Usual Adult Dose for Pain

Usual dose: 2 tablets orally every 4 to 6 hours as needed for pain
Maximum dose: 8 tablets per day
Maximum duration: 5 days

Comments:

• Each tablet contains Tramadol 37.5 mg and Acetaminophen 325 mg. Maximum daily doses are Tramadol: 300 mg per day and Acetaminophen 2600 mg per day.
• Use of more than 1 product at time containing acetaminophen is not recommended.
• Due to the risks of addiction, abuse, and misuse, this drug is reserved for patients who have not been or are not expected to tolerate non-opioid pain medications or who have not obtained or are not expected to obtain analgesia with other pain management treatments.

Use: For the short-term (use should be limited to 5 days or less) management of acute pain, severe enough to require an opioid analgesic and for whom alternative treatments are inadequate.

Renal Dose Adjustments

Severe renal impairment (CrCl less than 30 mL/min): Maximum dose: 2 tablets orally every 12 hours

Liver Dose Adjustments

Use is not recommended

Dose Adjustments

Elderly Patients: Dose selection should be cautious due to potential for greater sensitivity to adverse events.

Concomitant use of Drugs affecting CYP450 Isoenzymes:

• CYP450 3A4 inhibitors/inducers or CYP450 2D6 inhibitors: Interactions are complex, consult drug interaction monographs

In circumstances in which physical dependence has occurred, do not abruptly discontinue this drug.

• Use a gradual downward taper

Precautions

US BOXED WARNINGS: 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 CYP450 ISOENZYMES; HEPATOTOXICITY; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS:

• Addiction, Abuse, and Misuse: Use of this drug exposes patients and other users to the risks of opioid addiction and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing and monitor all patients regularly for the development of these behaviors or conditions.
• Opioid Analgesic REMS: To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required for these products. 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. Monitor for respiratory depression, especially during initiation or following a dose increase.
• Accidental Ingestion of even one dose, especially by children, can result in a fatal overdose of tramadol.
• 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 occurred following tonsillectomy and/or adenoidectomy, and in at least 1 case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP450 2D6 polymorphism. This drug is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid use 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.
• Neonatal Opioid Withdrawal Syndrome, a potentially life-threatening condition if not recognized and treated, may result from prolonged maternal opioid use during pregnancy; it 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 appropriate treatment be available.
• Concomitant use or discontinuation of CYP450 isoenzymes including CYP450 3A4 inducers/inhibitors, or CYP450 2D6 inhibitors are complex; concomitant use requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1.
• Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 mg per day, and often involve more than one acetaminophen-containing product.
• Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

CONTRAINDICATIONS:

• Less than 12 years
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy
• Hypersensitivity to active substance, any other active component, or opioids
• Significant respiratory depression
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Concomitant use or within 2 weeks of monoamine oxidase inhibitors (MAOIs)

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

US Controlled Substance: Schedule IV

Dialysis

Patients may receive their regular dose of acetaminophen-tramadol on the day of dialysis since less than 7% of tramadol is removed by hemodialysis.

Other Comments

Administration advice:

• May be taken with or without food

General:

• Seizures and/serotonin syndrome may occur when used concomitantly with serotonergic agents (SSRIs, SNRIs, and triptans) or with drugs that significantly reduce the metabolic clearance of tramadol.
• Taking this drug in excessive doses, either alone or in combination with other CNS depressants, including alcohol, is a major cause of drug-related deaths.
• This drug should not be used for longer than therapeutically necessary; evaluate continued use at regular intervals.

Monitoring:

• Monitor for respiratory depression, especially with therapy initiation and with dose increases
• Monitor regularly for the development of addiction, abuse, and misuse
• Consider monitoring renal function in elderly patients

Patient advice:

• Patients should be instructed to read the US FDA-approved Medication Guide each time this drug is dispensed; they should understand the safe use, serious risks, and proper storage and disposal of this drug.
• Patients should understand that taking this medication exposes them to the risk of addiction.
• Patients should be instructed not to exceed the recommended dose or take this product with any other product that contains acetaminophen without first speaking with their healthcare provider; if a patient takes more than 4000 mg of acetaminophen in a day, they should be instructed to seek medical advice, even if they feel fine.
• Patients should be instructed to speak with their healthcare provider regarding all concomitant medications including starting or stopping any products while taking this drug.
• Patients should avoid alcohol while taking this product.
• Patients should understand the risks of life-threatening respiratory depression, and be informed as to when this risk is greatest.
• This drug may cause drowsiness, dizziness, or impair thinking or motor skills; patients should avoid driving or operating machinery until adverse effects are determined.
• Advise patient to speak to physician or health care professional if pregnant, intend to become pregnant, or are breastfeeding.
• Women of child bearing potential should understand that prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome and that prompt recognition and treatment will be necessary.