Table 2 reports the incidence rate of treatment-emergent adverse events over five days of ULTRACET® use in clinical trials (subjects took an average of at least 6 tablets per day).

Table 2: Incidence of Treatment-Emergent Adverse Events (≥ 2.0%)

Incidence at least 1%, causal relationship at least possible or greater: the following lists adverse reactions that occurred with an incidence of at least 1% in single-dose or repeated-dose clinical trials of ULTRACET.

Body as a Whole - Asthenia, fatigue, hot flushes

Central and Peripheral Nervous System - Dizziness, headache, tremor

Gastrointestinal System -Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting

Psychiatric Disorders - Anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence

Skin and Appendages - Pruritus, rash, increased sweating.

Selected Adverse events occurring at less than 1%: the following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in ULTRACET clinical trials.

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, paresthesias, 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 - Hepatic function abnormal

Metabolic and Nutritional Disorders - Weight decrease

Psychiatric Disorders - Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, 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 with tramadol hydrochloride.

Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating, depression, suicidal tendency, hepatitis liver failure and gastrointestinal bleeding. Reported laboratory abnormalities included elevated creatinine and liver function tests. 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.

Other clinically significant adverse experiences previously reported with acetaminophen.

Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to acetaminophen are rare and generally controlled by discontinuation of the drug and, when necessary, symptomatic treatment.

Drug Abuse And Dependence

Tramadol may induce psychic and physical dependence of the morphine-type (µ-opioid). (See WARNINGS.) Dependence and abuse, including drug-seeking behavior 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. Withdrawal symptoms may occur if tramadol 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 ULTRACET® 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.

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 Carbamazepine

Patients taking carbamazepine 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 ULTRACET® and carbamazepine is not recommended.

Use With Quinidine

Tramadol is metabolized to M1 by CYP2D6. 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 these findings are 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 ULTRACET and cimetidine has not been studied. Concomitant administration of tramadol and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRACET 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

Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.

Use With Warfarin Like Compounds

Post-marketing surveillance of both tramadol and acetaminophen individual products have revealed rare alterations of warfarin effect, including elevation of prothrombin times.

While such changes have been generally of limited clinical significance for the individual products, periodic evaluation of prothrombin time should be performed when ULTRACET and warfarin-like compounds are administered concurrently.

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