Tramadol Hydrochloride / Acetaminophen

Trade Names:
Ultracet
- Tablets 325 mg acetaminophen/37.5 mg tramadol HCl

Pharmacology

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Exact mechanism is unknown; however, it binds to certain opioid receptors and inhibits reuptake of norepinephrine and serotonin.

Inhibits prostaglandin in CNS and reduces fever through direct action on hypothalamic heat-regulating center.

Pharmacokinetics

Absorption

The absolute bioavailability of tramadol after administration of a single 100 mg dose is approximately 75%. The mean peak plasma concentration of racemic tramadol occurs at approximately 2 h. Oral absorption of acetaminophen occurs primarily in the small intestine. Peak concentrations of acetaminophen occur within 1 h.

Distribution

The Vd of tramadol is 2.6 and 2.9 L/kg in men and women, respectively, following IV administration of 100 mg. Tramadol is approximately 20% protein bound. Acetaminophen is widely distributed throughout the body tissue except fat. The Vd is approximately 0.9 L/kg. Less than 20% is bound to plasma protein.

Metabolism

Tramadol is extensively metabolized in the liver by a number of pathways, including CYP2D6 and 3A4, as well as by conjugation. The O-desmethyltramadol metabolite is pharmacologically active. Plasma levels of tramadol are approximately 20% higher in poor metabolizers (CYP2D6) compared with extensive metabolizers. Acetaminophen is primarily metabolized in the liver. In adults, the majority of acetaminophen is conjugated with glucuronic acid, and is not active. In premature infants, newborns and young infants, the predominant metabolite is the sulfate conjugate.

Elimination

Approximately 30% of the tramadol dose is excreted unchanged in the urine and 60% is excreted as metabolites. The plasma elimination t _½ of tramadol and the active metabolite are approximately 5 to 6 h and 7 h, respectively. The apparent t _½ of racemic tramadol increases to 7 to 9 h with multiple dosing. The t _½ of acetaminophen is approximately 2 to 3 h in adults and somewhat shorter in children, while being somewhat longer in neonates and patients with cirrhotic disease. Acetaminophen is eliminated in the urine, primarily as metabolites (less than 9% excreted unchanged).

Special Populations

Use in patients with hepatic function impairment is not recommended. Clearance of tramadol is 20% higher in women compared with men.

Indications and Usage

Short-term (5 days or less) management of acute pain.

Contraindications

Any situation in which opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids, or psychotropic drugs; hypersensitivity to any component of the product or opioids.

Dosage and Administration

PO 2 tablets (37.5 mg tramadol/325 mg acetaminophen/tablet) every 4 to 6 h as needed for pain relief (max, 8 tablets/day). In patients with Ccr less than 30 mL/min, it is recommended that the dosing interval be increased not to exceed 2 tablets every 12 h.

Storage/Stability

Store at controlled room temperature (59° to 86°F).

Drug Interactions

Do not use.

Concurrent use with tramadol is not recommended because carbamazepine increases tramadol metabolism and tramadol increases the risk of seizures.

Use with caution and in reduced doses.

Use with caution because of increased risk of side effects, including seizures and serotonin syndrome.

Plasma concentrations of tramadol may be increased; the clinical importance of these interactions is not known.

Anticoagulant effect of warfarin may be altered (eg, elevation in PT).

Laboratory Test Interactions

Acetaminophen may cause more than a 20% decrease in mean glucose as measured with Chemstrip bG home blood glucose system.

Adverse Reactions

Cardiovascular

Hypertension; hypotension; arrhythmia; palpitation; tachycardia.

CNS

Somnolence; anorexia; insomnia; dizziness; headache; tremor; anxiety; confusion; euphoria; nervousness; amnesia; hallucination.

Dermatologic

Increased sweating; pruritus; rash.

GI

Constipation; diarrhea; nausea; dry mouth; abdominal pain; dyspepsia; flatulence; vomiting.

Genitourinary

Prostatic disorder; urinary retention.

Hematologic

Anemia.

Hepatic

Abnormal hepatic function.

Respiratory

Dyspnea.

Miscellaneous

Asthenia; fatigue; hot flushes; allergic reactions.

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease and multiple drug therapy.

Abdominal conditions

Assessment of patients with acute abdominal conditions may be more difficult.

Acetaminophen-containing products

Do not use concurrently with other acetaminophen-containing products because of increased risk of hepatotoxicity.

Anaphylactoid reactions

Serious and rarely fatal anaphylactoid reactions may occur.

Head injury

Use with caution in patients with increased intracranial pressure or head injury.

Dependence

Psychic and physical dependence of the morphine-type may occur with tramadol.

Hepatic disease

Use is not recommended in patients with hepatic function impairment.

Respiratory depression

Use with caution in patients at risk of respiratory depression.

Seizures

May occur.

Withdrawal

Symptoms (eg, anxiety, sweating, insomnia, rigors, pain, tremors) may occur if tramadol is discontinued abruptly.

Overdosage

Symptoms

Respiratory depression, seizures, lethargy, coma, cardiac arrest, death.

Anorexia, nausea, vomiting, malaise, pallor, diaphoresis, hepatic centrilobular necrosis (leading to hepatic failure and death), renal tubular necrosis, hypoglycemia, coagulation defects.

Patient Information

• Advise patient to take 2 tablets every 4 to 6 h if needed for pain but to not take more than 8 tablets in 24 h.
• Advise patient to take without regard to meals but to take with food if GI upset occurs.
• Caution patient to not take more tablets than prescribed or more frequently than prescribed. Serious toxicity may develop if prescribed dose is exceeded or doses are taken too close together.
• Advise patient that medication is for short-term use (5 days or less) only and if symptoms persist to contact health care provider regarding other therapies for pain control.
• Instruct patient to avoid taking acetaminophen or other acetaminophen-containing products, tramadol, or other tramadol-containing products.
• Instruct patient to avoid alcoholic beverages and other depressants while taking this medication.
• Advise patient that drug may impair judgment, thinking, or motor skills or cause dizziness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.

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