PRODUCED by Pharmaqx Report For

PRODUCED BY PharmaQx report for

JOHN SMITH Take charge of your health

THE OBJECTIVES OF PHARMAQX

The PharmaQx pharmacogenetic analysis useful for :

1. determining whether you are at risk of experiencing side effects following the administration of a medication;

2. determining which medications are likely to be inefficient for you;

3. provide your healthcare professional recommendations regarding the dosage and use of medications.

According to your genetic profile, a notification is provided for each medication, highlighting which medications are likely to cause side effects or be inefficient. This report is provided for information purposes only and cannot be considered as a diagnostic tool.

WHAT IS ANALYZED?

PharmaQx identifies the presence of genetic variations in six (6) genes. In turn, these genes determine how to build six (6) enzymes implicated in the response to the twenty-five (25) medications included in this test. By identifying these genetic variations, we can predict whether the resulting enzyme will be functional or not. Each enzyme is then categorized in terms of is level of activity, which can go from non-fonctional to ultra-rapid.

PharmaQx offers its products and services in order to better inform healthcare professionals on the genetic backgound of its clients and the link between genetics and drug response. Do not change current and/or future therapies without first consulting your doctor. © BIOGENIQ INC.

1 DOES PHARMAQX PROVIDE INFORMATION ABOUT MY SUSCEPTIBILITY FOR DISEASES OR CONDITIONS?

No. None of the genetic variations analyzed by PharmaQx have been convincingly associated with a disease or condition.

WHAT TYPE OF ANALYSIS IS DONE?

Your DNA is extracted from the saliva sample you provided. Then, we determine the presence of genetic variations using a technique called genotyping. Unlike DNA sequencing, which consists of "reading" each DNA unit (nucleotide) one after the other, genotyping only analyzes specific positions that are of interest to us. In other words, PharmaQx only offers information regarding the response to medication.

WHAT ARE THE LIMITS OF PHARMAQX?

Despite the fact that our tests are more than 99% accurate, there is always a small probability that an error may occur.

The genetic variations analyzed by PharmaQx are known by the scientific community. It is possible that an individual carries a new variation, that has not yet been identified as being implicated in the response to medication. In this case, the PharmaQx analysis will not detect this rare variation and the individual could receive an inappropriate recommendation. It is also possible that other genes are also implicated in the response to medication but that are not included in PharmaQx.

2 TABLE OF CONTENTS

Intoduction ...... 1 ANALGESIA Genetic summary ...... 4 Codeine ...... 33 Pharmacogenetic summary ...... 5 Oxycodone ...... 35 Tramadol ...... 37 CANCER, IMMUNOLOGY AND INFLAMMATION PSYCHIATRY Azathioprine ...... 9 Amitriptyline ...... 39 Mercaptopurine ...... 11 Aripiprazole ...... 41 Tamoxifen ...... 13 Atomoxetine ...... 43 Thioguanine ...... 15 Clomipramine ...... 45 CARDIOLOGY Desipramine ...... 47 Clopidogrel ...... 17 Doxepin ...... 49 Flecainide ...... 19 Haloperidol ...... 51 Metoprolol ...... 21 Imipramine ...... 53 Simvastatin ...... 23 Nortriptyline ...... 55 Warfarin ...... 25 Trimipramine ...... 57 GASTROENTEROLOGY

Esomeprazole ...... 27 Glossary ...... 59 Lansoprazole ...... 29 Omeprazole ...... 31

3 GENETIC SUMMARY

JOHN SMITH

Sex M Date of report 2014-12-17 Ethnicity Caucasian Type of specimen Saliva Birthdate 1952-10-15 Sample number BIO-001-00001

A total of six (6) genes were analyzed to generate your PharmaQx report (see table below).

In general, you carry two versions of each gene, called alleles. By taking into consideration the individual activity of each one of your alleles, we deteremined your resulting enzymatic activity.

Of note: according the scientific nomenclature, each gene and its associated enzyme share the same name (ex : CYP2C9).

GENE ALLELES PHENOTYPE

Name given to the Versions Resulting enzymatic activity DNA sequence of your gene (based on all of your alleles)

CYP2C9 *1/*1 extensive metabolizer (normal function)

CYP2C19 *1/*2 intermediate metabolizer (reduced function)

CYP2D6 *2A/*2A extensive metabolizer (normal function)

TPMT *3B/*3C poor activity (non-functional)

VKORC1 *1/*3 high activity (increased function)

SLCO1B1 *1A/*1A extensive activity (normal function)

The genes analyzed for PharmaQx are presented in the table above. You have two copies of each gene (your alleles). The resulting enzymatic activity is indicated under the phenotype column (phenotype),

APPROVED BY: ______DATE:______

4 Date of report 2014-12-17 Sample number BIO-001-00001

PHARMACOGENETIC SUMMARY

Now that your genes have been analyzed and that we determined your resulting enzymatic activity, we identified the medications that should be used with caution.

CAUTION IS ADVISED FOR THE FOLLOWING MEDICATIONS

MEDICATION ENZYME : PHENOTYPE NOTIFICATION

CANCER, IMMUNOLOGY AND INFLAMMATION

AZATHIOPRINE TPMT : Increased risk of side effects with p.9 poor activity conventional dosing of azathioprine.

MERCAPTOPURINE TPMT : Increased risk of side effects with p.11 poor activity conventional dosing of mercaptopurine.

THIOGUANINE TPMT : Increased risk of side effects with p.15 poor activity conventional dosing of thioguanine.

CARDIOLOGY

CLOPIDOGREL CYP2C19 : Increased probability of treatment failure p.17 intermediate metabolizer with conventional dosing of clopidogrel.

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NO WARNING FOR THE FOLLOWING MEDICATIONS

MEDICATION ENZYME : PHENOTYPE NOTIFICATION

CANCER, IMMUNOLOGY AND INFLAMMATION

TAMOXIFEN CYP2D6 : No genetic variations were identified that p.13 extensive metabolizer would prompt changes in therapy.

CARDIOLOGY

FLECAINIDE CYP2D6 : No genetic variations were identified that p.19 extensive metabolizer would prompt changes in therapy.

METOPROLOL CYP2D6 : No genetic variations were identified that p.21 extensive metabolizer would prompt changes in therapy.

SIMVASTATIN SLCO1B1 : No genetic variations were identified that p.23 extensive activity would prompt changes in therapy.

WARFARIN CYP2C9 : No genetic variations were identified that p.25 extensive metabolizer would prompt changes in therapy.

VKORC1 : high activity

GASRTOENTEROLOGY

ESOMEPRAZOLE CYP2C19 : No genetic variations were identified that p.27 intermediate metabolizer would prompt changes in therapy.

LANSOPRAZOLE CYP2C19 : No genetic variations were identified that p.29 intermediate metabolizer would prompt changes in therapy.

OMEPRAZOLE CYP2C19 : No genetic variations were identified that p.31 intermediate metabolizer would prompt changes in therapy.

ANALGESIA

CODEINE CYP2D6 : No genetic variations were identified that p.33 extensive metabolizer would prompt changes in therapy.

OXYCODONE CYP2D6 : No genetic variations were identified that p.35 extensive metabolizer would prompt changes in therapy.

TRAMADOL CYP2D6 : No genetic variations were identified that p.37 extensive metabolizer would prompt changes in therapy.

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NO WARNING FOR THE FOLLOWING MEDICATIONS

MEDICATION ENZYME : PHENOTYPE NOTIFICATION

PSYCHIATRY

AMITRIPTYLINE CYP2C19 : No genetic variations were identified that p.39 intermediate metabolizer would prompt changes in therapy.

CYP2D6 : extensive metabolizer

ARIPIPRAZOLE CYP2D6 : No genetic variations were identified that p.41 extensive metabolizer would prompt changes in therapy.

ATOMOXETINE CYP2D6 : No genetic variations were identified that p.43 extensive metabolizer would prompt changes in therapy.

CLOMIPRAMINE CYP2C19 : No genetic variations were identified that p.45 intermediate metabolizer would prompt changes in therapy.

CYP2D6 : extensive metabolizer

DESIPRAMINE CYP2D6 : No genetic variations were identified that p.47 extensive metabolizer would prompt changes in therapy.

DOXEPIN CYP2C19 : No genetic variations were identified that p.49 intermediate metabolizer would prompt changes in therapy.

CYP2D6 : extensive metabolizer

HALOPERIDOL CYP2D6 : No genetic variations were identified that p.51 extensive metabolizer would prompt changes in therapy.

IMIPRAMINE CYP2C19 : No genetic variations were identified that p.53 intermediate metabolizer would prompt changes in therapy.

CYP2D6 : extensive metabolizer

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NO WARNING FOR THE FOLLOWING MEDICATIONS

MEDICATION ENZYME : PHENOTYPE NOTIFICATION

PSYCHIATRY

NORTRIPTYLINE CYP2D6 : No genetic variations were identified that p.55 extensive metabolizer would prompt changes in therapy.

TRIMIPRAMINE CYP2C19 : No genetic variations were identified that p.57 intermediate metabolizer would prompt changes in therapy.

CYP2D6 : extensive metabolizer

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AZATHIOPRINE (IMURAN®)

NOTIFICATION

Increased risk of side effects with conventional dosing of azathioprine.

RECOMMENDATIONS MEDICATION USE

Being a TPMT poor metabolizer, a significant decrease in AND INFLAMMATION IMMUNOLOGY CANCER, azathioprine metabolism is expected, which increases the risk of side effects.

• A dose adjustment could reduce the risk of side effects. immunosuppression Please consult your healthcare professional to optimize your therapy.

GENE GENOTYPE PHENOTYPE

TPMT *3B/*3C poor activity

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PREMISE FOR TPMT GENOTYPING

TPMT is the major enzyme responsible for the inactivation of azathioprine. For chronic therapy using conventional doses of azathioprine, individuals carrying one or two nonfunctional TPMT alleles are at significantly higher risk for side effects (e.g. life-threatening myelosuppression), due to significantly increased concentrations of active thioguanine nucleotide (TGNs) metabolites (these metabolites would normally be metabolized by TPMT). TPMT-guided therapy is most beneficial prior to initiating thiopurine therapy for nonmalignant immunologic disorders, to ensure that starting dosages can be adjusted accordingly.

REFERENCES Black, A.J. et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 129, 716-8 (1998). Evans, W.E., et al.Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase- deficient child with acute lymphocytic leukemia. J Pediatr 119, 985-9 (1991). Kaskas, B.A. et al. Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with azathioprine. Gut 52, 140-2 (2003). Lennard, L. Clinical implications of thiopurine methyltransferase--optimization of drug dosage and potential drug interactions. Ther Drug Monit 20, 527-31 (1998). Lennard, L., et al. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336, 225-9 (1990). Lennard, L., et al. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 46, 149-54 (1989). Meggitt, S.J., et al. Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial. Lancet 367, 839-46 (2006). Relling, M.V. et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91, 2001-8 (1999). Relling, M.V., et al. Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood 107, 843-4 (2006). Relling, M.V. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 89, 387-91 (2011). Relling, M.V. et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin Pharmacol Ther 93, 324-5 (2013).

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MERCAPTOPURINE (PURINETHOL®)

NOTIFICATION

Increased risk of side effects with conventional dosing of mercaptopurine.

RECOMMENDATIONS MEDICATION USE

Being a TPMT poor metabolizer, a significant decrease in AND INFLAMMATION IMMUNOLOGY CANCER, mercaptopurine metabolism is expected, which increases the risk of side effects.

• A dose adjustment could reduce the risk of side effects. immunosuppression Please consult your healthcare professional to optimize your therapy.

GENE GENOTYPE PHENOTYPE

TPMT *1/*3A or *3B/*3C poor activity

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PREMISE FOR TPMT GENOTYPING

TPMT is the major enzyme responsible for the inactivation of mercaptopurine. For chronic therapy using conventional doses of mercaptopurine, individuals carrying one or two nonfunctional TPMT alleles are at significantly higher risk for side effects (e.g. life-threatening myelosuppression), due to significantly increased concentrations of active thioguanine nucleotide (TGNs) metabolites (these metabolites would normally be metabolized by TPMT). TPMT-guided therapy is most beneficial prior to initiating thiopurine therapy for nonmalignant immunologic disorders, to ensure that starting dosages can be adjusted accordingly.

REFERENCES Anstey, A.V., et al. Guidelines for prescribing azathioprine in dermatology. Br J Dermatol 151, 1123-32 (2004). Arico, M. et al. The seventh international childhood acute lymphoblastic leukemia workshop report: Palermo, Italy, January 29- -30, 2005. Leukemia 19, 1145-52 (2005). Black, A.J. et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 129, 716-8 (1998). Colletti, R.B. et al. Variation in care in pediatric Crohn disease. J Pediatr Gastroenterol Nutr 49, 297-303 (2009). Evans, W.E., et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase- deficient child with acute lymphocytic leukemia. J Pediatr 119, 985-9 (1991). Evans, W.E. et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 19, 2293-301 (2001). Higgs, J.E., et al. Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics 11, 177-88 (2010). Krynetski, E.Y. & Evans, W.E. Pharmacogenetics of cancer therapy: getting personal. Am J Hum Genet 63, 11-6 (1998). Lennard, L., et al. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 46, 149-54 (1989). Lennard, L., et al. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336, 225-9 (1990). Lennard, L. Clinical implications of thiopurine methyltransferase--optimization of drug dosage and potential drug interactions. Ther Drug Monit 20, 527-31 (1998). Nygaard, U., et al. Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Clin Pharmacol Ther 75, 274-81 (2004). Relling, M.V. et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91, 2001-8 (1999). Relling, M.V., et al. Clinical implementation of pharmacogenomics: overcoming genetic exceptionalism. Lancet Oncol 11, 507-9 (2010). Relling, M.V. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 89, 387-91 (2011). Relling, M.V. et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin Pharmacol Ther 93, 324-5 (2013).

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TAMOXIFEN (TAMOXIFEN, NOLVADEX®)

NOTIFICATION

No genetic variations were identified that would prompt changes to tamoxifen therapy.

RECOMMENDATIONS MEDICATION USE CANCER, IMMUNOLOGY AND AND INFLAMMATION IMMUNOLOGY CANCER, Being a CYP2D6 extensive metabolizer, your response to tamoxifen is expected to be normal.

• No change to label-recommended dose is warranted based on CYP2D6 genotype. breast cancer

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

PREMISE FOR CYP2D6 GENOTYPING

Being a pro-drug, tamoxifen must be activated by the enzyme CYP2D6 to be effective. However, the level of activity of CYP2D6 varies from one individual to another, which can alter the response to tamoxifen. In addition, many genetic variations have been identified that influence the level of activity of CYP2D6. Therefore, knowledge of your genotype for CYP2D6 can be used to predict the efficacy of tamoxifen and to minimize the risk of breast cancer relapse.

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REFERENCES Bonanni, B. et al. Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. J Clin Oncol 24, 3708-9; author reply 3709 (2006). Borges, S. et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80, 61-74 (2006). Gjerde, J. et al. Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. Ann Oncol 19, 56-61 (2008). Goetz, M.P. et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23, 9312-8 (2005). Goetz, M.P. et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101, 113-21 (2007). Jin, Y. et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97, 30-9 (2005). Lim, H.S. et al. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25, 3837-45 (2007). Nowell, S.A. et al. Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 91, 249-58 (2005). Schroth, W. et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25, 5187-93 (2007). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011).

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THIOGUANINE (LANVIS®)

NOTIFICATION

Increased risk of side effects with conventional dosing of thioguanine.

RECOMMENDATIONS MEDICATION USE

Being a TPMT poor metabolizer, a significant decrease in AND INFLAMMATION IMMUNOLOGY CANCER, thioguanine metabolism is expected, which increases the risk of side effects.

• A dose adjustment could reduce the risk of side effects. immunosuppression Please consult your healthcare professional to optimize your therapy.

GENE GENOTYPE PHENOTYPE

TPMT *1/*3A or *3B/*3C poor activity

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PREMISE FOR TPMT GENOTYPING

Inactivation of thioguanine is mainly done through the action of TPMT, an enzyme that contributes to the clearance of this medication. For chronic therapy using conventional doses of thioguanine, individuals carrying one or two nonfunctional TPMT alleles are at significantly higher risk for side effects (e.g. life- threatening myelosuppression), due to significantly increased concentrations of active thioguanine nucleotide (TGNs) metabolites (these metabolites would normally be metabolized by TPMT). TPMT- guided therapy is most beneficial prior to initiating thiopurine therapy for nonmalignant immunologic disorders, to ensure that starting dosages can be adjusted accordingly.

REFERENCES Black, A.J. et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from thioguanine. Ann Intern Med 129, 716-8 (1998). Evans, W.E., et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase- deficient child with acute lymphocytic leukemia. J Pediatr 119, 985-9 (1991). Kaskas, B.A. et al. Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with thioguanine. Gut 52, 140-2 (2003). Lennard, L., et al. Pharmacogenetics of acute thioguanine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 46, 149-54 (1989). Lennard, L.,et al. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336, 225-9 (1990). Lennard, L. Clinical implications of thiopurine methyltransferase--optimization of drug dosage and potential drug interactions. Ther Drug Monit 20, 527-31 (1998). Meggitt, S.J., et al. thioguanine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial. Lancet 367, 839-46 (2006). Relling, M.V. et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91, 2001-8 (1999). Relling, M.V., et al. Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood 107, 843-4 (2006). Relling, M.V. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 89, 387-91 (2011). Relling, M.V. et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin Pharmacol Ther 93, 324-5 (2013).

16 Date of report 2014-12-17 Sample number BIO-001-00001 CARDIOLOGY CLOPIDOGREL (PLAVIX®)

NOTIFICATION

Increased probability of treatment failure with conventional dosing of clopidogrel.

RECOMMENDATIONS MEDICATION USE

Being a CYP2C19 intermediate metabolizer, a significant decrease in biotransformation of clopidogrel is expected, which increases the probability of treatment failure.

• The use of an alternative medication could help achieve the anticoagulation desired therapeutic effect. Please consult your healthcare professional to optimize your therapy.

GENE GENOTYPE PHENOTYPE

CYP2C19 *1/*2 intermediate metabolizer

PREMISE FOR CYP2C19 GENOTYPING

Clopidogrel is a prodrug that requires biotransformation into its active form in order to inhibit blood coagulation. CYP2C19 is the major enzyme responsible for this biotransformation and substantial evidence exists linking CYP2C19 genetics with the efficacy in preventing coagulation. CYP2C19-guided clopidogrel therapy applies predominantly for the treatment of acute coronary syndrome (ACS), particularly when undergoing percutaneaous coronary intervention (PCI).

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REFERENCES Cayla, G. et al. Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA 306, 1765-74 (2011). Collet, J.P. et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 373, 309-17 (2009). Giusti, B. et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol 103, 806-11 (2009). Gurbel, P.A., et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 107, 2908-13 (2003). Mega, J.L. et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360, 354-62 (2009). Mega, J.L. et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 304, 1821-30 (2010). O'Donoghue, M. & Wiviott, S.D. Clopidogrel response variability and future therapies: clopidogrel: does one size fit all? Circulation 114, e600-6 (2006). Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 94, 317-23 (2013). Shuldiner, A.R. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302, 849-57 (2009). Sibbing, D. et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J 30, 916-22 (2009). Simon, T. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 360, 363-75 (2009).

18 Date of report 2014-12-17 Sample number BIO-001-00001 CARDIOLOGY FLECAINIDE (TAMBOCORTM)

NOTIFICATION

No genetic variations were identified that would prompt changes to flecainide therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2D6 extensive metabolizer, your response to flecainide is expected to be normal.

• No change to label-recommended flecainide dose is warranted based on CYP2D6 genotype. cardiac rhythm

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

PREMISE FOR CYP2D6 GENOTYPING

Flecainide plasma concentrations can vary considerably from one individual to another. These differences are largely attributed to genetic variations in the main metabolizing enzyme, CYP2D6. In order to be safe and efficient, flecainide plasma concentrations must be kept within a narrow therapeutic range. Therefore, knowledge of your genotype for CYP2D6 can be used to achieve the desired therapeutic effect while minimizing the risk of side effects that can occur with high plasma concentrations, such as inappropriate changes in heart rhythm.

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REFERENCES Doki, K. et al. Effect of CYP2D6 genotype on flecainide pharmacokinetics in Japanese patients with supraventricular tachyarrhythmia. Eur J Clin Pharmacol 62, 919-26 (2006). Lim, K.S. et al. Pharmacokinetic interaction of flecainide and paroxetine in relation to the CYP2D6*10 allele in healthy Korean subjects. Br J Clin Pharmacol 66, 660-6 (2008). Morganroth, J. & Horowitz, L.N. Flecainide: its proarrhythmic effect and expected changes on the surface electrocardiogram. Am J Cardiol 53, 89B-94B (1984). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011).

20 Date of report 2014-12-17 Sample number BIO-001-00001 CARDIOLOGY METOPROLOL (BETALOC®, LOPRESOR®)

NOTIFICATION

No genetic variations were identified that would prompt changes to metoprolol therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2D6 extensive metabolizer, your response to metoprolol is expected to be normal.

• No change to label-recommended metoprolol dose is warranted based on CYP2D6 genotype. heart failure

blood pressure

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

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PREMISE FOR CYP2D6 GENOTYPING

Metoprolol plasma concentrations can vary considerably between individuals, which influences the therapeutic effect. While elevated plasma concentrations can induce side effects (low heart rate, called bradycardia), lower plasma concentrations will likely not acheive the desired therapeutic effect. Response to metoprolol is significantly affected by genetic variations in the main metabolizing enzyme CYP2D6, which directly influences plasma concentrations (up to five-fold increase in plasma concentration in poor metabolizers). Knowledge of your genotype for CYP2D6 can be used to reach optimal therapeutic plasma concentration of metoprolol and to minimize the risk of treatment failure or side effects, such as bradycardia.

REFERENCES Bijl, M.J. et al. Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users. Clin Pharmacol Ther 85, 45-50 (2009). Ismail, R. & Teh, L.K. The relevance of CYP2D6 genetic polymorphism on chronic metoprolol therapy in cardiovascular patients. J Clin Pharm Ther 31, 99-109 (2006). Nozawa, T. et al. Influence of CYP2D6 genotype on metoprolol plasma concentration and beta-adrenergic inhibition during long-term treatment: a comparison with bisoprolol. J Cardiovasc Pharmacol 46, 713-20 (2005). Rau, T. et al. Impact of the CYP2D6 genotype on the clinical effects of metoprolol: a prospective longitudinal study. Clin Pharmacol Ther 85, 269-72 (2009). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011). Wuttke, H. et al. Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects. Clin Pharmacol Ther 72, 429-37 (2002). Yuan, H. et al. Effects of polymorphism of the beta(1) adrenoreceptor and CYP2D6 on the therapeutic effects of metoprolol. J Int Med Res 36, 1354-62 (2008).

22 Date of report 2014-12-17 Sample number BIO-001-00001 CARDIOLOGY SIMVASTATIN (ZOCOR®)

NOTIFICATION

No genetic variations were identified that would prompt changes to simvastatin therapy.

RECOMMENDATIONS MEDICATION USE

Having extensive SLCO1B1 activity, your response to simvastatin is expected to be normal.

• No change to label-recommended dose is warranted based on SLCO1B1 genotype. cholesterol

GENE GENOTYPE PHENOTYPE

SLCO1B1 *1A/*1A extensive activity

PREMISE FOR SLCO1B1 GENOTYPING

Simvastatin is eliminated through the liver, but in order to reach this organ, the medication must pass through a specialized transporter called SLCO1B1. However, certain genetic variations can alter the behaviour of the SLCO1B1 transporter, which can delay the entry of simvastatin into the liver (and thus its elimination). Although statin-related side effects (e.g. muscle pain, called myopathy) are relatively uncommon (1-5%), the widespread use of these drugs has resulted in a substantial absolute number of patients to experience side effects. For example, muscle toxicity, which occurs with increased systemic exposure to simvastatin, is the most common side effect and a common cause for statin nonadherence. Therefore, genotyping of SLO1B1 is useful for determining whether simvastatin appropriate for you.

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REFERENCES Niemi, M. et al. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 63, 157-81 (2011). Pasanen, M.K. et al. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 16, 873-79 (2007). Ramsey, L.B. et al. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 Update. Clin Pharmacol Ther (2014). Wilke, R.A. et al. Clinical Pharmacogenomics Implementation Consortium (CPIC). The Clinical Pharmacogenomics Implementation Consortium: CPIC guidelines for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther 92, 112-17 (2012).

24 Date of report 2014-12-17 Sample number BIO-001-00001 CARDIOLOGY WARFARIN (COUMADIN®)

NOTIFICATION

No genetic variations were identified that would suggest warfarin sensitivity.

RECOMMENDATIONS MEDICATION USE

According to your genotypes for CYP2C9 and VKORC1, your response to warfarin is expected to be normal.

• Nevertheless, please consult your healthcare professional to determine the optimal dose for you. anticoagulation

GENES GENOTYPE PHENOTYPES

CYP2C9 *1/*1 extensive metabolizer VKORC1 *1/*3 high activity

PREMISE FOR CYP2C9 AND VKORC1 GENOTYPING

To reach the desired therapeutic effect of warfarin (i.e. controlled anticoagulation), a long process of dose adjustments is often required. During this time, you may experience unwanted bleeding or treatment may fail to be efficient. Two enzymes are known to significantly effect warfarin response: CYP2C9 and VKORC1. Many genetic variations have been identified that influence the level of activity of these enzymes and contribute to dose adjustments (up to 30%). Therefore, your genotype for CYP2C9 and VKORC1 can be useful in quickly reaching the optimal dose.

25 Date of report 2014-12-17 Sample number BIO-001-00001

REFERENCES Epstein, R.S. et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol 55, 2804-12 (2010). Johnson, J.A. et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 90, 625-9 (2011). Klein, T.E. et al. International Warfarin Pharmacogenetic Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360, 753-64 (2009). Schwarz, U.I. et al. Genetic determinants of response to Warfarin during initial anticoagulation. N Engl J Med 358, 999-1008 (2008).

26 Date of report 2014-12-17 Sample number BIO-001-00001

ESOMEPRAZOLE (NEXIUM®, VIMOVO®) GASTROENTEROLOGY

NOTIFICATION

No genetic variations were identified that would prompt changes to esomeprazole therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2C19 intermediate metabolizer, your response to esomeprazole is expected to be normal.

• No change to label-recommended dose is warranted based on CYP2C19 genotype. gastric acid

GENE GENOTYPE PHENOTYPE

CYP2C19 *1/*2 intermediate metabolizer

PREMISE FOR CYP2C19 GENOTYPING

Unlike other proton pump inhibitors (PPI), metabolism of esomeprazole is less dependent upon the hepatic enzyme CYP2C19. However, studies have not fully evaluated the effectiveness of esomeprazole therapy in individuals that are extremely efficient at metabolizing this medication (ultrarapid metabolizers). Therefore, CYP2C19 genotyping may be useful in obtaining desired therapeutic effect, especially in the case of ultrarapid metabolizers, which may require an increase in dosage of esomeprazole.

27 Date of report 2014-12-17 Sample number BIO-001-00001

REFERENCES Andersson, T., et al. Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther 15, 1563-9 (2001). Lou, H.Y., et al. Optimal dose regimens of esomeprazole for gastric acid suppression with minimal influence of the CYP2C19 polymorphism. Eur J Clin Pharmacol 65, 55-64 (2009). Schwab, M. et al. Esomeprazole-induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19: evidence from clinical and pharmacokinetic data. Clin Pharmacol Ther 78, 627-34 (2005). Sheu, B.S. et al. Esomeprazole 40 mg twice daily in triple therapy and the efficacy of Helicobacter pylori eradication related to CYP2C19 metabolism. Aliment Pharmacol Ther 21, 283-8 (2005). Sheu, B.S., et al. Body mass index can determine the healing of reflux esophagitis with Los Angeles Grades C and D by esomeprazole. Am J Gastroenterol 103, 2209-14 (2008). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011). Thitiphuree, S. & Talley, N.J. Esomeprazole, a new proton pump inhibitor: pharmacological characteristics and clinical efficacy. Int J Clin Pract 54, 537-41 (2000).

28 Date of report 2014-12-17 Sample number BIO-001-00001

LANSOPRAZOLE (DEXILANT®, PREVACID®) GASTROENTEROLOGY

NOTIFICATION

No genetic variations were identified that would prompt changes to lansoprazole therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2C19 intermediate metabolizer, your metabolism of lansoprazole is expected to be normal.

• No change to label-recommended dose is warranted based on CYP2D6 genotype. gastric acid

GENE GENOTYPE PHENOTYPE

CYP2C19 *1/*2 intermediate metabolizer

PREMISE FOR CYP2C19 GENOTYPING

Interindividual variations in plasma concentration of lansoprazole, as well as gastric pH and treatment efficacy, are largely dependent on genetic variations in CYP2C19, the primary enzyme involved in lansoprazole metabolism. Knowledge of your CYP2C19 genotype can help achieve optimal plasma concentration of lansoprazole and more efficient gastric acid inhibition. CYP2C19-guided lansoprazole therapy is aimed at optimizing treatment of acid-related diseases (e.g. peptide ulcer, gastroesophageal reflux disease (GERD) and Zollinger Ellison syndrome) and eradication of Helicobacter pylori infections (with concomitant use of antibiotics).

29 Date of report 2014-12-17 Sample number BIO-001-00001

REFERENCES Furuta, T. et al. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 69, 158-68 (2001). Furuta, T. et al. Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole. Clin Pharmacol Ther 72, 453-60 (2002). Furuta, T. et al. Effect of concomitant dosing of famotidine with lansoprazole on gastric acid secretion in relation to CYP2C19 genotype status. Aliment Pharmacol Ther 22, 67-74 (2005). Furuta, T. et al. Influence of CYP2C19 polymorphism and Helicobacter pylori genotype determined from gastric tissue samples on response to triple therapy for H pylori infection. Clin Gastroenterol Hepatol 3, 564-73 (2005). Furuta, T. et al. Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. pylori. Clin Pharmacol Ther 81, 521-8 (2007). Furuta, T. et al. CYP2C19 genotype is associated with symptomatic recurrence of GERD during maintenance therapy with low- dose lansoprazole. Eur J Clin Pharmacol 65, 693-8 (2009). Hunfeld, N.G. et al. Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians. Br J Clin Pharmacol 65, 752-60 (2008). Inaba, T. et al. Randomized open trial for comparison of proton pump inhibitors in triple therapy for Helicobacter pylori infection in relation to CYP2C19 genotype. J Gastroenterol Hepatol 17, 748-53 (2002). Kawabata, H. et al. Effect of different proton pump inhibitors, differences in CYP2C19 genotype and antibiotic resistance on the eradication rate of Helicobacter pylori 0infection by a 1-week regimen of proton pump inhibitor, amoxicillin and clarithromycin. Aliment Pharmacol Ther 17, 259-64 (2003). Kawamura, M. et al. Cytochrome P450 2C19 polymorphism influences the preventive effect of lansoprazole on the recurrence of erosive reflux esophagitis. J Gastroenterol Hepatol 22, 222-6 (2007). Kawamura, M. et al. The effects of lansoprazole on erosive reflux oesophagitis are influenced by CYP2C19 polymorphism. Aliment Pharmacol Ther 17, 965-73 (2003). Padol, S., et al. The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis. Am J Gastroenterol 101, 1467-75 (2006). Pearce, R.E., et al. Identification of the human P450 enzymes involved in lansoprazole metabolism. J Pharmacol Exp Ther 277, 805-16 (1996). Sakurai, Y. et al. Population pharmacokinetics and proton pump inhibitory effects of intravenous lansoprazole in healthy Japanese males. Biol Pharm Bull 30, 2238-43 (2007). Shirai, N. et al. Comparison of lansoprazole and famotidine for gastric acid inhibition during the daytime and night-time in different CYP2C19 genotype groups. Aliment Pharmacol Ther 16, 837-46 (2002). Sohn, D.R.,et al. Metabolic disposition of lansoprazole in relation to the S-mephenytoin 4'-hydroxylation phenotype status. Clin Pharmacol Ther 61, 574-82 (1997). Sugimoto, M. et al. Influences of proinflammatory and anti-inflammatory cytokine polymorphisms on eradication rates of clarithromycin-sensitive strains of Helicobacter pylori by triple therapy. Clin Pharmacol Ther 80, 41-50 (2006). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011). Zhao, F. et al. Effect of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple therapy for Helicobacter pylori eradication: a meta-analysis. Helicobacter 13, 532-41 (2008).

30 Date of report 2014-12-17 Sample number BIO-001-00001

OMEPRAZOLE (GASTROGARD®, LOSEC®, OLEX®) GASTROENTEROLOGY

NOTIFICATION

No genetic variations were identified that would prompt changes to omeprazole therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2C19 intermediate metabolizer, your response to omeprazole is expected to be normal.

• No change to label-recommended dose is warranted based on CYP2C19 genotype. gastric acid

GENE GENOTYPE PHENOTYPE

CYP2C19 *1/*2 intermediate metabolizer

PREMISE FOR CYP2C19 GENOTYPING

Omeprazole is primarily metabolized through CYP2C19, an enzyme that can have various levels of activity, depending on your genetic profile. In turn, the level of activity of CYP2C19 influences the efficacy of treatment with omeprazole, i.e. the inhibition of gastric acid. Therefore, knowledge of your CYP2C19 genotype can help achieve optimal plasma concentration of omeprazole and acid inhibition. CYP2C19 genotyping can be used to optimize treatment of acid-related diseases (e.g. peptide ulcer, gastroesophageal reflux disease (GERD) and Zollinger Ellison syndrome) and eradication of Helicobacter pylori infections (with concomitant use of antibiotics), with proton pump inhibitors like omeprazole.

31 Date of report 2014-12-17 Sample number BIO-001-00001

REFERENCES Andersson, T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet 31, 9-28 (1996). Ando, T. et al. A comparative study on endoscopic ulcer healing of omeprazole versus rabeprazole with respect to CYP2C19 genotypic differences. Dig Dis Sci 50, 1625-31 (2005). Ando, T. et al. Endoscopic analysis of gastric ulcer after one week's treatment with omeprazole and rabeprazole in relation to CYP2C19 genotype. Dig Dis Sci 53, 933-7 (2008). Baldwin, R.M. et al. Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. Br J Clin Pharmacol 65, 767-74 (2008). Furuta, T. et al. CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther 65, 552-61 (1999). Furuta, T. et al. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 69, 158-68 (2001). Gawronska-Szklarz, B. et al. Effect of CYP2C19 and MDR1 polymorphisms on cure rate in patients with acid-related disorders with Helicobacter pylori infection. Eur J Clin Pharmacol 61, 375-9 (2005). Hunfeld, N.G. et al. Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians. Br J Clin Pharmacol 65, 752-60 (2008). Ohkusa, T. et al. Effect of CYP2C19 polymorphism on the safety and efficacy of omeprazole in Japanese patients with recurrent reflux oesophagitis. Aliment Pharmacol Ther 21, 1331-9 (2005). Roh, H.K. et al. Omeprazole treatment of Korean patients: effects on gastric pH and gastrin release in relation to CYP2C19 geno- and phenotypes. Basic Clin Pharmacol Toxicol 95, 112-9 (2004). Sagar, M., et al. Effects of omeprazole on intragastric pH and plasma gastrin are dependent on the CYP2C19 polymorphism. Gastroenterology 119, 670-6 (2000). Sapone, A. et al. The clinical role of cytochrome p450 genotypes in Helicobacter pylori management. Am J Gastroenterol 98, 1010-5 (2003). Sheu, B.S. et al. Esomeprazole 40 mg twice daily in triple therapy and the efficacy of Helicobacter pylori eradication related to CYP2C19 metabolism. Aliment Pharmacol Ther 21, 283-8 (2005). Shimatani, T. et al. Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H2-receptor antagonist. Aliment Pharmacol Ther 18, 1149-57 (2003). Shirai, N. et al. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH. Aliment Pharmacol Ther 15, 1929-37 (2001). Sim, S.C. et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79, 103-13 (2006). Sugimoto, M. et al. Initial 48-hour acid inhibition by intravenous infusion of omeprazole, famotidine, or both in relation to cytochrome P450 2C19 genotype status. Clin Pharmacol Ther 80, 539-48 (2006). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011). Zhao, F. et al. Effect of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple therapy for Helicobacter pylori eradication: a meta-analysis. Helicobacter 13, 532-41 (2008).

32 Date of report 2014-12-17 Sample number BIO-001-00001

CODEINE ANALGESIA (CODEINE CONTIN®)

NOTIFICATION

No genetic variations were identified that would prompt changes to clopidogrel therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2C19 extensive metabolizer, your response to clopidogrel is expected to be normal.

• No change to label-recommended dose is warranted based on CYP2C19 genotype. pain management

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

PREMISE FOR CYP2D6 GENOTYPING

33 Date of report 2014-12-17 Sample number BIO-001-00001

REFERENCES Crews, K.R. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 91, 321-6 (2012). Crews, K.R. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 95, 376-82 (2014). Eckhardt, K. et al. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 76, 27-33 (1998). Gasche, Y. et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 351, 2827-31 (2004). Kelly, L.E. et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 129, e1343-7 (2012). Kirchheiner, J. et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J 7, 257-65 (2007). Lalovic, B. et al. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 79, 461-79 (2006). Lotsch, J. et al. Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation? Pain 144, 119-24 (2009). Stamer, U.M. et al. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther 82, 41-7 (2007).

34 Date of report 2014-12-17 Sample number BIO-001-00001

OXYCODONE ANALGESIA (OXYNEO®, SUPEUDOL®)

NOTIFICATION

No genetic variations were identified that would prompt changes to oxycodone therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2D6 extensive metabolizer, your response to oxycodone is expected to be normal.

• No change to label-recommended dose is warranted based on CYP2D6 genotype. pain management

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

PREMISE FOR CYP2D6 GENOTYPING

CYP2D6 converts oxycodone into oxymorphone, an essentiel step in obtaining the analgesic effect of this medication. Many genetic variations have been identified in the enzyme CYP2D6, which can have a significant impact on the level of activity of this enzyme. In turn, this can influence the efficacy and safety of treatment with oxycodone. Knowledge of your genotype for CYP2D6 can be used to guide treatment choice, reach optimal therapeutic plasma concentration of oxycodone, and to minimize the risk of treatment failure or side effects.

35 Date of report 2014-12-17 Sample number BIO-001-00001

REFERENCES de Leon, J., et al. Adverse drug reactions to oxycodone and hydrocodone in CYP2D6 ultrarapid metabolizers. J Clin Psychopharmacol 23, 420-1 (2003). Foster, A., et al. Complicated pain management in a CYP450 2D6 poor metabolizer. Pain Pract 7, 352-6 (2007). Jannetto, P.J. & Bratanow, N.C. Utilization of pharmacogenomics and therapeutic drug monitoring for opioid pain management. Pharmacogenomics 10, 1157-67 (2009). Maddocks, I., et al. Attenuation of morphine-induced delirium in palliative care by substitution with infusion of oxycodone. J Pain Symptom Manage 12, 182-9 (1996). Susce, M.T., et al. Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Prog Neuropsychopharmacol Biol Psychiatry 30, 1356-8 (2006). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011). Zwisler, S.T. et al. The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism. Basic Clin Pharmacol Toxicol 104, 335-44 (2009).

36 Date of report 2014-12-17 Sample number BIO-001-00001

TRAMADOL ANALGESIA (DURELATM, RALIVIAMC, TRIDURALMD, ULTRAM®, ZYTRAM XL®)

NOTIFICATION

No genetic variations were identified that would prompt changes to tramadol therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2D6 extensive metabolizer, your response to tramadol is expected to be normal.

• No change to label-recommended dose is warranted based on CYP2D6 genotype. pain management

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

PREMISE FOR CYP2D6 GENOTYPING

The analgesic effect of tramadol is ensured by the contribution of two molecules: tramadol and O- desmethyl tramadol. While tramadol acts by inhibiting the recapture of serotonine et norepinephrine (non-μ-opioid effect), O-desmethyl tramadol has a much stronger μ-opioid effect. The reaction that converts tramadol into O-desmethyl tramadol is attributed to the action of the CYP2D6 enzyme. How- ever, many genetic variations exist that influence the level of activity of this enzyme. While a reduction in CYP2D6's activity reduces the efficacy of tramadol, an increase in CYP2D6 activity can induce side effects due to the high plasma concentration of O-desmethyl tramadol. Therefore, knowledge of your genotype for CYP2D6 can be used to reach optimal therapeutic plasma concentration of tramadol, thereby minimizing the risk of treatment failure or side effects.

37 Date of report 2014-12-17 Sample number BIO-001-00001

REFERENCES Abdel-Rahman, S.M. et al. Concordance between tramadol and dextromethorphan parent/metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation. J Clin Pharmacol 42, 24-9 (2002). Borlak, J., et al. A rapid and simple CYP2D6 genotyping assay--case study with the analgetic tramadol. Metabolism 52, 1439- 43 (2003). Enggaard, T.P. et al. The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesth Analg 102, 146-50 (2006). Fliegert, F., et al. The effects of tramadol on static and dynamic pupillometry in healthy subjects--the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status. Eur J Clin Pharmacol 61, 257-66 (2005). Garcia-Quetglas, E. et al. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res 55, 122-30 (2007). Gleason, P.P., et al. Debilitating reaction following the initial dose of tramadol. Ann Pharmacother 31, 1150-2 (1997). Halling, J., et al. CYP2D6 polymorphism in relation to tramadol metabolism: a study of faroese patients. Ther Drug Monit 30, 271-5 (2008). Kirchheiner, J., et al. Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. J Clin Psychopharmacol 28, 78-83 (2008). Paar, W.D., et al. Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 53, 235-9 (1997). Poulsen, L., et al. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 60, 636-44 (1996). Slanar, O. et al. Miotic action of tramadol is determined by CYP2D6 genotype. Physiol Res 56, 129-36 (2007). Stamer, U.M. et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 105, 231-8 (2003). Stamer, U.M. et al. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther 82, 41-7 (2007). Stamer, U.M., et al. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg 107, 926-9 (2008). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011). Wang, G., et al. Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. Eur J Clin Pharmacol 62, 927-31 (2006).

38 Date of report 2014-12-17 Sample number BIO-001-00001 PSYCHIATRY AMITRIPTYLINE (ELAVIL, LEVATE, TRILAVIL®)

NOTIFICATION

No genetic variations were identified that would prompt changes to amitriptyline therapy.

RECOMMENDATIONS MEDICATION USE

Since your are a CYP2D6 extensive metabolizer and a CYP2C19 intermediate metabolizer, your response to amitriptyline is expected to be normal.

• No change to label-recommended dose is warranted depression based on CYP2C19 and CYP2D6 genotypes.

neuropathic pain

GENES GENOTYPES PHENOTYPES

CYP2D6 *2A/*2A extensive metabolizer CYP2C19 *1/*2 intermediate metabolizer

39 Date of report 2014-12-17 Sample number BIO-001-00001

PREMISE FOR CYP2C19 AND CYP2D6 GENOTYPING

The plasma concentration of tricyclic antidepressants, such as amitriptyline, can vary considerably from one individual to another. These variations are associated with tolerance and treatment efficacy. In order to predict your response to amitriptyline, we analyzed two enzymes that are important for metabolism of this medication, a determining factor for plasma concentrations. While amitriptyline is mostly metabolized by CYP2C19 to nortriptyline, an antidepressant drug itself with distinct clinical features that differ from amitriptyline, CYP2D6 is the major enzyme responsible for drug clearance. Many genetic variations have been identified for both CYP2D6 and CYP2C19, and these variations are associated with the metabolism of tricyclics antidepressants. Therefore your genotype for CYP2D6 and CYP2C19 can be used to guide amitriptyline dosing for psychological disorders and pain management, and to reduce the risk of treatment failure and side effects. The recommendations regarding CYP2D6- and CYP2C19-guided amitriptyline therapy are for treatment of psychological disorders such as depression. Since lower dosages of amitriptyline are used for treatment of neuropathic pain, it is less likely that genetic variations of CYP2D6 and CYP2C19 will alter the risk of side effects. However, if larger doses of amitriptyline are warranted, the CYP2D6- and CYP2C19- guided dosing can be followed.

REFERENCES Benz, R.D. & Irausquin, H. Priority-based assessment of food additives database of the U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition. Environ Health Perspect 96, 85-9 (1991). Crews, K.R. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 91, 321-6 (2012). Dalen, P., et al.10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther 63, 444-52 (1998). Hicks, J.K. et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 93, 402-8 (2013). Jiang, Z.P. et al. The role of CYP2C19 in amitriptyline N-demethylation in Chinese subjects. Eur J Clin Pharmacol 58, 109-13 (2002). Kirchheiner, J. & Seeringer, A. Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes. Biochim Biophys Acta 1770, 489-94 (2007). Lee, S.J. et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 37, 1464-70 (2009). Rudorfer, M.V. & Potter, W.Z. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol 19, 373-409 (1999). Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 90, 328-32 (2011). Stingl, J.C., et al. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry 18, 273-87 (2013). Zhou, Q. et al. Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese. Pharmacogenomics J 9, 380-94 (2009).

40 Date of report 2014-12-17 Sample number BIO-001-00001 PSYCHIATRY ARIPIPRAZOLE (ABILIFYTM, ABILIFY MAINTENATM)

NOTIFICATION

No genetic variations were identified that would prompt changes to aripiprazole therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2D6 extensive metabolizer, your response to aripiprazole is expected to be normal.

• No change to label-recommended dose is warranted based on CYP2D6 genotype. antipsychotic

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

PREMISE FOR CYP2D6 GENOTYPING

Aripiprazole is primarily metabolized by the enzyme CYP2D6. Many versions of this enzyme exist, which have different levels of activity. This is one of the reasons why some people respond differently to treatment with aripiprazole. This variability is due to different plasma concentrations of aripiprazole in individuals having genetic variations in the CYP2D6 gene. Higher than normal plasma concentrations can result in long-term toxicity, such as dose-dependent adrenocortical toxicity and increased incidence of adrenocortical and combined carcinomas, especially because of the good tolerability of aripiprazole. Therefore, knowledge of your genotype for CYP2D6 can be used to reach optimal therapeutic plasma concentration of aripiprazole and to minimize the risk of treatment failure and side effects.

41 Date of report 2014-12-17 Sample number BIO-001-00001

REFERENCES Hendset, M. et al. Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole. Eur J Clin Pharmacol 63, 1147-51 (2007). Kubo, M. et al. Influence of itraconazole co-administration and CYP2D6 genotype on the pharmacokinetics of the new antipsychotic ARIPIPRAZOLE. Drug Metab Pharmacokinet 20, 55-64 (2005) Kubo, M. et al. J. Pharmacokinetics of aripiprazole, a new antipsychotic, following oral dosing in healthy adult Japanese volunteers: influence of CYP2D6 polymorphism. Drug Metab Pharmacokinet 22, 358-66 (2007) Mallikaarjun, S. et al. Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers. J Clin Pharmacol 44, 179-87 (2004). Oosterhuis, M. et al. Safety of aripiprazole: high serum levels in a CYP2D6 mutated patient. Am J Psychiatry 164, 175 (2007). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011).

42 Date of report 2014-12-17 Sample number BIO-001-00001 PSYCHIATRY ATOMOXETINE (STRATTERA®)

NOTIFICATION

No genetic variations were identified that would prompt changes to atomoxetine therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2D6 extensive metabolizer, your response to atomoxetine is expected to be normal.

• No change to label-recommended dose is warranted based on CYP2D6 genotype. attention deficit disorder

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

PREMISE FOR CYP2D6 GENOTYPING

The enzyme mainly responsible for the metabolism of atomoxetine is CYP2D6, which has a large spectrum of activity depending on a person's genetics. Although atomoxetine is generally well- tolerated, some poor metabolizers can experience side effects, such as increased heart rate and weight loss. On the other hand, ultrarapid metabolizers could not benefit from the desired therapeutic effect. Despite the fact that label-recommended dosage is often efficient, knowledge of your CYP2D6 genotype can help dose adjustments.

43 Date of report 2014-12-17 Sample number BIO-001-00001

REFERENCES Michelson, D. et al. CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry 46, 242-51 (2007). Ramoz, N. et al. A haplotype of the norepinephrine transporter (Net) gene Slc6a2 is associated with clinical response to atomoxetine in attention-deficit hyperactivity disorder (ADHD). Neuropsychopharmacology 34, 2135-42 (2009). Sauer, J.M. et al. Disposition and metabolic fate of atomoxetine hydrochloride: the role of CYP2D6 in human disposition and metabolism. Drug Metab Dispos 31, 98-107 (2003). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011). Trzepacz, P.T. et al. CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD. Eur Neuropsychopharmacol 18, 79-86 (2008).

44 Date of report 2014-12-17 Sample number BIO-001-00001 PSYCHIATRY CLOMIPRAMINE (ANAFRANIL®)

NOTIFICATION

No genetic variations were identified that would prompt changes to clomipramine therapy.

RECOMMENDATIONS MEDICATION USE

Since you are a CYP2D6 extensive metabolizer and a CYP2C19 intermediate metabolizer phenotype, your response to clomipramine is expected to be normal.

• No change to label-recommended dose is warranted depression based on CYP2C19 and CYP2D6 genotypes.

neuropathic pain

GENES GENOTYPES PHENOTYPES

CYP2D6 *2A/*2A extensive metabolizer CYP2C19 *1/*2 intermediate metabolizer

45 Date of report 2014-12-17 Sample number BIO-001-00001

PREMISE FOR CYP2C19 AND CYP2D6 GENOTYPING

The plasma concentration of tricyclic antidepressants, such as clomipramine, can vary considerably from one individual to another. These variations are associated with tolerance and treatment efficacy. In order to predict your response to clomipramine we analyzed two enzymes that are important for metabolism of this medication, a determining factor for plasma concentrations. While clomipramine is mostly metabolized by CYP2C19 to desmethyl-clomipramine, CYP2D6 is the major enzyme responsible for drug clearance. Many genetic variations have been identified for both CYP2D6 and CYP2C19, and these variations are associated with the metabolism of tricyclics antidepressants. Therefore, your genotype for CYP2D6 and CYP2C19 can be used to guide clomipramine dosing for psychological disorders and to reduce the risk of treatment failure and side effects. The recommendations regarding CYP2D6- and CYP2C19-guided clomipramine therapy are for treatment of psychological disorders such as depression. Since lower dosages of clomipramine are used for treatment of neuropathic pain, it is less likely that genetic variations of CYP2D6 and CYP2C19 will alter the risk of side effects. However, if larger doses of clomipramine are warranted, the CYP2D6- and CYP2C19-guided dosing can be followed.

REFERENCES Benz, R.D. & Irausquin, H. Priority-based assessment of food additives database of the U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition. Environ Health Perspect 96, 85-9 (1991). Bertilsson, L., et al. Extremely rapid hydroxylation of debrisoquine: a case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther Drug Monit 7, 478-80 (1985). Crews, K.R. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 91, 321-6 (2012). Dalen, P., et al. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther 63, 444-52 (1998). Hicks, J.K. et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 93, 402-8 (2013). Kirchheiner, J. & Seeringer, A. Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes. Biochim Biophys Acta 1770, 489-94 (2007). Lee, S.J. et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 37, 1464-70 (2009). Rudorfer, M.V. & Potter, W.Z. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol 19, 373-409 (1999). Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 90, 328-32 (2011). Stingl, J.C., et al. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry 18, 273-87 (2013). Zhou, Q. et al. Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese. Pharmacogenomics J 9, 380-94 (2009).

46 Date of report 2014-12-17 Sample number BIO-001-00001 PSYCHIATRY DESIPRAMINE (NORPRAMIN®)

NOTIFICATION

No genetic variations were identified that would prompt changes to desipramine therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2D6 extensive metabolizer, your response to desipramine is expected to be normal.

• No change to label-recommended dose is warranted based on CYP2D6 genotype. depression

neuropathic pain

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

47 Date of report 2014-12-17 Sample number BIO-001-00001

PREMISE FOR CYP2D6 GENOTYPING

The plasma concentration of tricyclic antidepressants, such as desipramine, can vary considerably from one individual to another. These variations are associated with tolerance and treatment efficacy. In order to predict your response to desipramine we analyzed the main enzyme responsible for metabolism, CYP2D6. Knowledge of your CYP2D6 genotype can be used to guide dosing and reach optimal therapeutic plasma concentration of desipramine, minimizing the risk of treatment failure or side effects. The recommendations regarding CYP2D6-guided desipramine therapy are for treatment of psychological disorders such as depression. Since lower dosages of desipramine are used for treatment of neuropathic pain, it is less likely that genetic variations of CYP2D6 will alter the risk of side effects. However, if larger doses of desipramine are warranted, the CYP2D6-guided dosing can be followed.

REFERENCES Benz, R.D. & Irausquin, H. Priority-based assessment of food additives database of the U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition. Environ Health Perspect 96, 85-9 (1991). Bertilsson, L., et al. Extremely rapid hydroxylation of debrisoquine: a case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther Drug Monit 7, 478-80 (1985). Crews, K.R. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 91, 321-6 (2012). Dalen, P., et al. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther 63, 444-52 (1998). Hicks, J.K. et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 93, 402-8 (2013). Kirchheiner, J. & Seeringer, A. Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes. Biochim Biophys Acta 1770, 489-94 (2007). Lee, S.J. et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 37, 1464-70 (2009). Potter, W.Z., et al. Single-dose kinetics predict steady-state concentrations on imipramine and desipramine. Arch Gen Psychiatry 37, 314-20 (1980). Rudorfer, M.V. & Potter, W.Z. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol 19, 373-409 (1999). Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 90, 328-32 (2011). Stingl, J.C., et al. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry 18, 273-87 (2013). Zhou, Q. et al. Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese. Pharmacogenomics J 9, 380-94 (2009).

48 Date of report 2014-12-17 Sample number BIO-001-00001 PSYCHIATRY DOXEPIN (SINEQUANTM, SILENOR®)

NOTIFICATION

No genetic variations were identified that would prompt changes to doxepin therapy.

RECOMMENDATIONS MEDICATION USE

Since you are a CYP2D6 extensive metabolizer and a CYP2C19 intermediate metabolizer, your response to doxepin is expected to be normal.

• No change to label-recommended dose is warranted depression based on CYP2C19 and CYP2D6 genotypes.

neuropathic pain

GENES GENOTYPES PHENOTYPES

CYP2D6 *2A/*2A extensive metabolizer CYP2C19 *1/*2 intermediate metabolizer

49 Date of report 2014-12-17 Sample number BIO-001-00001

PREMISE FOR CYP2C19 AND CYP2D6 GENOTYPING

The plasma concentration of tricyclic antidepressants, such as doxepin, can vary considerably from one individual to another. These variations are associated with tolerance and treatment efficacy. In order to predict your response to doxepin, we analyzed two enzymes that are important for metabolism of this medication, a determining factor for plasma concentrations. While doxepin is mostly metabolized by CYP2C19 to desmethyl-doxepin CYP2D6 is the major enzyme responsible for drug clearance. Many genetic variations have been identified for both CYP2D6 and CYP2C19, and these variations are associated with the metabolism of tricyclics antidepressants. Therefore an individual's genotype for CYP2D6 and CYP2C19 can be used to guide doxepin dosing for psychological disorders and to reduce the risk of treatment failure and side effects. The recommendations regarding CYP2D6- and CYP2C19-guided doxepin therapy are for treatment of psychological disorders such as depression. Since lower dosages of doxepin are used for treatment of neuropathic pain, it is less likely that genetic variations of CYP2D6 and CYP2C19 will alter the risk of side effects. However, if larger doses of doxepin are warranted, the CYP2D6- and CYP2C19-guided dosing can be followed.

REFERENCES Benz, R.D. & Irausquin, H. Priority-based assessment of food additives database of the U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition. Environ Health Perspect 96, 85-9 (1991). Bertilsson, L., et al. Extremely rapid hydroxylation of debrisoquine: a case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther Drug Monit 7, 478-80 (1985). Crews, K.R. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 91, 321-6 (2012). Dalen, P., et al. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther 63, 444-52 (1998). Hicks, J.K. et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 93, 402-8 (2013). Kirchheiner, J. & Seeringer, A. Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes. Biochim Biophys Acta 1770, 489-94 (2007). Lee, S.J. et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 37, 1464-70 (2009). Rudorfer, M.V. & Potter, W.Z. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol 19, 373-409 (1999). Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 90, 328-32 (2011). Stingl, J.C., et al. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry 18, 273-87 (2013). Zhou, Q. et al. Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese. Pharmacogenomics J 9, 380-94 (2009).

50 Date of report 2014-12-17 Sample number BIO-001-00001 PSYCHIATRY HALOPERIDOL (HALDOL, HALDOL LA)

NOTIFICATION

No genetic variations were identified that would prompt changes to haloperidol therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2D6 extensive metabolizer, your response to haloperidol is expected to be normal.

• No change to label-recommended haloperidol dose is warranted based on CYP2D6 genotype. antipsychotic

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

PREMISE FOR CYP2D6 GENOTYPING

While haloperidol is prescribed as a high-potency antipsychotic drug, plasma concentrations can vary considerably between individuals, especially when given orally. This variation is affected by the rate of metabolism of haloperidol, which occurs mainly through the action of the enzyme, CYP2D6. As this enzyme's level of activity is determined genetically, knowledge of your CYP2D6 genotype can be used to optimize oral haloperidol therapy by providing predictive information for the risk of adverse drug reactions or the expected efficacy. Since variability in plasma concentrations is lower when haloperidol is given parenterally, these recommendations apply only to orally administered haloperidol. Despite this, genotyping of CYP2D6 can be useful in selected cases of ineffective therapy or adverse drug reactions.

51 Date of report 2014-12-17 Sample number BIO-001-00001

REFERENCES Brockmoller, J. et al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin Pharmacol Ther 72, 438-52 (2002). Desai, M. et al. Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6. Pharmacogenomics J 3, 105-13 (2003). Inada, T., et al. Cytochrome P450 II D6 gene polymorphisms and the neuroleptic-induced extrapyramidal symptoms in Japanese schizophrenic patients. Psychiatr Genet 13, 163-8 (2003). Llerena, A., et al. Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: increased plasma levels of the reduced metabolite in poor metabolizers. Ther Drug Monit 14, 261-4 (1992). Llerena, A. et al. Relationship between haloperidol plasma concentration, debrisoquine metabolic ratio, CYP2D6 and CYP2C9 genotypes in psychiatric patients. Pharmacopsychiatry 37, 69-73 (2004). Mihara, K. et al. Effects of the CYP2D6*10 allele on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia. Clin Pharmacol Ther 65, 291-4 (1999). Ohara, K. et al. Effects of smoking and cytochrome P450 2D6*10 allele on the plasma haloperidol concentration/dose ratio. Prog Neuropsychopharmacol Biol Psychiatry 27, 945-9 (2003). Ohnuma, T., et al. Haloperidol plasma concentration in Japanese psychiatric subjects with gene duplication of CYP2D6. Br J Clin Pharmacol 56, 315-20 (2003). Panagiotidis, G., et al. Depot haloperidol treatment in outpatients with schizophrenia on monotherapy: impact of CYP2D6 polymorphism on pharmacokinetics and treatment outcome. Ther Drug Monit 29, 417-22 (2007). Park, J.Y. et al. Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects. J Clin Psychopharmacol 26, 135-42 (2006) Shimoda, K. et al. CYP2D6*10 alleles are not the determinant of the plasma haloperidol concentrations in Asian patients. Ther Drug Monit 22, 392-6 (2000). Someya, T. et al. Effect of CYP2D6 genotypes on the metabolism of haloperidol in a Japanese psychiatric population. Neuropsychopharmacology 28, 1501-5 (2003). Swen, J.J. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther 89, 662-73 (2011). Yasui-Furukori, N. et al. Effect of the CYP2D6 genotype on prolactin concentration in schizophrenic patients treated with haloperidol. Schizophr Res 52, 139-42 (2001).

52 Date of report 2014-12-17 Sample number BIO-001-00001 PSYCHIATRY IMIPRAMINE (IMPRIL, TOFRANIL®)

NOTIFICATION

No genetic variations were identified that would prompt changes to imipramine therapy.

RECOMMENDATIONS MEDICATION USE

Since you are a CYP2D6 extensive metabolizer and a CYP2C19 intermediate metabolizer, your response to imipramine is expected to be normal.

• No change to label-recommended dose is warranted depression based on CYP2C19 and CYP2D6 genotypes.

neuropathic pain

GENES GENOTYPES PHENOTYPES

CYP2D6 *2A/*2A extensive metabolizer CYP2C19 *1/*2 intermediate metabolizer

53 Date of report 2014-12-17 Sample number BIO-001-00001

PREMISE FOR CYP2C19 AND CYP2D6 GENOTYPING

The plasma concentration of tricyclic antidepressants, such as imipramine, can vary considerably from one individual to another. These variations are associated with tolerance and treatment efficacy. In order to predict your response to imipramine, we analyzed two enzymes that are important for metabolism of this medication, a determining factor for plasma concentrations. While imipramine is mostly metabolized by CYP2C19 to desipramine, which is an antidepressant drug itself with distinct clinical features that differ from imipramine, CYP2D6 is the major enzyme responsible for drug clearance. Many genetic variations have been identified for both CYP2D6 and CYP2C19, and these variations are associated with the metabolism of tricyclics antidepressants. Therefore your genotype for CYP2D6 and CYP2C19 can be used to guide imipramine dosing for psychological disorders and to reduce the risk of treatment failure and side effects. The recommendations regarding CYP2D6- and CYP2C19-guided imipramine therapy are for treatment of psychological disorders such as depression. Since lower dosages of imipramine are used for treatment of neuropathic pain, it is less likely that genetic variations of CYP2D6 and CYP2C19 will alter the risk of side effects. However, if larger doses of imipramine are warranted, the CYP2D6- and CYP2C19-guided dosing can be followed.

REFERENCES Benz, R.D. & Irausquin, H. Priority-based assessment of food additives database of the U.S. Food and Drug Administration Cen- ter for Food Safety and Applied Nutrition. Environ Health Perspect 96, 85-9 (1991). Crews, K.R. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 91, 321-6 (2012). Dalen, P., et al. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharma- col Ther 63, 444-52 (1998). Hicks, J.K. et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 93, 402-8 (2013). Kirchheiner, J. & Seeringer, A. Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes. Bio- chim Biophys Acta 1770, 489-94 (2007). Lee, S.J. et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 37, 1464-70 (2009). Potter, W.Z.,et al. Single-dose kinetics predict steady-state concentrations on imipramine and desipramine. Arch Gen Psychia- try 37, 314-20 (1980). Rudorfer, M.V. & Potter, W.Z. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol 19, 373-409 (1999). Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 90, 328-32 (2011). Stingl, J.C., et al. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry 18, 273-87 (2013). Zhou, Q. et al. Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese. Pharmacogenomics J 9, 380-94 (2009).

54 Date of report 2014-12-17 Sample number BIO-001-00001 PSYCHIATRY NORTRIPTYLINE (AVENTYL®)

NOTIFICATION

No genetic variations were identified that would prompt changes to nortriptyline therapy.

RECOMMENDATIONS MEDICATION USE

Being a CYP2D6 extensive metabolizer, your metabolism of nortriptyline is expected to be normal.

• No change to label-recommended nortriptyline dose is warranted based on CYP2D6 genotype. depression

neuropathic pain

GENE GENOTYPE PHENOTYPE

CYP2D6 *2A/*2A extensive metabolizer

55 Date of report 2014-12-17 Sample number BIO-001-00001

PREMISE FOR CYP2D6 GENOTYPING

The plasma concentration of tricyclic antidepressants, such as nortriptyline, can vary considerably from one individual to another. These variations are associated with tolerance and treatment efficacy. In order to predict your response to nortriptyline, we analyzed the main enzyme responsible for metabolism, CYP2D6. Knowledge of your CYP2D6 genotype can be used to guide dosing and reach optimal therapeutic plasma concentration of nortriptyline, minimizing the risk of treatment failure or side effects. The recommendations regarding CYP2D6-guided nortriptyline therapy are for treatment of psychological disorders such as depression. Since lower dosages of desipramine are used for treatment of neuropathic pain, it is less likely that genetic variations of CYP2D6 will alter the risk of side effects. However, if larger doses of nortriptyline are warranted, the CYP2D6-guided dosing can be followed.

REFERENCES Benz, R.D. & Irausquin, H. Priority-based assessment of food additives database of the U.S. Food and Drug Administration Cen- ter for Food Safety and Applied Nutrition. Environ Health Perspect 96, 85-9 (1991). Bertilsson, L., et al. Extremely rapid hydroxylation of debrisoquine: a case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther Drug Monit 7, 478-80 (1985). Crews, K.R. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 91, 321-6 (2012). Dalen, P., et al. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharma- col Ther 63, 444-52 (1998). Hicks, J.K. et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 93, 402-8 (2013). Kirchheiner, J. & Seeringer, A. Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes. Bio- chim Biophys Acta 1770, 489-94 (2007). Lee, S.J. et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 37, 1464-70 (2009). Rudorfer, M.V. et al. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol 19, 373-409 (1999). Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 90, 328-32 (2011). Stingl, J.C., et al. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry 18, 273-87 (2013). Zhou, Q. et al. Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese. Pharmacogenomics J 9, 380-94 (2009).

56 Date of report 2014-12-17 Sample number BIO-001-00001 PSYCHIATRY TRIMIPRAMINE (SURMONTIL®, RHOTRIMINE®)

NOTIFICATION

No genetic variations were identified that would prompt changes to trimipramine therapy.

RECOMMENDATIONS MEDICATION USE

Since you are a CYP2D6 extensive metabolizer and a CYP2C19 intermediate metabolizer, your response to trimipramine is expected to be normal.

• No change to label-recommended dose is warranted depression based on CYP2C19 and CYP2D6 genotypes.

neuropathic pain

GENES GENOTYPES PHENOTYPES

CYP2D6 *2A/*2A extensive metabolizer CYP2C19 *1/*2 intermediate metabolizer

57 Date of report 2014-12-17 Sample number BIO-001-00001

PREMISE FOR CYP2C19 AND CYP2D6 GENOTYPING

The plasma concentration of tricyclic antidepressants, such as trimipramine, can vary considerably from one individual to another. These variations are associated with tolerance and treatment efficacy. In order to predict your response to trimipramine, we analyzed two enzymes that are important for metabolism of this medication, a determining factor for plasma concentrations. While trimipramine is mostly metabolized by CYP2C19 to desmethyl-trimipramine, CYP2D6 is the major enzyme responsible for drug clearance. Many genetic variations have been identified for both CYP2D6 and CYP2C19, and these variations are associated with the metabolism of tricyclics antidepressants. Therefore an individual's genotype for CYP2D6 and CYP2C19 can be used to guide trimipramine dosing for psychological disorders and to reduce the risk of treatment failure and side effects. The recommendations regarding CYP2D6- and CYP2C19-guided trimipramine therapy are for treatment of psychological disorders such as depression. Since lower dosages of trimipramine are used for treatment of neuropathic pain, it is less likely that genetic variations of CYP2D6 and CYP2C19 will alter the risk of side effects. However, if larger doses of trimipramine are warranted, the CYP2D6- and CYP2C19-guided dosing can be followed.

REFERENCES Benz, R.D. & Irausquin, H. Priority-based assessment of food additives database of the U.S. Food and Drug Administration Cen- ter for Food Safety and Applied Nutrition. Environ Health Perspect 96, 85-9 (1991). Crews, K.R. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 91, 321-6 (2012). Dalen, P., et al. 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharma- col Ther 63, 444-52 (1998). Hicks, J.K. et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 93, 402-8 (2013). Jiang, Z.P. et al. The role of CYP2C19 in trimipramine N-demethylation in Chinese subjects. Eur J Clin Pharmacol 58, 109-13 (2002). Kirchheiner, J. & Seeringer, A. Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes. Bio- chim Biophys Acta 1770, 489-94 (2007). Lee, S.J. et al. Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 37, 1464-70 (2009). Rudorfer, M.V. & Potter, W.Z. Metabolism of tricyclic antidepressants. Cell Mol Neurobiol 19, 373-409 (1999). Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 90, 328-32 (2011). Stingl, J.C., et al. Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry 18, 273-87 (2013). Zhou, Q. et al. Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese. Pharmacogenomics J 9, 380-94 (2009).

58 GLOSSARY

DNA Your DNA is a long sequence of six (6) billion units, called nucleotides. Only four (4) different types of nucleotides make up all of your DNA.

ALLELE An allele represents one version of a gene. In general, we all have two (2) alleles for each gene, which come from each of our parents. However, some people carry additional alleles, which increases the number of gene copies to three (3) or more.

PLASMA CONCENTRATION The plasma concentration of a medication refers to the quantity of medication circulating in the blood. This value is dependent upon four (4) main factors : absoprtion, distribution, metabolism and excretion of the medication and its metabolites (metabolites are altered versions of the medication produced by metabolic enzymes).

ENZYME An enzyme enables a chemical reaction. The enzymes implicated during the metabolism of medication will normally transform the medication into a form that can easily mix with water (hydrophilic). This allows the body to eliminate the medication through urine.

GENE A gene is a part of your DNA that contains the information needed to produce a protein. Proteins are the workers of our body, constructed according to our DNA.

GENOTYPE For the PharmaQx report, the term genotype is used to represent the alleles that you carry for a particular gene. For example, you could carry version *1 and version *2 of a gene, and your resulting genotype would be *1/*2.

59 METABOLISM OF MEDICATION, SIDE EFFECTS AND EFFICACY When a medication is administered, our body reacts in a way that transforms the medication into other forms in order to facilitate elimination. This is called metabolism of medication and metabolic enzymes are responsible for this process. Metabolism of a medication can have many effects. In some cases, metabolism inactivates the medication while in other, the medication is activated through metabolism. If a medication, in its active form, takes a longer time than expected to be eliminated (due to reduced metabolism), the risks of side effects are higher. On the other hand, if a medication must be activated through metabolism but that the enzymes responsible for this process are not functional, the therapeutic efficacy will be compromised.

PHENOTYPE A phenotype represents the manifestation of a characteristic of an individual and depends upon genetic and environmental factors. For example, blond hair can be the result of the natural colour of a person (genetic factor) or it can be the result of coloration (environmental factor). The phenotypes included in the PharmaQx report are determined by using your genotypes and are a good way to represent the efficiency of your metabolism of a particular medication.

PROTEIN Each one of us has thousands of proteins working within our body (as many as we have genes, which is about 22,000). A protein can be compared to a worker that accomplishes a specific task. For example, hemoglobin is a protein that carries oxygen through our blood. Metabolic enzymes are also proteins. Since we create our proteins and that these are constructed according to our DNA, we can deduce how our proteins will behave by analyzing our genes.

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