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ULTRAM ER (tramadol hcl extended-release) 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 non-malignant 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||ULTRAMER||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)|
|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
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.
Ear and labyrinth disorders: tinnitus, vertigo
General disorders: feeling jittery, edema lower limb, shivering, joint swelling, malaise, drug withdrawal syndrome, peripheral swelling
Injury and poisoning: joint sprain, muscle injury
Investigations: alanine aminotransferase increased, blood pressure increased, aspartate aminotransferase increased, heart rate increased, blood glucose increased, liver function tests abnormal
Musculoskeletal, connective tissue and bone disorders: muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, osteoarthritis aggravated
Psychiatric disorders: euphoric mood, irritability, libido decreased, sleep disorder, agitation, disorientation, abnormal dreams
Respiratory, thoracic and mediastinal disorders: yawning
Vascular disorders: hypertension aggravated, hypertension, peripheral ischemia
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.
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 ER (tramadol hcl extended-release) 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 (tramadol hcl extended-release) 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 ER (tramadol hcl extended-release) is coadministered with a triptan. If concomitant treatment of ULTRAM ER (tramadol hcl extended-release) 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, 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 (tramadol hcl extended-release) and carbamazepine is not recommended.
Use With Quinidine
Coadministration of quinidine with ULTRAM ER (tramadol hcl extended-release) 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 (tramadol hcl extended-release) 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.
Drug Abuse And Addiction
ULTRAM ER (tramadol hcl extended-release) is a mu-agonist opioid. Tramadol, like other opioids used in analgesia, can be abused and is subject to criminal diversion.
Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.
“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. ULTRAM ER (tramadol hcl extended-release) , like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
ULTRAM ER (tramadol hcl extended-release) is intended for oral use only. The crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Risk of Overdosage
Serious potential consequences of overdosage with ULTRAM ER (tramadol hcl extended-release) are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE).
Read the Ultram ER Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/18/2010
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