Administration of tramadol may enhance the seizure risk in patients taking:
Two titration trials showed that the incidence of withdrawal due to AEs could be significantly reduced by using dose titration.
Periodic evaluation of prothrombin time should be performed when ULTRAM tablets and warfarin-like compounds are administered concurrently.
Table 1.2: Adverse Events in CAPSS-047 - Double-Blind Phase - Frequently Reported ( ≥ 2%a) Adverse Eventsb and Total Incidence of AEs Summarized by WHOART Body System, Treatment Group and Preferred Term AEs in CAPSS-047 Double-Blind Phase ≥ 2% of patients Tramadol Group/Titration Schedule Body System 10-days to 200 mg/day N =54 16-days to 200 mg/day N =59 13-days to 150 mg/day N =54 Preferred Term n % n % n % Any Adverse Event 41 75.9 41 69.5 33 61.1 Body as a Whole - General Disorders Influenza-like symptoms 0 0.0 2 3.4 0 0.0 Pain 1 1.9 2 3.4 0 0.0 Fatigue 0 0.0 0 0.0 2 3.7 Central and Peripheral Nervous System Disorders Dizziness 4 7.4 4 6.8 4 7.4 Headache 10 18.5 9 15.3 7 13.0 Gastrointestinal System Disorders Mouth Dry 0 0.0 1 1.7 3 5.6 Constipation 4 7.4 2 3.4 6 11.1 Diarrhea 4 7.4 3 5.1 1 1.9 Vomiting 10 18.5 7 11.9 4 7.4 Nausea 29 53.7 25 42.4 18 33.3 Psychiatric Disorders Insomnia 1 1.9 2 3.4 2 3.7 Somnolence 5 9.3 4 6.8 0 0.0 Reproductive Disorders, Female Menstrual Disorder 0 0.0 2 2.0 0 0.0 Reproductive Disorders, Male Epididymitis 0 0.0 0 0.0 1 11.1 Respiratory Systems Disorders Coughing 0 0.0 3 5.1 0 0.0 Sinusitis 1 1.9 2 3.4 2 3.7 Upper Resp Tract Infection 2 3.7 0 0.0 0 0.0 Skin and Appendages Disorders Pruritus 2 3.7 1 1.7 4 7.4 Rash 0 0.0 2 3.4 2 3.7 a Preferred terms reported by ≥ 2% of subjects in one or more treatment groups, intent-to-treat population. b Number of patients with adverse event; numbers shown are all events regardless of relationship to study drug.
Clinical experience suggests that withdrawal symptoms may be avoided by tapering ULTRAM at the time of discontinuation. Other symptoms that have been seen less frequently with ULTRAM discontinuation include panic attacks, severe anxiety, and paresthesias. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may occur if ULTRAM is discontinued abruptly (see Drug Abuse, Addiction and Dependence ).
Inactive ingredients in the tablet are carnauba wax, corn starch, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide.
Cardiovascular: Abnormal ECG, Hypertension, Hypotension, Myocardial ischemia, Palpitations, Pulmonary edema, Pulmonary embolism.
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.
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. For patients with moderate to moderay 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.).
The recommended dose for adult patients with cirrhosis is 50 mg every 12 hours.
Molecular formula and molecular mass: C 16 H 25 NO 2 •HCl and 299.84 Structural formula:
Urogenital: Dysuria, Menstrual disorder.
ULTRAM is contraindicated in patients receiving MAO inhibitors or who have used them within the previous 14 days (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS ).
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.
Gastrointestinal: Gastrointestinal bleeding, Hepatitis, Stomatitis, Liver failure.
Laboratory Abnormalities: Creatinine increase, Elevated liver enzymes, Hemoglobin decrease, Proteinuria.
The most commonly reported adverse reactions are dizziness, nausea, constipation, headache, somnolence and vomiting as presented in Table 1.1.
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).
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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.
Concomitant use of ULTRAM increases the seizure risk in patients taking:. 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.
Sensory: Cataracts, Deafness, Tinnitus.
Due to the differences in pharmacokinetic properties, ULTRAM tablets are not interchangeable with tramadol extended-release formulations.
For elderly patients over 75 years old, total dose should not exceed 300 mg/day. 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.
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.
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. Withdrawal symptoms may occur if ULTRAM is discontinued abruptly.
Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of ULTRAM and carbamazepine is not recommended. Patients taking carbamazepine may have a significantly reduced analgesic effect of ULTRAM.
Tramadol is associated with craving and tolerance development. The risk in patients with substance abuse has been observed to be higher. 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.
Physicochemical properties: Tramadol hydrochloride is a white to off-white, crystalline, odourless powder with a melting point between 180-184°C.
In ULTRAM overdose, naloxone administration may increase the risk of seizure. 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).
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.
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 ). 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.
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.
M3C 1L9. This leaflet was prepared by : Janssen Inc., Toronto, Ontario. Last revised: March 2014.
The following are considered to be the essential components of the Risk Management program:. A Risk Management program to support the safe and effective use of ULTRAM has been established.
Central Nervous System: Migraine, Speech disorders.
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.
Cases of hypoglycemia have been reported in patients taking tramadol, mostly in patients with pre-disposing risk factors, including diabetes, elderly and renal insufficiency. More frequent monitoring of blood glucose levels may be appropriate, including at initiation or dose increase. Caution should be exercised when prescribing tramadol to diabetic patients.
Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.
Stop using tramadol and call your doctor at once if you have any of these serious side effects: Less serious side.
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. Based on the mechanism of action of tramadol and the potential for serotonin syndrome, caution is advised when ULTRAM is coadministered with a triptan.
In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. 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.
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 ).
Cardiovascular: Vasodilation. Body as a Whole: Malaise.
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
ULTRAM (tramadol hydrochloride) Tablets, USP 50 mg Opioid Analgesic.
The maximum recommended dose of ULTRAM should not be exceeded.
Central Nervous System: Anxiety, Confusion, Coordination disturbance, Euphoria, Miosis, Nervousness, Sleep disorder.
ULTRAM is not recommended for minor pain that may be treated adequay through lesser means where benefit does not outweigh the possible opioid -related side effects.
Proper name: tramadol hydrochloride.
Other adverse experiences, causal relationship unknown.
Serious and rarely, fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. 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 ). Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. When these rare reactions do occur, it is often following the first dose.
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.
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.
25 mg t.i.d. 25 mg q.i.d. 50 mg q.i.d. Table 1.3: Initiation Titration Dose of ULTRAM by Days Days 1 to 3 Days 4 to 6 Days 7 to 9 Days 10 to 12 Days 13 to 15 Days 16 to 18 Initiate at 25 mg (AM) (half ULTRAM scored tablet) 25 mg b.i.d. 50 mg t.i.d.
Instead, they should take the next scheduled dose. If a patient misses a dose, they should take their next dose as soon as they remember. They should not make up for the missed dose by taking a double dose. If it is almost time for their next dose, they should not take the missed dose.
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. 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.
Skin: Rash. Musculoskeletal: Hypertonia. Gastrointestinal: Abdominal pain, Anorexia, Flatulence.
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.
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. 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.
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.
Urogenital: Menopausal symptoms, Urinary frequency, Urinary retention.
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.
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.
Cardiovascular: Orthostatic hypotension, Syncope, Tachycardia.
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Do not co-administer ULTRAM tablets with other tramadol-containing products.
ULTRAM (tramadol hydrochloride) is indicated for the management of moderate to moderay severe pain in adults.
Chemical name: (±)cis-2--1-(3-methoxyphenyl) cyclohexanol hydrochloride.
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.
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.
Special Senses: Visual disturbance.
ULTRAM can be administered without regard to food.
Skin: Stevens-Johnson syndrome /Toxic epidermal necrolysis, Urticaria, Vesicles. Special Senses: Dysgeusia.
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 ).
Dispense in a tight container. Store at 15 -30°C.
They are available in HDPE bottles of 100 tablets. ULTRAM tablets contain 50 mg of tramadol hydrochloride. They are white in colour, capsule-shaped, coated tablet imprinted “ULTRAM” on one side and “06 59” on the scored side.
Included as part of the PRECAUTIONS section.
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.
Respiratory: Dyspnea. Central Nervous System: Abnormal gait, Amnesia, Cognitive dysfunction, Depression, Difficulty in concentration, Hallucinations, Paresthesia, Seizure (see WARNINGS AND PRECAUTIONS ), Tremor.
Table 1.1: Cumulative Incidence of Adverse Reactions for ULTRAM in Chronic Trials of Non-Malignant Pain Percentage of Patients with Adverse Reaction N = 427 Up to 7 Days Up to 30 Days Up to 90 Days Dizziness/Vertigo 26% 31% 33% Nausea 24% 34% 40% Constipation 24% 38% 46% Headache 18% 26% 32% Somnolence 16% 23% 25% Vomiting 9% 13% 17% Pruritus 8% 10% 11% “CNS Stimulation” a 7% 11% 14% Asthenia 6% 11% 12% Sweating 6% 7% 9% Dyspepsia 5% 9% 13% Dry Mouth 5% 9% 10% Diarrhea 5% 6% 10% a “CNS Stimulation” is a composite of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability and hallucinations.
The most frequently reported events were in the central nervous system and gastrointestinal system. 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 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). ULTRAM was administered to 550 patients during the double-blind or open-label extension periods in studies of chronic non- malignant pain. 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. Of these patients, 375 were 65 years old or older.Tramadol