Tramadol-Acetaminophen

Tramadol/acetaminophen is a combination medication used for treating acute pain

• Tramadol/acetaminophen is available under the following different brand names: Ultracet

Adult and pediatric dosage

Tablet: Schedule IV

• 37.5mg/325mg

Acute, Short-Term Pain

Adult dosage

• 2 tablets orally every 4-6 hours as needed; not to exceed 8 tablets/day
• Treatment duration: 5 days or less

Limitations of Use

• Because of risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve therapy 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

Pediatric dosage

• Children below 16 years: Safety and efficacy not established
• Children above 16 years: 2 tabs orally every 4-6 hours or as needed; not to exceed 8 tablets/day
• Treatment duration: 5 days or less

Dosage Considerations – Should be Given as Follows: 

• See "Dosages."

Common side effects of Tramadol/Acetaminophen include:

• dizziness,
• drowsiness,
• stomach pain, 
• nausea, 
• loss of appetite,
• diarrhea, 
• constipation, and
• sweating.

Serious side effects of Tramadol/Acetaminophen include:

• noisy breathing, 
• sighing, 
• shallow breathing,
• breathing that stops during sleep,
• slow heart rate or weak pulse,
• light-headed feeling,
• seizure (convulsions),
• chest pain,
• liver problems--upper stomach pain, loss of appetite, dark urine, jaundice (yellowing of the skin or eyes),
• low cortisol levels-- nausea, vomiting, loss of appetite, dizziness, worsening tiredness or weakness, and
• high levels of serotonin in the body--agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea.

Rare side effects of Tramadol/Acetaminophen include:

• none 

This is not a complete list of side effects and other serious side effects or health problems that may occur as a result of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Tramadol/Acetaminophen has severe interactions with the following drugs:
  • alvimopan
  • procarbazine
  • rasagiline
  • safinamide
  • selegiline
• Tramadol/Acetaminophen has serious interactions with at least 56 other drugs.
• Tramadol/Acetaminophen has moderate interactions with at least 302 other drugs.
• Tramadol/Acetaminophen has minor interactions with at least 67 other drugs. 

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions, concerns.

Contraindications

• Hypersensitivity
• Children less than 12 years
• Postoperative management in children below 18 years following tonsillectomy and/or adenoidectomy
• Significant respiratory depression
• Acute or severe bronchial asthma in an unmonitored setting or absence of resuscitative equipment
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Previous hypersensitivity to tramadol hydrochloride, acetaminophen, any other component of this product, or opioids
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days

Effects of drug abuse

• Addiction
• Overdose
• Death

Short-Term Effects

• See “What Are Side Effects Associated with Using Tramadol/Acetaminophen?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Tramadol/Acetaminophen?”

Cautions

• Use with caution in hepatitis, liver failure, myocardial ischemia, pulmonary edema, vasodilation
• As an opioid, the drug exposes users to risks of addiction, abuse, and misuse; assess each patient's risk for opioid addiction, abuse, or misuse before prescribing the drug, and monitor all patients for the development of addictive behaviors and conditions; reduce risks by prescribing the drug in smallest appropriate quantity and advising the patient on proper disposal of unused drug risk is greatest during initiation of therapy or following a dosage increase; monitor patients closely for respiratory depression, especially within first 24-72 hours of initiating therapy and following dosage increases; to reduce risk, proper dosing and titration are essential; overestimating; dosage when converting patients from another opioid product can result in fatal overdose with the first dose
• Monitor for sedation and respiratory depression in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness; avoid use in patients with impaired consciousness or coma
• Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases the risk of CSA in a dose-dependent fashion; in patients who present with CSA, consider decreasing opioid dosage using best practices for opioid taper
• May cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs; monitor for severe hypotension: during dosage initiation and titration; avoid in patients with circulatory shock
• Adrenal insufficiency may occur; if diagnosed, treat with physiologic replacement of corticosteroids, and wean the patient off the opioid
• Monitor closely for life-threatening respiratory depression in patients with chronic pulmonary disease or elderly, cachectic, or debilitated patients, particularly during initiation and titration
• As of January 2011, the FDA has mandated a dosage limit for all prescription medications that contain acetaminophen, allowing no more than 325 mg/dosage unit
• Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplantation or death; risk increases in individuals with underlying liver disease, alcohol ingestion, and/or use of more than 1 acetaminophen-containing product (see Black Box Warnings)
• QT prolongation/torsade de Pointes; cases of QT prolongation and/or torsade de Pointes have been reported with tramadol use; many cases were reported in patients taking another drug labeled, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the overdose setting
• Acetaminophen may cause rare serious skin reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson Syndrome, toxic epidermal necrolysis), which can be fatal; discontinued at the first appearance of skin rash
• At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine; a baby nursing from an ultra-rapid metabolizer mother could potentially be exposed to high levels of M1, and experience life-threatening respiratory depression; for this reason, breastfeeding is not recommended during therapy
• Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory depression
• Do not abruptly discontinue therapy in a patient physically dependent on opioids; when discontinuing therapy, in a physically dependent patient, gradually taper the dosage; rapid tapering in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain
• Concomitant use with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower tramadol levels; this may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal
• Follow patients receiving any CYP3A4 inhibitor or inducer for risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when used in conjunction with inhibitors and inducers of CYP3A4
• If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use; in patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in absence of an opioid, and titrate based on clinical response; follow patients closely for signs and symptoms of respiratory depression and sedation; if concomitant use with benzodiazepine or muscle relaxant is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose
• Life-threatening respiratory depression and death have occurred in children who received tramadol; tramadol is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to increased exposure to active metabolite M1; children below 12 years appear to be more susceptible to respiratory depressant effects of tramadol, particularly if there are risk factors for respiratory depression; many reported cases of death occurred in the postoperative period following tonsillectomy and/or adenoidectomy, and many of children had evidence of being ultra-rapid metabolizers of tramadol
• Avoid use in adolescents 12-18 years of age who have other risk factors that may increase sensitivity to respiratory depressant effects of tramadol unless benefits outweigh risks; risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression; when prescribing tramadol for adolescents, healthcare providers should choose lowest effective dose for the shortest period and inform patients and caregivers about risks and the signs of opioid overdose
• 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 tramadol above the recommended range
• Do not prescribe therapy to patients who are suicidal or addiction-prone; consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed
• Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus; drug may cause spasm of the sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms
• Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; in these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms
• May impair mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery; warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of opioids and know how they will react to the medication
• Serotonin syndrome (potentially life-threatening) may develop
• Cases of tramadol-associated hypoglycemia were reported; some resulting in hospitalization; in most cases, patients had predisposing risk factors (e.g., diabetes); if hypoglycemia suspected, monitor blood glucose levels and consider drug discontinuation as appropriate
• Hyponatremia
  • Hyponatremia reported, many cases severe; most cases occurred in females over 65 and within the first week of therapy; in some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH)
  • Monitor for signs and symptoms of hyponatremia (e.g., confusion, disorientation), during treatment, especially during initiation of therapy; if signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue therapy
  • 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 Risk Evaluation and Mitigation Strategy (REMS) for these products
  • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed; use the following link to obtain the Patient Counseling Guide (PCG): www.fda.gov/OpioidAnalgesicREMSPCG
  • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them
  • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities
  • To obtain further information on opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com; the FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint
• Patient access to naloxone for emergency treatment of opioid overdose
  • Assess potential need for naloxone; consider prescribing for emergency treatment of opioid overdose
  • Consult on availability and ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines
  • Educate patients regarding the signs and symptoms of respiratory depression and to call 911 or seek immediate emergency medical help in the event of a known or suspected overdose
• Off-label use in children
  • Severe respiratory depression reported with off-label use in children
  • Tramadol undergoes extensive hepatic metabolism; it is metabolized by CYP2D6 to the active metabolite O-desmethyltramadol (M1), which has a 200-fold greater affinity for opioid receptors than does tramadol
  • CYP2D6 poor metabolizers have shown a 20% increase in tramadol levels and a 40% decrease in O-desmethyltramadol (M1)

Pregnancy and Lactation

• Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome; available data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage
• Labor and delivery
  • Use of tramadol during labor may lead to respiratory depression in the neonate
  • Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate; use is not recommended in pregnant women during or immediately prior to labor when other analgesic techniques are more appropriate; opioid analgesics, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor; monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression
• Lactation
  • Tramadol and its active metabolite, O-desmethyltramadol (M1), are present in human milk; there are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to M1 via breast milk; women who are ultra-rapid metabolizers of tramadol achieve higher than expected serum levels of opioids, potentially leading to higher levels of M1 in breast milk that can be dangerous in their breastfed infants; in women with normal tramadol metabolism (normal CYP2D6 activity), the amount of tramadol secreted into human milk is low and dose-dependent