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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%)
|Gastrointestinal System Disorders|
|Central & Peripheral Nervous System|
|Skin and Appendages|
|Reproductive Disorders, Male *|
|*Number of males = 62|
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
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
Hearing and Vestibular Disorders – Tinnitus
Liver and Biliary System – Hepatic function abnormal
Metabolic and Nutritional Disorders – Weight decrease
Red Blood Cell Disorders – Anemia
Respiratory System – Dyspnea
Vision Disorders – Abnormal vision
The following adverse reactions, not noted above, have been identified during post approval use of tramadol-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Nervous system disorders – movement disorder, speech disorder
Psychiatric disorders – delirium
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. Cases of hypoglycemia have been reported very rarely in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients.
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
ULTRACET® (tramadol hydrochloride/acetaminophen) Tablets are classified as a Schedule IV controlled substance.
Tramadol has mu-opioid agonist activity. ULTRACET®, a tramadol-containing product, can be abused and may be subject to criminal diversion.
Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. Drug addiction is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, use for nonmedical purposes, continued use despite harm or risk of harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
“Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of ULTRACET® can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances.
Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Proper assessment of the patient and periodic re-evaluation of therapy are appropriate measures that help to limit the potential abuse of this product.
ULTRACET® is intended for oral use only.
Tolerance is the need for increasing doses of drugs to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist (see also WARNINGS, Withdrawal).
The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous therapy with ULTRACET®.
Read the Ultracet (tramadol hydrochloride and acetaminophen tablets) Side Effects Center for a complete guide to possible side effects
CYP2D6 And CYP3A4 Inhibitors
Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Pharmacokinetics ), such as quinidine, fluoxetine, paroxetine, and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol, increasing the risk for serious adverse events including seizures and serotonin syndrome.
There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when ULTRACET® is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John's Wort. If concomitant treatment of ULTRACET® 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, Serotonin Syndrome Risk).
Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ULTRACET® is coadministered with a triptan. If concomitant treatment of ULTRACET® with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome Risk).
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.
Potential For Other Drugs To Affect Tramadol
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. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with ULTRACET® may affect the metabolism of tramadol, leading to altered tramadol exposure.
Potential For Tramadol To Affect Other Drugs
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 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 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.
Read the Ultracet Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 9/13/2016
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