ULTRAM- tramadol hydrochloride tablet, coated
Janssen Pharmaceuticals, Inc.
WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
ADDICTION, ABUSE AND MISUSE
ULTRAM exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing ULTRAM, and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].
OPIOID ANALGESIC RISK EVALUATION AND MITIGATION STRATEGY (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [see Warnings and Precautions (5.2)]. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to:
- complete a REMS-compliant education program,
- counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
- emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
- consider other tools to improve patient, household, and community safety.
LIFE-THREATENING RESPIRATORY DEPRESSION
Serious, life-threatening, or fatal respiratory depression may occur with use of ULTRAM. Monitor for respiratory depression, especially during initiation of ULTRAM or following a dose increase [see Warnings and Precautions (5.3)].
Accidental ingestion of ULTRAM, especially by children, can be fatal. [see Warnings and Precautions (5.3)].
ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN
Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism [see Warnings and Precautions (5.4)]. ULTRAM is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of ULTRAM in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol [see Warnings and Precautions (5.4)].
NEONATAL OPIOID WITHDRAWAL SYNDROME
Prolonged use of ULTRAM during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.5)].
INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES
The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with ULTRAM requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1 [see Warnings and Precautions (5.6); Drug Interactions (7)].
RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.7); Drug Interactions (7)].
- Reserve concomitant prescribing of ULTRAM and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
- Limit treatment to the minimum effective dosages and durations.
- Follow patients for signs and symptoms of respiratory depression and sedation.
ULTRAM is indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
Limitations of Use
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.1)] , reserve ULTRAM for use in patients for whom alternative treatment options [e.g., non-opioid analgesics]:
- Have not been tolerated or are not expected to be tolerated.
- Have not provided adequate analgesia or are not expected to provide adequate analgesia.
- Do not use ULTRAM concomitantly with other tramadol-containing products.
- Do not administer ULTRAM at a dose exceeding 400 mg per day.
- Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.1)].
- Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
- Monitor patients closely for respiratory depression, especially within the first 24–72 hours of initiating therapy and following dosage increases with ULTRAM and adjust the dosage accordingly [see Warnings and Precautions (5.3)].
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with ULTRAM [see Warnings and Precautions (5.3), Patient Counseling Information (17)].
Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).
Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.3, 5.7)].
Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose.
Initiating Treatment with ULTRAM
For patients not requiring rapid onset of analgesic effect, the tolerability of ULTRAM can be improved by initiating therapy with the following titration regimen: Start ULTRAM at 25 mg/day and titrated in 25 mg increments as separate doses every 3 days to reach 100 mg/day (25 mg four times a day). Thereafter the total daily dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg four times a 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.
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 four to six hours, not to exceed 400 mg per day.
Conversion from ULTRAM to Extended-Release Tramadol
The relative bioavailability of ULTRAM compared to extended-release tramadol is unknown, so conversion to extended-release formulations must be accompanied by close observation for signs of excessive sedation and respiratory depression.
Dosage Modification in Patients with Hepatic Impairment
The recommended dose for adult patients with severe hepatic impairment is 50 mg every 12 hours.
Dosage Modification in Patients with 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.
Dosage Modification in Geriatric Patients
Do not exceed a total dose of 300 mg/day in patients over 75 years old.
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