Tramadol - oral


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Moderate to severe pain 50-100 mg 4-6 hrly. Extended-release tab: 50-100 mg 1-2 times/day. Max: 400 mg/day. IV/IM Moderate to severe pain 50-100 mg 4-6 hrly. Post-op pain Initial: 100 mg, then 50 mg every 10-20 min if needed, up to 250 mg for the 1st hr. Maintenance: 50-100 mg 4-6 hrly. Max: 600 mg/day.
Dosage Details
Oral
Moderate to severe pain
Adult: 50-100 mg 4-6 hrly. Extended-release tab: 50-100 mg once or twice daily. Max: 400 mg/day.
Elderly: >75 yr Increase dosing interval.

Parenteral
Postoperative pain
Adult: Initially, 100 mg followed by 50 mg every 10-20 min if necessary, to a total of 250 mg in the 1st hr including initial dose. Thereafter, 50-100 mg 4-6 hrly up to a total daily dose of 600 mg.
Elderly: >75 yr Increase dosing interval.

Parenteral
Moderate to severe pain
Adult: IM/IV: 50-100 mg 4-6 hrly over 2-3 min.
Elderly: >75 yr Increase dosing interval.
Special Patient Group
Pharmacogenomics:

Variations in CYP2D6 polymorphism occur at different frequencies among subpopulations of different ethnic or racial origin. Some individuals may be ultra-rapid metabolisers. The prevalence of CYP2D6 ultra-rapid metabolisers varies widely and has been estimated to be 1-10% in Whites (European, North American), 3-4% in Black (African American), 1-2% in East Asians (Chinese, Japanese, Korean), and >10% in certain racial/ethnic groups (e.g. Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). Approximately 7-10% Caucasian population has a deficiency or is completely lacking of functional CYP2D6 activity.

Ultra-rapid metabolisers:
Carrier of more than two active copies of CYP2D6 (gene duplication noted as *1/*1xN or *1/*2xN). These individuals convert tramadol into its active metabolite, O-desmethyltramadol (M1), more rapidly and completely than other people. This rapid conversion results in higher than expected serum M1 levels. Reduce dose by 30% and be alert to adverse drug reactions (e.g. nausea, vomiting, constipation, respiratory depression, confusion, urinary retention). Analgesics which are not affected by CYP2D6 polymorphism (e.g. morphine, non-opioid analgesics) may be given as alternative.

Intermediate metabolisers:
Carrier of one or more reduced or inactive copies of CYP2D6. Monitor for decreased efficacy. Consider increasing the dose and if the response is still inadequate, either select alternative drug (not oxycodone or codeine) or be alert to symptoms of insufficient pain relief.

Poor metabolisers:
Carrier of two inactive copies of CYP2D6. Analgesics which are not affected by CYP2D6 polymorphism (e.g. morphine, non-opioid analgesics) may be given as alternative.
Renal Impairment
Oral:
CrCl Dosage
<10 Contraindicated.
10 to <30 Increase dosing interval to 12 hrly. Max: 200 mg/day; Contraindicated (extended-release tab).
Parenteral:
CrCl Dosage
<10 Contraindicated.
10-30 Increase dosing interval to 12 hrly.
Hepatic Impairment
Oral:
Severe: Increase dosing interval to 12 hrly; Contraindicated (extended-release).
Parenteral:
Severe: Increase dosing interval to 12 hrly.
Administration
May be taken with or without food.
Incompatibility
Diazepam, diclofenac Na, flunitrazepam, glyceryl trinitrate, indometacin, midazolam, piroxicam, phenylbutazone, aciclovir, clindamycin.
Contraindications
Suicidal patients; acute intoxication w/ hypnotics, centrally acting analgesics, opioids, psychotropic drugs or alcohol; uncontrolled epilepsy, acute or severe bronchial asthma, hypercapnia or significant resp depression in unmonitored settings or absence of resuscitative equipment. Not intended for narcotic withdrawal treatment. Severe renal and hepatic impairment. CYP2D6 ultra-rapid metabolisers. Concomitant use w/ MAOIs or w/in 2 wk after withdrawal of MAOIs.
Special Precautions
Patients who suffer from emotional disturbance or depression, history of epilepsy or risk of seizure, head injury, increased intracranial pressure. CYP2D6 intermediate and poor metabolisers. Renal and hepatic impairment. Elderly. Pregnancy and lactation.
Adverse Reactions
Resp depression, seizure, dizziness, headache, somnolence, weakness, CNS stimulation (e.g. anxiety, euphoria, hallucinations), asthenia, sweating, confusion, coordination disturbance, paraesthesia, hypoaesthesia, amnesia, cognitive dysfunction, depression, dysphoria, constipation, nausea, vomiting, dyspepsia, diarrhoea, abdominal pain, anorexia, flatulence, wt loss, gastroenteritis, pruritus, rash, dermatitis, urticaria, bronchospasm, angioedema, anaphylaxis, allergic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasodilation, orthostatic hypotension, syncope, tachycardia, flushing, chest pain, palpitations, MI, HTN, peripheral ischaemia, menopausal symptoms, dysuria, menstrual disorder, micturition difficulty, haematuria.
Patient Counseling Information
May impair ability to drive or operate machinery.
MonitoringParameters
Monitor pain relief, resp rate, BP, pulse rate; signs of tolerance, abuse, or suicidal ideation.
Overdosage
Symptoms: Miosis, vomiting, cold and clammy skin, resp depression, lethargy, flaccid skeletal muscle, coma, seizures, bradycardia, hypotension, cardiac arrest, cardiac collapse. Management: Supportive treatment w/ maintenance of adequate ventilation. Although naloxone will reverse some symptoms of overdosage, there is an increased risk of seizures.
Drug Interactions
Increased risk of convulsions or serotonin syndrome w/ SSRI, serotonin-norepinephrine reuptake inhibitors (SNRI), TCA and other seizure threshold lowering drugs (e.g. bupropion, mirtazapine, tetrahydrocannabinol). Decreased serum concentrations w/ carbamazepine. May potentiate the anti-depressant effect of norepinephrine, 5-HT agonists or lithium. Increased INR and ecchymoses w/ coumarin derivatives (e.g. warfarin).
Potentially Fatal: Increased risk of seizures w/ MAOIs.
Food Interaction
Enhanced CNS depressant effect w/ alcohol.
Action
Description: Tramadol inhibits reuptake of norepinephrine, serotonin and enhances serotonin release. It alters perception and response to pain by binding to mu-opiate receptors in the CNS.
Onset: Approx 1 hr.
Duration: 9 hr.
Pharmacokinetics:
Absorption: Readily absorbed from the GI tract. Bioavailability: Approx 70-75% (oral); 100% (IM).
Distribution: Widely distributed. Crosses the placenta and enters breast milk.
Metabolism: Extensive hepatic first-pass metabolism. Converted to O-desmethyltramadol (active) via N- and O-demethylation by CYP3A4 and CYP2D6 isoenzymes and also via glucuronidation or sulfation.
Excretion: Via urine (as metabolites). Elimination half-life: Approx 6 hr.
Storage
Store between 20-25°C. Protect from light.
MIMS Class
ATC Classification
N02AX02 - tramadol ; Belongs to the class of other opioids. Used to relieve pain.
References
Annotation of FDA Label for Tramadol and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 24/09/2018.

Anon. CYP2D6 – Tramadol (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 12/10/2018.

Anon. Tramadol. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 30/07/2014.

Anon. Tramadol. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 30/07/2014.

Buckingham R (ed). Tramadol Hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/07/2014.

Clinical Annotation for CYP2D6*1, CYP2D6*10, CYP2D6*1xN, CYP2D6*2, CYP2D6*2xN, CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6 Related to Tramadol - Dosage/Efficacy/Toxicity/PK (1B). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 24/09/2018.

Tramadol Hydrochloride Extended-Release Tablet, Film Coated (Par Pharmaceuticals Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 30/07/2014.

Tramadol Hydrochloride Tablet, Extended Release (Aurobindo Pharma Limited). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 12/10/2018.

Wickersham RM. Tramadol Hydrochloride. Facts and Comparisons [online]. St. Louis, MO. Wolters Kluwer Clinical Drug Information, Inc. https://www.wolterskluwercdi.com/facts-comparisons-online/. Accessed 30/07/2014.

Disclaimer: This information is independently developed by MIMS based on Tramadol from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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