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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.
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:
- 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.
- Inclusion of a PAAB-approved fair balance statement in all ULTRAM® advertising and promotional materials.
- 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 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).
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).
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.
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.
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.
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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/18/2015
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