TRAMACET (tramadol hydrochloride/acetaminophen) is indicated for the short-term (five days or less) management of acute pain.

No overall differences with regard to safety or pharmacokinetics were noted between subjects ≥65 years of age and younger subjects. However, 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.

The safety and effectiveness of TRAMACET has not been studied in the pediatric population. Therefore, use of TRAMACET tablets is not recommended in patients under 18 years of age.

• TRAMACET (tramadol hydrochloride/acetaminophen) tablets should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, acetaminophen, opioids or any other component of this product. For a complete listing of nonmedicinal ingredients, see Dosage Forms, Composition and Packaging.

  
  

• TRAMACET 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. TRAMACET may worsen central nervous system and respiratory depression in these patients.

  
  

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 re-uptake inhibitors (SSRI antidepressants or anorectics);

  
  

• tricyclic antidepressants (TCAs) and other tricyclic compounds (e.g. cyclobenzaprine, promethazine, etc.) or;

  
  

• opioids.

  
  

 

Administration of tramadol may enhance the seizure risk in patients taking:

• MAO inhibitors (see Use with MAO Inhibitors and Serotonin Re-uptake 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.

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these rare reactions 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 TRAMACET tablets (see Contraindications).

Tramadol has a potential to cause psychic and physical dependence of the morphine-type (µ-opioid). The drug has been associated with craving, drug-seeking behaviour and tolerance development. Cases of abuse and dependence on tramadol have been reported. TRAMACET tablets should not be used in opioid-dependent patients. Tramadol can re-initiate physical dependence in patients who have been previously dependent or chronically using other opioids. In patients with a tendency to abuse drugs or a history of drug dependence, and in patients who are chronically using opioids, treatment with TRAMACET is not recommended.

A Risk Management strategy to support the safe and effective use of TRAMACET under Schedule F has been established. The following are considered to be the essential components of the Risk Management strategy:

 

Withdrawal symptoms may occur if tramadol is discontinued abruptly. 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 TRAMACET discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.

TRAMACET 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 TRAMACET (see Respiratory, Respiratory Depression).

TRAMACET tablets should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anaesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol increases the risk of CNS and respiratory depression in these patients.

TRAMACET should not be used concomitantly with alcohol consumption. The use of TRAMACET in patients with liver disease is not recommended.

Use TRAMACET 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 SSRIs increases the risk of adverse events, including seizure and serotonin syndrome (see Seizure Risk and Drug Interactions).

Acute Abdominal Conditions: The administration of TRAMACET may complicate the clinical assessment of patients with acute abdominal conditions.

Use in Hepatic Disease: TRAMACET has not been studied in patients with impaired hepatic function. The use of TRAMACET tablets in patients with severe hepatic impairment is not recommended.

Use with Other Acetaminophen-containing Products: Due to the potential for acetaminophen hepatotoxicity at doses higher than the recommended dose, TRAMACET should not be used concomitantly with other acetaminophen-containing products

Use in Renal Disease: TRAMACET has not been studied in patients with impaired renal function. Experience with tramadol suggests 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 TRAMACET be increased to not exceed 2 tablets every 12 hours (see Dosage and Administration).

Respiratory Depression: Administer TRAMACET 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 anaesthetic 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 Seizure Risk and Overdosage).

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 tumours, 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.

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.

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).

TRAMACET may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.

There are no adequate and well-controlled studies in pregnant women. TRAMACET 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 stillbirth have been reported with tramadol hydrochloride during post-marketing.

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

TRAMACET is not recommended for obstetrical pre-operative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.

Following a single 100 mg i.v. 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.

The safety and effectiveness of TRAMACET has not been studied in the pediatric population. Therefore, use of TRAMACET tablets is not recommended in patients under 18 years of age.

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.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

TRAMACET (tramadol hydrochloride/acetaminophen) tablets were administered to 1437 patients during the double-blind or open-label extension periods in studies of chronic non-malignant pain. Of these patients, 503 were 65 years old or older.

Table 1 reports the cumulative incidence rate of the most common treatment-emergent adverse reactions by preferred term and extent of exposure for any time period for the most frequent reactions (4.5% or more for any time period). The most frequently reported events were in the central nervous and gastrointestinal systems.

Table 1: TRAMACET

Cumulative Incidence of Treatment-emergent Adverse Events by Preferred Term and Extent of Exposure^a for All Tramadol/Acetaminophen-exposed Subjects in Pain Trials up to 3 months duration

37.5 tramadol/325 acetaminophen (N=1437)
Body System Preferred Term	Up to 7 days %	Up to 30 days %	Up to 90 days %
Gastrointestinal System
Nausea	13	17	22
Constipation	5	10	13
Vomiting	4	5	8
Dry Mouth	4	4	5
Dyspepsia	2	4	6
Diarrhea	2	5	7
Central and Peripheral Nervous System
Dizziness	12	14	16
Headache	6	8	13
CNS Stimulationb	3	5	7
Psychiatric Disorders
Somnolence	9	12	13
Insomnia	2	2	5
Skin and Appendages
Pruritus	4	5	6
Body as a Whole
Fatigue	3	4	5
Respiratory System
Upper Respiratory Tract Infection	1	2	7

^a. Preferred term reported by ≥4.5% of subjects for any exposure period; estimates were obtained using the life table analysis.
^b. Composite of nervousness, anxiety, agitation, euphoria, emotional lability and hallucinations (coded under psychiatric disorders), and hypertonia and tremor (coded under CNS disorders).

The following lists treatment-emergent adverse reactions that occurred with an incidence of at least 1% in clinical trials with a population of 2836 tramadol/acetaminophen-exposed subjects in the 18 acute and chronic pain studies combined.

asthenia, fatigue, hot flushes.

dizziness, headache, tremor.

abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting.

anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence.

pruritus, rash, increased sweating.

Among these, the most common (≥5% of subjects) treatment-emergent adverse events were nausea (14%), dizziness (10%), somnolence (9%), constipation (8%), vomiting (5%), and headache (5%). These data are consistent with data presented in Table 1.

The following lists clinically relevant treatment-emergent adverse reactions that occurred with an incidence of less than 1% in tramadol/acetaminophen clinical trials.

chest pain, rigors, syncope, withdrawal syndrome, allergic reaction.

hypertension, aggravated hypertension, hypotension, dependent edema.

ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesia, stupor, vertigo.

dysphagia, melena, tongue edema.

tinnitus.

arrhythmia, palpitation, tachycardia.

abnormal hepatic function, ALT increased, AST increased.

weight decrease, hypoglycemia, increased alkaline phosphatase, weight increase.

arthralgia.

increased coagulation time, purpura.

amnesia, depersonalisation, depression, drug abuse, emotional lability, hallucination, impotence, bad dreams, abnormal thinking.

anemia.

dyspnea, bronchospasm.

dermatitis, erythematous rash.

albuminuria, micturition disorder, oliguria, urinary retention.

abnormal vision.

granulocytopenia and leukocytosis.

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.

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. There have been several reports that suggest that acetaminophen may produce hypoprothrombinemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.

Tramadol may induce psychic and physical dependence of the morphine-type (µ-opioid) (see Warnings and Precautions, Drug Abuse and Dependence). Dependence and abuse, including drug-seeking behaviour and taking illicit actions to obtain the drug are not limited to those patients with a prior history of opioid dependence. The risk in patients with substance abuse has been observed to be higher. Tramadol is associated with craving and tolerance development.

A Risk Management strategy to support the safe and effective use of TRAMACET under Schedule F has been established. The following are considered to be the essential components of the Risk Management strategy:

 

Withdrawal symptoms may occur if tramadol is discontinued abruptly. 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 TRAMACET discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.

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.

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 TRAMACET and carbamazepine is not recommended.

Tramadol is metabolized to M1 by the CYP2D6 P450 isoenzyme. 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.

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.

Concomitant administration of TRAMACET 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 TRAMACET dosage regimen is recommended.

Due to interference with detoxification mechanisms, interactions with MAO inhibitors have been reported for some centrally acting drugs (see Warnings and Precautions, Use with MAO Inhibitors and Serotonin Re-uptake Inhibitors).

Postmarketing surveillance of tramadol has revealed rare reports of digoxin toxicity.

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 TRAMACET tablets and warfarin-like compounds are administered concurrently.

When TRAMACET 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 concentration or the extent of absorption of either tramadol or acetaminophen were not affected. The clinical significance of this difference is unknown.

TRAMACET (tramadol hydrochloride/acetaminophen) is not recommended for minor pain that may be treated adequately through lesser means where benefit does not outweigh the possible opioid-related side effects.

Do not co-administer TRAMACET tablets with other tramadol- or acetaminophen-containing products.

TRAMACET can be administered without regard to food.

The recommended dose of TRAMACET (tramadol hydrochloride/acetaminophen) should not be exceeded.

For the short-term (five days or less) management of acute pain, the recommended dose of TRAMACET is 1 or 2 tablets every 4 to 6 hours as needed for pain relief up to a maximum of 8 tablets per day.

In patients with creatinine clearances of less than 30 mL/min, it is recommended that the dosing interval of TRAMACET be increased to not exceed 2 tablets every 12 hours.

No overall differences with regard to safety or pharmacokinetics were noted between subjects ≥65 years of age and younger subjects. However, dose selection for an elderly patient should be cautious, in view of the greater frequency of decreased hepatic, renal or cardiac function, concomitant disease or drug therapy, and the potential for greater sensitivity to adverse events.

The safety and effectiveness of TRAMACET has not been studied in the pediatric population. Therefore, use of TRAMACET is not recommended in patients under 18 years of age.

Withdrawal symptoms may occur if TRAMACET is discontinued abruptly. 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 TRAMACET discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be avoided by tapering TRAMACET at the time of discontinuation (see Drug Abuse and Dependence, Withdrawal Symptoms).

TRAMACET is a combination product. The clinical presentation of overdose may include the signs and symptoms of tramadol toxicity, acetaminophen toxicity or both.

Serious potential consequences of overdosage are respiratory depression, lethargy, coma, seizure, cardiac arrest and death. Fatalities have been reported in post-marketing in association with both intentional and unintentional overdose with tramadol. The initial symptoms of tramadol overdosage may include respiratory depression and/or seizures. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment.

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. The initial symptoms seen within the first 24 hours following an acetaminophen overdose are: anorexia, nausea, vomiting, malaise, pallor and diaphoresis. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Emergency help should be sought immediately and treatment initiated immediately if overdose is suspected, even if symptoms are not apparent.

A single or multiple overdose with TRAMACET may be a potentially lethal polydrug overdose, and consultation with a regional poison control centre is recommended. In treating an overdose of TRAMACET, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. 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 tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Based on experience with tramadol, 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.

Standard recommendations should be followed for the treatment of acetaminophen overdose.

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 re-uptake 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 Pharmacokinetics).

Tramadol has been shown to inhibit re-uptake 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 opioids.

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

When evaluated in a standard animal model, the combination of tramadol and acetaminophen exhibited a synergistic effect. That is, when tramadol and acetaminophen were administered together, significantly less of each drug was needed to produce a given analgesic effect than would be expected if their effects were merely additive. Tramadol reaches peak activity in 2 to 3 hours with a prolonged analgesic effect, so that its combination with acetaminophen, a rapid-onset, short-acting analgesic agent, provides substantial benefit to patients over either component alone.

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 tablet are shown in Table 2. Tramadol has a slower absorption and longer half-life when compared to acetaminophen.

Table 2: TRAMACET

Summary of Mean (±SD) Pharmacokinetic Parameters of the (+) and (−) Enantiomers of Tramadol and M1, and Acetaminophen Following a Single Oral Dose of One Tramadol/Acetaminophen Combination Tablet (37.5 mg/325 mg) in Volunteers

Parametera	(+)-Tramadol	(−)-Tramadol	(+)-M1	(−)-M1	Acetaminophen
Cmax (ng/mL)	64.3 (9.3)	55.5 (8.1)	10.9 (5.7)	12.8 (4.2)	4.2 (0.8)
tmax (h)	1.8 (0.6)	1.8 (0.7)	2.1 (0.7)	2.2 (0.7)	0.9 (0.7)
CL/F (mL/min)	588 (226)	736 (244)	—	—	365 (84)
t½ (h)	5.1 (1.4)	4.7 (1.2)	7.8 (3.0)	6.2 (1.6)	2.5 (0.6)

^a. For acetaminophen, C_max was measured as µg/mL.

A single dose pharmacokinetic study of TRAMACET 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 TRAMACET, no significant change in acetaminophen pharmacokinetics was observed when compared to acetaminophen given alone.

The absolute bioavailability of tramadol from TRAMACET 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 tramadol HCl tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two TRAMACET 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 TRAMACET occurs primarily in the small intestine.

When TRAMACET 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 concentration or the extent of absorption of either tramadol or acetaminophen were not affected. The clinical significance of this difference is unknown.

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 relatively small portion (~20%) of acetaminophen is bound to plasma protein.