Professional Information — Ultracet

Indications and Usage

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

Dosage and Administration

For the short-term (five days or less) management of acute pain, the recommended dose of ULTRACET^® is 2 tablets every 4 to 6 hours as needed for pain relief, up to a maximum of 8 tablets per day.

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.

Adverse Reactions

Table 2 reports the incidence rate of treatment-emergent adverse events over five days of ULTRACET^® use in clinical trials (subjects took an average of at least 6 tablets per day).

Incidence at least 1%, causal relationship at least possible or greater: the following lists adverse reactions that occurred with an incidence of at least 1% in single-dose or repeated-dose clinical trials of ULTRACET^®.

Body as a Whole – Asthenia, fatigue, hot flushes

Central and Peripheral Nervous System – Dizziness, headache, tremor

Gastrointestinal System – Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting

Psychiatric Disorders – Anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence

Skin and Appendages – Pruritus, rash, increased sweating

Selected Adverse events occurring at less than 1%: the following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in ULTRACET^® clinical trials.

Body as a Whole – Chest pain, rigors, syncope, withdrawal syndrome

Cardiovascular Disorders – Hypertension, aggravated hypertension, hypotension

Central and Peripheral Nervous System – Ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo

Gastrointestinal System – Dysphagia, melena, tongue edema

Hearing and Vestibular Disorders – Tinnitus

Heart Rate and Rhythm Disorders – Arrhythmia, palpitation, tachycardia

Liver and Biliary System – Hepatic function abnormal

Metabolic and Nutritional Disorders – Weight decrease

Psychiatric Disorders – Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, abnormal thinking

Red Blood Cell Disorders – Anemia

Respiratory System – Dyspnea

Urinary System – Albuminuria, micturition disorder, oliguria, urinary retention

Vision Disorders – Abnormal vision

Other clinically significant adverse experiences previously reported with tramadol hydrochloride

Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating, depression, suicidal tendency, hepatitis, liver failure, and gastrointestinal bleeding. Reported laboratory abnormalities included elevated creatinine and liver function tests. Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures, and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs.

Other clinically significant adverse experiences previously reported with acetaminophen

Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to acetaminophen are rare and generally controlled by discontinuation of the drug and, when necessary, symptomatic treatment.

Drug Interactions

CYP2D6 and CYP3A4 Inhibitors

Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (see CLINICAL PHARMACOLOGY, Pharmacokinetics ), such as quinidine, fluoxetine, paroxetine. and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol, increasing the risk for serious adverse events including seizures and serotonin syndrome.

Serotonergic Drugs

There have been postmarketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when ULTRACET^® is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John's Wort. If concomitant treatment of ULTRACET^® with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome ).

Triptans

Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ULTRACET^® is coadministered with a triptan. If concomitant treatment of ULTRACET^® with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome ).

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.

Potential for Other Drugs to Affect Tramadol

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. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with ULTRACET^® may affect the metabolism of tramadol, leading to altered tramadol exposure.

Potential for Tramadol to Affect Other Drugs

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 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 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.

Drug Abuse and Dependence

Abuse

Tramadol has mu-opioid agonist activity. ULTRACET^®, a tramadol-containing product, can be abused and may be subject to criminal diversion.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. Drug addiction is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, use for non-medical purposes, continued use despite harm or risk of harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.

"Drug-seeking" behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating physician(s). "Doctor shopping" to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of ULTRACET^® can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances.

Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Proper assessment of the patient and periodic re-evaluation of therapy are appropriate measures that help to limit the potential abuse of this product.

ULTRACET^® is intended for oral use only.

Dependence

Tolerance is the need for increasing doses of drugs to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist (see also WARNINGS, Withdrawal ).

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Generally, tolerance and/or withdrawal are more likely to occur the longer a patient is on continuous therapy with 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. An overdosage of ULTRACET^® may be a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended.

Tramadol

Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, seizures, bradycardia, hypotension, cardiac arrest, and death.

Deaths due to overdose have been reported with abuse and misuse of tramadol (see WARNINGS, Misuse, Abuse, and Diversion ). Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.

In the treatment of tramadol overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.

While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals, convulsions following the administration of toxic doses of ULTRACET^® could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.

Acetaminophen

In acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, 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.

In the treatment of acetaminophen overdosage, gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 or more hours after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs early in the course of intoxication.

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, corn starch, magnesium stearate, hypromellose, polyethylene glycol, polysorbate 80, titanium dioxide, iron oxide, and carnauba wax.

Clinical Pharmacology

The following information is based on studies of tramadol alone or acetaminophen alone, except where otherwise noted:

Pharmacodynamics

ULTRACET^® contains tramadol and acetaminophen. Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to µ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.

Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see CLINICAL PHARMACOLOGY, Pharmacokinetics ).

Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol.

Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating, and pruritus) similar to that of other opioids.

Acetaminophen is a non-opiate, non-salicylate analgesic.

Pharmacokinetics

Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of plasma tramadol and acetaminophen following oral administration of one ULTRACET^® tablet are shown in Table 1. Tramadol has a slower absorption and longer half-life when compared to acetaminophen.

A single-dose pharmacokinetic study of ULTRACET^® in volunteers showed no drug interactions between tramadol and acetaminophen. Upon multiple oral dosing to steady state, however, the bioavailability of tramadol and metabolite M1 was lower for the combination tablets compared to tramadol administered alone. The decrease in AUC was 14% for (+)-tramadol, 10.4% for (-)-tramadol, 11.9% for (+)-M1, and 24.2% for (-)-M1. The cause of this reduced bioavailability is not clear. Following single- or multiple-dose administration of ULTRACET^®, no significant change in acetaminophen pharmacokinetics was observed when compared to acetaminophen given alone.

Absorption

The absolute bioavailability of tramadol from ULTRACET^® tablets has not been determined. Tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of ULTRAM^® tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two ULTRACET^® tablets occurs at approximately two and three hours, respectively, post-dose.

Peak plasma concentrations of acetaminophen occur within one hour and are not affected by co-administration with tramadol. Oral absorption of acetaminophen following administration of ULTRACET^® occurs primarily in the small intestine.

Food Effects

When ULTRACET^® was administered with food, the time to peak plasma concentration was delayed for approximately 35 minutes for tramadol and almost one hour for acetaminophen. However, peak plasma concentrations, and the extents of absorption, of tramadol and acetaminophen were not affected. The clinical significance of this difference is unknown.

Distribution

The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 µg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.

Acetaminophen appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relative small portion (~20%) of acetaminophen is bound to plasma protein.

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:

1. a)conjugation with glucuronide;
2. b)conjugation with sulfate; and
3. 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.

How Supplied / Storage and Handling

ULTRACET^® (tramadol hydrochloride/acetaminophen) Tablets with tramadol 37.5 mg and acetaminophen 325 mg are light yellow, coated, capsule-shaped tablets imprinted "O-M" on one side and "650" on the other and are available as follows:

Dispense in a tight container. Store at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F).

Patient Counseling Information

• Do not take ULTRACET^® if you are allergic to any of its ingredients.
• If you develop signs of allergy such as a rash or difficulty breathing, stop taking ULTRACET^® and contact your healthcare provider immediately.
• Do not take more than 4,000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose.
• Do not take ULTRACET^® in combination with other tramadol or acetaminophen-containing products, including over-the-counter preparations.
• ULTRACET^® may cause seizures and/or serotonin syndrome with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol.
• 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 concomitantly with alcohol-containing beverages during the course of treatment with ULTRACET^®.
• ULTRACET^® should be used with caution when taking medications such as tranquilizers, hypnotics, or other opiate-containing analgesics.
• Inform the physician if you are pregnant, think you might become pregnant, or are trying to become pregnant (see PRECAUTIONS, Labor and Delivery ).
• 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.