ULTRACET (Page 2 of 6)

Metabolism

Following oral administration, tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N — and O — demethylation and glucuronidation or sulfation in the liver. Metabolite M1 (O -desmethyltramadol) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see PRECAUTIONS, Drug Interactions).

Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan, and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers,” while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline, and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of SEROTONIN re-uptake INHIBITORS and MAO INHIBITORS may enhance the risk of adverse events, including seizure (see WARNINGS) and serotonin syndrome.

Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways:

a)
conjugation with glucuronide;
b)
conjugation with sulfate; and
c)
oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates. The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways.

In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates.

Elimination

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The plasma elimination half-lives of racemic tramadol and M1 are approximately 5–6 and 7 hours, respectively, after administration of ULTRACET®. The apparent plasma elimination half-life of racemic tramadol increased to 7–9 hours upon multiple dosing of ULTRACET®.

The half-life of acetaminophen is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of acetaminophen is excreted unchanged in the urine.

Special Populations

Renal

The pharmacokinetics of ULTRACET® in patients with renal impairment has not been studied. Based on studies using tramadol alone, excretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min. Adjustment of dosing regimen in this patient population is recommended (see DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose based on studies using tramadol alone.

Hepatic

The pharmacokinetics and tolerability of ULTRACET® in patients with impaired hepatic function have not been studied. Since tramadol and acetaminophen are both extensively metabolized by the liver, the use of ULTRACET® in patients with hepatic impairment is not recommended (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Geriatric

A population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain treated with ULTRACET® , which included 55 patients between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes in the pharmacokinetics of tramadol and acetaminophen in elderly patients with normal renal and hepatic function (see PRECAUTIONS, Geriatric Use).

Gender

Tramadol clearance was 20% higher in female subjects compared to males on four phase I studies of ULTRACET® in 50 male and 34 female healthy subjects. The clinical significance of this difference is unknown.

Pediatric

The pharmacokinetics of ULTRACET® tablets has not been studied in pediatric patients below 16 years of age.

CLINICAL STUDIES

Single-Dose Studies for Treatment of Acute Pain

In pivotal single-dose studies in acute pain, two tablets of ULTRACET® administered to patients with pain following oral surgical procedures provided greater relief than placebo or either of the individual components given at the same dose. The onset of pain relief after ULTRACET® was faster than tramadol alone. Onset of analgesia occurred in less than one hour. The duration of pain relief after ULTRACET® was longer than acetaminophen alone. Analgesia was generally comparable to that of the comparator, ibuprofen.

ULTRACET Indications and Usage

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

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.

WARNINGS

Hepatotoxicity

ULTRACET® contains tramadol HCl and acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products (see Boxed Warning).

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.

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:

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, or CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure.

Suicide Risk

  • Do not prescribe ULTRACET ® for patients who are suicidal or addiction-prone.
  • Prescribe ULTRACET ® with caution for patients taking tranquilizers or antidepressant drugs 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).

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