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 Hydrochloride 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 Opioid drugs.

· MAO inhibitors (see also WARNINGS - Use with MAO Inhibitors),

· Neuroleptics, or

· Other drugs that reduce the seizure threshold.

Serious and rarely fatal anaphylactoid 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 (see CONTRAINDICATIONS ).

Administer Tramadol Hydrochloride 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 WARNINGS , Seizure Risk and OVERDOSAGE ).

Tramadol Hydrochloride should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, other opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol increases the risk of CNS and respiratory depression in these patients.

Tramadol Hydrochloride 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 Tramadol Hydrochloride (See Respiratory Depression .)

Patients with a history of sensitivity to phenylketones may be at increased risk and therefore should not receive Tramadol Hydrochloride .

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

Withdrawal symptoms may occur if Tramadol Hydrochloride is discontinued abruptly. (See DRUG ABUSE AND DEPENDENCE .) 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 tramadol discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication.

Tramadol Hydrochloride may induce psychic and physical dependence of the morphine-type (µ-opioid) (see DRUG ABUSE AND DEPENDENCE ). Tramadol Hydrochloride should not be used in opioid-dependent patients. Tramadol has been shown to reinitiate physical dependence in some patients who have been previously dependent on other opioids. Dependence and abuse, including drug-seeking behavior and taking illicit actions to obtain the drug, are not limited to those patients with prior history of opioid dependence.

Serious potential consequences of overdosage with tramadol hydrochloride tablets are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE ).

The administration of Tramadol Hydrochloride may complicate the clinical assessment of patients with acute abdominal conditions.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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. Mice were dosed orally up to 30 mg/kg (90 mg/m² or 0.36 times the maximum daily human dosage of 246 mg/m ² ) 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 (dosing orally up to 30 mg/kg, 180 mg/m² , or 0.73 times the maximum daily human dosage).

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.

No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (300 mg/m² ) in male rats and 75 mg/kg (450 mg/m² ) in female rats. These dosages are 1.2 and 1.8 times the maximum daily human dosage of 246 mg/m² , respectively.

Pregnancy, Teratogenic Effects: Pregnancy Category C .

Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m² ), rats (>25 mg/kg or 150 mg/m² ) and rabbits ( >75 mg/kg or 900 mg/m² ) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on a mg/m² basis are 1.4, >0.6, and >3.6 times the maximum daily human dosage (246 mg/m² ) for mouse, rat and rabbit, respectively.

No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg or 420 mg/m² ), rats (up to 80 mg/kg or 480 mg/m² ) or rabbits (up to 300 mg/kg or 3600 mg/m² ) treated with tramadol by various routes. 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 (3600 mg/m ² ), a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the maximum daily human dosage (246 mg/m² ), respectively.

Non-teratogenic Effects

Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m ² or 1.2 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m² or 1.9 and higher the maximum daily human dose).

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. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing.

Labor and Delivery

Tramadol Hydrochloride 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 dependence and post-partum withdrawal symptoms in the newborn (see DRUG ABUSE AND DEPENDENCE ). 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 Hydrochloride 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 µg of tramadol (0.1% of the maternal dose) and 27 µg of M1.

Pediatric Use

The safety and efficacy of Tramadol Hydrochloride in patients under 16 years of age have not been established. The use of Tramadol Hydrochloride in the pediatric population is not recommended.

Geriatric Use

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol in controlled clinical trials. Of those, 145 subjects were 75 years of age and older.

In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.

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