WARNINGS

Hepatotoxicity Tramadol hydrochloride and acetaminophen tablets contain tramadol hydrochloride and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 mg per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products (see BOXED WARNING). The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 mg of acetaminophen per day, even if they feel well. Serious Skin Reactions Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Seizure Risk Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking: • Selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), • Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or • Other opioids. Administration of tramadol may enhance the seizure risk in patients taking: • MAO inhibitors (see also : Use with MAO Inhibitors and Serotonin Reuptake Inhibitors), • Neuroleptics, or • Other drugs that reduce the seizure threshold. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal or CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure. Suicide Risk • Do not prescribe tramadol hydrochloride and acetaminophen for patients who are suicidal or addiction-prone. • Prescribe tramadol hydrochloride and acetaminophen with caution for patients taking tranquilizers or antidepressant drugs and patients who use alcohol in excess and who suffer from emotional disturbance or depression. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol and other CNS-active drugs (see : Risk of Overdosage). Serotonin Syndrome Risk The development of a potentially life threatening serotonin syndrome may occur with the use of tramadol products, including tramadol hydrochloride and acetaminophen, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Hypersensitivity/Anaphylaxis Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson Syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride and acetaminophen tablets (see CONTRAINDICATIONS). There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth and throat, respiratory distress, urticaria, rash, pruritus and vomiting. There were infrequent reports of life threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue tramadol hydrochloride and acetaminophen immediately and seek medical care if they experience these symptoms. Do not prescribe tramadol hydrochloride and acetaminophen for patients with acetaminophen allergy. Respiratory Depression Administer tramadol hydrochloride and acetaminophen tablets cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see : Seizure Risk and OVERDOSAGE). Interaction with Central Nervous System (CNS) Depressants Tramadol hydrochloride and acetaminophen tablets should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol increases the risk of CNS and respiratory depression in these patients. Interactions with Alcohol and Drugs of Abuse Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids or illicit drugs that cause central nervous system depression. Increased Intracranial Pressure or Head Trauma Tramadol hydrochloride and acetaminophen tablets should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status in these patients if they are receiving tramadol hydrochloride and acetaminophen tablets (see : Respiratory Depression). Use in Ambulatory Patients Tramadol may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly. Use with MAO Inhibitors and Serotonin Reuptake Inhibitors Use tramadol hydrochloride and acetaminophen tablets with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration of MAO inhibitors and tramadol. Concomitant use of tramadol with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome. Use with Alcohol Tramadol hydrochloride and acetaminophen tablets should not be used concomitantly with alcohol consumption. The use of tramadol hydrochloride and acetaminophen tablets in patients with liver disease is not recommended. Use with Other Acetaminophen-Containing Products Due to the potential for acetaminophen hepatotoxicity at doses higher than the recommended dose, tramadol hydrochloride and acetaminophen tablets should not be used concomitantly with other acetaminophen-containing products. Misuse, Abuse and Diversion: Tramadol has mu-opioid agonist activity. Tramadol hydrochloride and acetaminophen, a tramadol-containing product, can be sought by drug abusers and people with addiction disorders and may be subject to criminal diversion. The possibility of illegal or illicit use should be considered when prescribing or dispensing tramadol hydrochloride and acetaminophen in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Misuse or abuse poses a significant risk to the abuser that could result in overdose and death (see DRUG ABUSE AND DEPENDENCE and OVERDOSAGE). Concerns about abuse, addiction and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Risk of Overdosage Patients taking tramadol should be warned not to exceed the dose recommended by their physician. Tramadol products in excessive doses, either alone or in combination with other CNS depressants, including alcohol, are a cause of drug-related deaths. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, tricyclic antidepressants or other CNS depressant drugs. Patients should be advised of the additive depressant effects of these combinations. Serious potential consequences of overdosage with tramadol are central nervous system depression, respiratory depression and death. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE). A serious potential consequence of overdosage with acetaminophen is hepatic (centrilobular) necrosis, leading to hepatic failure and death. Emergency help should be sought immediately and treatment initiated immediately if overdose is suspected, even if symptoms are not apparent. Withdrawal Withdrawal symptoms may occur if tramadol hydrochloride and acetaminophen tablets are discontinued abruptly (see DRUG ABUSE AND DEPENDENCE). Reported symptoms have included anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection and rarely hallucinations. Other symptoms that have been reported less frequently with tramadol hydrochloride and acetaminophen tablet discontinuation include: panic attacks, severe anxiety and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering tramadol hydrochloride and acetaminophen tablets at the time of discontinuation.