Data from FDA - Curated by EPG Health - Last updated 21 December 2016

Indication(s)

INDICATIONS AND USAGE Tramadol hydrochloride tablets USP are indicated for the management of moderate to moderately severe pain in adults.

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Advisory information

contraindications

CONTRAINDICATIONS Tramadol hydrochloride tablets should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, any other component of this product or opioids.

Tramadol hydrochloride tablets are contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs.

Tramadol hydrochloride tablets may worsen central nervous system and respiratory depression in these patients.

Special warnings and precautions

PRECAUTIONS Acute Abdominal Conditions The administration of tramadol hydrochloride may complicate the clinical assessment of patients with acute abdominal conditions.

Use in Renal and Hepatic Disease Impaired renal function results in 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 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.

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?2-adrenergic blockers.

Caution is advised when tramadol hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is 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.

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/m2) for approximately two years, although the study was not done with the Maximum Tolerated Dose.

This finding is not believed to suggest risk in humans.

No such finding occurred in 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/m2), 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.

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/m2 or 1.2 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m2 or 1.9 and higher the maximum daily human dose).

There are no adequate and well-controlled studies in pregnant women.

Tramadol hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during postmarketing.

Labor and Delivery Tramadol hydrochloride should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks.

Safe use in pregnancy has not been established.

Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn (see DRUG ABUSE AND DEPENDENCE).

Tramadol has been shown to cross the placenta.

The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.

The effect of tramadol hydrochloride, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers Tramadol hydrochloride is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.

Following 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 safety and efficacy of tramadol hydrochloride in patients under 16 years of age have not been established.

The use of tramadol hydrochloride in the pediatric population is not recommended.

Geriatric Use In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride in controlled clinical trials.

Of those, 145 subjects were 75 years of age and older.

In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age.

Specifically, 30 % of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17 % of those under 65 years of age.

Constipation resulted in discontinuation of treatment in 10 % of those over 75.

Adverse reactions

ADVERSE REACTIONS Tramadol hydrochloride was administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignant pain.

Of these patients, 375 were 65 years old or older.

Table 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 hydrochloride administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication.

The overall incidence rates of adverse experiences in these trials were similar for tramadol hydrochloride and the active control groups, TYLENOL®* with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg), and aspirin 325 mg with codeine phosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the tramadol hydrochloride groups.

Table 2: Cumulative Incidence of Adverse Reactions for Tramadol hydrochloride in Chronic Trials of Nonmalignant Pain (N=427) Up to 7 Days Up to 30 Days Up to 90 Days Dizziness/Vertigo 26 % 31 % 33 % Nausea 24 % 34 % 40 % Constipation 24 % 38 % 46 % Headache 18 % 26 % 32 % Somnolence 16 % 23 % 25 % Vomiting 9 % 13 % 17 % Pruritus 8 % 10 % 11 % " CNS Stimulation " " CNS Stimulation " is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations 7 % 11 % 14 % Asthenia 6 % 11 % 12 % Sweating 6 % 7 % 9 % Dyspepsia 5 % 9 % 13 % Dry Mouth 5 % 9 % 10 % Diarrhea 5 % 6 % 10 % 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 hydrochloride 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 postmarketing 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 hydrochloride during clinical trials and/or reported in postmarketing experience.

A causal relationship between tramadol hydrochloride and these events has not been determined.

However, the most significant events are listed below as alerting information to the physician.

Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.

Central Nervous System: Migraine, Speech disorders.

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

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

Sensory: Cataracts, Deafness, Tinnitus.

Usage information

Dosing and administration

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.

Pregnancy and lactation
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.

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?2-adrenergic blockers.

Caution is advised when tramadol hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is 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.

More information

Category Value
Authorisation number ANDA202390
Orphan designation No
Product NDC 16729-167
Date Last Revised 30-09-2014
Type HUMAN PRESCRIPTION DRUG
RXCUI 835603
Marketing authorisation holder Accord Healthcare, Inc.