NSW HEALTH PATHOLOGY 2018 - AUGUST UPDATE
Therapeutic Ranges, Alert Thresholds and Interpretive Text for use in NSW Health Pathology Laboratories Prepared July 2017; Into production August 2018
REPORTING ALERT THRESHOLD/ TEST THERAPEUTIC RANGE INTERPRETIVE TEXT REFERENCE SOURCE UNIT TOXICITY
Levels do not correlate to clinical effect. TDM not recommended for dose C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Alprazolam ug/L 5-50 ≥100 titration. Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 TDM not required for therapy not exceeding 48hrs. For once-daily or less frequent dosing, achieving an adequate area under Amikacin peak/random mg/L the concentration–time curve (AUC) of aminoglycoside, while having an Therapeutic Guidelines Ltd (eTG March 2017 edition) undetectable trough (predose) plasma concentration, is associated with clinical efficacy and minimises toxicity. TDM not required for therapy not exceeding 48hrs. For once-daily or less frequent dosing, achieving an adequate area under the concentration–time curve (AUC) of aminoglycoside, while having an http://www.schn.health.nsw.gov.au/_policies/pdf/2011-8018.pdf Amikacin trough mg/L <5 >10 undetectable trough (predose) plasma concentration, is associated with Therapeutic Guidelines Ltd (eTG March 2017 edition) clinical efficacy and minimises toxicity. Once daily dosing: Trough level (pre-dose) : Less than 5mg/L Twice daily dosing: Trough level (pre-dose): Less than 10mg/L
Amitriptyline is metabolised to nortriptyline. The parent drug and the metabolite are pharmacologically active. TDM should include assay of both amitriptyline and nortriptyline. The therapeutic interval is 80 to 200ug/L C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Amitriptyline plus Nortriptyline ug/L 80-200 ≥300 when the concentrations of both compounds are summed. Toxicity may Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 been seen with concentrations of nortriptyline greater than 300ug/L. NORTRIPTYLINE: Therapeutic interval is 70 to 170ug/L.
Amphetamine may be present in blood due to illicit use. Amphetamine may be used legitimately to treat attention deficit hyperactivity disorder (ADHD). Illicit use of methamphetamine will result in amphetamine being detected in plasma. In a study of drivers suspected by police of being drug Amphetamine ug/L ≥200 affected, amphetamine was detected in 128 of 153 suspects. The median Clarke's analytical forensic toxicology, 2nd edition, p235, 2013 concentration of amphetamine was 455ug/L. The range of concentrations was 45 to 2,750ug/L. If illicit use of amphetamine or methamphetamine is suspected an immunoassay drug screen for drugs of abuse is advised.
Therapeutic interval is 8-20mg/L when used to treat apnoea in premature Caffeine mg/L 8-20 >20 http://ltd.aruplab.com/Tests/Pub/2011603 neonates.
Carbamazepine mg/L 6-12 >12 Greater than 7mg/L recommended for bipolar disorder. Carbamazepine The Maudsley Prescribing Guidelines in Psychiatry, p3, 12th Edition, 2015 induces own metabolism, time to steady state is approximately 2 weeks.
Carbamazepine, Free mg/L 1.0-3.0 ≥4.0 Mayo Medical Laboratories Handbook 2015
50-300 ≥750 Chlorpromazine ug/L http://ltd.aruplab.com/Tests/Pub/0090870 (adult) (adult)
Page 1 of 7 NSW HEALTH PATHOLOGY 2018 - AUGUST UPDATE
Therapeutic Ranges, Alert Thresholds and Interpretive Text for use in NSW Health Pathology Laboratories Prepared July 2017; Into production August 2018
REPORTING ALERT THRESHOLD/ TEST THERAPEUTIC RANGE INTERPRETIVE TEXT REFERENCE SOURCE UNIT TOXICITY
Clomipramine is metabolised to norclomipramine. The parent drug and the metabolite are pharmacologically active. TDM should include assay of both Clomipramine plus Norclomipramine ug/L 220-500 ≥900 and clomipramine and norclomipramine. The therapeutic interval is 220 to http://ltd.aruplab.com/Tests/Pub/0099336 500ug/L when the concentration of both compounds is summed. Toxicity may be seen at total concentrations greater than 900ug/L.
Levels do not correlate to clinical effect. TDM not recommended for dose http://ltd.aruplab.com/Tests/Pub/0090055 Clonazepam ug/L 20-70 ≥80 titration. C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 Clozapine is metabolised to norclozapine. The antipsychotic activity of the C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in metabolite is uncertain. The therapeutic interval for the parent drug is 350 Clozapine (and Norclozapine) ug/L 350-600 ≥1,000 Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011. to 600ug/L. Toxicity may be seen at concentrations greater than 1000ug/L. Bleakley S, Taylor D. Clozapine Handbook, p.111, 2013 Upper limit of target range is ill-defined.
There is no well-defined therapeutic interval. Volunteers given a 22mg oral dose of codeine had a mean plasma concentration of 70ug/L two hours Clarke’s Analysis of Drugs and Poisons, p1157, 4th Edition, 2011 after taking the drug (n=8). The mean concentration of codeine in post Codeine ug/L ≥1,000 Clarke’s Analytical Forensic Toxicology, p236, 2nd edition, 2013 mortem blood of overdose victims was 1,200ug/L (n=38). No clear relationship between drug dose and levels due to genetic variability. As codeine is a prodrug of morphine, morphine levels may be more useful. Limit of Detection is 8 ug/L. Typical serum/plasma cotinine level in non-tobacco users, non-tobacco users with passive exposure and tobacco users after two weeks of https://www.mayomedicallaboratories.com/test- Cotinine ug/L complete abstinence: < 8 ug/L. catalog/Clinical+and+Interpretive/82509 Typical peak serum/plasma cotinine level in tobacco users and during use of high dose nicotine replacement: 200 – 800 ug/L. Limit of Detection is 8 ug/L. Typical urine cotinine concentrations are as follows: Non-tobacco users: < 8 ug/L https://www.mayomedicallaboratories.com/test- Cotinine, Urine ug/L Non-tobacco users with passive exposure: < 20 ug/L catalog/Clinical+and+Interpretive/82510 Tobacco users after two weeks of complete abstinence: < 50 ug/L Tobacco users: peak cotinine concentration 1000 – 8000 ug/L
Cyclosporin ug/L Refer to local protocol Diazepam is metabolised to nordiazepam which is pharmacologically active. The therapeutic interval for the summed concentration of diazepam http://www.mayomedicallaboratories.com/testcatalog/Clinical+and+Interpretive Diazepam plus Nordiazepam ug/L 200-2,500 ≥3,000 and nordiazepam is 200 to 2,500ug/L. Toxicity may be seen at total /8629 concentration of > 3,000ug/L.
Digoxin ug/L 0.5-1.0 ≥2.0 CCF 0.5 -1.0ug/L; AF 0.5 - 1.8ug/L RCPA Manual of Use and Interpretation of Pathology Tests Feb 2015
C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Dothiepin ug/L 45-100 ≥200 Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011
Page 2 of 7 NSW HEALTH PATHOLOGY 2018 - AUGUST UPDATE
Therapeutic Ranges, Alert Thresholds and Interpretive Text for use in NSW Health Pathology Laboratories Prepared July 2017; Into production August 2018
REPORTING ALERT THRESHOLD/ TEST THERAPEUTIC RANGE INTERPRETIVE TEXT REFERENCE SOURCE UNIT TOXICITY
Doxepin is metabolised to nordoxepin. Nordoxepin is pharmacologically active. Therapeutic interval for Doxepin plus Nordoxepin is 50 to 150ug/L. C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Doxepin plus Nordoxepin ug/L 50-150 ≥300 Toxicity may be seen for concentrations of Doxepin plus Nordoxepin that Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 are greater than 300ug/L.
Everolimus ug/L Refer to local protocol
Fluoxetine is metabolised to norfluoxetine. Norfluoxetine is pharmacologically active. Therapeutic interval for Fluoxetine plus C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Fluoxetine plus Norfluoxetine ug/L 120-500 ≥1,000 Norfluoxetine is 120 to 500ug/L. Toxicity may be seen for concentrations Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 of Fluoxetine plus Norfluoxetine that are greater than 1,000ug/L. Therapeutic range is 2 to 20mg/L. Toxicity may be seen for concentrations http://www.mayomedicallaboratories.com/test- Gabapentin mg/L 2 - 20 ≥25 of gabapentin exceeding 25mg/L. Correlation between concentration and catalog/Clinical+and+Interpretive/80826 clinical effect not well established. TDM not required for therapy not exceeding 48hrs. For once-daily or less frequent dosing, achieving an adequate area under Gentamicin peak/random mg/L the concentration–time curve (AUC) of aminoglycoside, while having an Therapeutic Guidelines Ltd (eTG March 2017 edition) undetectable trough (predose) plasma concentration, is associated with clinical efficacy and minimises toxicity. TDM not required for therapy not exceeding 48hrs. For once-daily or less frequent dosing, achieving an adequate area under the concentration–time curve (AUC) of aminoglycoside, while having an http://www.schn.health.nsw.gov.au/_policies/pdf/2011-8018.pdf Gentamicin trough mg/L <1.0 ≥2.0 undetectable trough (predose) plasma concentration, is associated with Therapeutic Guidelines Ltd (eTG March 2017 edition) clinical efficacy and minimises toxicity. Once daily dosing: Trough level (pre-dose) : Less than 1mg/L Multiple daily dosing: Trough level (pre-dose): Less than 2mg/L
Imipramine is metabolised to desipramine. Desipramine is pharmacologically active. Therapeutic interval for Imipramine plus C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Imipramine plus Desipramine ug/L 175-300 >300 Desipramine is 175 to 300ug/L. Toxicity may be seen for concentrations of Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 Imipramine plus Desipramine that are greater than 300ug/L.
Toxicity may be increased >15mg/L but is normally well tolerated. Dose http://ltd.aruplab.com/Tests/Pub/0090177 Lamotrigine mg/L 2.5-15.0 >15.0 based on clinical response rather than concentration. The Maudsley Prescribing Guidelines in Psychiatry, p3, 12th Edition, 2015 A 12 hour post dose concentration of 0.4-0.6mmol/L is recommended in: patients with diabetes insipidus, renal impairment or thyroid dysfunction; patients administered diuretics, ACE inhibitors or NSAIDS/COX-2 inhibitors; 0.5-1.0 (< 60 yrs) ≥1.2 (<60 yrs) the management of acute unipolar depression; and prophylaxis of bipolar International Society for Bipolar Disorders Older Adult with Bipolar Disorder Lithium mmol/L 0.4-0.8 (60 - 79 yrs) ≥1.0 (≥60 yrs) Taskforce recommendations 2017 (unpublished at present) 0.4-0.7 (> 80 yrs) II disorder. A 12 hour post dose concentration of 0.7-1.0mmol/L is recommended in: the management of acute mania; and prophylaxis of bipolar I disorder.
Page 3 of 7 NSW HEALTH PATHOLOGY 2018 - AUGUST UPDATE
Therapeutic Ranges, Alert Thresholds and Interpretive Text for use in NSW Health Pathology Laboratories Prepared July 2017; Into production August 2018
REPORTING ALERT THRESHOLD/ TEST THERAPEUTIC RANGE INTERPRETIVE TEXT REFERENCE SOURCE UNIT TOXICITY
This assay is used in the context of isolated limb perfusion with melphalan to treat melanoma. Drug concentrations may be measured in the perfusate H. Kroon, Journal of Skin Cancer, 211, 1, 2011. H. Kroon et al, Journal of Surgical Melphalan ug/L to assess exposure of the limb to the cytotoxic agent. The drug Oncology, 109, 352, 2014 concentration in the systemic circulation may also be measured to assess leakage of drug from the isolated limb into the systemic circulation. Therapeutic interval is 400 to 600ug/L when methadone is used in opiate C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Methadone ug/L 400-600 >600 substitution programs. Toxic concentrations are higher for opiate addicted Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 subjects because of drug tolerance. Methamphetamine is the most commonly abused drug of the amphetamine class. A 30mg IV dose of methamphetamine resulted in a mean peak plasma concentration of 110ug/L. Smoking a 30mg quantity of the free base gives a mean peak plasma concentration of 50ug/L. Plasma Methamphetamine ug/L ≥100 C.C. Cruikshank & K.R. Dyer, Addiction, 104, 1085-1099, 2009 concentration of more than 100ug/L are associated with symptoms of toxicity (tachycardia, motor restlessness, agitation, hypertension and sweating). Plasma concentrations of more than 300ug/L are associated with violent behaviour. Low dose: 0.50 - 1.00umol/L High dose after 24 hours: 5.00umol/L or less Methotrexate umol/L http://ltd.aruplab.com/Tests/Pub/2005405 After 48 hours: 0.50umol/L or less After 72 hours: 0.10umol/L or less Therapeutic interval is 15 to 70ug/L. Toxicity may be seen for C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Mianserin ug/L 15-70 ≥140 concentrations of mianserin that are greater than 140ug/L. Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 Tolerance makes interpretation of blood or plasma morphine Morphine ug/L 65-80 >200 http://www.clr-online.com/clr201213-table-of-cutoff-toxicity-doa.pdf concentrations extremely difficult.
Mycophenolate mg/L Refer to local protocol
Naltrexone is metabolised to 6-ß-naltrexone. 6-ß-naltrexone is pharmacologically active. The therapeutic interval for Naltrexone plus 6-ß- C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Naltrexone plus 6-ß-Naltrexol ug/L 25-100 ≥200 naltrexone is 25 to 100ug/L. Toxicity may be seen for concentrations of Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 Naltrexone plus 6-ß-naltrexone that are greater than 200ug/L.
Levels do not correlate to clinical effect. TDM not recommended for dose C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Nitrazepam ug/L 30-100 ≥200 titration. Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 Levels do not correlate to clinical effect. TDM not recommended for dose C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Oxazepam ug/L 200-1,500 ≥2,000 titration. Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011
Page 4 of 7 NSW HEALTH PATHOLOGY 2018 - AUGUST UPDATE
Therapeutic Ranges, Alert Thresholds and Interpretive Text for use in NSW Health Pathology Laboratories Prepared July 2017; Into production August 2018
REPORTING ALERT THRESHOLD/ TEST THERAPEUTIC RANGE INTERPRETIVE TEXT REFERENCE SOURCE UNIT TOXICITY
Mass Units mg/L are now used. The critical level at four hours is 150mg/L. * Treat ALL patients with serum paracetamol levels above the nomogram treatment line. * The nomogram is validated for single ingestions taken at a known time. * Do not use the nomogram to determine need for treatment (consult with the NSW Poisons Information Centre (131126)) if: - Ingestion is taken over many hours, Paracetamol mg/L ≥75 NSW Poisons Information Centre, May 2017 - Time of ingestion is unknown, - Sustained release paracetamol is ingested, - There is already evidence of hepatic toxicity. * Also seek advice if the paracetamol concentration is greater than double the treatment line. Nomogram: http://www.pathology.health.nsw.gov.au/latest-news-/clinical- alerts/therapeutic-drug-reporting-changes
The therapeutic interval is 150 to 600ug/L. There are slow and fast metabolisers due to polymorphism of CYP2D6. Slow metabolisers have a H. Ashrafian, J. D. Horowitz, and M.P. Frenneaux, Cardiovascular Drug Reviews, Perhexiline ug/L 150-600 hydroxy-perhexiline to perhexiline concentration ratio of less than 0.3 and 25, 76–97, 2007 are at risk of developing toxicity if given standard doses of perhexiline.
C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011 and 10-40 (adult) Phenobarb mg/L ≥ 50 Steady-state plasma concentration may not be achieved for 2-4 weeks http://www.mayomedicallaboratories.com/test- 10-30 (child <12 yrs) catalog/Clinical+and+Interpretive/37049. Alert level from AGNP Consensus Guidelines 2011. < 3 months: 6-14; <3 months: ≥15; http://ltd.aruplab.com/Tests/Pub/0090090. Adult alert level from AGNP Phenytoin mg/L Phenytoin is highly protein bound. Interpret levels with consideration of > 3 months: 10-20 >3 months: ≥25 albumin levels. Consensus Guidelines 2011.
Phenytoin Free mg/L 1.0-2.0 ≥2.5 http://ltd.aruplab.com/Tests/Pub/2010481
Promethazine mg/L No defined therapeutic interval
Concentrations greater than 10mg/L are associated with toxicity. Observation is recommended if more than 540mg quinine (650mg quinine Quinine mg/L >10 Clarke’s Analysis of Drugs and Poisons, p2000, 4th Edition, 2011 sulfate) is ingested or if a patient is symptomatic. Monitor ECG and signs of visual or auditory impairment.
Salicylate mg/L >300 No defined therapeutic interval. For use in detection of overdose. RCPA Manual of Use and Interpretation of Pathology Tests Feb 2015
Sirolimus ug/L Refer to local protocol
Tacrolimus ug/L Refer to local protocol
Levels do not correlate to clinical effect. TDM not recommended for dose C. Hiemke et al, AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Temazepam ug/L 20-900 ≥1000 titration. Psychiatry, Pharmacopsychiatry, 44, 195-235, 2011
Page 5 of 7 NSW HEALTH PATHOLOGY 2018 - AUGUST UPDATE
Therapeutic Ranges, Alert Thresholds and Interpretive Text for use in NSW Health Pathology Laboratories Prepared July 2017; Into production August 2018
REPORTING ALERT THRESHOLD/ TEST THERAPEUTIC RANGE INTERPRETIVE TEXT REFERENCE SOURCE UNIT TOXICITY
Neonates <1 month: 6 -12; Neonates: >12; Theophylline mg/L RCPA Manual of Use and Interpretation of Pathology Tests Feb 2015 >1 month: 10 - 20 >I month: >20
In patients with severe head injury assay for thiopentone is sometimes https://www.rcpa.edu.au/Library/Practising-Pathology/RCPA- Manual/Items/Pathology-Tests/B/Barbiturates required to differentiate brain death from reversible CNS depression due Australian and New Zealand Intensive Care Society. ‘The ANZICS Statement on Thiopentone <10 ≥10 mg/L to thiopentone administration. The diagnosis of brain death may require Death and Organ Donation’ (Edition 3.2). Melbourne: ANZICS, 2013. establishing that the plasma thiopentone concentration is less than http://www.anzics.com.au/Downloads/ANZICS%20Statement%20on%20%20Deat 10mg/L. h%20and%20Organ%20Donation%20Edition%203.2.pdf TDM not required for therapy not exceeding 48hrs. For once-daily or less frequent dosing, achieving an adequate area under Tobramycin peak/random mg/L the concentration–time curve (AUC) of aminoglycoside, while having an Therapeutic Guidelines Ltd (eTG March 2017 edition) undetectable trough (predose) plasma concentration, is associated with clinical efficacy and minimises toxicity. TDM not required for therapy not exceeding 48hrs. For once-daily or less frequent dosing, achieving an adequate area under the concentration–time curve (AUC) of aminoglycoside, while having an http://www.schn.health.nsw.gov.au/_policies/pdf/2011-8018.pdf Tobramycin trough mg/L <1.0 ≥ 2.0 undetectable trough (predose) plasma concentration, is associated with Therapeutic Guidelines Ltd (eTG March 2017 edition) clinical efficacy and minimises toxicity. Once daily dosing: Trough level (pre-dose) : Less than 1mg/L Multiple daily dosing: Trough level (pre-dose): Less than 2mg/L Toxic levels not well established. Correlation between concentration and http://www.mayomedicallaboratories.com/test- Topiramate mg/L 5-20 clinical effect not well established. catalog/Clinical+and+Interpretive/81546 There is poor correlation between theapeutic efficacy and plasma RCPA Manual of Use and Interpretation of Pathology Tests Feb 2015, Australian Valproate mg/L 50-100 >100 concentration but concentrations may be useful to confirm toxicity or Medical Handbook (AMH) January 2017. complicance
Valproate Free mg/L 7-23 >23 http://ltd.aruplab.com/Tests/Pub/0099310
Achieving an adequate area under the concentration–time curve (AUC) Vancomycin peak/random mg/L should be considered in difficult cases.
Note that the trough range is a surrogate for area under the South Australian expert Advisory Group on Antibiotic Resistance (SAAGAR). Vancomycin trough mg/L 15-20 ≥30 concentration–time curve (AUC). AUC should be considered in difficult Clinical Practice Guideline for Dosing and Monitoring of Vancomycin in Adults. cases. December 2016; Therapeutic Guidelines Ltd (eTG March 2017 edition)
A dose of 1.5g twice daily results in trough concentrations of 36mg/L but there is no defined therapeutic interval. Levels are useful to confirm Vigabatrin mg/L compliance. Correlation between concentration and clinical effect not well Danièle Bentué-Ferrer, Thérapie 2010 Janvier-Février; 65 (1): 23-27 established.
IMPORTANT INFORMATION:
• The NSW Health Pathology table of Drug Therapeutic Reference Ranges is intended to standardise ranges and Interpretive text that appears on reports/charts across the Public Pathology laboratories in NSW.
Page 6 of 7 NSW HEALTH PATHOLOGY 2018 - AUGUST UPDATE
Therapeutic Ranges, Alert Thresholds and Interpretive Text for use in NSW Health Pathology Laboratories Prepared July 2017; Into production August 2018
REPORTING ALERT THRESHOLD/ TEST THERAPEUTIC RANGE INTERPRETIVE TEXT REFERENCE SOURCE UNIT TOXICITY
• A limitation of this document is that in some instances there is little evidence-based data to support the ranges quoted. However the best available and most contempory ranges have been sought and clinical oversight of referenced data has been pursued.
• The therapeutic reference range for drugs used in psychiatry is an orienting, population-based range which may not necessarily be applicable to all patients. Individual patients may show optimal therapeutic response under a drug concentration that differs from the therapeutic reference range. Ultimately, psycho pharmacotherapy can be best guided by identification of the patient’s “individual therapeutic concentration”.
• It is also noted that different instrument biases may affect results, and it is incumbent on the laboratory chemical pathologist to review such biases before endorsing such ranges for use in their laboratory.
• This document is subject to document control and will be updated with further clinical input, evidence and contemporaneous data.
Endorsed by the Chief Pathologist and Chemical Pathology Clinical Stream NSW Health Pathology, July 2017
All correspondence to : Dr Margaret Janu [email protected]
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