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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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