Ultram

Adults

ULTRAM® (tramadol hydrochloride) is indicated for the management of moderate to moderately severe pain in adults.

Geriatrics ( > 65 Years of Age)

Healthy elderly subjects aged 65 to 75 years administered tramadol have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. ULTRAM® should be administered with greater caution in patients older than 75 years, due to the greater potential for adverse events in this population (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION).

Pediatrics ( < 18 Years of Age)

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

Dosing Considerations

ULTRAM® 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.

ULTRAM® can be administered without regard to food.

Do not co-administer ULTRAM® tablets with other tramadol-containing products.

Due to the differences in pharmacokinetic properties, ULTRAM® tablets are not interchangeable with tramadol extended-release formulations.

The maximum recommended dose of ULTRAM® should not be exceeded.

Recommended Dose And Dosage Adjustment

Good pain management practice dictates that the dose be individualized according to patient need using the lowest beneficial dose. Studies with tramadol in adults have shown that starting at the lowest possible dose and titrating upward will result in fewer discontinuations and increased tolerability.

Adults (18 Years of Age and Over)

For patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the tolerability of ULTRAM® can be improved by initiating therapy with the following titration regimen: ULTRAM® should be started at 25 mg/day (half ULTRAM® scored tablet) qAM and titrated in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg q.i.d.). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg q.i.d.) as shown in Table 1.3 below.

Table 1.3: Initiation Titration Dose of ULTRAM® by Days

After titration, ULTRAM® 50 to 100 mg can be administered as needed for pain relief every 4 to 6 hours not to exceed 400 mg/day.

For the subset of patients for whom rapid onset of analgesic effect is required and for whom the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses, ULTRAM® 50 mg to 100 mg can be administered as needed for pain relief every 4 to 6 hours, not to exceed 400 mg per day.

Use in Renal Impairment

In all patients with creatinine clearance less than 30 mL/min, it is recommended that the dosing interval of ULTRAM® be increased to 12 hours, with a maximum daily dose of 200 mg. Since only 7% of an administered dose is removed by hemodialysis, dialysis patients can receive their regular dose on the day of dialysis.

Use in Hepatic Impairment

The recommended dose for adult patients with cirrhosis is 50 mg every 12 hours.

Elderly Patients ( > 65 years old)

In general, dose selection for an elderly patient over 65 years old should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. For elderly patients over 75 years old, total dose should not exceed 300 mg/day.

Pediatric Patients ( < 18 years old)

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

Management of Patients Requiring Rescue Medication

If ULTRAM® is used as rescue medication in conjunction with extended-release tramadol tablets, the total daily dose of tramadol should not exceed 400 mg. Fentanyl products should not be used as rescue medication in patients taking ULTRAM®.

Missed Dose

If a patient misses a dose, they should take their next dose as soon as they remember. If it is almost time for their next dose, they should not take the missed dose. Instead, they should take the next scheduled dose. They should not make up for the missed dose by taking a double dose.

Discontinuation

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

• ULTRAM® should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, opioids or to any component of this product.
• ULTRAM® is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. ULTRAM® may worsen central nervous system and respiratory depression in these patients.
• The concomitant use of ULTRAM® and MAO inhibitors (or within 14 days following discontinuation of such therapy) is contraindicated.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 ULTRAM® above the recommended range. Concomitant use of ULTRAM® increases the seizure risk in patients taking:

• selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics) (see Use with Serotonin Reuptake Inhibitors);
• 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 CONTRAINDICATIONS);
• 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 ULTRAM® 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 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 ULTRAM® tablets (see CONTRAINDICATIONS).

Drug Abuse, Addiction And Dependence

ULTRAM® has the 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 ULTRAM® have been reported. ULTRAM® tablets should not be used in opioid-dependent patients. ULTRAM® 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 ULTRAM® is not recommended.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

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

1. Commitment to not emphasize or highlight the scheduling status of ULTRAM® (i.e., not listed under a schedule to the CDSA) in its advertising or promotional activities.
2. Inclusion of a PAAB-approved fair balance statement in all ULTRAM® advertising and promotional materials.
3. Assurance that health-care education activities on pain management with ULTRAM® include balanced, evidence-based and current information. Commitment to take reasonable actions to inform health-care professionals that there is Health Canada-approved patient information on benefits and risks, and to ensure that this information can be readily accessed through electronic and/or hard copy sources.

ULTRAM® should not be used in opioid-dependent patients since it cannot suppress morphine withdrawal symptoms, even though it is an opioid agonist.

Abuse and addiction are separate and distinct from physical dependence and tolerance. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Tolerance as well as both physical and psychological dependence may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.

Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Withdrawal Symptoms

Withdrawal symptoms may occur if ULTRAM® 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 ULTRAM® 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.

Risk Of Overdosage

Serious potential consequences of overdosage with ULTRAM® 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).

Do not prescribe ULTRAM® for patients who are suicidal or addiction-prone.

ULTRAM® should not be taken in doses higher than those recommended by the physician. 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. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.

Intracranial Pressure Or Head Trauma

ULTRAM® 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 ULTRAM® 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 ULTRAM® (see Respiratory, Respiratory Depression below).

Respiratory

Respiratory Depression

Administer ULTRAM® cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When large doses of ULTRAM® 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 Seizure Risk and OVERDOSAGE).

Interaction With Central Nervous System (CNS) Depressants

ULTRAM® 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. ULTRAM® increases the risk of CNS and respiratory depression in these patients.

ULTRAM® may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Use With Alcohol

ULTRAM® should not be used concomitantly with alcohol consumption.

Use In Ambulatory Patients

ULTRAM® may impair mental 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

Concomitant use of ULTRAM® with MAO inhibitors is contraindicated (see CONTRAINDICATIONS).

Animal studies have shown increased deaths with combined administration of MAO inhibitors and tramadol. Concomitant use of ULTRAM® with MAO inhibitors increases the risk of adverse events, including seizure (see Seizure Risk and DRUG INTERACTIONS) and serotonin syndrome.

Use With Serotonin Reuptake Inhibitors

Concomitant use of ULTRAM® with SSRIs increases the risk of adverse events, including seizure (see Seizure Risk) and serotonin syndrome. When co-administration of ULTRAM® and SSRIs is indicated, monitor the patient for seizures and possible early signs and symptoms of serotonin syndrome. Early symptoms of serotonin syndrome may include myoclonus, tremors, hyper-reflexia, diaphoresis, fever, tachycardia, tachypnea, labile blood pressure, altered mental status (agitation, hallucinations, coma, excitement) and /or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Gastrointestinal

Acute Abdominal Conditions

The administration of ULTRAM® may complicate the clinical assessment of patients with acute abdominal conditions.

Use In Drug And Alcohol Addiction

ULTRAM® is an opioid with no approved use in the management of addictive disorders.

Carcinogenesis And Mutagenesis

See Product Monograph PART II, Toxicology.

Special Populations

Use in Renal and Hepatic Disease

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, a dose reduction is recommended (see DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION).

With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.

Pregnant Women

There are no adequate and well-controlled studies in pregnant women. ULTRAM® 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.

ULTRAM® should not be used in pregnant women prior to or during labour 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 postpartum withdrawal symptoms in the newborn (see Drug Abuse, Addiction 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 labour.

The effect of ULTRAM®, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Women

ULTRAM® 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.

Pediatrics ( < 18 years of age)

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

Geriatrics ( > 65 years of age)

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

A total of 455 elderly (65 years of age or older) subjects were exposed to ULTRAM® in controlled clinical trials. Of those, 145 subjects were 75 years of age and older. In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.

SIDE EFFECTS

Adverse Drug Reaction Overview

The most commonly reported adverse reactions are dizziness, nausea, constipation, headache, somnolence and vomiting as presented in Table 1.1.

Clinical Trial Adverse Drug Reactions

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.

Incidence of Adverse Reactions for ULTRAM® in Chronic Trials of Non-Malignant Pain (Non-titration Trials)

ULTRAM® was administered to 550 patients during the double-blind or open-label extension periods in studies of chronic non-malignant pain. Of these patients, 375 were 65 years old or older. Table 1.1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. The overall incidence rates of adverse experiences in these trials were similar for ULTRAM® and the active control groups, acetaminophen with codeine, and aspirin with codeine; however, the rates of withdrawals due to adverse events appeared to be higher in the ULTRAM® group. In the tramadol treatment groups, 16.8-24.5% of patients withdrew due to an AE, compared to 9.6-11.6% for acetaminophen with codeine and 18.5% for aspirin with codeine.

Table 1.1: Cumulative Incidence of Adverse Reactions for ULTRAM® in Chronic Trials of Non-Malignant Pain

Two titration trials showed that the incidence of withdrawal due to AEs could be significantly reduced by using dose titration.

Incidence of Adverse Reactions for ULTRAM® CAPSS-047 Titration Trial

In the double–blind phase of this pivotal trial, gastrointestinal complaints (primarily nausea and vomiting) and dizziness were the adverse events reported most frequently by tramadol-treated subjects, Table 1.2. Most of the adverse events were assessed as mild or moderate in intensity and resolved.

Table 1.2:  Adverse Events in CAPSS-047 - Double-Blind Phase - Frequently Reported ( ≥ 2%^a) Adverse Events^b and Total Incidence of AEs Summarized by WHOART Body System, Treatment Group and Preferred Term

Incidence 1% to less than 5% possibly causally related: the following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with ULTRAM® exists.

Body as a Whole: Malaise. 

Cardiovascular: Vasodilation.

Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.

Gastrointestinal: Abdominal pain, Anorexia, Flatulence.

Musculoskeletal: Hypertonia.

Skin: Rash.

Special Senses: Visual disturbance.

Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.

Incidence less than 1%, possibly causally related: the following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in post-marketing experience.

Body as a Whole: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma).

Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia.

Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure (see WARNINGS AND PRECAUTIONS), Tremor.

Respiratory: Dyspnea.

Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles.

Special Senses: Dysgeusia.

Urogenital: Dysuria, Menstrual disorder.

Other adverse experiences, causal relationship unknown

A variety of other adverse events were reported infrequently in patients taking ULTRAM® during clinical trials and/or reported in post-marketing experience. A causal relationship between ULTRAM® and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.

Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.

Central Nervous System: Migraine, Speech disorders.

Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.

Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.

Sensory: Cataracts, Deafness, Tinnitus.

Other Adverse Experiences Previously Reported in Clinical Trials or Post-Marketing Reports with Tramadol Hydrochloride

Adverse events which have been reported with the use of tramadol products include: allergic reactions (including anaphylaxis, angioneurotic edema and urticaria), bradycardia, convulsions, drug dependence, drug withdrawal (including agitation, anxiety, gastrointestinal symptoms, hyperkinesia, insomnia, nervousness, tremors), hyperactivity, hypoactivity, hypotension, worsening of asthma and respiratory depression. Other adverse events which have been reported with the use of tramadol products and for which a causal association has not been determined include: difficulty concentrating, hepatitis, liver failure, pulmonary edema, Stevens-Johnson syndrome and suicidal tendency.

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. Post-marketing experience with the use of tramadol-containing products included rare reports of delirium, miosis, mydriasis, and speech disorder, and very rare reports of movement disorder including dyskinesia and dystonia.

Cases of hypoglycemia have been reported in patients taking tramadol, mostly in patients with pre-disposing risk factors, including diabetes, elderly and renal insufficiency. Caution should be exercised when prescribing tramadol to diabetic patients. More frequent monitoring of blood glucose levels may be appropriate, including at initiation or dose increase.

Drug Abuse, Addiction And Dependence

Tramadol may induce psychic and physical dependence of the morphine-type (μ-opioid) (see WARNINGS AND PRECAUTIONS, Drug Abuse, Addiction 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 program to support the safe and effective use of ULTRAM® has been established. The following are considered to be the essential components of the Risk Management program:

1. Commitment to not emphasize or highlight the scheduling status of ULTRAM® (i.e., not listed under a schedule to the CDSA) in its advertising or promotional activities.
2. Inclusion of a PAAB-approved fair balance statement in all ULTRAM® advertising and promotional materials.
3. Assurance that health-care education activities on pain management with ULTRAM® include balanced, evidence-based and current information. Commitment to take reasonable actions to inform health-care professionals that there is Health Canada-approved patient information on benefits and risks, and to ensure that this information can be readily accessed through electronic and/or hard copy sources.

Withdrawal Symptoms

Withdrawal symptoms may occur if ULTRAM® 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 ULTRAM® 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.

DRUG INTERACTIONS

Overview

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.

Drug-Drug Interactions

Use with MAO Inhibitors

ULTRAM® is contraindicated in patients receiving MAO inhibitors or who have used them within the previous 14 days (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS).

Drugs that Lower Seizure Threshold

Tramadol can increase the potential for selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), anti-psychotics and other seizure threshold lowering drugs to cause convulsions. If concomitant treatment of ULTRAM® 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 AND PRECAUTIONS, Use with Serotonin Reuptake Inhibitors).

CNS Depressants

Concurrent administration of tramadol with other centrally acting drugs, including alcohol, centrally acting analgesics, opioids and psychotropic drugs may potentiate CNS depressant effects (see WARNINGS AND PRECAUTIONS).

Use with Carbamazepine

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

Use with Quinidine

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 ULTRAM® 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 CYP2D6 and CYP3A4 Inhibitors

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

Use with Cimetidine

Concomitant administration of ULTRAM® and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRAM® 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 tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.

Periodic evaluation of prothrombin time should be performed when ULTRAM® tablets and warfarin-like compounds are administered concurrently.

Triptans

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

Drug-Food Interactions

Oral administration of ULTRAM® with food does not significantly affect its rate or extent of absorption; therefore, ULTRAM® can be administered without regard to food.

Adverse Drug Reaction Overview

The most commonly reported adverse reactions are dizziness, nausea, constipation, headache, somnolence and vomiting as presented in Table 1.1.

Clinical Trial Adverse Drug Reactions

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.

Incidence of Adverse Reactions for ULTRAM® in Chronic Trials of Non-Malignant Pain (Non-titration Trials)

ULTRAM® was administered to 550 patients during the double-blind or open-label extension periods in studies of chronic non-malignant pain. Of these patients, 375 were 65 years old or older. Table 1.1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. The overall incidence rates of adverse experiences in these trials were similar for ULTRAM® and the active control groups, acetaminophen with codeine, and aspirin with codeine; however, the rates of withdrawals due to adverse events appeared to be higher in the ULTRAM® group. In the tramadol treatment groups, 16.8-24.5% of patients withdrew due to an AE, compared to 9.6-11.6% for acetaminophen with codeine and 18.5% for aspirin with codeine.

Table 1.1: Cumulative Incidence of Adverse Reactions for ULTRAM® in Chronic Trials of Non-Malignant Pain

Two titration trials showed that the incidence of withdrawal due to AEs could be significantly reduced by using dose titration.

Incidence of Adverse Reactions for ULTRAM® CAPSS-047 Titration Trial

In the double–blind phase of this pivotal trial, gastrointestinal complaints (primarily nausea and vomiting) and dizziness were the adverse events reported most frequently by tramadol-treated subjects, Table 1.2. Most of the adverse events were assessed as mild or moderate in intensity and resolved.

Table 1.2:  Adverse Events in CAPSS-047 - Double-Blind Phase - Frequently Reported ( ≥ 2%^a) Adverse Events^b and Total Incidence of AEs Summarized by WHOART Body System, Treatment Group and Preferred Term

Incidence 1% to less than 5% possibly causally related: the following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with ULTRAM® exists.

Body as a Whole: Malaise. 

Cardiovascular: Vasodilation.

Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.

Gastrointestinal: Abdominal pain, Anorexia, Flatulence.

Musculoskeletal: Hypertonia.

Skin: Rash.

Special Senses: Visual disturbance.

Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.

Incidence less than 1%, possibly causally related: the following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials and/or reported in post-marketing experience.

Body as a Whole: Accidental injury, Allergic reaction, Anaphylaxis, Death, Suicidal tendency, Weight loss, Serotonin syndrome (mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma).

Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia.

Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure (see WARNINGS AND PRECAUTIONS), Tremor.

Respiratory: Dyspnea.

Skin: Stevens-Johnson syndrome/Toxic epidermal necrolysis, Urticaria, Vesicles.

Special Senses: Dysgeusia.

Urogenital: Dysuria, Menstrual disorder.

Other adverse experiences, causal relationship unknown

A variety of other adverse events were reported infrequently in patients taking ULTRAM® during clinical trials and/or reported in post-marketing experience. A causal relationship between ULTRAM® and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.

Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.

Central Nervous System: Migraine, Speech disorders.

Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.

Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.

Sensory: Cataracts, Deafness, Tinnitus.

Other Adverse Experiences Previously Reported in Clinical Trials or Post-Marketing Reports with Tramadol Hydrochloride

Adverse events which have been reported with the use of tramadol products include: allergic reactions (including anaphylaxis, angioneurotic edema and urticaria), bradycardia, convulsions, drug dependence, drug withdrawal (including agitation, anxiety, gastrointestinal symptoms, hyperkinesia, insomnia, nervousness, tremors), hyperactivity, hypoactivity, hypotension, worsening of asthma and respiratory depression. Other adverse events which have been reported with the use of tramadol products and for which a causal association has not been determined include: difficulty concentrating, hepatitis, liver failure, pulmonary edema, Stevens-Johnson syndrome and suicidal tendency.

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. Post-marketing experience with the use of tramadol-containing products included rare reports of delirium, miosis, mydriasis, and speech disorder, and very rare reports of movement disorder including dyskinesia and dystonia.

Cases of hypoglycemia have been reported in patients taking tramadol, mostly in patients with pre-disposing risk factors, including diabetes, elderly and renal insufficiency. Caution should be exercised when prescribing tramadol to diabetic patients. More frequent monitoring of blood glucose levels may be appropriate, including at initiation or dose increase.

Drug Abuse, Addiction And Dependence

Tramadol may induce psychic and physical dependence of the morphine-type (μ-opioid) (see WARNINGS AND PRECAUTIONS, Drug Abuse, Addiction 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 program to support the safe and effective use of ULTRAM® has been established. The following are considered to be the essential components of the Risk Management program:

1. Commitment to not emphasize or highlight the scheduling status of ULTRAM® (i.e., not listed under a schedule to the CDSA) in its advertising or promotional activities.
2. Inclusion of a PAAB-approved fair balance statement in all ULTRAM® advertising and promotional materials.
3. Assurance that health-care education activities on pain management with ULTRAM® include balanced, evidence-based and current information. Commitment to take reasonable actions to inform health-care professionals that there is Health Canada-approved patient information on benefits and risks, and to ensure that this information can be readily accessed through electronic and/or hard copy sources.

Withdrawal Symptoms

Withdrawal symptoms may occur if ULTRAM® 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 ULTRAM® 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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Symptoms

Symptoms of overdosage with ULTRAM® are 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 AND PRECAUTIONS, Drug Abuse, Addiction and Dependence). 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.

Treatment

A single or multiple overdose with ULTRAM® may be a potentially lethal polydrug overdose, and consultation with a regional poison control centre is recommended.

In treating an overdose of ULTRAM®, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. 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. Seizures may be controlled with diazepam.

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.

Emptying of the gastric contents is useful to remove any unabsorbed drug.

Use with Cimetidine

Concomitant administration of ULTRAM® and cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the ULTRAM® 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 tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.

Periodic evaluation of prothrombin time should be performed when ULTRAM® tablets and warfarin-like compounds are administered concurrently.

Triptans

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

Drug-Food Interactions

Oral administration of ULTRAM® with food does not significantly affect its rate or extent of absorption; therefore, ULTRAM® can be administered without regard to food.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 ULTRAM® above the recommended range. Concomitant use of ULTRAM® increases the seizure risk in patients taking:

• selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics) (see Use with Serotonin Reuptake Inhibitors);
• 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 CONTRAINDICATIONS);
• 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 ULTRAM® 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 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 ULTRAM® tablets (see CONTRAINDICATIONS).

Drug Abuse, Addiction And Dependence

ULTRAM® has the 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 ULTRAM® have been reported. ULTRAM® tablets should not be used in opioid-dependent patients. ULTRAM® 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 ULTRAM® is not recommended.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

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

1. Commitment to not emphasize or highlight the scheduling status of ULTRAM® (i.e., not listed under a schedule to the CDSA) in its advertising or promotional activities.
2. Inclusion of a PAAB-approved fair balance statement in all ULTRAM® advertising and promotional materials.
3. Assurance that health-care education activities on pain management with ULTRAM® include balanced, evidence-based and current information. Commitment to take reasonable actions to inform health-care professionals that there is Health Canada-approved patient information on benefits and risks, and to ensure that this information can be readily accessed through electronic and/or hard copy sources.

ULTRAM® should not be used in opioid-dependent patients since it cannot suppress morphine withdrawal symptoms, even though it is an opioid agonist.

Abuse and addiction are separate and distinct from physical dependence and tolerance. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Tolerance as well as both physical and psychological dependence may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients.

Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Withdrawal Symptoms

Withdrawal symptoms may occur if ULTRAM® 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 ULTRAM® 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.

Risk Of Overdosage

Serious potential consequences of overdosage with ULTRAM® 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).

Do not prescribe ULTRAM® for patients who are suicidal or addiction-prone.

ULTRAM® should not be taken in doses higher than those recommended by the physician. 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. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.

Intracranial Pressure Or Head Trauma

ULTRAM® 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 ULTRAM® 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 ULTRAM® (see Respiratory, Respiratory Depression below).

Respiratory

Respiratory Depression

Administer ULTRAM® cautiously in patients at risk for respiratory depression. In these patients, alternative non-opioid analgesics should be considered. When large doses of ULTRAM® 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 Seizure Risk and OVERDOSAGE).

Interaction With Central Nervous System (CNS) Depressants

ULTRAM® 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. ULTRAM® increases the risk of CNS and respiratory depression in these patients.

ULTRAM® may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Use With Alcohol

ULTRAM® should not be used concomitantly with alcohol consumption.

Use In Ambulatory Patients

ULTRAM® may impair mental 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

Concomitant use of ULTRAM® with MAO inhibitors is contraindicated (see CONTRAINDICATIONS).

Animal studies have shown increased deaths with combined administration of MAO inhibitors and tramadol. Concomitant use of ULTRAM® with MAO inhibitors increases the risk of adverse events, including seizure (see Seizure Risk and DRUG INTERACTIONS) and serotonin syndrome.

Use With Serotonin Reuptake Inhibitors

Concomitant use of ULTRAM® with SSRIs increases the risk of adverse events, including seizure (see Seizure Risk) and serotonin syndrome. When co-administration of ULTRAM® and SSRIs is indicated, monitor the patient for seizures and possible early signs and symptoms of serotonin syndrome. Early symptoms of serotonin syndrome may include myoclonus, tremors, hyper-reflexia, diaphoresis, fever, tachycardia, tachypnea, labile blood pressure, altered mental status (agitation, hallucinations, coma, excitement) and /or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Gastrointestinal

Acute Abdominal Conditions

The administration of ULTRAM® may complicate the clinical assessment of patients with acute abdominal conditions.

Use In Drug And Alcohol Addiction

ULTRAM® is an opioid with no approved use in the management of addictive disorders.

Carcinogenesis And Mutagenesis

See Product Monograph PART II, Toxicology.

Special Populations

Use in Renal and Hepatic Disease

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, a dose reduction is recommended (see DOSAGE AND ADMINISTRATION). Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, adjustment of the dosing regimen is recommended (see DOSAGE AND ADMINISTRATION).

With the prolonged half-life in these conditions, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.

Pregnant Women

There are no adequate and well-controlled studies in pregnant women. ULTRAM® 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.

ULTRAM® should not be used in pregnant women prior to or during labour 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 postpartum withdrawal symptoms in the newborn (see Drug Abuse, Addiction 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 labour.

The effect of ULTRAM®, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Women

ULTRAM® 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.

Pediatrics ( < 18 years of age)

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

Geriatrics ( > 65 years of age)

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy. In patients over 75 years of age, daily doses in excess of 300 mg are not recommended (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

A total of 455 elderly (65 years of age or older) subjects were exposed to ULTRAM® in controlled clinical trials. Of those, 145 subjects were 75 years of age and older. In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.

OVERDOSE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Symptoms

Symptoms of overdosage with ULTRAM® are 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 AND PRECAUTIONS, Drug Abuse, Addiction and Dependence). 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.

Treatment

A single or multiple overdose with ULTRAM® may be a potentially lethal polydrug overdose, and consultation with a regional poison control centre is recommended.

In treating an overdose of ULTRAM®, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. 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. Seizures may be controlled with diazepam.

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.

Emptying of the gastric contents is useful to remove any unabsorbed drug.

CONTRAINDICATIONS

• ULTRAM® should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, opioids or to any component of this product.
• ULTRAM® is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. ULTRAM® may worsen central nervous system and respiratory depression in these patients.
• The concomitant use of ULTRAM® and MAO inhibitors (or within 14 days following discontinuation of such therapy) is contraindicated.

CLINICAL PHARMACOLOGY

Mechanism Of Action

ULTRAM® 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 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 ULTRAM®. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

Apart from analgesia, ULTRAM® administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, ULTRAM® has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.

Pharmacokinetics

The analgesic activity of ULTRAM® is due to both parent drug and the M1 metabolite (see Mechanism of Action). Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. Tramadol is well absorbed orally with an absolute bioavailability of 75%. Tramadol has a volume of distribution of approximately 2.7 L/kg and is only 20% bound to plasma proteins. Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. One metabolite, M1, is pharmacologically active in animal models. The formation of M1 is dependent upon CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see DRUG INTERACTIONS). Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

Absorption

Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present.

Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with q.i.d. dosing. There is no evidence of self-induction (see Figure 1.1 and Table 1.4 below).

Figure 1.1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl Given q.i.d.

Table 1.4: Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite

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.

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 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 I 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 reuptake inhibitors and MAO inhibitors may enhance the risk of adverse events, including seizure (see WARNINGS AND PRECAUTIONS) and serotonin syndrome.

Excretion

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.

Special Populations and Conditions

Pediatrics

Pharmacokinetics of ULTRAM® tablets have not been studied in pediatric patients below 18 years of age.

Geriatrics

Healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/mL) and the elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (see DOSAGE AND ADMINISTRATION).

Gender

The absolute bioavailability of tramadol was 73% in males and 79% in females. The plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a 100 mg i.v. dose of tramadol. Following a single oral dose, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.

Hepatic Insufficiency

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hrs for tramadol and 19 hrs for M1). In cirrhotic patients, adjustment of the dosing regimen is recommended (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Insufficiency

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. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION). 

Clinical Trials

ULTRAM® was evaluated in single-dose trials (dental and surgery), multiple-dose, [short-term trials (dental and surgery), long-term trials (chronic malignant and non-malignant pain), and trials evaluating the impact of dose titration on tolerability]. Clinical trials in non-malignant pain included patients with osteoarthritis, low back pain, diabetic neuropathy and fibromyalgia. These trials included a randomized, double-blind, parallel group design, and in each of the single-dose and short-term multiple-dose trials tramadol was compared to a standard reference analgesic (either codeine, ASA/codeine or APAP/propoxyphene), placebo or to both. The active controls were included to establish model sensitivity. The efficacy of tramadol in these trials was established based on Total Pain Relief (TOTPAR), Sum of Pain Intensity Difference (SPID) and time to remedication.

Collectively, a total of 2549 patients with dental pain, 1940 patients with surgical pain, 170 patients with chronic malignant pain, 119 patients with sub-acute low back pain, and 2046 patients with chronic non-malignant pain were enrolled into the 28 efficacy trials. Of the 6824 total patients enrolled into these trials, 4075 were randomized to a tramadol treatment arm.

Study Results

Acute Pain, Single- and Multiple-Dose Studies

ULTRAM® has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).

Results of these trials demonstrated statistically superior pain relief for tramadol compared to placebo. Data from these key trials provide information regarding the optimal analgesic dosage range of tramadol.

In single-dose dental trials, tramadol was superior to placebo at doses of 100 mg or greater (p ≤ 0.05). In addition, tramadol at doses of 100mg or greater were equivalent to or statistically superior to the reference analgesics for Total Pain Relief (TOTPAR) and Sum of Pain Intensity Difference (SPID) across the entire evaluation interval. The results of the multiple-dose short-term trials in acute pain also provide evidence for efficacy of tramadol in the management of acute pain.

Tramadol has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol. Patients with a variety of chronic painf