Ultracet Description

ULTRACET® (tramadol hydrochloride/acetaminophen) Tablets combines two analgesics, tramadol 37.5 mg and acetaminophen 325 mg .

The chemical name for tramadol hydrochloride is (±) cis -2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

The molecular weight of tramadol hydrochloride is 299.84. Tramadol hydrochloride is a white, bitter, crystalline and odorless powder.

The chemical name for acetaminophen is N -acetyl- p -aminophenol. Its structural formula is:

The molecular weight of acetaminophen is 151.17. Acetaminophen is an analgesic and antipyretic agent which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste.

ULTRACET tablets contain 37.5 mg tramadol hydrochloride and 325 mg acetaminophen and are light yellow in color. Inactive ingredients in the tablet are powdered cellulose, pregelatinized corn starch, sodium starch glycolate, starch, purified water, magnesium stearate, OPADRY® Light Yellow, and carnauba wax.

Ultracet Indications And Usage

ULTRACET® is indicated for the short-term (five days or less) management of acute pain.

Ultracet Contraindications

ULTRACET® should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, acetaminophen, any other component of this product or opioids. ULTRACET is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. ULTRACET may worsen central nervous system and respiratory depression in these patients.

Ultracet Side Effects

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 administered, 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 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 .

Increased Intracranial Pressure Or Head Trauma

ULTRACET® 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 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 discontinuation 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 depression 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.

Ultracet Precautions

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).

Information For Patients

• ULTRACET® may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
• ULTRACET should not be taken with alcohol containing beverages.
• The patient should be instructed not to take ULTRACET in combination with other tramadol or acetaminophen-containing products, including over-the-counter preparations.
• ULTRACET should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.
• The patient should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (see PRECAUTIONS, 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, seizures, hepatic toxicity and death.

Drug Interactions

In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses. Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.

Use With Carbamazepine

Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRACET® and carbamazepine is not recommended.

Use With Quinidine

Tramadol is metabolized to M1 by CYP2D6. Quinidine is a selective inhibitor of that isoenzyme; so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.

Use With Inhibitors Of Cyp2d6

In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.

Use With Cimetidine

Concomitant administration of ULTRACET and cimetidine has not been studied. Concomitant administration of tramadol and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRACET dosage regimen is recommended.

Use With Mao Inhibitors

Interactions with MAO Inhibitors , due to interference with detoxification mechanisms, have been reported for some centrally acting drugs (see WARNINGS, Use with MAO Inhibitors).

Use With Digoxin

Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.

Use With Warfarin Like Compounds

Post-marketing surveillance of both tramadol and acetaminophen individual products have revealed rare alterations of warfarin effect, including elevation of prothrombin times.

While such changes have been generally of limited clinical significance for the individual products, periodic evaluation of prothrombin time should be performed when ULTRACET and warfarin-like compounds are administered concurrently.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

There are no animal or laboratory studies on the combination product (tramadol and acetaminophen) to evaluate carcinogenesis, 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 carcinogenicity 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, 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 (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.

Ultracet Overdosage

ULTRACET® is a combination product. The clinical presentation of overdose may include the signs and symptoms of tramadol toxicity, acetaminophen toxicity or both. The initial symptoms of tramadol overdosage may include respiratory depression and or seizures. The initial symptoms seen within the first 24 hours following an acetaminophen overdose are: anorexia, nausea, vomiting, malaise, pallor and diaphoresis.

Tramadol

Serious potential consequences of overdosage are respiratory depression, lethargy, coma, seizure, cardiac arrest and death. (See WARNINGS.) Fatalities have been reported in post marketing in association with both intentional and unintentional overdose with tramadol.

Acetaminophen

Serious potential consequences of overdosage with acetaminophen are hepatic centrilobular necrosis, leading to hepatic failure and death. Renal tubular necrosis, hypoglycemia and coagulation defects also may occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post ingestion.

Ultracet Risk Of Overdosage

Serious potential consequences of overdosage with tramadol 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.)

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.

Ultracet Information For Patients

• ULTRACET® may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.
• ULTRACET should not be taken with alcohol containing beverages.
• The patient should be instructed not to take ULTRACET in combination with other tramadol or acetaminophen-containing products, including over-the-counter preparations.
• ULTRACET should be used with caution when taking medications such as tranquilizers, hypnotics or other opiate containing analgesics.
• The patient should be instructed to inform the physician if they are pregnant, think they might become pregnant, or are trying to become pregnant (see PRECAUTIONS, 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, seizures, hepatic toxicity and death.