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Interactions with Other Medicinal Products and Other Forms of Interaction
Use with MAO Inhibitors and Serotonin Reuptake Inhibitors
Interaction with MAO inhibitors have been reported for some centrally acting drugs. (See
CLINICAL PARTICULARS: Use with MAO Inhibitors and Serotonin Reuptake Inhibitors.)
Use with Carbamazepine
Concomitant administration of tramadol hydrochloride and carbamazepine causes a
significant increase in tramadol metabolism. Patients taking carbamazepine may have a
significantly reduced analgesic effect from the tramadol component of ULTRACET.
Use with Quinidine
Tramadol is metabolized to M1 by CYP2D6. Concomitant administration of quinidine
and tramadol results in increased concentrations of tramadol. The clinical
consequences of these findings are unknown.
Use with Warfarin Like Compounds
As medically appropriate, periodic evaluation of prothrombin time should be
performed when ULTRACET and these agents are administered concurrently due
to reports of increased INR in some patients.
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 ULTRACE and cimetidine has not been studied.
Concomitant administration of tramadol and cimetidine does not result in clinically
significant changes in tramadol pharmacokinetics.
Pregnancy and Lactation
Tramadol has been shown to cross the placenta.
There are no adequate and well-controlled studies in pregnant women.
Safe use in pregnancy has not been established.
ULTRACET is not recommended
for nursing mothers because its safety in infants and newborns has not been studied.
Effects on Ability to Drive and Use Machines
ULTRACET may impair mental or physical abilities required for the performance of
potentially hazardous tasks such as driving a car or operating machinery.
Undesirable Effects
The most frequently reported events were in the central nervous system and
gastrointestinal system.
The most common reported events were nausea, dizziness, and somnolence.
In addition, the following
effects have been frequently observed, though the frequency is generally
lower:
Body as a Whole – Asthenia, fatigue, hot flushes
Central and Peripheral Nervous
System – Headache, tremor
Gastrointestinal System – Abdominal pain, constipation, diarrhea, dyspepsia,
flatulence, dry mouth, vomiting
Psychiatric Disorders – Anorexia, anxiety, confusion, euphoria, insomnia, nervousness
Skin and Appendages – Pruritus, rash, increased sweating
Uncommon reported clinically significant adverse experiences with at least a
possible causal link to ULTRACET include:
Body as a Whole – Chest pain, rigors, syncope, withdrawal syndrome
Cardiovascular Disorders
– Hypertension, aggravated hypertension, hypotension
Central and Peripheral Nervous System
– Ataxia, convulsions, hypertonia, migraine,
aggravated migraine, involuntary muscle contractions, paraesthesia, stupor, vertigo
Gastrointestinal System – Dysphagia, melena, tongue edema
Hearing and Vestibular Disorders
– Tinnitus
Heart Rate and Rhythm Disorders
– Arrhythmia, palpitation, tachycardia
Liver and Biliary System
– Liver test abnormalities
Metabolic and Nutritional Disorders
– Weight decrease
Psychiatric Disorders – Amnesia, depersonalization, depression, drug abuse,
emotional lability, hallucination, impotence, bad dreams, abnormal thinking
Red Blood Cell Disorders
– Anemia
Respiratory System – Dyspnea
Urinary System – Albuminuria, micturition disorder, oliguria, urinary retention
Vision Disorders – Abnormal vision
Other clinically significant adverse experiences previously reported in clinical trials or
post-marketing reports with tramadol hydrochloride
Other events which have been reported with the use of tramadol products include:
orthostatic hypotension, allergic reactions (including anaphylaxis and urticaria, Stevens
Johnson Syndrome/TENS), cognitive dysfunction, suicidal tendency, and hepatitis.
Reported laboratory abnormalities included elevated creatinine. Serotonin syndrome
(whose symptoms may include fever, excitation, shivering and agitation) has been
reported with tramadol when used concomitantly with other senotonergic agents such
as SSRIs and MAO inhibitors. Post-marketing surveillance of tramadol has revealed
rare alterations of warfarin effect, including elevation of prothrombin times.
Other clinically significant adverse experiences previously reported in clinical trials of
post-marketing reports with paracetamol
Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to
paracetamol are rare and generally controlled by discontinuation of the drug, and
when necessary, symptomatic treatment. There have been several reports that
suggest that paracetamol may produce hypoprothrombinemia when administered
with warfarin like compounds. In other studies, prothrombin time did not change.
Overdose
ULTRACET is a combination product, The clinical presentation of overdose may
include the signs and symptoms of tramadol toxicity, paracetamol toxicity or both.
The initial symptoms of tramadol overdosage may include respiratory depression
and/or seizures. The initial symptoms seen within the first 24 hours following a
paracetamol overdose may include: gastrointestinal irritability, anorexia, nausea,
vomiting, malaise, pallor and diaphoresis.
Human Experience
Tramadol
Serious potential consequences of overdosage of the tramadol component are
respiratory depression, lethargy, coma, seizure, cardiac arrest and death.
Paracetamol
Paracetamol in massive overdosage may cause hepatic toxicity in some patients.
Early symptoms following a potentially hepatotoxic overdosage may include:
gastrointestinal irritability, anorexia, nausea, vomiting, malaise, pallor, and
diaphoresis. Clinical and laboratory evidence of hepatic toxicity may not be apparent
until 48 to 72 hours post-ingestion.
Treatment
A single or multiple overdose with
ULTRACET may be a potentially lethal polydrug
overdose, and appropriate expert consultation, it available, is recommended.
While naloxone will reverse some, but not all, symptoms caused by overdosage with
tramadol the risk of seizures is also increased with naloxone administration. Based on
experience with tramadol, hemodialysis s not expected to be helpful in an overdose
because it removes less than 7% of the administered dose in a 4-hour dialysis period.
In treating an overdosage of
ULTRACET, primary attention should be given to
maintaining adequate ventilation along with general supportive treatment. Measures
should be taken to reduce drug absorption. Vomiting should be induced
mechanically, or with syrup of ipecac, if the patient is alert (adequate pharyngeal and
laryngeal reflexes). Oral activated charcoal (1 g/kg) should follow gastric emptying.
The first dose should be accompanied by an appropriate cathartic. If repeated doses
are used, the cathartic might be included with alternate doses as required.
Hypotension is usually hypovolemic in etiology and should respond to fluids.
Vasopressors and other supportive measures should be employed as indicated. A
cuffed endotracheal tube should be inserted before gastric lavage of the
unconscious patient and, when necessary, to provide assisted respiration.
In adult and pediatric patients, any individual presenting with an unknown amount of paracetamol ingested or with a questionable or unreliable history about the time of
ingestion should have a plasma paracetamol level drawn and be treated with
acetylcysteine. If an assay cannot be obtained and the estimated paracetamol ingestion
exceeds 7.5 to 10 grams for adults and adolescents or 150 mg/kg for children, dosing
with N-acetylcysteine should be initiated and continued for a full course of therapy.
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