 2 basis are 1.4, ≥0.6, and ≥3.6 times the maximum daily human dosage (246 mg/m 2) 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/m 2), rats (up to 80 mg/kg or 480 mg/m 2) or rabbits (up to 300 mg/kg or 3600 mg/m 2) 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/m 2), respectively. Nonteratogenic 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/m 2 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 postmarketing.
NUSRING MOTHERS
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 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.
INFORMATION FOR PATIENTS
Information for Patients Patients 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. 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. The 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 ). 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.
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, the tolerability of tramadol hydrochloride 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 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. 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.