WARNINGS

Seizure Risk: Seizures have been reported in patients receiving tramadol HCl within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol HCl above the recommended range. Concomitant use of tramadol HCl increases the seizure risk in patients taking:

Selective serotonin reuptake inhibitors (SSRI antidepressants or anoretics),
Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.), or
Opioids.

Administration of tramadol HCl may enhance the seizure risk in patients taking:

MAO inhibitors (see also Use with MAO 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 tramadol HCl overdose, naloxone administration may increase the risk of seizure.

Anaphylactoid Reactions: Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol HCl. These reactions often occur following the first dose. Other reported reactions include pruritus, hives, bronchospasm, and angioedema. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive tramadol HCl (see CONTRAINDICATIONS).

Use in Opioid-dependent Patients: Tramadol HCl should not be used in opioid-dependent patients. Tramadol HCl has been shown to reinitiate physical dependence in some patients that have been previously dependent on other opioids. Consequently, in patients with a tendency to opioid abuse or opioid dependence, treatment with tramadol HCl is not recommended.

Use with CNS Depressants: Tramadol should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, phenothiazines, tranquilizers or sedative hypnotics.

Use with MAO Inhibitors: Tramadol should be used with great caution in patients taking monoamine oxidase inhibitors, because animal studies have shown increased deaths with combined administration.

PRECAUTIONS

Respiratory Depression: Administer tramadol HCl cautiously in patients at risk for respiratory depression. When large doses of tramadol HCl are administered with anesthetic medications or alcohol, respiratory depression may result. Treat such cases as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS , Seizure Risk and OVERDOSAGE).

Increased Intracranial Pressure or Head Trauma: Tramadol should be used with caution in patients with increased intracranial pressure or head injury. 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 tramadol.

Acute Abdominal Conditions: The administration of tramadol may complicate the clinical assessment of patients with acute abdominal conditions.

Withdrawal: Withdrawal symptoms may occur if tramadol HCl is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhoea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication.

Patients Physically Dependent on Opioids: Tramadol is not recommended for patients who are dependent on opioids. Patients who have recently taken substantial amounts of opioids may experience withdrawal symptoms. Because of the difficulty in assessing dependence in patients who have previously received substantial amounts of opioid medication, administer tramadol cautiously to such patients.

Use in Renal and Hepatic Disease: Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 ml/min, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION).

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION).

With the prolonged half-life in these conditions, achievement of steady state is delayed, so that it may take several days for elevated plasma concentrations to develop.

Information for the Patient

Tramadol HCl may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
Tramadol HCl should not be taken with alcohol containing beverages.
Tramadol HCl should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.
Patients should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (see Labor and Delivery).
The patient should understand the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression and seizures.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.

A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice (dosing orally up to 30 mg/kg for approximately two years, although the study was not done with the Maximum Tolerated Dose). This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study.

No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats.

Pregnancy, Teratogenic Effects, Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Tramadol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats and rabbits at maternally toxic doses 3 to 15 times the maximum human dose or higher (120 mg/kg in mice, 25 mg/kg or higher in rats and 75 mg/kg or higher in rabbits), but was not teratogenic at these dose levels. No harm to the fetus due to tramadol was seen at doses that were not maternally toxic.

No drug-related teratogenic effects were observed in progeny of mice, rats or rabbits treated with tramadol by various routes (up to 140 mg/kg for mice, 80 mg/kg for rats or 300 mg/kg for rabbits). Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit.

In peri- and post-natal studies in rats, progeny of dams receiving oral (gavage) dose levels of 50 mg/kg or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (6 to 10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.

Labor and Delivery: Tramadol should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependance and post-partum withdrawl symptoms in the newborn. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.

The effect of tramadol, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers: Tramadol is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.

Pediatric Use: The pediatric use of tramadol is not recommended because safety and efficacy in patients under 16 years of age have not been established.

Geriatric Use: In subjects over the age of 75 years, serum concentrations are slightly elevated and the elimination half-life is slightly prolonged. The aged also can be expected to vary more widely in their ability to tolerate adverse drug effects. Daily doses in excess of 300 mg are not recommended in patients over 75 (see DOSAGE AND ADMINISTRATION).