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ULTRAM ER was administered to a total of 3108 patients during studies conducted in the U.S. These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic nonmalignant pain. A total of 901 patients were 65 years or older. The frequency of adverse events generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see Table 2).
Table 2: Incidence (%) of patients with adverse event
rates ≥ 5% from two 12-week placebo-controlled studies in patients with
moderate to moderately severe chronic pain by dose (N=1811).
|MedDRA Preferred Term||ULTRAM ER||Placebo|
|Dizziness (not vertigo)||64 (15.9)||81 (20.3)||90 (22.5)||57 (28.2)||28 ( 6.9)|
|Nausea||61 (15.1)||90 (22.5)||102 (25.5)||53 (26.2)||32 ( 7.9)|
|Constipation||49 (12.2)||68 (17.0)||85 (21.3)||60 (29.7)||17 ( 4.2)|
|Headache||49 (12.2)||62 (15.5)||46 (11.5)||32 (15.8)||43 (10.6)|
|Somnolence||33 ( 8.2)||45 (11.3)||29 ( 7.3)||41 (20.3)||7 ( 1.7)|
|Flushing||31 ( 7.7)||40 (10.0)||35 ( 8.8)||32 (15.8)||18 ( 4.4)|
|Pruritus||25 ( 6.2)||34 ( 8.5)||30 ( 7.5)||24 (11.9)||4 ( 1.0)|
|Vomiting||20 ( 5.0)||29 ( 7.3)||34 ( 8.5)||19 ( 9.4)||11 ( 2.7)|
|Insomnia||26 ( 6.5)||32 ( 8.0)||36 ( 9.0)||22 (10.9)||13 ( 3.2)|
|Dry Mouth||20 ( 5.0)||29 ( 7.3)||39 ( 9.8)||18 ( 8.9)||6 ( 1.5)|
|Diarrhea||15 ( 3.7)||27 ( 6.8)||37 ( 8.5)||10 ( 5.0)||17 ( 4.2)|
|Asthenia||14 ( 3.5)||24 ( 6.0)||26 ( 6.5)||13 ( 6.4)||7 ( 1.7)|
|Postural hypotension||7 ( 1.7)||17 ( 4.3)||8 ( 2.0)||11 ( 5.4)||9 ( 2.2)|
|Sweating increased||6 ( 1.5)||8 ( 2.0)||15 ( 3.8)||13 ( 6.4)||1 ( 0.2)|
|Anorexia||3 ( 0.7)||7 ( 1.8)||21 ( 5.3)||12 ( 5.9)||1 ( 0.2)|
The following adverse events were reported from all the chronic pain studies (N=3108).
The lists below include adverse events not otherwise noted in Table 2.
Adverse events with incidence rates of 1.0% to < 5.0%
Eye disorders: vision blurred
Investigations: blood creatine phosphokinase increased, weight decreased
Metabolism and nutrition disorders: appetite decreased
Psychiatric disorders: nervousness, anxiety, depression, restlessness
Skin and subcutaneous tissue disorders: sweating increased, dermatitis
Vascular disorders: hot flushes, vasodilatation
Adverse events with incidence rates of 0.5% to < 1.0% and serious adverse events reported in at least 2 patients.
Cardiac disorders: palpitations, myocardial infarction
General disorders: feeling jittery, edema lower limb, shivering, joint swelling, malaise, drug withdrawal syndrome, peripheral swelling
Injury and poisoning: joint sprain, muscle injury
Respiratory, thoracic and mediastinal disorders: yawning
Vascular disorders: hypertension aggravated, hypertension, peripheral ischemia
The following adverse reactions, not noted above, have been identified during post approval use of tramadol-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
Metabolism and nutrition disorders: Cases of hypoglycemia have been reported very rarely in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients.
Nervous system disorders: movement disorder, speech disorder
Psychiatric disorders: delirium
Read the Ultram ER (tramadol hcl extended-release) Side Effects Center for a complete guide to possible side effects
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.
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 ER 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 ER 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 Risk).
Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ULTRAM ER is coadministered with a triptan. If concomitant treatment of ULTRAM ER with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome Risk).
Use With Carbamazepine
Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRAM ER and carbamazepine is not recommended.
Use With Quinidine
Coadministration of quinidine with ULTRAM ER resulted in a 50-60% increase in tramadol exposure and a 50-60% decrease in M1 exposure (see CLINICAL PHARMACOLOGY, Drug Interactions). The clinical consequences of these findings are unknown.
Use With Digoxin and Warfarin
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
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 ER may affect the metabolism of tramadol leading to altered tramadol exposure.
Potential for Tramadol to Affect Other Drugs
In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered concomitantly at therapeutic doses. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.
Read the Ultram ER Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/30/2015
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