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Adverse Drug Reaction Overview
The most commonly reported adverse reactions are dizziness, nausea, constipation, headache, somnolence and vomiting as presented in Table 1.1.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Incidence of Adverse Reactions for ULTRAM® in Chronic Trials of Non-Malignant Pain (Non-titration Trials)
ULTRAM® was administered to 550 patients during the double-blind or open-label extension periods in studies of chronic non-malignant pain. Of these patients, 375 were 65 years old or older. Table 1.1 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. The overall incidence rates of adverse experiences in these trials were similar for ULTRAM® and the active control groups, acetaminophen with codeine, and aspirin with codeine; however, the rates of withdrawals due to adverse events appeared to be higher in the ULTRAM® group. In the tramadol treatment groups, 16.8-24.5% of patients withdrew due to an AE, compared to 9.6-11.6% for acetaminophen with codeine and 18.5% for aspirin with codeine.
Table 1.1: Cumulative Incidence of Adverse Reactions
for ULTRAM® in Chronic Trials of Non-Malignant Pain
|Percentage of Patients with Adverse Reaction
N = 427
|Up to 7 Days||Up to 30 Days||Up to 90 Days|
|“CNS Stimulation” a||7%||11%||14%|
|a “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations|
Two titration trials showed that the incidence of withdrawal due to AEs could be significantly reduced by using dose titration.
Incidence of Adverse Reactions for ULTRAM® CAPSS-047 Titration Trial
In the double–blind phase of this pivotal trial, gastrointestinal complaints (primarily nausea and vomiting) and dizziness were the adverse events reported most frequently by tramadol-treated subjects, Table 1.2. Most of the adverse events were assessed as mild or moderate in intensity and resolved.
Table 1.2: Adverse Events in CAPSS-047 - Double-Blind
Phase - Frequently Reported ( ≥ 2%a) Adverse Eventsb and Total Incidence of
AEs Summarized by WHOART Body System, Treatment Group and Preferred Term
|AEs in CAPSS-047 Double-Blind Phase ≥ 2% of patients Tramadol Group/Titration Schedule|
|Body System||10-days to 200 mg/day
|16-days to 200 mg/day
|13-days to 150 mg/day
|Any Adverse Event||41||75.9||41||69.5||33||61.1|
|Body as a Whole - General Disorders|
|Central and Peripheral Nervous System Disorders|
|Gastrointestinal System Disorders|
|Reproductive Disorders, Female|
|Reproductive Disorders, Male|
|Respiratory Systems Disorders|
|Upper Resp Tract Infection||2||3.7||0||0.0||0||0.0|
|Skin and Appendages Disorders|
|a Preferred terms reported by ≥ 2% of
subjects in one or more treatment groups, intent-to-treat population.
b Number of patients with adverse event; numbers shown are all events regardless of relationship to study drug.
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 ULTRAM® exists.
Body as a Whole: Malaise.
Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.
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 post-marketing 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).
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 ULTRAM® during clinical trials and/or reported in post-marketing experience. A causal relationship between ULTRAM® and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.
Central Nervous System: Migraine, Speech disorders.
Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.
Sensory: Cataracts, Deafness, Tinnitus.
Other Adverse Experiences Previously Reported in Clinical Trials or Post-Marketing Reports with Tramadol Hydrochloride
Adverse events which have been reported with the use of tramadol products include: allergic reactions (including anaphylaxis, angioneurotic edema and urticaria), bradycardia, convulsions, drug dependence, drug withdrawal (including agitation, anxiety, gastrointestinal symptoms, hyperkinesia, insomnia, nervousness, tremors), hyperactivity, hypoactivity, hypotension, worsening of asthma and respiratory depression. Other adverse events which have been reported with the use of tramadol products and for which a causal association has not been determined include: difficulty concentrating, hepatitis, liver failure, pulmonary edema, Stevens-Johnson syndrome and suicidal tendency.
Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs. Post-marketing experience with the use of tramadol-containing products included rare reports of delirium, miosis, mydriasis, and speech disorder, and very rare reports of movement disorder including dyskinesia and dystonia.
Cases of hypoglycemia have been reported in patients taking tramadol, mostly in patients with pre-disposing risk factors, including diabetes, elderly and renal insufficiency. Caution should be exercised when prescribing tramadol to diabetic patients. More frequent monitoring of blood glucose levels may be appropriate, including at initiation or dose increase.
Drug Abuse, Addiction And Dependence
Tramadol may induce psychic and physical dependence of the morphine-type (μ-opioid) (see WARNINGS AND PRECAUTIONS, Drug Abuse, Addiction and Dependence). Dependence and abuse, including drug-seeking behaviour and taking illicit actions to obtain the drug are not limited to those patients with a prior history of opioid dependence. The risk in patients with substance abuse has been observed to be higher. Tramadol is associated with craving and tolerance development.
A Risk Management program to support the safe and effective use of ULTRAM® has been established. The following are considered to be the essential components of the Risk Management program:
- Commitment to not emphasize or highlight the scheduling status of ULTRAM® (i.e., not listed under a schedule to the CDSA) in its advertising or promotional activities.
- Inclusion of a PAAB-approved fair balance statement in all ULTRAM® advertising and promotional materials.
- Assurance that health-care education activities on pain management with ULTRAM® include balanced, evidence-based and current information. Commitment to take reasonable actions to inform health-care professionals that there is Health Canada-approved patient information on benefits and risks, and to ensure that this information can be readily accessed through electronic and/or hard copy sources.
Withdrawal symptoms may occur if ULTRAM® is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Other symptoms that have been seen less frequently with ULTRAM® discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.
Read the Ultram (tramadol hcl) Side Effects Center for a complete guide to possible side effects
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 MAO Inhibitors
Drugs that Lower Seizure Threshold
Tramadol can increase the potential for selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), anti-psychotics and other seizure threshold lowering drugs to cause convulsions. 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 AND PRECAUTIONS, Use with Serotonin Reuptake Inhibitors).
Concurrent administration of tramadol with other centrally acting drugs, including alcohol, centrally acting analgesics, opioids and psychotropic drugs may potentiate CNS depressant effects (see WARNINGS AND PRECAUTIONS).
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 the CYP2D6 P450 isoenzyme. 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.
Use with CYP2D6 and CYP3A4 Inhibitors
Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics), such as quinidine, fluoxetine, paroxetine, amitriptyline (CYP2D6 inhibitors), ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol, increasing the risk for serious adverse events including seizures and serotonin syndrome.
Use with Cimetidine
Concomitant administration of ULTRAM® and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRAM® dosage regimen is recommended.
Use with Digoxin
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Use with Warfarin-like Compounds
Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.
Periodic evaluation of prothrombin time should be performed when ULTRAM® tablets and warfarin-like compounds are administered concurrently.
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.
Oral administration of ULTRAM® with food does not significantly affect its rate or extent of absorption; therefore, ULTRAM® can be administered without regard to food.
Read the Ultram Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 3/18/2015
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