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 WARNINGS - 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 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. 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 ULTRACET (see CONTRAINDICATIONS).

Respiratory Depression

Administer ULTRACET® 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 adminis-tered, use cautiously because it may precipitate seizures (see WARNINGS, Seizure Risk and OVERDOSAGE).

Interaction With Central Nervous System (CNS) Depressants

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

Increased Intracranial Pressure or Head Trauma

ULTRACET® should be used with caution in patients with increased intracranial pressure or head injury. The respiratory de-pressant 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 ULTRACET (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 Re-uptake Inhibitors

Use ULTRACET® 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 SSRI's increases the risk of adverse events, including seizure and serotonin syndrome.

Use With Alcohol

ULTRACET® should not be used concomitantly with alcohol consumption. The use of ULTRACET 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, ULTRACET® should not be used concomitantly with other acetaminophen-containing products.

Withdrawal

Withdrawal symptoms may occur if ULTRACET® 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 ULTRACET discontinua-tion include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering ULTRACET at the time of discontinuation.

Physical Dependence and Abuse

Tramadol may induce psychic and physical dependence of the morphine-type (µ-opioid). (See DRUG ABUSE AND DEPENDENCE.) Tramadol should not be used in opioid-dependent patients. Tramadol has been shown to reinitiate physical dependence in some patients that 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.

Risk of Overdosage

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

Serious potential consequences of overdosage with acetaminophen are 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.

General

The recommended dose of ULTRACET® should not be exceeded.

Do not co-administer ULTRACET with other tramadol or acetaminophen-containing products. (See WARNINGS, Use With Other Acetaminophen-containing Products and Risk of Overdosage.)

Pediatric Use

The safety and effectiveness of ULTRACET® has not been studied in the pediatric population.

Geriatric Use

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function; of concomitant disease and multiple drug therapy.

Acute Abdominal Conditions

The administration of ULTRACET® may complicate the clinical assessment of patients with acute abdominal conditions.

Use in Renal Disease

ULTRACET® has not been studied in patients with impaired renal function. Experience with tramadol suggest that 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, it is recommended that the dosing interval of ULTRACET be increased not to exceed 2 tablets every 12 hours.

Use in Hepatic Disease

ULTRACET® has not been studied in patients with impaired hepatic function. The use of ULTRACET in patients with hepatic impairment is not recommended (see WARNINGS, Use With Alcohol).

Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no animal or laboratory studies on the combination product (tramadol and acetaminophen) to evaluate carcino-genesis, mutagenesis, or 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 0.5 times the maximum daily human tramadol dosage of 185 mg/m²) 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 rat car-cinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m², or 1 time the maximum daily human tramadol 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, chro-mosome 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 (350 mg/m²) in male rats and 75 mg/kg (450 mg/m²) in female rats. These dosages are 1.6 and 2.4 times the maximum daily human tramadol dosage of 185 mg/m².

Pregnancy

Teratogenic Effects: Pregnancy Category C

No drug-related teratogenic effects were observed in the progeny of rats treated orally with tramadol and acetaminophen.The tramadol/acetaminophen combination product was shown to be embryotoxic and fetotoxic in rats at a maternally toxic dose, 50/434 mg/kg tramadol/acetaminophen (300/2604 mg/m² or 1.6 times the maximum daily human tramadol/acetaminophen dosage of 185/1591 mg/m²), but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs.

Non-teratogenic effects:

Tramadol alone was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m² or 1.6 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 2.6 times the maximum daily human tramadol dosage).

There are no adequate and well-controlled studies in pregnant women. ULTRACET® 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 with tramadol hydrochloride during post-marketing.

Labor and Delivery

ULTRACET® 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 ULTRACET, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers

ULTRACET® 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 post-dose was 100 µg of tramadol (0.1% of the maternal dose) and 27 µg of M1.

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