tramadol/acetaminophen (Rx)

Brand and Other Names:Ultracet
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tramadol/acetaminophen

tablet: Schedule IV

  • 37.5mg/325mg

Acute, Short-Term Pain

2 tablets PO q4-6hr PRN; 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 (eg, 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

Dosage Modifications

Renal impairment: If CrCl <30 mL/min, 2 tablets PO q12hr; not to exceed 2 tablets q12hr; treatment duration should not exceed 5 days

Hepatic impairment: Do not administer

Healthcare professionals can direct patients to take 1 or 2 tablets, capsules, or other dosage units of a prescription product containing 325 mg of acetaminophen up to 6 times daily (12 dosage units) and still not exceed the maximum daily dose of acetaminophen (ie, 4000 mg/day)

Dosing Considerations

In circumstances where physical dependence is possible, use a gradual downward taper and do not stop therapy abruptly

Do not co-administer with other tramadol or acetaminophen containing products

Use lowest effective dosage for shortest duration consistent with individual patient treatment goals

Initiate dosing regimen for each patient individually, taking into account patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse

Monitor patients closely for respiratory depression, especially within first 24-72 hr of initiating therapy and following dosage increases and adjust the dosage accordingly

Dosage Forms & Strengths

tramadol/acetaminophen

tablet: Schedule IV

  • 37.5mg/325mg

Acute, Short-Term Pain

<16 years: Safety and efficacy not established

≥16 years: 2 tabs PO q4-6hr PRN; not to exceed 8 tablets/day

Treatment duration: ≤5 days

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Interactions

Interaction Checker

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            Adverse Effects

            1-10%

            Abdominal pain

            Anxiety

            Anorexia

            Asthenia

            Confusion

            Constipation

            Diarrhea

            Dizziness

            Dry mouth

            Dyspepsia

            Euphoria

            Fatigue

            Flatulence

            Headache

            Hot flushes

            Insomnia

            Nausea

            Nervousness

            Pruritus

            Rash

            Somnolence

            Sweating

            Tremor

            Vomiting

            <1%

            Abnormal hepatic function

            Abnormal thinking

            Abnormal vision

            Aggravated hypertension

            Aggravated migraine

            Albuminuria

            Amnesia

            Anemia

            Arrhythmia

            Ataxia

            Chest pain

            Convulsions

            Depersonalization

            Depression

            Drug abuse

            Dysphagia

            Dyspnea

            Emotional lability

            Hallucination

            Hypertension

            Hypertonia

            Hypotension

            Impotence

            Involuntary muscle contractions

            Melena

            Micturition disorder

            Migraine

            Oliguria

            Palpitation

            Paresthesias

            Paroniria

            Rigors

            Stupor

            Syncope

            Tachycardia

            Tinnitus

            Tongue edema

            Urinary retention

            Vertigo

            Weight decrease

            Withdrawal syndrome

            Frequency Not Defined

            Allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson Syndrome/TENS)

            Cognitive dysfunction

            Depression

            Difficulty concentrating

            Gastrointestinal bleeding

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            Warnings

            Black Box Warnings

            Contains acetaminophen

            Hepatotoxicity may occur with acetaminophen doses that exceed 4 g/day; take into account all acetaminophen-containing products the patient is taking, including PRN doses and OTC products

            Acetaminophen associated with cases of acute liver failure, at times resulting in liver transplant and death

            New dosage limit allows no more than 325 mg/dosage unit for prescription medications that contain acetaminophen

            Healthcare professionals can direct patients to take 1 or 2 tablets, capsules, or other dosage units of a prescription product containing 325 mg of acetaminophen up to 6 times daily (12 dosage units) and still not exceed the maximum daily dose of acetaminophen (ie, 4000 mg/day)

            Risk of opioid addiction, abuse, 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

            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 1 dose, especially by children, can result in a fatal overdose

            Prolonged use 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

            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 requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1

            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; reserve concomitant prescribing of this drug combination and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to minimum required; follow patients for signs and symptoms of respiratory depression and sedation

            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 an increased exposure to active metabolite O-desmethyltramadol (M1), children < 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 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 shortest period of time and inform patients and caregivers about risks and the signs of M1 overdose

            Opioid analgesic risk evaluation and mitigation strategy (REMS)

            • To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products; under 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
              • Consider other tools to improve patient, household, and community safety

            Contraindications

            Hypersensitivity

            Obstetric postoperative or post-delivery analgesia

            Acute intoxication with alcohol, narcotics, hypnotics, opioids, centrally-acting analgesics, or other psychotropic drugs

            Children <12 years

            Postoperative management in children <18 years following tonsillectomy and/or adenoidectomy

            Significant respiratory depression

            Acute or severe bronchial asthma in an unmonitored setting or in 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

            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 prior to prescribing the drug, and monitor all patients for development of addiction behaviors and conditions; reduce risks by prescribing drug in smallest appropriate quantity and advising 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 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

            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 patient off of the opioid

            Monitor closely for life-threatening respiratory depression in patients with chronic pulmonary disease or in 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 for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in overdose setting

            Acetaminophen may cause rare serious skin reactions (eg, 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 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

            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 decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with opioid analgesic, prescribe 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; if an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response; follow patients closely for signs and symptoms of respiratory depression and sedation

            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 an increased exposure to active metabolite M1; children < 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 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 shortest period of time 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 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 sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

            Avoid 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 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 opioid and know how they will react to the medication

            Serotonin syndrome (potentially life-threatening) may develop

            Opioid analgesic risk evaluation and mitigation strategy (REMS)

            • To ensure that benefits of opioid analgesics outweigh 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

            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)
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            Pregnancy & Lactation

            Pregnancy

            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 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

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Tramadol: Nonopioid-derived synthetic opioid, centrally acting analgesic, but may act at least partially by binding to opioid mu receptors

            Acetaminophen: Acts on the hypothalamus to produce antipyresis and analgesia

            Absorption

            Bioavailability: 75%

            Peak plasma time: 2-3 hr

            Distribution

            VD: 2.6-2.9 L/kg

            Protein bound: 20%

            Metabolism

            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)

            Acetaminophen

            • Undergoes glucuronide and sulfate conjugation

            Elimination

            Half-life

            • Tramadol: 5-7 hr
            • Acetaminophen: 2-4 hr

            Excretion

            • Tramadol: Primarily renal excretion
            • Acetaminophen: Less than 9% excreted unchanged in urine

            Pharmacogenomics

            Genetic testing laboratories

            • The Roche Cytochrome AmpliChip P450 2D6/2C19 Genotyping and Phenotyping Assay can be used to identify 26 different alleles of CYP2D6
            • The following companies offer testing for CYP2D6 variants
            • DxS (http://www.dxsdiagnostics.com/)
            • Genelex (http://www.genelex.com)
            • LabCorp (http://www.labcorp.com/)
            • Luminex (http://www.luminexcorp.com)
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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

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            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.