Tramadol

Seizure Risk

Seizures have been reported in patients receiving ULTRAM® within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of ULTRAM® above the recommended range.

Concomitant use of ULTRAM® increases the seizure risk in patients taking:

• Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or
• Other opioids.

Administration of ULTRAM® may enhance the seizure risk in patients taking:

• MAO inhibitors (see also WARNINGS, Use with MAO Inhibitors and Serotonin Re-Uptake 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, CNS infections) . In ULTRAM® overdose, naloxone administration may increase the risk of seizure.

Suicide Risk

• Do not prescribe ULTRAM® for patients who are suicidal or addiction-prone.
• Prescribe ULTRAM® Tablets with caution for patients who are taking tranquilizers or antidepressant drug 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 WARNINGS, Risk of Overdosage).

Serotonin Syndrome Risk

The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including ULTRAM®, 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).

Anaphylactoid Reactions

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with ULTRAM®. 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 ULTRAM® (see CONTRAINDICATIONS).

Respiratory Depression

Administer ULTRAM® cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. When large doses of ULTRAM® 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 WARNINGS, Seizure Risk and OVERDOSAGE).

Interaction With Central Nervous System (CNS) Depressants

ULTRAM® 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. ULTRAM® 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

ULTRAM® 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 reaction when evaluating altered mental status in these patients if they are receiving ULTRAM® (see WARNINGS, Respiratory Depression).

Use in Ambulatory Patients

ULTRAM® 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 Re-uptake Inhibitors

Use ULTRAM® with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of ULTRAM® with MAO inhibitors or SSRI’s increases the risk of adverse events, including seizure and serotonin syndrome.

Misuse, Abuse and Diversion

Tramadol has mu-opioid agonist activity. ULTRAM® 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 ULTRAM® 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, antidepressants, or other CNS depressant drugs. Patients should be advised of the additive depressant effects of these combinations.

Serious potential consequences of overdosage with ULTRAM® (tramadol hydrochloride) tablets 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).

Withdrawal

Withdrawal symptoms may occur if ULTRAM® is discontinued abruptly (see also 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 ULTRAM® discontinuation include panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering ULTRAM® at the time of discontinuation.