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

Access to naloxone for opioid overdose

Assess need for naloxone upon initiating and renewing treatment

Consider prescribing naloxone
  • Based on patient’s risk factors for overdose (eg, concomitant use of CNS depressants, a history of opioid use disorder, prior opioid overdose); presence of risk factors should not prevent proper pain management
  • Household members (including children) or other close contacts at risk for accidental ingestion or overdose
Consult patients and caregivers on the following:
  • Availability of naloxone for emergency treatment of opioid overdose
  • Ways differ on how to obtain naloxone as permitted by individual state dispensing and prescribing requirements or guidelines (eg, by prescription, directly from a pharmacist, as part of a community-based program)

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

Dosing Considerations

Access to naloxone for opioid overdose

  • Assess need for naloxone upon initiating and renewing treatment
Consider prescribing naloxone
  • Based on patient’s risk factors for overdose (eg, concomitant use of CNS depressants, a history of opioid use disorder, prior opioid overdose); presence of risk factors should not prevent proper pain management
  • Household members (including children) or other close contacts at risk for accidental ingestion or overdose
Consult patients and caregivers on the following:
  • Availability of naloxone for emergency treatment of opioid overdose
  • Ways differ on how to obtain naloxone as permitted by individual state dispensing and prescribing requirements or guidelines (eg, by prescription, directly from a pharmacist, as part of a community-based program)
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Interactions

Interaction Checker

and tramadol/acetaminophen

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Contraindicated (5)

            • alvimopan

              alvimopan, tramadol. receptor binding competition. Contraindicated. Alvimopan is contraindicated in opioid tolerant patients (ie, those who have taken therapeutic doses of opioids for >7 consecutive days immediately prior to taking alvimopan). Patients recently exposed to opioids are expected to be more sensitive to the effects of alvimopan and therefore may experience abdominal pain, nausea and vomiting, and diarrhea. No significant interaction is expected with concurrent use of opioid analgesics and alvimopan in patients who received opioid analgesics for 7 or fewer consecutive days prior to alvimopan.

            • procarbazine

              procarbazine and tramadol both increase serotonin levels. Contraindicated.

            • rasagiline

              rasagiline and tramadol both increase serotonin levels. Contraindicated.

            • safinamide

              tramadol, safinamide. Either increases toxicity of the other by serotonin levels. Contraindicated. Concomitant use could result in life-threatening serotonin syndrome.

            • selegiline

              selegiline and tramadol both increase serotonin levels. Contraindicated. At least 14 days should elapse between discontinuation of selegiline and initiation of analgesic.

            Serious - Use Alternative (56)

            • abametapir

              abametapir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

            • alfentanil

              tramadol, alfentanil. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • apalutamide

              apalutamide will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

            • belladonna and opium

              tramadol, belladonna and opium. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • benzhydrocodone/acetaminophen

              benzhydrocodone/acetaminophen, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • bremelanotide

              bremelanotide will decrease the level or effect of tramadol by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.

            • buprenorphine

              tramadol, buprenorphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

              buprenorphine, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

            • buprenorphine buccal

              buprenorphine buccal, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

              tramadol, buprenorphine buccal. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • butorphanol

              tramadol, butorphanol. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

              butorphanol, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

            • calcium/magnesium/potassium/sodium oxybates

              tramadol, calcium/magnesium/potassium/sodium oxybates. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • clonidine

              clonidine, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration enhances CNS depressant effects.

            • codeine

              tramadol, codeine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • cyclobenzaprine

              tramadol and cyclobenzaprine both increase serotonin levels. Avoid or Use Alternate Drug.

            • dacomitinib

              dacomitinib will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Avoid use with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities.

            • desvenlafaxine

              tramadol and desvenlafaxine both increase serotonin levels. Avoid or Use Alternate Drug.

            • dextromoramide

              tramadol, dextromoramide. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • diamorphine

              tramadol, diamorphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • diazepam intranasal

              diazepam intranasal, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • difenoxin hcl

              tramadol, difenoxin hcl. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • diphenoxylate hcl

              tramadol, diphenoxylate hcl. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • dipipanone

              tramadol, dipipanone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • duloxetine

              duloxetine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug.

            • eluxadoline

              tramadol, eluxadoline. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid coadministration with other drugs that cause constipation. Increases risk for constipation related serious adverse reactions. .

            • fentanyl

              fentanyl, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

            • fentanyl intranasal

              fentanyl intranasal, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

            • fentanyl transdermal

              fentanyl transdermal, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

            • fentanyl transmucosal

              fentanyl transmucosal, tramadol. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Coadministration with other CNS depressants, such as skeletal muscle relaxants, may cause respiratory depression, hypotension, profound sedation, coma, and/or death. Consider dose reduction of either or both agents to avoid serious adverse effects. Monitor for hypotension, respiratory depression, and profound sedation.

            • fexinidazole

              fexinidazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

            • givosiran

              givosiran will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP2D6 substrates with givosiran. If unavoidable, decrease the CYP2D6 substrate dosage in accordance with approved product labeling.

            • hydrocodone

              tramadol, hydrocodone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

              hydrocodone, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • hydromorphone

              tramadol, hydromorphone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • idelalisib

              idelalisib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates

            • iobenguane I 131

              tramadol will decrease the level or effect of iobenguane I 131 by Other (see comment). Avoid or Use Alternate Drug. Based on the mechanism of action of iobenguane, drugs that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells, and thus, reduce iobenguane efficacy. Discontinue interfering drugs for at least 5 half-lives before administration of either the dosimetry or an iobenguane dose. Do not administer these drugs until at least 7 days after each iobenguane dose.

            • isocarboxazid

              isocarboxazid and tramadol both increase serotonin levels. Avoid or Use Alternate Drug.

              isocarboxazid increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

            • ivosidenib

              ivosidenib will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

            • levorphanol

              tramadol, levorphanol. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • linezolid

              linezolid and tramadol both increase serotonin levels. Avoid or Use Alternate Drug. Linezolid may increase serotonin as a result of MAO-A inhibition. If linezolid must be administered, discontinue serotonergic drug immediately and monitor for CNS toxicity. Serotonergic therapy may be resumed 24 hours after last linezolid dose or after 2 weeks of monitoring, whichever comes first.

              linezolid increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

            • lonafarnib

              acetaminophen will increase the level or effect of lonafarnib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of lonafarnib (a sensitive CYP3A substrate) with weak CYP3A inhibitors is unavoidable, reduce to, or continue lonafarnib at starting dose. Closely monitor for arrhythmias and events (eg, syncope, heart palpitations) since lonafarnib effect on QT interval is unknown.

              lonafarnib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with sensitive CYP3A substrates. If coadministration unavoidable, monitor for adverse reactions and reduce CYP3A substrate dose in accordance with product labeling.

            • lorcaserin

              tramadol and lorcaserin both increase serotonin levels. Avoid or Use Alternate Drug.

            • pexidartinib

              acetaminophen and pexidartinib both increase Other (see comment). Avoid or Use Alternate Drug. Pexidartinib can cause hepatotoxicity. Avoid coadministration of pexidartinib with other products know to cause hepatoxicity.

            • meperidine

              tramadol, meperidine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • methadone

              tramadol, methadone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • methylene blue

              methylene blue and tramadol both increase serotonin levels. Avoid or Use Alternate Drug. Methylene blue may increase serotonin as a result of MAO-A inhibition. If methylene blue must be administered, discontinue serotonergic drug immediately and monitor for CNS toxicity. Serotonergic therapy may be resumed 24 hours after last methylene blue dose or after 2 weeks of monitoring, whichever comes first.

            • metoclopramide intranasal

              tramadol, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.

            • morphine

              tramadol, morphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • nalbuphine

              tramadol, nalbuphine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

              nalbuphine, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

            • opium tincture

              tramadol, opium tincture. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • oxycodone

              tramadol, oxycodone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • oxymorphone

              tramadol, oxymorphone. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • ozanimod

              ozanimod increases toxicity of tramadol by sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug. Because the active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Therefore, coadministration of ozanimod with drugs that can increase norepinephrine or serotonin is not recommended. Monitor for hypertension with concomitant use.

            • papaveretum

              tramadol, papaveretum. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

            • pentazocine

              tramadol, pentazocine. Other (see comment). Avoid or Use Alternate Drug. Comment: Tramadol may reinitiate opiate dependence in pts. previously addicted to other opiates; it may also provoke withdrawal Sx. in pts. who are currently opiate dependent.

              pentazocine, tramadol. Other (see comment). Avoid or Use Alternate Drug. Comment: Mixed opiate agonist/antagonists usually produce additive sedation with narcotics; however, in narcotic addicted pts., the antagonist activity may provoke withdrawal Sx.

            • phenelzine

              phenelzine and tramadol both increase serotonin levels. Avoid or Use Alternate Drug.

              phenelzine increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. Risk of hypotension, hyperpyrexia, somnolence, or death; separate by 14 d.

            • posaconazole

              posaconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • pretomanid

              acetaminophen, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.

            • procarbazine

              procarbazine increases toxicity of tramadol by unknown mechanism. Avoid or Use Alternate Drug. MAOIs may potentiate CNS depression and hypotension. Do not use within 14 days of MAOI use. .

            Monitor Closely (299)

            • 5-HTP

              5-HTP and tramadol both increase serotonin levels. Use Caution/Monitor.

            • abiraterone

              abiraterone increases levels of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Avoid coadministration of abiraterone with substrates of CYP2D6. If alternative therapy cannot be used, exercise caution and consider increasing tramadol dose if clinically appropriate; if abiraterone is discontinued, consider reducing tramadol dose and frequently monitor for signs of respiratory depression and sedation.

            • albuterol

              tramadol increases and albuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • alfentanil

              alfentanil and tramadol both increase sedation. Use Caution/Monitor.

            • almotriptan

              almotriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

            • alprazolam

              alprazolam and tramadol both increase sedation. Use Caution/Monitor.

            • amifampridine

              tramadol increases toxicity of amifampridine by Other (see comment). Modify Therapy/Monitor Closely. Comment: Amifampridine can cause seizures. Coadministration with drugs that lower seizure threshold may increase this risk.

            • amiodarone

              amiodarone decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              amiodarone decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

            • amitriptyline

              tramadol and amitriptyline both increase sedation. Use Caution/Monitor.

              amitriptyline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • amobarbital

              amobarbital and tramadol both increase sedation. Use Caution/Monitor.

            • amoxapine

              tramadol and amoxapine both increase sedation. Use Caution/Monitor.

              amoxapine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • apalutamide

              apalutamide will decrease the level or effect of acetaminophen by increasing elimination. Use Caution/Monitor. Apalutamide induces UGT and may decrease systemic exposure of drugs that are UGT substrates.

            • apomorphine

              tramadol and apomorphine both increase sedation. Use Caution/Monitor.

            • arformoterol

              tramadol increases and arformoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • aripiprazole

              tramadol and aripiprazole both increase sedation. Use Caution/Monitor.

            • armodafinil

              tramadol increases and armodafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • artemether/lumefantrine

              artemether/lumefantrine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

            • atazanavir

              atazanavir increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

            • atogepant

              acetaminophen will increase the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • avapritinib

              acetaminophen will increase the level or effect of avapritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • axitinib

              acetaminophen increases levels of axitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • azelastine

              azelastine and tramadol both increase sedation. Use Caution/Monitor.

            • baclofen

              baclofen and tramadol both increase sedation. Use Caution/Monitor.

            • belladonna and opium

              belladonna and opium and tramadol both increase sedation. Use Caution/Monitor.

            • benperidol

              tramadol and benperidol both increase sedation. Use Caution/Monitor.

            • benzphetamine

              tramadol increases and benzphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • bosentan

              bosentan will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • brexanolone

              brexanolone, tramadol. Either increases toxicity of the other by sedation. Use Caution/Monitor.

            • brompheniramine

              brompheniramine and tramadol both increase sedation. Use Caution/Monitor.

            • bupivacaine implant

              acetaminophen, bupivacaine implant. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Local anesthetics may increase the risk of developing methemoglobinemia when concurrently exposed to drugs that also cause methemoglobinemia.

            • buprenorphine

              buprenorphine and tramadol both increase sedation. Use Caution/Monitor.

            • buprenorphine buccal

              buprenorphine buccal and tramadol both increase sedation. Use Caution/Monitor.

            • buprenorphine, long-acting injection

              tramadol increases toxicity of buprenorphine, long-acting injection by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of buprenorphine and benzodiazepines or other CNS depressants increases risk of adverse reactions including overdose, respiratory depression, and death. Cessation of benzodiazepines or other CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering CNS depressants may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

            • bupropion

              bupropion will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

            • buspirone

              buspirone and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • busulfan

              acetaminophen increases levels of busulfan by decreasing metabolism. Use Caution/Monitor. Use of acetaminophen prior to (< 72 hours) or concurrently with busulfan may result in decreased clearance of busulfan due to acetaminophen-induced decreases in glutathione levels.

            • butabarbital

              butabarbital and tramadol both increase sedation. Use Caution/Monitor.

            • butalbital

              butalbital and tramadol both increase sedation. Use Caution/Monitor.

            • butorphanol

              butorphanol and tramadol both increase sedation. Use Caution/Monitor.

            • caffeine

              tramadol increases and caffeine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • carbamazepine

              carbamazepine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • carbinoxamine

              carbinoxamine and tramadol both increase sedation. Use Caution/Monitor.

            • carisoprodol

              carisoprodol and tramadol both increase sedation. Use Caution/Monitor.

            • celecoxib

              celecoxib decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              celecoxib decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

            • cenobamate

              cenobamate, tramadol. Either increases effects of the other by sedation. Use Caution/Monitor.

            • chloral hydrate

              chloral hydrate and tramadol both increase sedation. Use Caution/Monitor.

            • chlordiazepoxide

              chlordiazepoxide and tramadol both increase sedation. Use Caution/Monitor.

            • chloroquine

              chloroquine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              chloroquine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

            • chlorpheniramine

              chlorpheniramine and tramadol both increase sedation. Use Caution/Monitor.

            • chlorpromazine

              tramadol and chlorpromazine both increase sedation. Use Caution/Monitor.

            • chlorzoxazone

              chlorzoxazone and tramadol both increase sedation. Use Caution/Monitor.

            • cimetidine

              cimetidine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              cimetidine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

            • cinnarizine

              cinnarizine and tramadol both increase sedation. Use Caution/Monitor.

            • citalopram

              citalopram and tramadol both increase serotonin levels. Use Caution/Monitor. Combination may increase risk of serotonin syndrome or neuroleptic malignant syndrome-like reactions.

            • clarithromycin

              clarithromycin will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • clemastine

              clemastine and tramadol both increase sedation. Use Caution/Monitor.

            • clobazam

              clobazam will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Lower doses of drugs metabolized by CYP2D6 may be required when used concomitantly.

              tramadol, clobazam. Other (see comment). Use Caution/Monitor. Comment: Concomitant administration can increase the potential for CNS effects (e.g., increased sedation or respiratory depression).

            • clomipramine

              tramadol and clomipramine both increase sedation. Use Caution/Monitor.

              clomipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • clonazepam

              clonazepam and tramadol both increase sedation. Use Caution/Monitor.

            • clorazepate

              clorazepate and tramadol both increase sedation. Use Caution/Monitor.

            • clozapine

              tramadol and clozapine both increase sedation. Use Caution/Monitor.

            • cobicistat

              cobicistat will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. A decreased dose of tramadol may be required

              cobicistat will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. A decreased dose of tramadol may be required

            • cocaine

              cocaine and tramadol both increase serotonin levels. Use Caution/Monitor.

            • codeine

              codeine and tramadol both increase sedation. Use Caution/Monitor.

            • crizotinib

              crizotinib increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A.

            • crofelemer

              crofelemer increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.

            • cyclizine

              cyclizine and tramadol both increase sedation. Use Caution/Monitor.

            • cyclobenzaprine

              cyclobenzaprine and tramadol both increase sedation. Use Caution/Monitor.

            • cyproheptadine

              cyproheptadine and tramadol both increase sedation. Use Caution/Monitor.

            • dabrafenib

              dabrafenib will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • dantrolene

              dantrolene and tramadol both increase sedation. Use Caution/Monitor.

            • dapsone topical

              acetaminophen increases toxicity of dapsone topical by altering metabolism. Modify Therapy/Monitor Closely. May induce methemoglobinemia .

            • darunavir

              darunavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. A decreased dose of tramadol may be required

            • desflurane

              desflurane and tramadol both increase sedation. Use Caution/Monitor. Opioids may decrease MAC requirements, less inhalation anesthetic may be required.

            • desipramine

              tramadol and desipramine both increase sedation. Use Caution/Monitor.

              desipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • desvenlafaxine

              desvenlafaxine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Desvenlafaxine inhibits CYP2D6; with higher desvenlafaxine doses (ie, 400 mg) decrease the CYP2D6 substrate dose by up to 50%; no dosage adjustment needed with desvenlafaxine doses <100 mg

            • deutetrabenazine

              tramadol and deutetrabenazine both increase sedation. Use Caution/Monitor.

            • dexamethasone

              dexamethasone will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • dexchlorpheniramine

              dexchlorpheniramine and tramadol both increase sedation. Use Caution/Monitor.

            • dexfenfluramine

              tramadol increases and dexfenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              dexfenfluramine and tramadol both increase serotonin levels. Use Caution/Monitor.

            • dexmedetomidine

              dexmedetomidine and tramadol both increase sedation. Use Caution/Monitor.

            • dexmethylphenidate

              tramadol increases and dexmethylphenidate decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dextroamphetamine

              tramadol increases and dextroamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              dextroamphetamine and tramadol both increase serotonin levels. Use Caution/Monitor.

            • dextromethorphan

              dextromethorphan and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • dextromoramide

              dextromoramide and tramadol both increase sedation. Use Caution/Monitor.

            • diamorphine

              diamorphine and tramadol both increase sedation. Use Caution/Monitor.

            • diazepam

              diazepam and tramadol both increase sedation. Use Caution/Monitor.

            • diethylpropion

              tramadol increases and diethylpropion decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • difenoxin hcl

              difenoxin hcl and tramadol both increase sedation. Use Caution/Monitor.

            • dihydroergotamine

              dihydroergotamine and tramadol both increase serotonin levels. Use Caution/Monitor.

            • dihydroergotamine intranasal

              dihydroergotamine intranasal and tramadol both increase serotonin levels. Use Caution/Monitor.

            • dimenhydrinate

              dimenhydrinate and tramadol both increase sedation. Use Caution/Monitor.

            • diphenhydramine

              diphenhydramine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              diphenhydramine and tramadol both increase sedation. Use Caution/Monitor.

              diphenhydramine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

            • diphenoxylate hcl

              diphenoxylate hcl and tramadol both increase sedation. Use Caution/Monitor.

            • dipipanone

              dipipanone and tramadol both increase sedation. Use Caution/Monitor.

            • dobutamine

              tramadol increases and dobutamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dopamine

              tramadol increases and dopamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dopexamine

              tramadol increases and dopexamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • dosulepin

              tramadol and dosulepin both increase sedation. Use Caution/Monitor.

            • doxepin

              tramadol and doxepin both increase sedation. Use Caution/Monitor.

              doxepin and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • doxylamine

              doxylamine and tramadol both increase sedation. Use Caution/Monitor.

            • droperidol

              tramadol and droperidol both increase sedation. Use Caution/Monitor.

            • duloxetine

              duloxetine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • efavirenz

              efavirenz will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • elagolix

              elagolix decreases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

            • eletriptan

              eletriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

            • eliglustat

              eliglustat increases levels of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the concomitant drug and titrate to clinical effect.

            • eltrombopag

              eltrombopag increases levels of acetaminophen by decreasing metabolism. Use Caution/Monitor. UGT inhibition; significance of interaction unclear.

            • elvitegravir/cobicistat/emtricitabine/tenofovir DF

              elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Cobicistat is a CYP3A4 inhibitor; contraindicated with CYP3A4 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.

              elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Cobicistat is a CYP2D6 inhibitor; caution with CYP2D6 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.

            • encorafenib

              encorafenib, tramadol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.

            • enzalutamide

              enzalutamide will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • ephedrine

              tramadol increases and ephedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • epinephrine

              tramadol increases and epinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • epinephrine racemic

              tramadol increases and epinephrine racemic decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • ergotamine

              ergotamine and tramadol both increase serotonin levels. Use Caution/Monitor.

            • erythromycin base

              erythromycin base will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

            • erythromycin ethylsuccinate

              erythromycin ethylsuccinate will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

            • erythromycin lactobionate

              erythromycin lactobionate will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

            • erythromycin stearate

              erythromycin stearate will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

            • escitalopram

              escitalopram and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • esketamine intranasal

              esketamine intranasal, tramadol. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

            • eslicarbazepine acetate

              eslicarbazepine acetate will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • estazolam

              estazolam and tramadol both increase sedation. Use Caution/Monitor.

            • ethanol

              tramadol and ethanol both increase sedation. Use Caution/Monitor.

            • etomidate

              etomidate and tramadol both increase sedation. Use Caution/Monitor.

            • etravirine

              etravirine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • exenatide injectable solution

              exenatide injectable solution will decrease the level or effect of acetaminophen by unspecified interaction mechanism. Use Caution/Monitor. To avoid potential interaction, give acetaminophen at least 1 hour before or 4 hours after exenatide injection.

            • exenatide injectable suspension

              exenatide injectable suspension will decrease the level or effect of acetaminophen by unspecified interaction mechanism. Use Caution/Monitor. To avoid potential interaction, give acetaminophen at least 1 hour before or 4 hours after exenatide injection.

            • fedratinib

              fedratinib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

            • fenfluramine

              tramadol increases and fenfluramine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              fenfluramine and tramadol both increase serotonin levels. Use Caution/Monitor.

            • finerenone

              acetaminophen will increase the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor serum potassium during initiation and dosage adjustment of either finererone or moderate CYP3A4 inhibitors. Adjust finererone dosage as needed.

            • flibanserin

              tramadol and flibanserin both increase sedation. Modify Therapy/Monitor Closely. Risk for sedation increased if flibanserin is coadministration with other CNS depressants.

              acetaminophen will increase the level or effect of flibanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Increased flibanserin adverse effects may occur if coadministered with multiple weak CYP3A4 inhibitors.

            • fluoxetine

              fluoxetine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • imatinib

              imatinib decreases levels of acetaminophen by decreasing hepatic clearance. Modify Therapy/Monitor Closely. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation (Ki value of 58.5 micro-M) at therapeutic levels; avoid chronic acetaminophen therapy with imatinib; if occasional acetaminophen administered, do not exceed 1300 mg/day.

            • fluphenazine

              tramadol and fluphenazine both increase sedation. Use Caution/Monitor.

            • flurazepam

              flurazepam and tramadol both increase sedation. Use Caution/Monitor.

            • fluvoxamine

              fluvoxamine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • formoterol

              tramadol increases and formoterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • fosphenytoin

              fosphenytoin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • frovatriptan

              frovatriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

            • gabapentin

              gabapentin, tramadol. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

            • gabapentin enacarbil

              gabapentin enacarbil, tramadol. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

            • haloperidol

              tramadol and haloperidol both increase sedation. Use Caution/Monitor.

            • hydromorphone

              hydromorphone and tramadol both increase sedation. Use Caution/Monitor.

            • hydroxyzine

              hydroxyzine and tramadol both increase sedation. Use Caution/Monitor.

            • iloperidone

              tramadol and iloperidone both increase sedation. Use Caution/Monitor.

              iloperidone increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.

            • imipramine

              tramadol and imipramine both increase sedation. Use Caution/Monitor.

              imipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • indinavir

              indinavir increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

            • isoniazid

              isoniazid will increase the level or effect of acetaminophen by affecting hepatic enzyme CYP2E1 metabolism. Use Caution/Monitor.

              isoniazid and tramadol both increase serotonin levels. Use Caution/Monitor.

            • isoproterenol

              tramadol increases and isoproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • ivacaftor

              acetaminophen increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .

            • istradefylline

              istradefylline will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

            • itraconazole

              itraconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ketamine

              ketamine and tramadol both increase sedation. Use Caution/Monitor.

            • ketoconazole

              ketoconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

            • ketotifen, ophthalmic

              tramadol and ketotifen, ophthalmic both increase sedation. Use Caution/Monitor.

            • L-tryptophan

              L-tryptophan and tramadol both increase serotonin levels. Use Caution/Monitor.

            • lasmiditan

              lasmiditan, tramadol. Either increases effects of the other by sedation. Use Caution/Monitor. Coadministration of lasmiditan and other CNS depressant drugs, including alcohol have not been evaluated in clinical studies. Lasmiditan may cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions.

            • lemborexant

              lemborexant, tramadol. Either increases effects of the other by sedation. Modify Therapy/Monitor Closely. Dosage adjustment may be necessary if lemborexant is coadministered with other CNS depressants because of potentially additive effects.

              acetaminophen will increase the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Lower nightly dose of lemborexant recommended if coadministered with weak CYP3A4 inhibitors. See drug monograph for specific dosage modification.

            • levalbuterol

              tramadol increases and levalbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • levonorgestrel oral/ethinylestradiol/ferrous bisglycinate

              levonorgestrel oral/ethinylestradiol/ferrous bisglycinate will decrease the level or effect of acetaminophen by unknown mechanism. Use Caution/Monitor.

              acetaminophen increases levels of levonorgestrel oral/ethinylestradiol/ferrous bisglycinate by decreasing hepatic clearance. Use Caution/Monitor. Coadministration of ascorbic acid and certain combined hormonal contraceptives (CHCs) containing EE may increase plasma EE concentrations, possibly by inhibition of conjugation.

            • levomilnacipran

              levomilnacipran and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • levorphanol

              levorphanol and tramadol both increase sedation. Use Caution/Monitor.

            • lisdexamfetamine

              tramadol increases and lisdexamfetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

              tramadol, lisdexamfetamine. Either increases effects of the other by serotonin levels. Use Caution/Monitor. Initiate with lower doses and monitor for signs and symptoms of serotonin syndrome, particularly during initiation or dosage increase. If serotonin syndrome occurs, discontinue along with concomitant serotonergic drug(s).

            • lithium

              lithium and tramadol both increase serotonin levels. Use Caution/Monitor.

            • lixisenatide

              lixisenatide will decrease the level or effect of acetaminophen by inhibition of GI absorption. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. GLP1 agonists delay gastric emptying, which may affect absorption of concomitantly administered oral medications. No effects on acetaminophen Cmax and Tmax were observed when acetaminophen was administered 1 hr before lixisenatide. When administered 1 or 4 hr after lixisenatide, acetaminophen Cmax was decreased by 29% and 31% respectively and median Tmax was delayed by 2 and 1.75 hr, respectively.

            • lofepramine

              tramadol and lofepramine both increase sedation. Use Caution/Monitor.

              lofepramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • lofexidine

              tramadol and lofexidine both increase sedation. Use Caution/Monitor.

            • lomitapide

              acetaminophen increases levels of lomitapide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lomitapide dose should not exceed 30 mg/day.

            • lopinavir

              lopinavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • loprazolam

              loprazolam and tramadol both increase sedation. Use Caution/Monitor.

            • lorazepam

              lorazepam and tramadol both increase sedation. Use Caution/Monitor.

            • lorcaserin

              lorcaserin will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

            • lorlatinib

              lorlatinib will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • lormetazepam

              lormetazepam and tramadol both increase sedation. Use Caution/Monitor.

            • loxapine

              tramadol and loxapine both increase sedation. Use Caution/Monitor.

            • loxapine inhaled

              tramadol and loxapine inhaled both increase sedation. Use Caution/Monitor.

            • lsd

              lsd and tramadol both increase serotonin levels. Use Caution/Monitor.

            • lumefantrine

              lumefantrine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

            • lurasidone

              lurasidone, tramadol. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.

            • maprotiline

              tramadol and maprotiline both increase sedation. Use Caution/Monitor.

              maprotiline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • marijuana

              tramadol and marijuana both increase sedation. Use Caution/Monitor.

            • melatonin

              tramadol and melatonin both increase sedation. Use Caution/Monitor.

            • meperidine

              meperidine and tramadol both increase sedation. Use Caution/Monitor.

              meperidine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • meprobamate

              tramadol and meprobamate both increase sedation. Use Caution/Monitor.

            • metaproterenol

              tramadol increases and metaproterenol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • metaxalone

              metaxalone and tramadol both increase sedation. Use Caution/Monitor.

            • methadone

              methadone and tramadol both increase sedation. Use Caution/Monitor.

            • methamphetamine

              tramadol increases and methamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • methocarbamol

              methocarbamol and tramadol both increase sedation. Use Caution/Monitor.

            • methylenedioxymethamphetamine

              tramadol increases and methylenedioxymethamphetamine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • midazolam

              midazolam and tramadol both increase sedation. Use Caution/Monitor.

            • midazolam intranasal

              acetaminophen will increase the level or effect of midazolam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of mild CYP3A4 inhibitors with midazolam intranasal may cause higher midazolam systemic exposure, which may prolong sedation.

              midazolam intranasal, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

            • midodrine

              tramadol increases and midodrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • mipomersen

              mipomersen, acetaminophen. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Both drugs have potential to increase hepatic enzymes; monitor LFTs.

            • mifepristone

              mifepristone will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • milnacipran

              milnacipran and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • mirabegron

              mirabegron will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor.

            • mirtazapine

              tramadol and mirtazapine both increase sedation. Use Caution/Monitor.

              mirtazapine and tramadol both increase serotonin levels. Use Caution/Monitor.

            • mitotane

              mitotane decreases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.

            • modafinil

              tramadol increases and modafinil decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • morphine

              morphine and tramadol both increase sedation. Use Caution/Monitor.

              morphine and tramadol both increase serotonin levels. Use Caution/Monitor.

            • motherwort

              tramadol and motherwort both increase sedation. Use Caution/Monitor.

            • moxonidine

              tramadol and moxonidine both increase sedation. Use Caution/Monitor.

            • nabilone

              tramadol and nabilone both increase sedation. Use Caution/Monitor.

            • nafcillin

              nafcillin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • nalbuphine

              nalbuphine and tramadol both increase sedation. Use Caution/Monitor.

            • naratriptan

              naratriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

            • nefazodone

              nefazodone and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

              nefazodone will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nelfinavir

              nelfinavir increases levels of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .

            • nevirapine

              nevirapine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • norepinephrine

              tramadol increases and norepinephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • nortriptyline

              tramadol and nortriptyline both increase sedation. Use Caution/Monitor.

              nortriptyline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • olanzapine

              tramadol and olanzapine both increase sedation. Use Caution/Monitor.

            • oliceridine

              oliceridine, tramadol. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

              tramadol, oliceridine. Either increases effects of the other by serotonin levels. Modify Therapy/Monitor Closely.

            • opium tincture

              opium tincture and tramadol both increase sedation. Use Caution/Monitor.

            • orphenadrine

              orphenadrine and tramadol both increase sedation. Use Caution/Monitor.

            • oxazepam

              oxazepam and tramadol both increase sedation. Use Caution/Monitor.

            • oxcarbazepine

              oxcarbazepine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • oxycodone

              oxycodone and tramadol both increase sedation. Use Caution/Monitor.

            • oxymorphone

              oxymorphone and tramadol both increase sedation. Use Caution/Monitor.

            • paliperidone

              tramadol and paliperidone both increase sedation. Use Caution/Monitor.

            • papaveretum

              papaveretum and tramadol both increase sedation. Use Caution/Monitor.

            • papaverine

              tramadol and papaverine both increase sedation. Use Caution/Monitor.

            • paroxetine

              paroxetine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              paroxetine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • peginterferon alfa 2b

              peginterferon alfa 2b, tramadol. Other (see comment). Use Caution/Monitor. Comment: When patients are administered peginterferon alpha-2b with CYP2D6 substrates, the therapeutic effect of these drugs may be altered. Peginterferon alpha-2b may increase or decrease levels of CYP2D6 substrate.

            • pegvisomant

              tramadol decreases effects of pegvisomant by unknown mechanism. Use Caution/Monitor.

            • pentazocine

              pentazocine and tramadol both increase sedation. Use Caution/Monitor.

              pentazocine and tramadol both increase serotonin levels. Use Caution/Monitor.

            • pentobarbital

              pentobarbital and tramadol both increase sedation. Use Caution/Monitor.

              pentobarbital will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • perampanel

              perampanel and tramadol both increase sedation. Use Caution/Monitor.

            • perphenazine

              tramadol and perphenazine both increase sedation. Use Caution/Monitor.

            • phendimetrazine

              tramadol increases and phendimetrazine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • phenobarbital

              phenobarbital and tramadol both increase sedation. Use Caution/Monitor.

              phenobarbital will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • phentermine

              tramadol increases and phentermine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • phenylephrine

              tramadol increases and phenylephrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • phenytoin

              phenytoin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • pholcodine

              tramadol and pholcodine both increase sedation. Use Caution/Monitor.

            • pimozide

              tramadol and pimozide both increase sedation. Use Caution/Monitor.

            • pirbuterol

              tramadol increases and pirbuterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • pregabalin

              pregabalin, tramadol. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.

            • primidone

              primidone and tramadol both increase sedation. Use Caution/Monitor.

              primidone will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • prochlorperazine

              tramadol and prochlorperazine both increase sedation. Use Caution/Monitor.

            • promethazine

              promethazine and tramadol both increase sedation. Use Caution/Monitor.

            • propafenone

              propafenone decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              propafenone decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

            • propofol

              propofol and tramadol both increase sedation. Use Caution/Monitor.

            • propylhexedrine

              tramadol increases and propylhexedrine decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • protriptyline

              tramadol and protriptyline both increase sedation. Use Caution/Monitor.

              protriptyline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • quazepam

              quazepam and tramadol both increase sedation. Use Caution/Monitor.

            • quetiapine

              tramadol and quetiapine both increase sedation. Use Caution/Monitor.

            • quinacrine

              quinacrine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              quinacrine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

            • quinidine

              quinidine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              quinidine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

            • ramelteon

              tramadol and ramelteon both increase sedation. Use Caution/Monitor.

            • remifentanil

              tramadol, remifentanil. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Increases risk of serotonin syndrome.

            • remimazolam

              remimazolam, tramadol. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.

            • rifabutin

              rifabutin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • rifampin

              rifampin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • rifapentine

              rifapentine will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • risperidone

              tramadol and risperidone both increase sedation. Use Caution/Monitor.

            • ritonavir

              ritonavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May require decreased tramadol dose or adjustment of dosing interval; increased risk for serious adverse events including seizures and serotonin syndrome

            • rizatriptan

              rizatriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

            • rolapitant

              rolapitant will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Rolapitant may increase plasma concentrations of CYP2D6 substrates for at least 28 days following rolapitant administration.

            • rucaparib

              rucaparib will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.

            • salmeterol

              tramadol increases and salmeterol decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • SAMe

              SAMe and tramadol both increase serotonin levels. Use Caution/Monitor.

            • saquinavir

              saquinavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • scullcap

              tramadol and scullcap both increase sedation. Use Caution/Monitor.

            • secobarbital

              secobarbital and tramadol both increase sedation. Use Caution/Monitor.

            • selegiline transdermal

              selegiline transdermal and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • sertraline

              sertraline decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              sertraline and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

              sertraline decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

            • sevoflurane

              sevoflurane and tramadol both increase sedation. Use Caution/Monitor.

            • shepherd's purse

              tramadol and shepherd's purse both increase sedation. Use Caution/Monitor.

            • St John's Wort

              St John's Wort and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • stiripentol

              stiripentol, tramadol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.

              stiripentol, tramadol. Either increases effects of the other by sedation. Use Caution/Monitor. Concomitant use stiripentol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence.

            • sufentanil

              sufentanil and tramadol both increase sedation. Use Caution/Monitor.

            • sumatriptan

              sumatriptan and tramadol both increase serotonin levels. Use Caution/Monitor.

            • sumatriptan intranasal

              sumatriptan intranasal and tramadol both increase serotonin levels. Use Caution/Monitor.

            • suvorexant

              suvorexant and tramadol both increase sedation. Modify Therapy/Monitor Closely. Dosage adjustments of suvorexant and concomitant CNS depressants may be necessary

            • tapentadol

              tapentadol and tramadol both increase sedation. Use Caution/Monitor.

              tramadol and tapentadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • tazemetostat

              tazemetostat will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              acetaminophen will increase the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tecovirimat

              tecovirimat will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

            • tetracaine

              tetracaine, acetaminophen. Other (see comment). Use Caution/Monitor. Comment: Monitor for signs of methemoglobinemia when methemoglobin-inducing drugs are coadministered.

            • temazepam

              temazepam and tramadol both increase sedation. Use Caution/Monitor.

            • terbinafine

              terbinafine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Assess need to reduce dose of CYP2D6-metabolized drug.

            • terbutaline

              tramadol increases and terbutaline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            • thioridazine

              thioridazine decreases effects of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

              tramadol and thioridazine both increase sedation. Use Caution/Monitor.

              thioridazine decreases effects of tramadol by decreasing metabolism. Use Caution/Monitor. Decreased conversion of tramadol to active metabolite.

            • thiothixene

              tramadol and thiothixene both increase sedation. Use Caution/Monitor.

            • tinidazole

              acetaminophen will increase the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tipranavir

              tipranavir will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • topiramate

              tramadol and topiramate both increase sedation. Modify Therapy/Monitor Closely.

            • trazodone

              tramadol and trazodone both increase sedation. Use Caution/Monitor.

              trazodone and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • triazolam

              triazolam and tramadol both increase sedation. Use Caution/Monitor.

            • triclofos

              triclofos and tramadol both increase sedation. Use Caution/Monitor.

            • trifluoperazine

              tramadol and trifluoperazine both increase sedation. Use Caution/Monitor.

            • trimipramine

              tramadol and trimipramine both increase sedation. Use Caution/Monitor.

              trimipramine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • triprolidine

              triprolidine and tramadol both increase sedation. Use Caution/Monitor.

            • venlafaxine

              venlafaxine and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.

            • voriconazole

              voriconazole will increase the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • warfarin

              acetaminophen increases effects of warfarin by unknown mechanism. Use Caution/Monitor.

            • xylometazoline

              tramadol increases and xylometazoline decreases sedation. Effect of interaction is not clear, use caution. Use Caution/Monitor.

            Minor (66)

            • acetazolamide

              acetazolamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • albiglutide

              albiglutide decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.

            • antithrombin alfa

              acetaminophen increases effects of antithrombin alfa by unknown mechanism. Minor/Significance Unknown.

            • antithrombin III

              acetaminophen increases effects of antithrombin III by unknown mechanism. Minor/Significance Unknown.

            • argatroban

              acetaminophen increases effects of argatroban by unknown mechanism. Minor/Significance Unknown.

            • asenapine

              asenapine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • bemiparin

              acetaminophen increases effects of bemiparin by unknown mechanism. Minor/Significance Unknown.

            • bivalirudin

              acetaminophen increases effects of bivalirudin by unknown mechanism. Minor/Significance Unknown.

            • brimonidine

              brimonidine increases effects of tramadol by pharmacodynamic synergism. Minor/Significance Unknown. Increased CNS depression.

            • carbamazepine

              carbamazepine decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • cholestyramine

              cholestyramine decreases levels of acetaminophen by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • clonazepam

              clonazepam decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • colestipol

              colestipol decreases levels of acetaminophen by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • dalteparin

              acetaminophen increases effects of dalteparin by unknown mechanism. Minor/Significance Unknown.

            • darifenacin

              darifenacin will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • dextroamphetamine

              dextroamphetamine increases effects of tramadol by unspecified interaction mechanism. Minor/Significance Unknown.

            • diazepam

              diazepam decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • disulfiram

              disulfiram will increase the level or effect of acetaminophen by affecting hepatic enzyme CYP2E1 metabolism. Minor/Significance Unknown.

            • dronedarone

              dronedarone will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • enoxaparin

              acetaminophen increases effects of enoxaparin by unknown mechanism. Minor/Significance Unknown.

            • ethanol

              ethanol will decrease the level or effect of acetaminophen by affecting hepatic enzyme CYP2E1 metabolism. Minor/Significance Unknown.

              ethanol increases toxicity of acetaminophen by decreasing metabolism. Minor/Significance Unknown.

            • ethosuximide

              ethosuximide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • eucalyptus

              tramadol and eucalyptus both increase sedation. Minor/Significance Unknown.

            • felbamate

              felbamate decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • fondaparinux

              acetaminophen increases effects of fondaparinux by unknown mechanism. Minor/Significance Unknown.

            • fosphenytoin

              fosphenytoin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • gabapentin

              gabapentin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • gabapentin enacarbil

              gabapentin enacarbil decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • green tea

              green tea increases effects of acetaminophen by pharmacodynamic synergism. Minor/Significance Unknown. (Theoretical, due to caffeine content).

            • heparin

              acetaminophen increases effects of heparin by unknown mechanism. Minor/Significance Unknown.

            • isoniazid

              isoniazid increases toxicity of acetaminophen by unknown mechanism. Minor/Significance Unknown.

            • lacosamide

              lacosamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • lamotrigine

              lamotrigine decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • levetiracetam

              levetiracetam decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • lidocaine

              lidocaine increases toxicity of tramadol by pharmacodynamic synergism. Minor/Significance Unknown. Risk of increased CNS depression.

            • liraglutide

              liraglutide decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.

            • lorazepam

              lorazepam decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • maraviroc

              maraviroc will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • marijuana

              marijuana will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • methsuximide

              methsuximide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • metoclopramide

              metoclopramide increases levels of acetaminophen by enhancing GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • metronidazole

              metronidazole will increase the level or effect of acetaminophen by affecting hepatic enzyme CYP2E1 metabolism. Minor/Significance Unknown.

            • nilotinib

              nilotinib will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • oxcarbazepine

              oxcarbazepine decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • oxybutynin

              oxybutynin decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.

            • oxybutynin topical

              oxybutynin topical decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.

            • oxybutynin transdermal

              oxybutynin transdermal decreases levels of acetaminophen by unspecified interaction mechanism. Minor/Significance Unknown.

            • parecoxib

              parecoxib will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • paroxetine

              paroxetine decreases effects of tramadol by decreasing metabolism. Minor/Significance Unknown. Decreased conversion of tramadol to active metabolite.

            • phenindione

              acetaminophen increases effects of phenindione by unknown mechanism. Minor/Significance Unknown.

            • phenobarbital

              phenobarbital decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • phenytoin

              phenytoin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • primidone

              primidone decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • protamine

              acetaminophen increases effects of protamine by unknown mechanism. Minor/Significance Unknown.

            • ranolazine

              ranolazine will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • rifabutin

              rifabutin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • rifampin

              rifampin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • rufinamide

              rufinamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • ruxolitinib

              acetaminophen will increase the level or effect of ruxolitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • sage

              tramadol and sage both increase sedation. Minor/Significance Unknown.

            • tiagabine

              tiagabine decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • tipranavir

              tipranavir will increase the level or effect of tramadol by affecting hepatic enzyme CYP2D6 metabolism. Minor/Significance Unknown.

            • topiramate

              topiramate decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • valproic acid

              valproic acid decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • ziconotide

              ziconotide, tramadol. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Additive decreased GI motility. Additive analgesia. Ziconotide does NOT potentiate opioid induced respiratory depression.

            • zonisamide

              zonisamide decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism increase levels of hepatotoxic metabolites.

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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

            Hyponatremia

            Hypoglycemia

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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

            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

            Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia; opioid use increases 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 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

            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 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; 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 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

            Cases of tramadol-associated hypoglycemia reported; some resulting in hospitalization; in most cases, patients had predisposing risk factors (eg, 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 first week of therapy; in some reports, hyponatremia resulted from syndrome of inappropriate antidiuretic hormone secretion (SIADH)
            • Monitor for signs and symptoms of hyponatremia (eg, confusion, disorientation), during treatment, especially during initiation of therapy; if signs and symptoms of hyponatremia are present, initiate appropriate treatment (eg, fluid restriction) and discontinue therapy

            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

            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)
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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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            Images

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            Patient Handout

            A Patient Handout is not currently available for this monograph.
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            Formulary

            FormularyPatient Discounts

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            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.