Interaction

Some medical conditions may interact with Tramadol . Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding
• if you are taking any prescription (especially depression medicines) or nonprescription medicine, herbal preparation, or dietary supplement
• if you have allergies to medicines, foods, or other substances
• if you have liver, kidney, or thyroid problems; a blockage in the bladder; diabetes; heart problems; high blood pressure; prostate problems; or metabolism problems
• if you have or recently have had any head injury, brain injury or tumor, increased pressure in the brain, or infection of the brain or nervous system
• if you have a history of diarrhea caused by antibiotic use, recent stomach or bowel surgery, or any other stomach or bowel problems (eg, pain, inflammation, ulcers)
• if you have a history of lung or breathing problems (eg, asthma, chronic obstructive pulmonary disease [COPD]) or a seizure disorder (eg, epilepsy)
• if you are going through withdrawal from alcohol or other substances or if you have a history of alcohol or other substance abuse, mood or mental problems (eg, depression), or suicidal thoughts or actions

Some MEDICINES MAY INTERACT with Tramadol . Tell your health care provider if you are taking any other medicines, especially any of the following:

• Azole antifungals (eg, ketoconazole), linezolid, lithium, macrolide antibiotics (eg, erythromycin), nefazodone, quinidine, selective serotonin and norepinephrine reuptake inhibitors (SNRIs) (eg, duloxetine), selective serotonin reuptake inhibitors (SSRIs) (eg, fluoxetine, paroxetine), St. John’s wort, tricyclic antidepressants (eg, amitriptyline), or triptans (eg, sumatriptan) because serotonin syndrome may occur
• Anorexiants (eg, phentermine), buytrophenones (eg, haloperidol), certain medicines for mental or mood disorders (eg, olanzapine), cyclobenzaprine, furazolidone, loxapine, monoamine oxidase inhibitors (MAOIs) (eg, phenelzine, selegiline), molindone, other opioid pain medicine (eg, codeine, hydrocodone), phenothiazines (eg, promethazine), sodium oxybate (GHB), thioxanthenes (eg, thiothixene), or tiagabine, because the risk of side effects, including excessive drowsiness, trouble breathing, liver problems, or seizures, may be increased
• Other products containing tramadol because they may increase the risk of Tramadol ‘s side effects
• Rifampin because it may decrease Tramadol ‘s effectiveness
• Carbamazepine because it may decrease Tramadol ‘s effectiveness; the risk of seizures may also be increased
• Anticoagulants (eg, warfarin) or digoxin because the risk of their side effects may be increased by Tramadol

This may not be a complete list of all interactions that may occur. Ask your health care provider if Tramadol may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

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 ULTRAM® 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 ULTRAM® 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 ULTRAM® is coadministered with a triptan. If concomitant treatment of ULTRAM® 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 ULTRAM®. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRAM® 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 ULTRAM® 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 Ultram® may affect the metabolism of tramadol leading to alteted 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 ULTRAM® with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRAM® dosage regimen is recommended.

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.