Therapeutic Drug Monitoring (TDM) Guidelines in Blood for Pediatrics and Adults

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Acetaminophen 1,5 (Tylenol ) --- 2 hours post 5-20 g/ml >50 g/ml Peak: 1-2 hours Therapeutic Monitoring Acetaminophen 1,5 (Tylenol ) Possible Over Amikacin 7,9 --- 4 hours post --- >50 g/ml Serious toxicity occurs >200 ug/ml. --- 12 hours post --- >50 g/ml Peak 30-60 minutes post IV infusion 20-35 g/ml >35 g/ml Neonate: 10-45 hours (Amikin ) 60-90 minutes post IM injection Child: 3-13 hours For most infections, 20-35 μg/ml is recommended. Some serious infections may require a peak range of 28-35 μg/ml. Adult: 10-15 hours Within 30 minutes before next 0-3 g/ml >9 g/ml For most infections, <4 µg/ml is recommended. For severe infections, 4-8 µg/ml may be acceptable, with guidance from an infectious disease specialist. Amitriptyline 3 (Elavil ) Random Daily dosing: 8-12 hours after 4-35 g/ml >35 g/ml 10-14 hours post Total Amitriptyline + Nortriptyline: 120-250 ng/ml Total Amitriptyline + Nortriptyline: >500 ng/ml Adult: 3-8 days Amitriptyline is reported as the total concentration of Amitriptyline and Nortriptyline (metabolite of Amitriptyline). See Nortriptyline for more information. Page 1 of 10

Carbamazepine 2,9 (Tegretol ) Before next 4-12 g/ml Single drug regimen: 4-12 g/ml >15 g/ml Single Regimen: >15 g/ml Variable due to autoinduction Adult: 2-4 days Multiple drug regimen: 4-8 g/ml Multiple drug regimen: >8 g/ml Carbamazepine, Free 2,9 Clorazepate 1,9 Serious toxicity occurs >50 g/ml. Before next Free: 0.6-4.1 g/ml Not established Bound: 66-84% Before next Monitored as the metabolite, Nordiazepam, only. See Nordiazepam for more information. Adult: 8-21 days (Tranxene ) Cyclosporine 8,19 6 months post-transplant 225-338 ng/ml Indicating non-compliance: <20 ng/ml Desipramine 3,9 >6 months post-transplant 90-225 ng/ml 1 month post LIVER transplant 315-405 ng/ml Toxic: >450 ng/ml Varies by patient and type of transplant 2-6 months post LIVER 225-315 ng/ml transplant >6 months post LIVER 153-216 ng/ml transplant 6 weeks post CARDIAC 270-378 ng/ml transplant: 6-12 weeks post CARDIAC 162-270 ng/ml transplant: >12 weeks post-cardiac 108-162 ng/ml transplant: 12 hours post 150-250 ng/ml >500 ng/ml Adult: 4-19 days (Norpramin ) Diazepam 1,9 Before next 200-1000 ng/ml Not established Adult: 13-56 days (Valium ) Based on normal dosage amounts Nordiazepam and Oxazepam (metabolites of Diazepam) are reported with Diazepam. See Nordiazepam and Oxazepam for more information. Page 2 of 10

Digoxin 1,4 --- >6 hours, post 0.8-2.0 ng/ml 0-10 years: >3.0 ng/ml Adult: 5-7 days (Lanoxin ) Congestive Heart Failure: 0.8-1.5 ng/ml Arrhythmia: 1.5-2.0 ng/ml >10 years: >2.5 ng/ml Doxepin 3 (Sinequan, Adapin ) Ethosuximide 9 Concurrent use of Quinidine, DigiFab, and DigiBind will elevate the Digoxin level. --- 10-14 hours post Total Doxepin + Nordoxepin: 150-250 ng/ml Total Doxepin + Nordoxepin: >500 ng/ml Adult: 2-8 days Doxepin is reported as the total concentration of Doxepin and Nordoxepin (metabolite of Doxepin). Before next 40-100 g/ml >100 g/ml 11 days (Zaronin ) Felbamate Before next No ill effects demonstrated: 40-100 µg/ml >200 g/ml Adult: 3-4 days Page 3 of 10

Gentamicin 7,9 Peak 30-60 minutes post IV infusion 5.0-8.0 g/ml >10.0 g/ml Adult: 10-15 hours (Garamycin ) 60-90 minutes post IM injection For most infections, 5.0-8.0 µg/ml is recommended. For certain severe infections, 8.0-10.0 µg/ml may be acceptable, with guidance from an infectious disease specialist. For synergy against gram positive infections, a range of 3.0-5.0 µg/ml is recommended. Within 30 minutes before next 0.0-0.9 g/ml >2.0 g/ml For most infections, <1 µg/ml is recommended. For certain severe infections, <2 µg/ml may be acceptable, with guidance from an infectious disease specialist. Haloperidol 1,9 (Haldol ) Imipramine 3 12 hour Daily dosing: 12 hours after 0.0-3.4 g/ml >3.4 g/ml Before next 2-15 ng/ml Not well established Adult: 1-5 days 12 hours post Total Imipramine + Desipramine: 150-350 ng/ml Total Imipramine + Desipramine: >500 ng/ml Adult: 2-5 days (Tofranil ) Imipramine is reported as the total concentration of Imipramine and Desipramine (metabolite of Imipramine). See Desipramine for more information. Lamotrigine 2 Before next 3-14 μg/ml Not established Adult: 1-14 days Levitirecetam 19 Before next 5-30 μg/ml >150 μg/ml 30 40 hours Not well established. Lab will notify providers of potential toxicity for values >150 µg/ml. Page 4 of 10

Lidocaine 4 ---- <30 minutes post IV 1.5-5.0 g/ml >6.0 g/ml Adult: (Xylocaine ) Lithium 3 Signs and symptoms of toxicity: 0.5-1.5 hours with loading CNS, Cardiovascular depression: 6.0-8.0 g/ml 5-10 hours without Seizures, obtundation, decreased cardiac output: loading >8.0 g/ml 6-12 hours post 0.6-1.2 mmol/l >1.5 mmol/l Adult: 4-6 days (Eskalith ) Mephobarbital 19 Before next Monitored as the metabolite, Phenobarbital, only. See Phenobarbital for more information. Methadone 9 (Dolophine ) Single 30-80 ng/ml >2,000 ng/ml Maintenance 200-1,100 ng/ml Adult: 3-5 days Methotrexate 9,10 (Rheumatrex, Folex) Nordiazepam 19 (metabolite of Diazepam) Nortriptyline 9 Interpret with caution as therapeutic and toxic ranges have significant overlap due to large variation in patient opioid tolerance. Low Dose: 1-2 weeks post See toxic values: Varies with time and >0.02 mol/l Adult: 2-3 days High Dose: 24 hours post High Dose: 48 hours post High Dose: 72 hours post Before next 5.00 mol/l 0.50 mol/l 0.05 mol/l 60-1800 ng/ml >2500 8-41 days Based on normal dosage amounts 10-14 hours post 50-150 ng/ml >500 ng/ml Adult: 4-19 days (Aventyl ) Oxazepam 19 Before next 200-1400 ng/ml >2000 ng/ml 1-3 days (Serax ) Based on normal dosage amounts Page 5 of 10

Pentobarbital 9 Before next Sedation: 1-5 g/ml >10 g/ml (Sedation) Adult: 3-6 days (Nembutal ) Phenobarbital 2 (Luminal ) Intracranial pressure therapy: 30-40 g/ml Therapeutic coma: 20-50 g/ml Before next 15-40 g/ml <1 year: >40 g/ml (Serious toxicity occurs >60 µg/ml.) 1 year: >40 g/ml Signs and symptoms of toxicity: Slowness, ataxia nystagmus: 35-80 g/ml Coma with reflexes: 65-117 g/ml Newborn: 0-4 weeks: 21-28 days 1-12 months: 12-14 days Child: 10-29 days Adult: 10-29 days Phenytoin 2 Before next 0-3 months: 6-11 g/ml Coma without reflexes (serious): >100 g/ml >30 g/ml 1-3 weeks (Dilantin ) Minimum times for collection >3 months: 10-20 g/ml post, IM: >4 hours; IV: >2 hours. Phenytoin, Free Before next Free: 1.0-2.0 g/ml Serious toxicity occurs >160 μg/ml. Free: >3.0 g/ml Primidone 2,9 (Mysoline ) Bound: 85-95% Bound: Not established Before next 5-12 g/ml >15 g/ml Serious toxicity occurs >40 μg/ml. Phenobarbital (metabolite of Primidone) is reported with Primidone. See Phenobarbital for more information. Adult: 16-64 hours Page 6 of 10

Salicylates 9 Before next 2.0-10.0 mg/dl >10.0 mg/dl Adult: 12-15 hours Analgesia, antipyresis: 2.0-10.0 mg/dl Anti-inflammatory: 15.0-30.0 mg/dl Signs and symptoms of toxicity: Gastric intolerance, impaired homeostasis: >10.0 mg/dl Deafness, headache, vertigo, tinnitus: 15.0-30.0 mg/dl Nausea, vomiting, hyperventilation: 25.0-40.0 mg/dl Sirolimus 19 Intoxication: >50.0 mg/dl Before next 3.0-20.0 ng/ml >20.0 ng/ml 10-16 days (Rapamycin, Rapamune ) Tacrolimus 12 12 hours post-transplant 5.0-20.0 ng/ml Not established Child: 1-2 days (FK506, Prograf ) The therapeutic range is not clearly defined, but a target. Higher concentrations are associated with an increased incidence of adverse effects. Adult: 2-4 days 24 hours post-transplant 3.0-13.0 ng/ml Not established Temazepam 19 Before next Not established Not established 1-4 days Theophylline 1,6 Varies with type of administration. (Note: 1) Oxazepam (metabolite of Temazepam) is reported with Temazepam. See Oxazepam for more information. 0-5 months: 6-11 μg/ml 0-5 months: >14 g/ml >5 months: 8-20 μg/ml >5 months: >20 g/ml Premature: 6 days Newborn: 5 days Infant: 1-5 days Child: 1-2 days Adult: 2-3 days Page 7 of 10

Tobramycin 9 Peak Post IV infusion: 30-60 minutes 5.0-8.0 g/ml >10.0 g/ml Adult: 10-15 hours (Nebcin ) post IM infusion: 60-90 minutes For most infections, 5.0-8.0 μg/ml is recommended. For severe infections, 8.0-10.0 μg/ml may be acceptable, with guidance from an infectious disease specialist. For synergy against gram positive infections, a range of 3.0-5.0 μg/ml is recommended. Within 30 minutes before next 0.0-0.9 g/ml Additional Information: >2.0 g/ml For most infections, <1 μg/ml is recommended. For certain severe infections, <2 μg/ml may be acceptable, with guidance from an infectious disease specialist. Topiramate 2 (Topamax ) Valproic Acid 2, Total 12 Hour Daily Dosing: 8-12 hours after 0.0-3.4 g/ml >3.4 g/ml Before next 5-20 g/ml >40 g/ml Not well established. Lab will notify providers of potential toxicity for values >40 µg/ml. Before next 50-120 g/ml >120 g/ml 4-5 days Newborn: 41 hours (Depakene ) Valproic Acid, Free 2 Free: 2.0-20.0 g/ml Seizure control may improve at levels over 100 g/ml, but toxicity may occur at levels of 100-150 g/ml in some patients. Serious toxicity occurs >200 g/ml. Not established Child: 41-55 hours Adult: 41-74 hours Bound: 80-95% Page 8 of 10

Vancomycin 1,7,8 (Vancocin ) Peak Approximately 2 hours after a 60 minute infusion Within 30 minutes before next 20-40 g/ml >49 g/ml Adult: 24-39 hours 10-20 g/ml For complicated infections (i.e., endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia caused by MRSA) or MRSA with an MIC >1 μg/ml, 15-20 μg/ml is recommended. For all other infections, 10-15 μg/ml is recommended. >25 g/ml Random Varies 10-40 g/ml >49 g/ml NOTES AND COMMENTS: 1. Contact the physician or pharmacy pharmacokinetic specialist for patient-specific information. 2. Based on 5 half-lives. 9 REFERENCES: 1. Teitz NW, Textbook of Clinical Chemistry, WB Saunders, 3 rd edition, 1999, pp 1840-1845. 2. Warner A.; et al; Standards of Laboratory Practice: antiepileptic drug monitoring, Clin. Chem., 1998, 44:5, 1085-1095. 3. Linder M and Keck PE, Standards of Laboratory Practice: antidepressant drug monitoring, Clin. Chem., 1998, 44:5, 1073-1084. 4. Valdes RJ; et al; Standards of Laboratory Practice: cardiac drug monitoring, Clin. Chem., June 2004. 5. White S and Wong SHY, Standards of Laboratory Practice: analgesic drug monitoring, Clin. Chem., 1998, 44:5, 1110-1123. 6. Pesce AJ, et al; Standards of Laboratory Practice: theophylline and caffeine monitoring, Clin. Chem., 1998, 44:5, 1124-1128. 7. Hammett-Stabler CA and Johns T, Laboratory Guidelines for monitoring of antimicrobiol drugs, Clin. Chem., 1998, 44:5, 1129-1140. 8. University of Cincinnati Hospital Transplant Program, Personal Communication, March 1995. Page 9 of 10

9. Tietz NW, editor; Clinical Guide to Laboratory Tests, Section III, Therapeutic drugs, 1995, pp. 787-897. 10. McEvoy GK, editor, AHFS Information, ASH-SP Press, 1995. 11. Jacobs DS, Laboratory Test Handbook, 4 th edition, Lexi-Comp. Inc., 1996. 12. Leiken, J.B.; and Paloucek, F.P.; Poisoning & Toxicology Handbook; 2 nd edition., Lexi-Comp, Inc., 1996-1997. 13. Teitz NW, Fundamentals of Clinical Chemistry, Burtis CA and Ashwood ER; WB Saunders, 4 th edition, 1999, page 825. 14. Fishman DN, Once-Daily Dosing of Aminoglycoside Antibiotics, Infectious Disease Clinics of North America, 2000; 14:475-487. 15. Karem CM et al, Outcome Assessment of Minimizing Vancomycin Monitoring and Dosing Adjustments, Pharmacotherapy 1999; 19:257-267. 16. Perry J, Pharm D; Personal Communication; Legacy Good Samaritan Hospital Pharmacy; July 2002. 17. Cole E, et al, Recommendations for the Implementation of Neoral TM C2 Monitoring in Clinical Practice, Transplantation 73(9): S19-S22 and S1-S18, 2002. 18. Levy G, C2 Monitoring Strategy for Optimising Cyclosporine Immunosupression from the Neoral TM Formulation, Bios 15(5): 279-290, 2001. 19. Brunton LL, Lazo JS, Parker KL, Goodman & Gilman s The Pharmacological Basis of THERAPEUTICS, McGraw-Hill, 11 th edition, 2006, pages 1794-1888. Page 10 of 10