tramadol (Rx)

Brand and Other Names:Ultram, ConZip, more...Qdolo
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet, immediate-release: Schedule IV

  • 50mg (Ultram, generic)

capsule, extended release: Schedule IV

  • 100mg (ConZip)
  • 150mg (ConZip)
  • 200mg (ConZip)
  • 300mg (ConZip)

solution, oral: Schedule IV

  • 5mg/mL (Qdolo)
  • Equivalent to tramadol 4.4 mg/mL

Pain

Indicated for moderate-to-severe pain management in adults which alternative therapies are inadequate

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

Immediate release

  • Chronic: 25 mg PO every morning initially; increased by 25-50 mg/day every 3 days up to 50-100 mg PO q4-6hr PRN; not to exceed 400 mg/day
  • Acute: 50-100 mg PO q4-6hr PRN; not to exceed 400 mg/day

Extended release

  • 100 mg PO once daily initially; increased by 100 mg/day every 5 days; not to exceed 300 mg/day
  • Conversion from immediate release to extended release
    • Round total daily dose down to nearest 100 mg; titrate subsequent dose base on individual need

Oral solution

  • 25 mg/day PO initially; may titrate in 25-mg increments as separate doses every 3 days to 100 mg/day (25 mg QID), THEN
  • May increase total daily dose by 50-mg increments as tolerated every 3 days to 200 mg/day (50 mg QID)
  • After titration, 50-100 mg q4-6 hr PRN for pain relief, not to exceed 400 mg/day
  • For rapid onset of analgesic effect and benefits outweigh risks of discontinuation due to adverse events associated with high initial doses: 50-100 mg q4-6 hr PRN for pain relief, not to exceed 400 mg/day

Dosage Modifications

Renal impairment

  • CrCl ≥30 mL/minute: No dosage adjustments necessary; use with caution
  • Severe (CrCl <30 mL/min)
    • Oral solution: Increase dosing interval to q12hr, not to exceed 200 mg/day
    • Immediate release: 50-100 mg PO q12hr
    • Extended release: Not recommended
  • Patients on dialysis
    • May receive regular dose on dialysis days; only 7% of dose is removed by hemodialysis

Hepatic impairment

  • Mild-to-moderate: No dosage adjustments necessary; use with caution
  • Severe
    • Oral solution and immediate release: 50 mg PO q12hr
    • Extended release: Not recommended

Dosing Considerations

Closely monitor for respiratory depression, especially within the first 24–72 hr of initiating therapy and following dosage increases and adjust dosage accordingly

Do not use concomitantly with other tramadol-containing products

Access to naloxone

  • Discuss availability of naloxone and assess need for naloxone, both when initiating and renewing treatment
  • Consider prescribing naloxone based on the risk factors for overdose

Discontinuation

  • Do not abruptly discontinue in patients who may be physically dependent on opioids
  • Rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide
  • For physically opioid-dependent: Initiate small increment taper (eg, ≥10-25% of total daily dose) to avoid withdrawal symptoms, and proceed with decreasing the dose every 2-4 weeks
  • Patients who have been taking opioids for shorter periods of time may tolerate a more rapid taper

Limitations of use

  • Owing to risks of addiction, abuse, and misuse with opioids, reserve use in patients for whom alternative treatment options [eg, non-opioid analgesics]
    • Are not or not expected to be tolerated
    • Have not or are not expected to provide adequate analgesia

HIV-Associated Neuropathy (Orphan)

Orphan indication sponsor

  • TheraQuest Biosciences, LLC, 146 Medinah Drive, Blue Bell, PA 19422-3212

Postherpetic Neuralgia (Orphan)

Orphan indication sponsor

  • TheraQuest Biosciences, LLC, 146 Medinah Drive, Blue Bell, PA 19422-3212

Safety and efficacy not established

Life-threatening respiratory depression and death have occurred in children who received tramadol

Tramadol is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to increased exposure to an active metabolite

Pain

>65 years: Initiate at lower end of dosing range; not to exceed 300 mg/day if >75 years

>75 years

  • Immediate release or oral solution: Not to exceed 300 mg/day
  • Extended release: Use with caution

Dosage Modifications

Renal impairment

  • CrCl ≥30 mL/minute: No dosage adjustments necessary; use with caution
  • Severe (CrCl <30 mL/min)
    • Oral solution: Increase dosing interval to q12hr, not to exceed 200 mg/day
    • Immediate release: 50-100 mg PO q12hr
    • Extended release: Not recommended
  • Patients on dialysis
    • May receive regular dose on dialysis days; only 7% of dose is removed by hemodialysis

Hepatic impairment

  • Mild-to-moderate: No dosage adjustments necessary; use with caution
  • Severe
    • Oral solution and immediate release: 50 mg PO q12hr
    • Extended release: Not recommended
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Interactions

Interaction Checker

and tramadol

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Immediate release

            • Constipation (24-46%)
            • Nausea (24-40%)
            • Dizziness/vertigo (26-33%)
            • Headache (18-32%)
            • Somnolence (16-25%)
            • Vomiting (9-17%)
            • CNS stimulation (7-14%)
            • Dyspepsia (5-13%)
            • Asthenia (6-12%)
            • Pruritus (8-11%)

            Extended release

            • Nausea (5.7-25.1%)
            • Headache (19-23.1%)
            • Constipation (4.2-21.3%)
            • Somnolence (4-16.1%)
            • Dizziness (4.8-13.6%)
            • Dry mouth (3.4-13.1%)
            • Vomiting (1.9-10.4%)

            1-10%

            Immediate release

            • Dry mouth (5-10%)
            • Diarrhea (5-10%)
            • Sweating (6-9%)
            • 1 to <5%
              • Malaise
              • Vasodilation
              • Anxiety
              • Confusion
              • Coordination disturbance
              • Euphoria
              • Miosis
              • Nervousness
              • Sleep disorder
              • Abdominal pain
              • Anorexia
              • Flatulence
              • Hypertonia
              • Rash
              • Visual disturbance
              • Menopausal symptoms
              • Urinary frequency
              • Urinary retention

            Extended release

            • Asthenia (2.6-8.6%)
            • Pruritus (1.9-7.3%)
            • Anorexia (0.2-5.7%)
            • Arthralgia 23 (5-5.4%)
            • Sweating (0.6-5.3%)
            • Insomnia (1.7-5%)
            • 1 to <5%
              • Cardiac disorders: Hypertension
              • Gastrointestinal disorders: Dyspepsia, flatulence
              • General disorders: Abdominal pain, accidental injury, chills, fever, flu syndrome, neck pain, pelvic pain
              • Investigations: Hyperglycemia, urine abnormality
              • Metabolism and nutrition disorders: Peripheral edema, weight loss
              • Musculoskeletal, connective tissue and bone disorders: Myalgia
              • Nervous system disorders: Paresthesia, tremor, withdrawal syndrome
              • Psychiatric disorders: Agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness
              • Respiratory, thoracic and mediastinal disorders: Bronchitis, pharyngitis, rhinitis, sinusitis
              • Skin and subcutaneous tissue disorders: Rash
              • Urogenital disorders: Prostatic disorder, urinary tract infection
              • Vascular disorders: Vasodilatation

            <1%

            Immediate release

            • Body as a whole: Accidental injury, allergic reaction, anaphylaxis, death, suicidal tendency, weight loss, Serotonin syndrome
            • Cardiovascular: Orthostatic hypotension, syncope, tachycardia
            • Central Nervous System: Abnormal gait, amnesia, cognitive dysfunction, depression, difficulty in concentration, hallucinations, paresthesia, seizure, tremor
            • Respiratory: Dyspnea
            • Skin: Stevens Johnson syndrome, toxic epidermal necrolysis, urticaria, vesicles
            • Special Senses: Dysgeusia
            • Urogenital: Dysuria, menstrual disorder

            Extended release

            • Cardiac disorders: EKG abnormal, hypotension, tachycardia
            • Gastrointestinal disorders: Gastroenteritis
            • General disorders: Neck rigidity, viral infection
            • Hematologic/Lymphatic disorders: Anemia, ecchymoses
            • Metabolism and nutrition disorders: Blood urea nitrogen increased, GGT increased, gout, SGPT increased
            • Musculoskeletal disorders: Arthritis, arthrosis, joint disorder, leg cramps
            • Nervous system disorders: Emotional lability, hyperkinesia, hypertonia, thinking abnormal, twitching, vertigo
            • Respiratory disorders: Pneumonia
            • Skin and SC tissue disorders: Hair disorder, skin disorder, urticaria
            • Special Senses: Eye disorder, lacrimation disorder
            • Urogenital disorders: Cystitis, dysuria, sexual function abnormality, urinary retention
            • Frequency Not Defined H3
            • Cardiovascular: Abnormal ECG, hypertension, hypotension, myocardial ischemia, palpitations, pulmonary edema, pulmonary embolism
            • Central nervous system: Migraine
            • Gastrointestinal: Gastrointestinal bleeding, hepatitis, stomatitis, liver failure
            • Laboratory abnormalities: Creatinine increase, elevated liver enzymes, hemoglobin decrease, proteinuria
            • Sensory: Cataracts, deafness, tinnitus

            Postmarketing Reports

            Serotonin syndrome

            Adrenal insufficiency

            Androgen deficiency

            QT prolongation/torsade de pointes

            Mydriasis

            Hypoglycemia

            Nervous system disorders: Movement disorder, speech disorder

            Psychiatric disorders: Delirium

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            Warnings

            Black Box Warnings

            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

            Addiction, abuse, and misuse

            • 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

            Life-threatening respiratory depression

            • Serious, life-threatening, or fatal respiratory depression may occur
            • Monitor for respiratory depression, especially during initiation or following a dose increase

            Accidental ingestion

            • Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose

            Neonatal opioid withdrawal syndrome

            • 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

            Ultra-rapid metabolism and other risk factors for life-threatening respiratory depression in children

            • Life-threatening respiratory depression reported in children who received tramadol; some reported cases occurred following tonsillectomy and/or adenoidectomy, and at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism; therapy is contraindicated in children <12 years and in children <18 years of age following tonsillectomy and/or adenoidectomy; avoid use in adolescents 12-18 years who have other risk factors that may increase sensitivity to respiratory depressant effects

            Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

            • 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 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

            Contraindications

            Hypersensitivity to tramadol or opioids

            Known or suspected gastrointestinal obstruction, including paralytic ileus

            Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within last 14 days

            Children <12 years

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

            Severe/acute bronchial asthma in an unmonitored setting or in absence of resuscitative equipment

            Significant respiratory depression

            Cautions

            Contains a Schedule IV controlled substance; exposes users to risks of addiction, abuse, and misuse

            Serotonin syndrome may occur; may be life-threatening; may occur with use of tramadol alone, with concomitant use of serotonergic drugs, with drugs that impair metabolism of serotonin or tramadol

            Serious, life-threatening, or fatal respiratory depression has been reported; also occurred in children treated with tramadol

            Opioids can cause sleep-related breathing disorders including central sleep apnea and sleep-related hypoxemia

            Prolonged use during pregnancy can result in withdrawal in the neonate

            Seizures have been reported; spontaneous postmarketing reports indicate that seizure risk is increased with doses

            May increase the risk of suicide

            Cases of adrenal insufficiency have been reported with opioid use, more often following >1 month of use; if adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids

            May cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; monitor for signs of hypotension after initiating or titrating

            May impair mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery; advise not to drive or operate dangerous machinery unless tolerant to effects and aware of reaction to medication

            Spasm of the sphincter of Oddi reported; opioids may cause increases in serum amylase; monitor with biliary tract disease, including acute pancreatitis for worsening symptoms

            Serious and rarely fatal anaphylactic reactions have been reported

            Drug interaction overview

            • Substrate of CYP2B6, CYP2D6, CYP3A4
            • CYP2D6 Inhibitors
              • Coadministration with CYP2D6 inhibitors (eg, amiodarone, quinidine) may result in increased tramadol plasma levels and decreased levels of the active metabolite, M1
              • May result in signs and symptoms of opioid withdrawal and reduced efficacy; increased tramadol levels and toxicities including seizures and serotonin syndrome
            • CYP3A4 inhibitors or inducers
              • Coadministration with CYP3A4 inhibitors or discontinuation CYP3A4 inducers may result in an increase in tramadol plasma concentrations and toxicities
              • Coadministration of CYP3A4 inducers or discontinuation of aCYP3A4 inhibitors may result in lower tramadol levels
            • CNS depressants
              • Coadministration of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death
            • Serotonergic drugs
              • Coadministration with serotonergic drugs may increase the risk for serotonin syndrome
              • Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (eg, mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO-I)
            • Mixed agonist/antagonist and partial agonist opioid analgesics
              • Avoid coadministration
              • May reduce analgesic effect of tramadol or precipitate withdrawal symptoms
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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; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

            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

            Lactation

            Tramadol and its active metabolite, O-desmethyltramadol (M1), are present in human milk

            Published studies and cases reported excessive sedation, respiratory depression, and death in infants exposed to codeine 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

            Owing to the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, breastfeeding is not recommended during treatment

            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

            Non-opioid-derived synthetic opioid; centrally acting analgesic, but may act at least partially by binding to opioid mu receptors, causing inhibition of ascending pain pathways

            Absorption

            Mean absolute bioavailability: ~75% (100-mg dose)

            Steady-state of both tramadol and M1 are reached

            • Immediate release: 2 days (QID dosing)

            Peak plasma concentration

            • Oral solution: 180.20 ng/mL (tramadol); 47.77 ng/mL (M1 metabolite)
            • Immediate release: 173.51 ng/mL; 46.14 ng/mL (M1 metabolite)
            • Extended release: 308 ng/mL (single 300-mg dose)

            Peak plasma time

            • Oral solution: 1.5 hr (tramadol); 2 hr (M1 metabolite)
            • Immediate release: 1.5 hr (tramadol); 2.25 hr (M1 metabolite)
            • Extended release: 10-12 hr (single-dose)

            AUC

            • Oral solution: 1623.93 ng·hr/mL (tramadol); 624.12 ng·hr/mL (M1 metabolite)
            • Immediate release: 1681.64 ng·hr/mL ; 624.1 ng·hr/mL (M1 metabolite)
            • Extended release: 6777 ng·hr/mL(single 300-mg dose)

            Distribution

            Protein bound: ~20% (IV)

            Vd

            • IV: 2.6L/kg (males); 2.9 L/kg (females)

            Metabolism

            Extensively metabolized via CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites

            Elimination

            Tramadol metabolites are eliminated primarily by kidneys

            Excretion: ~30% (urine as unchanged drug); 60% as metabolites; remainder is excreted either as unidentified or as unextractable metabolites

            Half-life

            • Oral solution: 7.65 hr (tramadol); 7.94 hr (M1 metabolite)
            • Immediate release: 7.61 hr (tramadol); 8.06 hr (M1 metabolite)
            • Extended release: ~10 hr (tramadol); 11 hr (M1 metabolite)

            Pharmacogenomics

            Poor CYP2D6 metabolizers

            • Formation of the active metabolite, M1, is mediated by CYP2D6, a polymorphic enzyme
            • Based on a population PK analysis of Phase 1 studies with IR tablets in healthy subjects, tramadol concentrations were ~20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 40% lower
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            Administration

            Conversion from other opioids to extended release

            Discontinue all other around-the-clock opioid drugs when initiating extended-release therapy

            Initiate 100 mg PO qDay

            No established conversion ratios for conversion from other opioids have been defined by clinical trials. Initiate

            Conversion from oral solution to extended release

            Bioavailability of oral solution compared to extended release tramadol is unknown

            Closely monitor for signs of excessive sedation and respiratory depression when converting formulations

            Oral Administration

            Immediate release: Administer without regard to meals

            Oral solution: Strongly advise to always use calibrated oral syringes or other oral dosing device, with metric units of measurements (ie, mL), to correctly measure prescribed dose

            Extended release

            • Swallow whole; do not crush, chew, dissolve, or split
            • Administer without regard to meals

            Storage

            Store securely and dispose of properly

            All formulations: Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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            Images

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            Formulary

            FormularyPatient Discounts

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

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            • Compare formulary status to other drugs in the same class.
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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.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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