SIDE EFFECTS
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 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 and the
active control groups, acetaminophen 300 mg with codeine phosphate
30 mg, and aspirin 325 mg with codeine phosphate 30 mg. (TABLE
2)
| TABLE
2 Cumulative Incidence of Adverse Reactions for Tramadol
HCl 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"1 |
7% |
11% |
14% |
| Asthenia |
6% |
11% |
12% |
| Sweating |
6% |
7% |
9% |
| Dyspepsia |
5% |
9% |
13% |
| Dry Mouth |
5% |
9% |
10% |
| Diarrhea |
5% |
6% |
10% |
| 1 "CNS Stimulation" is a composite of nervousness,
anxiety, agitation, tremor, spasticity, euphoria, emotional
lability and hallucinations. |
Incidence 1% To Less Than 5%, Possibly Casually 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 casual relationship with tramadol
exists.
Body as a Whole: Malaise.
Cardiovascular: Vasodilation.
Central Nervous System: Anxiety, Confusion,
Coordination disturbance, Euphoria, Nervousness, Sleep disorder.
Gastrointestinal: Abdominal pain, Anorexia,
Flatulence.
Musculoskeletal: Hypertonia.
Skin: Rash.
Special Senses: Visual disturbance.
Urogenital: Urinary retention, Urinary frequency,
Menopausal symptoms.
Incidence Less Than 1%, Possible 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: Allergic reaction,
Accidental injury, Weight loss, Anaphylaxis.
Cardiovascular: Syncope, Orthostatic Hypotension,
Tachycardia.
Central Nervous System: Seizure (see WARNINGS),
Paresthesia, Cognitive dysfunction, Hallucinations, Tremor,
Amnesia, Difficulty in concentration, Abnormal gait, Depression.
Respiratory: Dyspnea.
Skin: Urticaria, Vesicles, Stevens-Johnson syndrome/Toxic
epidermal necrolysis.
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 during clinical trials
and/or reported in post-marketing experience. A causal relationship
between tramadol and these events has not been determined.
However, the most significant events are listed below as alerting
information to the physician.
Body as a whole: Suicidal tendency.
Cardiovascular: Abnormal ECG, Hypertension,
Hypotension, Myocardial ischemia, Palpitations.
Central Nervous System: Migraine, Speech disorders.
Gastrointestinal: Gastrointestinal bleeding,
Hepatitis, Stomatitis.
Laboratory abnormalities: Creatinine increase,
Elevated liver enzymes, Hemoglobin decrease, Proteinuria.
Sensory: Cataracts, Deafness, Tinnitus.
Skin: Pruritis.
DRUG ABUSE AND DEPENDENCE
Tramadol HCl has a potential to cause psychic
and physical dependence of the morphone-type (mc-opioid).
The drug has been associated with craving, drug-seeking behavior
and tolerance development. Cases of abuse and dependence on
tramadol HCl have been reported. Tramadol HCl should not be
used in opioid-dependent patients. Tramadol HCl can reinitiate
physical dependence in patients that have been previously
dependent or chronically using other opioids. In patients
with a tendency to drug abuse, a history of drug dependence,
or are chronically using opioids, treatment with tramadol
HCl is not recommended.
DRUG INTERACTIONS
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 Carbamazepine: Concomitant
administration of tramadol hydrochloride with carbamazepine causes a significant increase in tramadol metabolism, presumably
through metabolic induction by carbamazepine. Patients receiving
chronic carbamazepine doses of up to 800 mg daily may require
up to twice the recommended dose of tramadol.
Use with Quinidine: Tramadol is
metabolized to M1 by the CYP2D6 P-450 isoenzyme.Quinidine is a selective inhibitor of that isoenzyme; so that concomitant
administration of quinidine and tramadol results in increased
concentrations of tramadol and reduced concentrations of M1.
The clinical consequences of this effect have not been fully
investigated, and the effect on quinidine concentrations is
unknown. In vitro drug interaction studies in human
liver microsomes indicate that tramadol has no effect on quinidine
metabolism.
Use with Inhibitors of CYP2D6: 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.
Use with Cimetidine: Concomitant
administration of tramadol with cimetidine does not
result in clinically significant changes in tramadol pharmacokinetics.
Therefore, no alteration of the tramadol dosage regimen is
recommended.
Use with MAO Inhibitors: Interactions
with MAO Inhibitors due to interference with detoxification
mechanisms, have been reported for some centrally acting drugs
(see WARNINGS, Use with MAO Inhibitors).
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.
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