GeneDose Genetic Response Report

Transcription

1 ISPM Labs d/b/a Capstone Diagnostics 8601 Dunwoody Pl, Ste 444 Atlanta GA Phone: (678) Fax: (470) Laboratory Director: John Hanson, PhD CLIA ID Number: 11D This report combines (i) an analysis of the patient s DNA by ISPM Labs d/b/a Capstone Diagnostics, identifying relevant genetic variants that are informative for medication efficacy, safety, and dosing, with (ii) an interpretation of the identified DNA variants by Coriell Life Sciences to bring you immediately actionable clinical guidance regarding safer and more effective medications and dosages for the patient. P atient: Doe, Jane Ph Date of Birth: Jan 01, 1990 Gender: F Pr ysician: Dr Specimen type: Buccal swab. Example actice: Example Health Associates Sample ID: e x222 emale GeneDose Live Genetic Summary Individualized, additional therapeutic decision support information based on Jane Doe's genetics, drug regimen, indications, demographics, and lifestyle indicators are available at GeneDose Live via this secured URL: GeneDose Key: ACAZPCM6P Sample ID: ex222 Table of Contents Gene Result Activity ApoE ɛ3 ɛ3 See ApoE Genotype Info. ANKK1 *8 *8 Poor metabolizer ATM *8 *8 Poor metabolizer ABCB1 *1 *36 Altered Activity CYP1A2 *8 *8 Uncertain CYP2B6 *8 *8 Poor metabolizer CYP2C19 *8 *8 Poor metabolizer Genetic Summary Pg. 1 CYP2C9 *1 *1 Extensive metabolizer Current Regimen Risk Chart Pg. 3 CYP2D6 *1 *1x2 Ultrarapid metabolizer Current Regimen Risk Detail (by severity) Pg. 4 CYP3A4 *1B *1B Ultrarapid metabolizer Thrombosis Profile Pg. 6 CYP3A5 Pg. 7 *1A *1A; or *1A *1D; or Extensive metabolizer ApoE Genotype Information Medications Summary Pg. 8 6P C C n/a Medication Report Details (by therapeutic class) Pg. 11 Factor V Leiden Variant See thrombosis profile References Pg. 26 HLA-B*1502 WT WT WT Patient Information Card Pg. 27 MTHFR (A1298C) Variant See thrombosis profile MTHFR (C677T) Variant See thrombosis profile Prothrombin (F2) Normal See thrombosis profile SNP Report Genetic Summary Information Appendix When multiple activities are listed, check information in Medication Report Details (Pg. 11) for specific medication of interest. Uncertain = No known diplotype/result (name) or activity for this combination of genetic variants; Uninterpretable Genotype. K1 A T Altered Activity K C C Normal Activity T 2A C C Normal Activity Page 1 of 26

2 Gene Result Activity HTR2C A A Uncertain IFNL3 1 *2 Altered function OPRM1 *1 *1 Extensive Metabolizer SLC6A4 *1 *28 Normal function SLCO1B1 *1 *1 Normal liver uptake activity VKORC1 *1 *2 Reduced (with respect to Warfarin) Reported May 10, 2018 Page 2 of 25

3 Current Regimen Risk Chart This chart summarizes the various risk factors associated with each medication entered into GeneDose Live for Jane Doe. The length of each colored segment represents the relative contribution of a risk category (detailed in the below legend) to the overall risk associated with the use of a medication. For further information, consult the Current Regimen Risk Details Pg. 3 section. For further assistance in choosing alternative medications to reduce this patient s risk, use the modeling tool at Epitol, Tegretol (Carbam Codeine Zoloft (Sertraline) BRIVIACT (Brivaracetam) Folicet (Folic Acid) Absorica, Accutane, Am to 5 - Few risks; 6 to 20 - Moderate risk; Significant Genetic Drug interaction Anticholinergic burden Lifestyle ADR (Black box) Page 2 of 26

4 Current Regimen Risk Detail Severe Risks Strong regimen anticholinergic burden The cumulative effect of taking multiple medicines with anticholinergic properties termed as anticholinergic burden can adversely impact cognition, physical function and increase the risk of mortality. Major Risks Genetic warning for Zoloft (Sertraline) Individuals with poor metabolizer status may have higher plasma concentrations and decreased clearance. Reduce dose by 50%. Genetic warning for Codeine For analgesia, select alternative drug (e.g. acetaminophen, NSAID, morphine; not tramadol or oxycodone). Be extra alert to adverse drug events due to increased morphine plasma concentration. BRIVIACT (Brivaracetam) has its effect decreased by, and increases effect of Epitol, Tegretol (Carbamazepine) monitor for signs of drug toxicity monitor for altered clinical response to drug therapy warn against driving or operating machinery or performing other hazardous tasks until drug effects are known dosage reduction may be required Coadministration with carbamazepine may increase exposure to the active metabolite of carbamazepine, carbamazepineepoxide. A 26% decrease in the plasma concentration of brivaracetam has also been observed during co-administration. Moderate Risks Epitol, Tegretol (Carbamazepine) may decrease concentration of Codeine use combination with caution monitor for altered clinical response to drug therapy adjust drug dosage Inducers of CYP3A4 such as carbamazepine, may induce the hepatic metabolism of opiate agonists, which may lead to opiate withdrawal or inadequate pain control. Clinicians should be alert to changes in the effect of the opioid agonist. Epitol, Tegretol (Carbamazepine) reduces effect of Zoloft (Sertraline) use combination with caution Page 3 of 26

5 monitor patient clinically Sertraline is a substrate for CYP3A4 and CYP2C19. Drugs that induce hepatic isoenzymes, such as carbamazepine could decrease sertraline plasma concentrations, potentially causing decreased effectiveness of sertraline. Minor Risks Codeine has its effect reduced by Zoloft (Sertraline) use combination with caution monitor patient clinically The activity of codeine is due to its conversion to morphine via the cytochrome P450 CYP2D6 hepatic isoenzyme. The analgesic activity of codeinemay be reduced when it is combined with drugs that inhibit CYP2D6, such as sertraline. Page 4 of 26

6 Thrombosis Profile Tested Genes (Alleles) Genotype Predicted Phenotype Clinical Guidance Prothrombin (F2) Factor V Leiden MTHFR (A1298C) MTHFR (C677T) Normal Homozygous variant Homozygous variant Homozygous variant Variant alleles detected. It is important for individuals possessing this allelic variant to understand the clinical risks and the genetic implications of their result. Patients should be counseled by their physician or genetic counselor Individuals homozygous for the Factor V Leiden mutation have an approximately 80-fold increased risk of venous thrombosis as compared to individuals without the mutation. Patients who are homozygous for either MTHFR variant may have a further increased risk for venous thrombosis if they also possess the Factor V Leiden 1691A allele. General Description Genetic analyses of three genes (four alleles) considered to increase the risk for venous thrombosis were performed using molecular genetic techniques. The presence of the Prothrombin (Factor 2) gene allele 20210A and Factor V Leiden allele 1691A are risk factors for venous thrombosis. This risk may be further increased by the use of estrogen therapy, oral contraceptives, pregnancy, and surgery. Patients who are homozygous for MTHFR 677T or MTHFR 1298C may have a further increased risk for venous thrombosis if they also possess the Factor V Leiden 1691A allele. However the MTHFR alleles alone do not predict a significant risk for venous thrombosis. References and Useful Information: Factor V Leiden Working Group; ACMG Laboratory Quality Assurance Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee AMERICAN COLLEGE OF MEDICAL GENETICS; Standards and Guidelines for Clinical Genetics Laboratories; 2006 Edition Middeldorp S, Henkens CM, Koopman MM, van Pampus ECM,Hamulyák K, van der Meer J, Prins MH, Büller HR. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Intern Med 1998;128: Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994;344: Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995;85(6): Reich LM, Bower M, Key NS. Role of the geneticist in testing and counseling for inherited thrombophilia. Genet Med 2003;5: Tosetto A, Rodeghiero F, Martinelli I, De Stefano V, Missiaglia E, Chiusolo P, Mannucci PM. Additional genetic risk factors for venous thromboembolism in carriers of the factor V Leiden mutation. Br J Haematol 1998;103: De Stefano V, Martinelli I, Mannucci PM, Paciaroni K, Chiusolo P, Casorelli I, Rossi E, Leone G. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999;341: M. Adams, P.D. Smith, D. Martin, J.R. Thompson, D. Lodwick, N.J. Samani. Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. QJM Jun;89(6): Page 5 of 26

7 ApoE Genotype Information Tested Genes (Alleles) Genotype Predicted Phenotype Clinical Guidance ApoE (ɛ2, ɛ3, ɛ4) ɛ3 ɛ3 Often associated with normal lipid metabolism. Typical cardiovascular disease risk expected. General Description Genetic analysis in the ApoE gene was performed using molecular genetic techniques. The genotype is based on genotyping results for this patient at SNPs rs and rs7412. ApoE ɛ3 is the most common allele found in about 60% of people. The presence of ɛ2 or ɛ4 alleles may be a risk factor for multiple conditions including cardiovascular disease. ApoE ɛ2 carriers may be more likely to develop familial dysbetalipoproteinemia or type III hyperlipoproteinemia. Predicted phenotype, clinical significance, relative risk, and interpretations reported for each genotype are associated with cardiovascular risk only. The interpretations should not be used to determine the relative risk of other diseases. Other factors important to understanding total risk should be considered. Page 6 of 26

8 Medication Summary (more alternatives discoverable at GeneDose Live) Secured URL: Cardiac Therapeutic Class Standard Precautions Caution / Info Change recommended Antiarrhythmics Anticoagulants Anticonvulsants Acenocoumarol Phenytoin Flecainide Propafenone Warfarin Antiplatelet Agents Ticagrelor Clopidogrel Beta Blockers Carvedilol Metoprolol Statins Simvastatin Atorvastatin Gastroenterology Therapeutic Class Standard Precautions Caution / Info Change recommended Antidepressants Immunosuppressants Nonsteroidal Anti- Inflamatory Drugs (NSAIDs) Proton Pump Inhibitors (PPIs) Selective Serotonin Reuptake Inhibitors (SSRIs) Mirtazapine Azathioprine Mercaptopurine Thioguanine Celecoxib Amitriptyline Clomipramine Desipramine Doxepin Nortriptyline Trazodone Cyclosporine Dexlansoprazole Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole Citalopram Paroxetine Page 7 of 26

9 Infectious Disease Therapeutic Class Standard Precautions Caution / Info Change recommended Antifungals Voriconazole Ketoconazole Pain Therapeutic Class Standard Precautions Caution / Info Change recommended Anticonvulsants Antidepressants Antipsychotics Immunosuppressants Carbamazepine Phenytoin Duloxetine Flupenthixol Mirtazapine Moclobemide Olanzapine Azathioprine Mercaptopurine Clobazam Amitriptyline Clomipramine Desipramine Doxepin Nortriptyline Protriptyline Trazodone Venlafaxine Vortioxetine Cyclosporine Tacrolimus Muscle Relaxants Carisoprodol Nonsteroidal Anti- Inflamatory Drugs (NSAIDs) Opioids Selective Serotonin Reuptake Inhibitors (SSRIs) Celecoxib Diclofenac Flurbiprofen Meloxicam Oxycodone (CYP3A5) Buprenorphine Codeine Oxycodone Tramadol Citalopram Fluoxetine Paroxetine Sertraline Psychotropic Therapeutic Class Standard Precautions Caution / Info Change recommended Anti-ADHD Agents Anticonvulsants Carbamazepine Phenytoin Atomoxetine Clobazam Page 8 of 26

10 Psychotropic Therapeutic Class Standard Precautions Caution / Info Change recommended Antidementia Agents Antidepressants Antipsychotics Anxiolytics Hypnotics Selective Serotonin Reuptake Inhibitors (SSRIs) Donepezil Duloxetine Flupenthixol Mirtazapine Moclobemide Aripiprazole Clozapine Olanzapine Amitriptyline Clomipramine Desipramine Doxepin Nortriptyline Protriptyline Trazodone Venlafaxine Vortioxetine Haloperidol Quetiapine Risperidone Thioridazine Zuclopenthixol Alprazolam Buspirone Clonazepam Eszopiclone Citalopram Fluoxetine Paroxetine Sertraline Other Drugs Therapeutic Class Standard Precautions Caution / Info Change recommended Anticoagulants Antidiabetics Cholinergic Agonists Immunosuppressants Selective Serotonin Reuptake Inhibitors (SSRIs) Warfarin Glibenclamide Gliclazide Glimepiride Tolbutamide Saxagliptin Cevimeline Sirolimus Escitalopram Page 9 of 26

11 Legend Clinical Evidence Level Typical response is expected Additional information available Strong Change recommended Response is uncertain Moderate Consider alternative therapy Emerging Medication Report Details (by therapeutic class) Anti-ADHD Agents Atomoxetine (Strattera) increased metabolism; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. However, there is insufficient evidence to allow calculation of dose adjustment. Be alert to reduced efficacy or select alternative drug (e.g., methylphenidate, clonidine). Antiarrhythmics Flecainide (Tambocor) the potential for increased elimination. Record ECG and monitor plasma concentration or select alternative drug (e.g. sotalol, disopyramide, quinidine, amiodarone). Propafenone (Rythmol) increased metabolism to less active compounds; the resultant decreased plasma concentrations may increase the risk of pharmacotherapeutic failure. Insufficient evidence to allow calculation of dose adjustment. Adjust dose in response to plasma concentration and record ECG or select alternative drug (e.g. sotalol; disopyramide; quinidine; amiodarone). Page 10 of 26

12 Anticoagulants Acenocoumarol (Sintrom, Acitrom) CYP2C9: Extensive alleles Warfarin (Coumadin) Multigenic: VKORC1, CYP2C9: Two normal ; Extensive metabolizer. Two normal Individuals with this combination of alleles may benefit from an increased dose of Warfarin. The FDA table recommends a therapeutic dose of 5-7 mg/day. Warfarin (Coumadin) Multigenic: CYP2C9, VKORC1, CYP4F2: Extensive metabolizer. Two normal ; Two alleles ; Normal function. Two alleles with normal Individuals with this combination of alleles may benefit from a standard therapeutic dose of warfarin. Consider a regimen of mg/day (29-41 mg/week). ADR & Anticonvulsants Carbamazepine (Tegretol) HLA-B*1502: Negative; Absence of *15:02 alleles. Individuals with no variant alleles detected are at "normal" or reduced risk of carbamazepine-associated cutaneous adverse reactions. Clobazam (Onfi) null reduced Individuals with poor metabolizer status may be at an increased risk of adverse drug reaction due to the presence of higher concentrations of clobazam's active metabolite. Consider reducing the initial dose. The FDA approved labeling text for ONFI states that "For this reason, the initial dose in patients known to be CYP2C19 poor metabolizers should be 5 mg/day. These patients should be titrated initially to mg/day, and may be titrated further to a maximum daily dose of 40 mg if tolerated." ADR Phenytoin (Dilantin) CYP2C9: Extensive alleles Page 11 of 26

13 Antidementia Agents Donepezil CYP2D6: *1 *1x2 Page 12 of 26

14 Antidepressants Amitriptyline (Elavil) increased metabolism of amitriptyline to less active compounds; the resultant lower plasma concentrations will increase the probability of pharmacotherapy failure. Select an alternative drug or consider increasing the recommended starting dose. Clomipramine (Anafranil) increased metabolism to less active compounds; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Select alternative drug (e.g. citalopram; sertralin) or monitor (desmethyl) clomipramine plasma concentration. Desipramine (Norpramin) increased metabolism of tricyclic antidepressants; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Select an alternative drug or consider increasing the recommended starting dose. Doxepin (Deptran) increased metabolism to less active compounds. Lower plasma concentrations will increase the probability of pharmacotherapy failure. Select alternative drug (citalopram, sertraline) or increase dose by 100%. Adjust maintenance dose in response to (nor)doxepin plasma concentration. Duloxetine (Cymbalta) Flupenthixol Page 13 of 26

15 Imipramine (Tofranil) Multigenic: CYP2C19, CYP2D6: Poor null alleles likely showing little or no Ultrarapid Multiple results from uncorrelated genes. CYP2C19: Potential dosage adjustment or alternate drug suggested CYP2D6: Consider alternative therapy Mirtazapine Moclobemide null alleles likely showing reduced Nortriptyline (Pamelor) increased metabolism of tricyclics to less active compounds when compared to extensive metabolizers; the resultant lower plasma concentrations will increase probability of pharmacotherapy failure. Consider alternative therapy--select alternative drug (e.g. citalopram, sertraline) or increase dose by 60% and monitor nortriptyline 10-hydroxynortriptyline plasma concentrations. Protriptyline (Vivactil) increased metabolism of tricyclic antidepressants; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Select an alternative drug or consider increasing the recommended starting dose. Trazodone (Oleptro, Desyrel) CYP3A4: Ultra-rapid increased increased metabolism of trazodone; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Select an alternative drug or monitor patient for a need to increase the dose. Page 14 of 26

16 Venlafaxine (Effexor) Be alert to decreased venlafaxine and increased (Odesmethyl) venlafaxine plasma concentration. Titrate dose to a maximum of 150% of the normal dose or select alternative drug (e.g. citalopram, sertraline). Vortioxetine (Brintellix) CYP2D6: *1 *1x2 increased clearance of vortioxetine; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Consider increasing the dose. Antidiabetics Glibenclamide (Glyburide) CYP2C9: Extensive alleles Gliclazide CYP2C9: Extensive alleles Glimepiride CYP2C9: Extensive alleles Saxagliptin (Onglyza) CYP3A4: Ultra-rapid increased increased metabolism of saxagliptin; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Select an alternative drug or monitor patient for efficacy and adjust dose appropriately. Tolbutamide (Orinase) CYP2C9: Extensive alleles Page 15 of 26

17 Antifungals Ketoconazole (Nizoral) CYP3A4: Ultra-rapid increased increased metabolism of ketoconazole; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Ketoconazole is not recommended. Voriconazole null alleles likely showing reduced Individuals with poor metabolizer status may have higher voriconazole exposure. Adjust the dose and monitor for adverse events or lack of efficacy. ADR & Antiplatelet Agents Clopidogrel (Plavix) reduced Individuals with poor metabolizer status are at an increased risk of therapeutic failure due to reduced activation of the prodrug and low plasma concentrations of the active compound. Clopidogrel is not recommended. Ticagrelor (Brilinta) CYP3A4: Ultra-rapid increased Individuals with ultrarapid metabolizer status may be at an increased risk of adverse drug reactions and decreased efficacy due to reduced metabolism of the prodrug to the active metabolite. Insufficient evidence to allow calculation of dose adjustment. Consider alternative drug. ADR & Page 16 of 26

18 Antipsychotics Aripiprazole (Abilify) Clozapine Haloperidol (Haldol) increased metabolism to less active compounds; the resultant decreased plasma concentrations may increase the probability of pharmacotherapy failure. Insufficient evidence to allow calculation of dose adjustment. Monitor and adjust maintenance dose in response to haloperidol plasma concentration or select alternative drug (e.g. pimozide; flupenthixol; fluphenazine; quetiapine; olanzapine; clozapine). Olanzapine (Zalasta, Zyprexa) Quetiapine (Seroquel) CYP3A4: Ultra-rapid increased increased clearance of quetiapin; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Select an alternative drug or consider increasing the recommended starting dose. Risperidone (Risperdal) Insufficient evidence to allow calculation of dose adjustment. Select alternative drug (e.g. quetiapine, olanzapine, clozapine) or be extra alert to decreased response and titrate dose in response to clinical effect and adverse drug events. Page 17 of 26

19 Thioridazine Individuals with ultrarapid metabolizer status may be at risk of reduced efficacy due to increased metabolism of thioridazine. Select an alternative drug or consider increasing the recommended starting dose. Zuclopenthixol increased metabolism to less active compounds; the resultant decreased plasma concentrations may increase the probability of pharmacotherapy failure. Insufficient evidence to allow calculation of dose adjustment. Be alert to low zuclopenthixol plasma concentrations or select alternative drug (e.g. flupenthixol, quetiapine, olanzapine, clozapine). Anxiolytics Alprazolam (Xanax, Niravam) CYP3A4: Ultra-rapid increased increased metabolism of alprazolam; the resultant lower plasma levels may increase the probability of pharmacotherapy failure. Select an alternative drug or consider increasing the recommended starting dose. Buspirone (Buspar) CYP3A4: Ultra-rapid increased increased metabolism of buspirone; the resultant lower plasma levels may increase the probability of pharmacotherapy failure. Select an alternative drug or consider increasing the recommended starting dose. Clonazepam (Klonopin) CYP3A4: Ultra-rapid increased increased metabolism of clonazepam; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Select an alternative drug or monitor patient for efficacy and adjust dose appropriately. Page 18 of 26

20 Beta Blockers Carvedilol (Coreg) Metoprolol (Lopressor) increased metabolism when compared to extensive metabolizers; the resultant lower plasma concentrations may increase probability of pharmacotherapy failure. For heart failure (indication): select alternative drug (e.g. bisoprolol, carvedilol) or titrate dose to a maximum of 250% of the normal dose in response to efficacy and adverse drug events. For other indications: select alternative drug (e.g. atenolol, bisoprolol) or titrate dose to a maximum of 250% of the normal dose in response to efficacy and adverse drug events. ADR & Cholinergic Agonists Cevimeline (Evoxac) CYP2D6: *1 *1x2 increased clearance of cevimeline; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Insufficient evidence to allow calculation of dose adjustment. Consider alternative drug. Hypnotics Eszopiclone (Lunesta) CYP3A4: Ultra-rapid increased increased metabolism of eszopiclone; the resultant lower blood concentrations may increase the probability of pharmacotherapy failure. Consider selecting an alternative drug. Page 19 of 26

21 Immunosuppressants Azathioprine (Imuran) TPMT: Extensive alleles Individuals with extensive metabolizer status are expected to have a typical response to thiopurines. Cyclosporine (Gengraf, Neoral) CYP3A4: Ultra-rapid increased increased metabolism of cyclosporine; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Select an alternative drug or monitor circulating cyclosporine concentrations and adjust dose appropriately. Mercaptopurine (Purinethol) TPMT: Extensive alleles Individuals with extensive metabolizer status are expected to have a typical response to thiopurines.; no additional therapeutic Sirolimus (Rapamune) CYP3A4: Ultra-rapid increased increased metabolism of sirolimus; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. Select an alternative drug or monitor sirolimus trough concentrations and adjust dose appropriately. Tacrolimus (Prograf, Hecoria) CYP3A5: Two alleles Individuals with extensive metabolizer status have lower dose-adjusted trough concentrations of tacrolimus; the resultant decreased concentrations may increase the probability of pharmacotherapy failure. Consider increasing the recommended starting dose by 1.5 to 2 times (with a total starting dose not exceeding 0.3 mg/kg/ day). In liver transplant patients, donor genotype should be considered as well as the recipient's. Thioguanine (6-TG, Tabloid, Lanvis) TPMT: Extensive alleles Individuals with extensive metabolizer status are expected to have a typical response to thiopurines. Muscle Relaxants Carisoprodol (Soma) null alleles likely showing reduced Individuals with poor metabolizer status may be at an increased risk of adverse drug reactions due to reduced carisoprodol metabolism. Carisoprodol should be administered with caution. ADR Page 20 of 26

22 Non-drug ApoE ApoE: Often associated with normal lipid metabolism. Typical cardiovascular disease risk expected. Nonsteroidal Anti-Inflamatory Drugs (NSAIDs) Celecoxib (Celebrex) CYP2C9: Extensive alleles Diclofenac (Cataflam) CYP2C9:rs : Two normal Flurbiprofen (Ocufen) CYP2C9: Extensive alleles Meloxicam (Mobic) CYP2C9: Extensive alleles Page 21 of 26

23 Opioids Buprenorphine (Butrans, Buprenex) CYP3A4: Ultra-rapid increased Individuals with ultrarapid metabolizer status may have increased clearance of buprenorphine; the resultant lower plasma concentrations may increase the probability of pharmacotherapy failure. It is recommended that patients be monitored for signs and symptoms of opioid withdrawal. Consider an alternative medication. Codeine For analgesia, select alternative drug (e.g. acetaminophen, NSAID, morphine; not tramadol or oxycodone). Be extra alert to adverse drug events due to increased morphine plasma concentration. ADR Oxycodone (Oxycontin) Individuals with ultrarapid metabolizer status are at risk of possible adverse drug reaction. Insufficient evidence to allow calculation of dose adjustment. Select alternative drug (not tramadol or codeine) or be alert to adverse drug events (e.g. nausea; vomiting; constipation; respiratory depression; confusion; urinary retention). ADR Oxycodone (CYP3A5) (Oxycontin) CYP3A5: Two alleles Tramadol (Ultracet, Ultram) increased metabolism to more active compounds; the resultant increased plasma concentrations may increase the probability of adverse drug reactions. Reduce dose by 30% and be alert to adverse drug events (e.g. nausea; vomiting; constipation; respiratory depression; confusion; urinary retention) or select alternative drug (e.g. acetaminophen; NSAID; morphine - not oxycodone or codeine). ADR Page 22 of 26

24 Proton Pump Inhibitors (PPIs) Dexlansoprazole (Kapidex, Dexilant) null reduced Individuals with poor metabolizer status have decreased metabolism to less active compounds; the resultant increased concentrations may increase drug efficacy. Individual is expected to respond well to PPI treatment; no additional therapeutic Esomeprazole (Nexium) null reduced Individuals with poor metabolizer status have decreased metabolism to less active compounds; the resultant increased concentrations may increase drug efficacy. Individual is expected to respond well to PPI treatment; no additional therapeutic Lansoprazole (Prevacid) null reduced Individuals with poor metabolizer status have decreased metabolism to less active compounds; the resultant increased concentrations may increase drug efficacy. Individual is expected to respond well to PPI treatment; no additional therapeutic Omeprazole (Prilosec, Zegerid) null reduced Individuals with poor metabolizer status have decreased metabolism to less active compounds; the resultant increased concentrations may increase drug efficacy. Individual is expected to respond well to PPI treatment; no additional therapeutic Pantoprazole (Protonix) null reduced Individuals with poor metabolizer status have decreased metabolism to less active compounds; the resultant increased concentrations may increase drug efficacy. Individual is expected to respond well to PPI treatment; no additional therapeutic Rabeprazole (Aciphex) null reduced Individuals with poor metabolizer status have decreased metabolism to less active compounds; the resultant increased concentrations may increase drug efficacy. Individual is expected to respond well to PPI treatment; no additional therapeutic Page 23 of 26

25 Selective Serotonin Reuptake Inhibitors (SSRIs) Citalopram (Celexa) null alleles likely showing reduced Typical response is expected. However, individuals with poor metabolizer status have increased bioavailability increasing the probability of side effects. ADR Escitalopram (Lexapro) null alleles likely showing reduced Typical response is expected. However, individuals with poor metabolizer status have increased bioavailability increasing the probability of side effects. ADR Fluoxetine (Prozac) CYP2D6: *1 *1x2 Individuals taking fluoxetine should be alert to concomitant use of drugs metabolized by CYP2D6. For a more in-depth recommendation for individuals taking fluoxetine, please visit this individual's GeneDose Live profile. Briefly, fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway. Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g. TCAs), antipsychotics (e.g. phenothiazines and most atypicals), and antiarrhythmics (e.g. propafenone, flecainide, and others) should be approached with caution. ADR & Paroxetine (Paxil) Insufficient evidence to allow calculation of dose adjustment. Consider selecting alternative drug (e.g. citalopram, sertraline). Sertraline (Zoloft) null alleles likely showing reduced Individuals with poor metabolizer status may have higher plasma concentrations and decreased clearance. Reduce dose by 50%. ADR Statins Atorvastatin (Lipitor, Caduet) CYP3A4: Ultra-rapid increased Individuals with ultrarapid metabolizer status eliminate atorvastatin more rapidly than extensive/normal metabolizers and may not respond well to a standard dose. Increased dose may be needed. Simvastatin (Zocor) SLCO1B1: Normal liver uptake Individuals with normal SLCO1B1 liver uptake activity are expected to have a typical response to a standard dose of simvastatin. Page 24 of 26

26 Clinical Evidence Levels Strong Includes gene-drug pairs approved by the Coriell Institute for Medical Research Pharmacogenomics Advisory Group. Includes gene-drug pairs supported by multiple studies documenting consistent effects of specific genetic variant(s) on clinical outcomes. Includes gene-drug pairs approved by the Dutch Pharmacogenetics Working Group (DPWG) and/or guidelines published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC). Moderate Includes gene-drug pairs supported by pharmacokinetic, pharmacodynamic, or molecular/cellular functional studies showing consistent effects of genetic variant(s). Includes Drug product information (e.g. This interpretation is based on guidance available in the FDA (Food and Drug Administration) drug label for ABILIFY (10/2013). Includes gene-drug pairs for which potential clinical outcomes are inferred from similar gene-drug interactions approved by the Dutch Pharmacogenetics Working Group (DPWG), and/or guidelines published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC), and/or pharmacogenomic reports and submission from the Coriell Institute for Medical Research. Emerging Includes gene-drug pairs supported by published studies of the drug, related drug, or a probing compound of interest involving limited data and/or inconsistent findings. Reference Laboratory: Peachstate Health Management LLC d/b/a Aeon Clinical Laboratories Laboratory Certification: CLIA # 11D Laboratory Director: Dr. Richard E. Mullins Ph.D., D.A.B.C.C. Page 25 of 26

27 Patient Information Card This card contains an abbreviated genetic summary. It is not intended as a replacement for the complete GeneDose report. ISPM Labs d/b/a Capstone Diagnostics Patient: Doe, Jane DOB: Sample ID: GeneDose Key: ex222 ACAZPCM6P Pharmacogenomic Summary ApoE ɛ3 ɛ3 See full GeneDose report Factor V Leiden Variant See full GeneDose report MTHFR (A1298C) Variant See full GeneDose report MTHFR (C677T) Variant See full GeneDose report Prothrombin (F2) Normal See full GeneDose report Cut on dotted lines. This card shows information about your genetics that relate to drug metabolism. Show to your doctors before being prescribed new medications. For additional support and guidance: Physicians can visit CYP2C19 *8 *8 Poor metabolizer CYP2C9 *1 *1 Extensive metabolizer CYP2D6 *1 *1x2 Ultrarapid metabolizer CYP3A4 *1B *1B Ultrarapid metabolizer CYP3A5 *1A *1A; or *1A *1D; or *1D *1D CYP4F2 *1 *1 n/a HLA- B*1502 WT WT SLCO1B1 *1 *1 Extensive metabolizer WT Normal liver uptake activity TPMT *1 *1 Extensive metabolizer VKORC1 *1 *1 Fold Here Normal (with respect to Warfarin) Coriell Life Sciences Page 26 of 26