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Pgx Comprehensive Report

Pgx Comprehensive Report

PATIENT INFORMATION SPECIMEN DETAILS PROVIDER INFORMATION

NAME: Patient TSITest SPECIMEN TYPE: ACC #: TSITest COLLECTION DATE: Unknown DOB: 1/1/1900 RECEIVED DATE: SEX: REPORT DATE: 9/3/2019

PGx Comprehensive Report

Current Patient Medications Warfarin

Warfarin Average Dosing Requirements are Expected (CYP2C9 *1/*1; VKORC1 -1639G>A G/A) ACTIONABLE Coumadin® When initiating warfarin treatment for indications with a target INR of 2-3, consider one of the following methods to estimate dosing requirements:

FDA Label: CYP2C9 and VKORC1 genotype results indicate an expected therapeutic dose of 5-7 mg/day.

Pharmacogenomics algorithms/calculators available at www.warfarindosing.org:

Caucasians and Asians: Use the patient's demographics and other clinical factors along with CYP2C9 and VKORC1 genotypes to calculate the expected therapeutic dose.

Africans and African Americans: Use the patient's demographics and other clinical factors along with CYP2C9 and VKORC1 genotypes to calculate the expected therapeutic dose.

The provided recommendations in Africans and African Americans apply only when all the following CYP2C9 alleles are tested: *5, *6, *8, *11. • Johnson JA, Caudle KE, Gong L, Whirl-Carrillo M, Stein CM, Scott SA, Lee MT, Gage BF, Kimmel SE, Perera MA, Anderson JL, Pirmohamed M, Klein TE, Limdi NA, Cavallari LH, Wadelius M. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther 2017 Sep;102(3):397-404.

A medication has potentially reduced efficacy, increased Recommendations based upon publications by international toxicity or the patient has an increased risk for the pharmacogenetic expert groups, consortia or regulatory bodies indicated condition. ACTIONABLE (CPIC, DPWG, FDA, EMA). Recommendations are suitable for implementation in a clinical setting. Guidelines may change as Guidelines exist for adjusting dosage, increased vigilance or knowledge arises. the patient has a moderate risk for the indicated condition. There are insufficient or contradictory findings documenting the The medication can be prescribed according to standard impact of a given genetic polymorphism or drug interaction. INFORMATIVE regimens or the patient's risk for the indicated condition is Recommendations are informative and implementation in a clinical not increased. setting is optional.

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 1 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

Risk Management Type III Hyperlipoproteinemia Not Associated with Type III Hyperlipoproteinemia The patient is negative for the APOE c.388 T>C (Cys130Arg) mutation and positive for the APOE c.526 C>T (Arg176Cys) mutation. The patient's genotype is ε3/ε2 (frequency: 6.7-18%). The APOE E2 form is associated with a slower conversion of IDL to LDL, lower cholesterol, and higher triglycerides, compared to the normal APOE E3 form. The APOE ε3/ε2 genotype is not associated with increased risk of cardiovascular disease. Consider dietary adjustments based on lipid profiles. No action is needed when a patient is normolipidemic.

Hyperhomocysteinemia - Depression No Increased Risk of Hyperhomocysteinemia The patient carries one copy of the MTHFR c.665C>T variant (heterozygous). MTHFR activity is reduced (60% of normal activity). Patients diagnosed with depression often have low folate levels and homocysteine is a highly sensitive marker of folate status. Functional folate deficiency is indicated by elevated homocysteine. The patient's small reduction in MTHFR activity is not a risk factor for hyperhomocysteinemia. Patients diagnosed with depression: as lower folate levels are associated with poorer response, and baseline levels of folate within the normal range predict antidepressant response, testing for homocysteine levels and serum folate levels may be informative for this patient before prescribing methylfolate as an antidepressant-augmenting agent.

Thrombophilia Normal Risk of Thrombosis The patient does not carry the F5 c.1601G>A variant (also known as Factor V Leiden) or the F2 c.*97G>A variant (also known as Factor II 20210G>A). The patient's risk of thrombosis is not increased (average risk of clotting is about 1 in 1000 for anyone in a year). However, because this test cannot find all of the inherited reasons for abnormal clotting, other factors may affect this risk assessment. Assess thrombotic risk based on other genetic and/or circumstantial risk factors such as smoking, obesity, malignancy, prolonged immobilization or surgery.

Estrogen-containing contraceptive and replacement therapy: unless other genetic and/or circumstantial risk factors are present, consider standard prescribing and monitoring practices.

Hyperhomocysteinemia - Thrombosis No Increased Risk of Hyperhomocysteinemia The patient carries one copy of MTHFR c.665C>T variant and one copy of c.1286A>C variant (compound heterozygous). MTHFR enzyme activity is reduced. The patient's reduced MTHFR activity is not a risk factor for hyperhomocysteinemia. Unless other risk factors are present, the patient is not expected to have an increased risk for venous thromboembolism (VTE). Testing total plasma homocysteine level may be beneficial. Hyperhomocysteinemia can be treated with nutritional supplementation.

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 2 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

Potentially Impacted Medications

CATEGORY DRUG CLASS STANDARD PRECAUTIONS USE WITH CAUTION CONSIDER ALTERNATIVES

Anesthesia Injectable Anesthetics Propofol (Diprivan®)

Anticancer Agents Antifolates Methotrexate (Trexall®)

Azilsartan (Edarbi®, Edarbyclor®) Candesartan (Atacand®) Eprosartan (Teveten®) Angiotensin II Receptor Irbesartan (Avapro®) Antagonists Losartan (Cozaar®, Hyzaar®) Olmesartan (Benicar®) Telmisartan (Micardis®) Valsartan (Diovan®, Entresto®)

Antianginal Agents (Ranexa®)

Flecainide (Tambocor®) Antiarrhythmics Mexiletine (Mexitil®) Propafenone (Rythmol®)

Apixaban (Eliquis®) Betrixaban (Bevyxxa®) Dabigatran Etexilate (Pradaxa®) Anticoagulants Edoxaban (Savaysa®) Fondaparinux (Arixtra®) Rivaroxaban (Xarelto®) Warfarin (Coumadin®)

Cardiovascular Prasugrel (Effient®) Antiplatelets Ticagrelor (Brilinta®) Clopidogrel (Plavix®) Vorapaxar (Zontivity®)

Atenolol (Tenormin®) Bisoprolol (Zebeta®) Carvedilol (Coreg®) Labetalol (Normodyne®, Beta Blockers Trandate®) Metoprolol (Lopressor®) Nebivolol (Bystolic®) (Inderal®) Timolol (Timoptic®)

Diuretics Torsemide (Demadex®)

Atorvastatin (Lipitor®) Fluvastatin (Lescol®) Lovastatin (Mevacor®, Altoprev®, Advicor®) Statins Pitavastatin (Livalo®) Pravastatin (Pravachol®) Rosuvastatin (Crestor®) Simvastatin (Zocor®)

Nateglinide (Starlix®) Meglitinides Repaglinide (Prandin®, Prandimet®)

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 3 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

CATEGORY DRUG CLASS STANDARD PRECAUTIONS USE WITH CAUTION CONSIDER ALTERNATIVES

Diabetes Chlorpropamide (Diabinese®) Glimepiride (Amaryl®) Sulfonylureas Glipizide (Glucotrol®) Glyburide (Micronase®) Tolbutamide (Orinase®)

Aprepitant (Emend-oral®) (Anzemet®) Dronabinol (Marinol®) Fosaprepitant (Emend-i.v®) Fosnetupitant- (Akynzeo-i.v®) Antiemetics (Sancuso®, Sustol®) (Reglan®) Netupitant-Palonosetron (Akynzeo- oral®) Gastrointestinal (Zofran®, Zuplenz®) Palonosetron (Aloxi®) Rolapitant (Varubi®)

Dexlansoprazole (Dexilant®, Kapidex®) Esomeprazole (Nexium®) Proton Pump Inhibitors Lansoprazole (Prevacid®) Omeprazole (Prilosec®) Pantoprazole (Protonix®) Rabeprazole (Aciphex®)

Eliglustat (Cerdelga®) Imiglucerase (Cerezyme®) Endocrine-Metabolic Gaucher Disease Miglustat (Zavesca®) Agents Taliglucerase alfa (Elelyso®) Velaglucerase alfa (Vpriv®)

Endometriosis Pain Gynecology Elagolix (Orilissa®) Agents

Avatrombopag (Doptelet®) Hematology Hemostatic Agents Eltrombopag (Promacta®) Lusutrombopag (Mulpleta®)

Amphotericin B (AmBisome®, Abelcet®) Anidulafungin (Eraxis®) Caspofungin (Cancidas®) Antifungals Fluconazole (Diflucan®) Voriconazole (Vfend®) Isavuconazonium (Cresemba®) Infections (Sporanox®) Micafungin (Mycamine®) (Noxafil®)

Dolutegravir (Tivicay®, Triumeq®) Anti-HIV Agents Raltegravir (Isentress®, Dutrebis®)

Antimalarials Proguanil (Malarone®)

Disease-Modifying Multiple Sclerosis Siponimod (Mayzent®) Agents

Fibromyalgia Agents (Savella®)

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 4 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

CATEGORY DRUG CLASS STANDARD PRECAUTIONS USE WITH CAUTION CONSIDER ALTERNATIVES

Cyclobenzaprine (Flexeril®, Amrix®) Muscle Relaxants (Soma®) Metaxalone (Skelaxin®) Methocarbamol (Robaxin®)

Celecoxib (Celebrex®) Diclofenac (Voltaren®) Flurbiprofen (Ansaid®) Ibuprofen (Advil®, Motrin®) Indomethacin (Indocin®) Ketoprofen (Orudis®) NSAIDs Ketorolac (Toradol®) Meloxicam (Mobic®) Nabumetone (Relafen®) Naproxen (Aleve®) Piroxicam (Feldene®) Sulindac (Clinoril®)

Pain Alfentanil (Alfenta®) Benzhydrocodone (Apadaz®) (Butrans®, Buprenex®) Codeine (Codeine; Fioricet® with Codeine) Dihydrocodeine (Synalgos-DC®) Fentanyl (Actiq®) Hydrocodone (Vicodin®) Hydromorphone (Dilaudid®, (Dolophine®) Exalgo®) Morphine (MS Contin®) (Levo Dromoran®) Meperidine (Demerol®) Oxycodone (Percocet®, Oxycontin®) Oxymorphone (Opana®, Numorphan®) Sufentanil (Sufenta®) (Nucynta®) (Ultram®)

Bupropion (Wellbutrin®, Zyban®, Antiaddictives Lofexidine (Lucemyra®) Aplenzin®, Contrave®)

Amphetamine (Adderall®, Evekeo®) Clonidine (Kapvay®) (Focalin®) (Dexedrine®) Anti-ADHD Agents (Strattera®) (Intuniv®) (Vyvanse®) (Ritalin®, Aptensio XR®, Concerta®, Metadate ER®, Quillivant ER®)

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 5 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

CATEGORY DRUG CLASS STANDARD PRECAUTIONS USE WITH CAUTION CONSIDER ALTERNATIVES

Cannabidiol (Epidiolex®) Carbamazepine (Tegretol®, Carbatrol®, Epitol®) Eslicarbazepine (Aptiom®) Ethosuximide (Zarontin®) Ezogabine (Potiga®) (Felbatol®) Fosphenytoin (Cerebyx®) Gabapentin (Neurontin®) Lacosamide (Vimpat®) Brivaracetam (Briviact®) Lamotrigine (Lamictal®) (Luminal®) Anticonvulsants Levetiracetam (Keppra®) Primidone (Mysoline®) Oxcarbazepine (Trileptal®, Oxtellar Zonisamide (Zonegran®) XR®) (Fycompa®) Phenytoin (Dilantin®) Pregabalin (Lyrica®) Rufinamide (Banzel®) Tiagabine (Gabitril®) (Topamax®) Valproic Acid (Depakote®, Depakene®) Vigabatrin (Sabril®)

Donepezil (Aricept®) Antidementia Agents Galantamine (Razadyne®) (Namenda®)

Amoxapine (®) (Norpramin®) (Pristiq®) Psychotropic (Cymbalta®) (Prozac®, Sarafem®) (Luvox®) Levomilnacipran (Fetzima®) (Elavil®) (Ludiomil®) (Celexa®) (Anafranil®) (Remeron®) (Lexapro®) (Silenor®) (Serzone®) (Zoloft®) (Tofranil®) (Pamelor®) (Surmontil®) (Paxil®, Brisdelle®) (Vivactil®) (Oleptro®) (Effexor®) (Viibryd®) (Trintellix®)

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 6 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

CATEGORY DRUG CLASS STANDARD PRECAUTIONS USE WITH CAUTION CONSIDER ALTERNATIVES

Aripiprazole (Abilify®, Aristada®) (Saphris®) (Rexulti®) (Vraylar®) (Thorazine®) (Clozaril®) (Prolixin®) (Haldol®) (Fanapt®) (Loxitane®, Adasuve®) (Latuda®) (Zyprexa®) (Invega®) (Trilafon®) (Nuplazid®) (Orap®) (Seroquel®) (Risperdal®) (Mellaril®) Thiothixene (Navane®) (Stelazine®) (Geodon®)

Alprazolam (Xanax®) Clobazam (Onfi®) Benzodiazepines Clonazepam (Klonopin®) Diazepam (Valium®)

Deutetrabenazine (Austedo®) Other Neurological / Quinidine Flibanserin (Addyi®) Agents (Nuedexta®) (Xenazine®) (Ingrezza®)

Colchicine (Mitigare®) Anti-Hyperuricemics Febuxostat (Uloric®) and Anti-Gout Agents Rheumatology Lesinurad (Zurampic®) Leflunomide (Arava®) Immunomodulators Apremilast (Otezla®) Tofacitinib (Xeljanz®)

Sjogren's Syndrome Cholinergic Cevimeline (Evoxac®)

Transplantation Immunosuppressants Tacrolimus (Prograf®)

5-Alpha Reductase Dutasteride (Avodart®) Inhibitors for Benign Finasteride (Proscar®) Prostatic Hyperplasia

Alfuzosin (UroXatral®) Alpha-Blockers for Doxazosin (Cardura®) Benign Prostatic Silodosin (Rapaflo®) Hyperplasia Tamsulosin (Flomax®) Terazosin (Hytrin®)

Darifenacin (Enablex®) Urologicals Fesoterodine (Toviaz®) Mirabegron (Myrbetriq®) Antispasmodics for Oxybutynin (Ditropan®) Overactive Bladder Solifenacin (Vesicare®) Tolterodine (Detrol®) Trospium (Sanctura®)

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 7 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

CATEGORY DRUG CLASS STANDARD PRECAUTIONS USE WITH CAUTION CONSIDER ALTERNATIVES

Avanafil (Stendra®) Phosphodiesterase (Viagra®) Inhibitors for Erectile (Cialis®) Dysfunction (Levitra®)

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 8 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

Dosing Guidance

Amitriptyline Increased Amitriptyline Exposure (CYP2C19: Poor Metabolizer) ACTIONABLE Elavil® The patient's absent CYP2C19 activity is likely to result in a significantly decreased of amitriptyline to nortriptyline and a subsequent increase in amitriptyline exposure leading to side effects.

Psychiatric Conditions: Consider an alternative medication. If amitriptyline is warranted, consider a 50% reduction of the recommended dose and use therapeutic drug monitoring to guide dose adjustments.

Neuropathic Pain: Amitriptyline can be prescribed according to standard recommended dosage and administration when lower doses are considered. If higher doses are warranted, consider a 50% reduction of the recommended dose and monitor patient for side effects. • Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Müller DJ, Shimoda K, Bishop JR, Kharasch ED, Skaar TC, Gaedigk A, Dunnenberger HM, Klein TE, Caudle KE, Stingl JC. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of antidepressants: 2016 update. Clin Pharmacol Ther 2017 07;102(1):37-44.

Clomipramine Increased Clomipramine Exposure (CYP2C19: Poor Metabolizer) INFORMATIVE Anafranil® The patient's absent CYP2C19 activity is likely to result in a significantly decreased metabolism of clomipramine to desmethyl clomipramine and a subsequent increase in clomipramine exposure leading to side effects.

Psychiatric Conditions: Consider an alternative medication. If clomipramine is warranted, consider a 50% reduction of the recommended dose and use therapeutic drug monitoring to guide dose adjustments. • Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Müller DJ, Shimoda K, Bishop JR, Kharasch ED, Skaar TC, Gaedigk A, Dunnenberger HM, Klein TE, Caudle KE, Stingl JC. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther 2017 07;102(1):37-44.

Clopidogrel Significantly Reduced Response to Clopidogrel (CYP2C19: Poor Metabolizer) ACTIONABLE Plavix® Consider alternative therapy. Examples of alternative drugs: prasugrel (contraindicated in TIA/Stroke patients), ticagrelor, aspirin, aspirin plus dipyridamole. • Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR, . Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 2013 Sep;94(3):317-23.

Doxepin Increased Doxepin Exposure (CYP2C19: Poor Metabolizer) INFORMATIVE Silenor® The patient's absent CYP2C19 activity is likely to result in a significantly decreased metabolism of doxepin to desmethyl doxepin and a subsequent increase in doxepin exposure leading to side effects.

Psychiatric Conditions: Consider an alternative medication. If doxepin is warranted, consider a 50% reduction of the recommended dose and use therapeutic drug monitoring to guide dose adjustments.

Insomnia: Doxepin can be prescribed according to the standard recommended dosage and administration. • Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Müller DJ, Shimoda K, Bishop JR, Kharasch ED, Skaar TC, Gaedigk A, Dunnenberger HM, Klein TE, Caudle KE, Stingl JC. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther 2017 07;102(1):37-44.

Imipramine Increased Imipramine Exposure (CYP2C19: Poor Metabolizer) INFORMATIVE Tofranil® The patient's absent CYP2C19 activity is likely to result in a significantly decreased metabolism of imipramine to desipramine and a subsequent increase in imipramine exposure leading to side effects.

Psychiatric Conditions: Consider an alternative medication. If imipramine is warranted, consider a 50% reduction of the recommended dose and use therapeutic drug monitoring to guide dose adjustments. • Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Müller DJ, Shimoda K, Bishop JR, Kharasch ED, Skaar TC, Gaedigk A, Dunnenberger HM, Klein TE, Caudle KE, Stingl JC. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther 2017 07;102(1):37-44.

Trimipramine Increased Trimipramine Exposure (CYP2C19: Poor Metabolizer) INFORMATIVE Surmontil®

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 9 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

The patient's absent CYP2C19 activity is likely to result in a significantly decreased metabolism of trimipramine to desmethyl trimipramine and a subsequent increase in trimipramine exposure leading to side effects.

Psychiatric Conditions: Consider an alternative medication. If trimipramine is warranted, consider a 50% reduction of the recommended dose and use therapeutic drug monitoring to guide dose adjustments. • Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Müller DJ, Shimoda K, Bishop JR, Kharasch ED, Skaar TC, Gaedigk A, Dunnenberger HM, Klein TE, Caudle KE, Stingl JC. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther 2017 07;102(1):37-44.

Voriconazole Increased Sensitivity to Voriconazole (CYP2C19: Poor Metabolizer) ACTIONABLE Vfend® Voriconazole plasma concentrations are expected to be high if a standard dose is used, which may increase the risk of adverse events (hepatotoxicity, visual disturbances/halucinations and neurologic disorders). Consider an alternative medication that is not dependent on CYP2C19 metabolism, such as isavuconazole, liposomal amphotericin B or posaconazole. If voriconazole is warranted, consider a decreased dose and careful therapeutic drug monitoring. • Moriyama B, Obeng AO, Barbarino J, Penzak SR, Henning SA, Scott SA, Agúndez J, Wingard JR, McLeod HL, Klein TE, Cross SJ, Caudle KE, Walsh TJ. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther 2017 07;102(1):45-51.

Atomoxetine Possible Atomoxetine Overexposure Leading to Toxicity (CYP2D6: Normal ACTIONABLE Metabolizer) Strattera® The genotype result indicates that the patient is likely to have an increased risk of adverse events following standard dosing. Consider the following dosing strategy:

• Initiate treatment at 40 mg/day. • If after 2 weeks, optimal clinical response is not observed and adverse events are not present, consider a dose increase to 80 mg/day. • If after 2 weeks, optimal clinical response is not observed and adverse events are not present, consider therapeutic drug monitoring 2-4 hours post dose. If the plasma concentration is less than 200 ng/ml consider a dose increase to a target of 400 ng/ml. Doses greater than 100 mg/day may be needed to achieve a targeted therapeutic concentration. (Therapeutic range: 200-1000 ng/ml). • Brown JT, Bishop JR, Sangkuhl K, Nurmi EL, Mueller DJ, Dinh JC, Gaedigk A, Klein TE, Caudle KE, McCracken JT, de Leon J, Leeder JS. Clinical Pharmacogenetics Implementation Consortium Guideline for (CYP)2D6 Genotype and Atomoxetine Therapy. Clin Pharmacol Ther 2019 Jul;106(1):94-102.

Brivaracetam Possible Sensitivity to Brivaracetam (CYP2C19: Poor Metabolizer) ACTIONABLE Briviact® Brivaracetam is primarily metabolized by hydrolysis and to a minor extent by hydroxylation, which is mediated by CYP2C19. In CYP2C19 poor metabolizers, the plasma concentration of brivaracetam is increased by 42%. Brivaracetam dose reduction may be required. Monitor the patient for any signs of adverse reaction or drug toxicity. • Stockis A, Watanabe S, Rouits E, Matsuguma K, Irie S. Brivaracetam single and multiple rising oral dose study in healthy Japanese participants: influence of CYP2C19 genotype. Drug Metab Pharmacokinet 2014 ;29(5):394-9. • Briviact [package insert]. Smyrna, GA: UCB, Inc.; 2016.

Bupropion Unknown Response to Bupropion (CYP2B6: Unknown Phenotype) INFORMATIVE Wellbutrin®, Zyban®, Bupropion is metabolized to its active metabolite by CYP2B6. This metabolite contributes to the Aplenzin®, Contrave® therapeutic effects of bupropion when used as a smoking cessation agent or as an antidepressant. Until additional information is available for this genotype, bupropion can be prescribed at standard label-recommended dosage with careful monitoring of the patient's response. Therapeutic monitoring of hydroxybupropion levels may be considered to guide dosing adjustment if needed. • Zhu AZ, Cox LS, Nollen N, Faseru B, Okuyemi KS, Ahluwalia JS, Benowitz NL, Tyndale RF. CYP2B6 and bupropion's smoking-cessation : the role of hydroxybupropion. Clin Pharmacol Ther 2012 Dec;92(6):771-7. • Høiseth G, Haslemo T, Uthus LH, Molden E. Effect of CYP2B6*6 on Steady-State Serum Concentrations of Bupropion and Hydroxybupropion in Psychiatric Patients: A Study Based on Therapeutic Drug Monitoring Data. Ther Drug Monit 2015 Oct;37(5):589-93.

Carisoprodol Altered Sensitivity to Carisoprodol (CYP2C19: Poor Metabolizer) INFORMATIVE Soma® CYP2C19 poor metabolizers have a lower capacity to metabolize carisoprodol to , and may therefore have an increased risk of developing concentration-dependent side effects such as drowsiness and when receiving standard doses of carisoprodol. Carisoprodol should be used with caution in patients with reduced CYP2C19 activity. Because there is insufficient data to allow calculation of dose adjustment, consider reducing the dose or using an alternative medication. • Bramness JG, Skurtveit S, Fauske L, Grung M, Molven A, Mørland J, Steen VM. Association between blood carisoprodol:meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects? Pharmacogenetics 2003 Jul;13(7):383-8.

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 10 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

Citalopram Increased Sensitivity to Citalopram (CYP2C19: Poor Metabolizer) ACTIONABLE Celexa® At standard label-recommended dosage, citalopram plasma concentrations levels are expected to be high and adverse events may occur. Consider a 50% reduction of the recommended starting dose to help prevent concentration- dependent adverse events. Dose escalations over 20 mg/day for CYP2C19 poor metabolizers are not recommended. An alternative medication may also be considered. • Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, Ji Y, Leckband SG, Leeder JS, Graham RL, Chiulli DL, LLerena A, Skaar TC, Scott SA, Stingl JC, Klein TE, Caudle KE, Gaedigk A, . Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Reuptake Inhibitors. Clin Pharmacol Ther 2015 Aug;98(2):127-34.

Clobazam Increased Sensitivity to Clobazam (CYP2C19: Poor Metabolizer) ACTIONABLE Onfi® In CYP2C19 poor metabolizers, plasma levels of the active metabolite N-desmethylclobazam were 5-fold higher than those found in CYP2C19 normal metabolizers. Therefore, the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight. Patients should be titrated initially to 10 mg /day (≤30 kg body weight) or 20 mg/day (>30 kg body weight). If necessary and based upon clinical response, an additional titration to the maximum doses 20 mg/day (≤30 kg body weight) or 40 mg/day (>30 kg body weight) may be started on day 21. • Onfi [package insert]. Deerfield, IL: Lundbeck Inc.; 2013. • Seo T, Nagata R, Ishitsu T, Murata T, Takaishi C, Hori M, Nakagawa K. Impact of CYP2C19 polymorphisms on the efficacy of clobazam therapy. Pharmacogenomics 2008 May;9(5):527-37. • Kosaki K, Tamura K, Sato R, Samejima H, Tanigawara Y, Takahashi T. A major influence of CYP2C19 genotype on the steady-state concentration of N- desmethylclobazam. Brain Dev 2004 Dec;26(8):530-4.

Diazepam Increased Sensitivity to Diazepam (CYP2C19: Poor Metabolizer) INFORMATIVE Valium® CYP2C19 poor metabolizers have a lower capacity to metabolize diazepam and its active metabolite nordiazepam. Therefore, they may experience more concentration-dependent side effects, such as increased or prolonged sedation, if treated with standard doses of diazepam. Diazepam should be used with caution in these patients, and a reduced dose or longer dosing interval may be needed. • Inomata S, Nagashima A, Itagaki F, Homma M, Nishimura M, Osaka Y, Okuyama K, Tanaka E, Nakamura T, Kohda Y, Naito S, Miyabe M, Toyooka H. CYP2C19 genotype affects diazepam and emergence from general anesthesia. Clin Pharmacol Ther 2005 Dec;78(6):647-55. • Wan J, Xia H, He N, Lu YQ, Zhou HH. The elimination of diazepam in Chinese subjects is dependent on the mephenytoin oxidation phenotype. Br J Clin Pharmacol 1996 Oct;42(4):471-4.

Escitalopram Increased Sensitivity to Escitalopram (CYP2C19: Poor Metabolizer) ACTIONABLE Lexapro® At standard label-recommended dosage, escitalopram plasma concentrations levels are expected to be high and adverse events may occur. Consider a 50% reduction of the recommended starting dose to help prevent concentration- dependent adverse events. An alternative medication may also be considered. • Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, Ji Y, Leckband SG, Leeder JS, Graham RL, Chiulli DL, LLerena A, Skaar TC, Scott SA, Stingl JC, Klein TE, Caudle KE, Gaedigk A, . Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther 2015 Aug;98(2):127-34.

Flibanserin Increased Exposure to Flibanserin (CYP2C19: Poor Metabolizer) ACTIONABLE Addyi® For treating premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD): Flibanserin is primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2C19. CYP2C19 poor metabolizers have increased flibanserin exposure compared to CYP2C19 normal metabolizers. As this change in exposure may increase the risk of hypotension, syncope, and CNS depression, advise and monitor patient more closely for serious adverse effects. • Addyi [package insert]. Raleigh, NC: Sprout Pharmaceuticals, Inc.; 2015.

Leflunomide Increased Sensitivity to Leflunomide (CYP2C19: Poor Metabolizer) INFORMATIVE Arava® Leflunomide is metabolized by CYP2C19 and CYP1A2 to its active metabolite teriflunomide. Preliminary studies indicate that patients with decreased CYP2C19 activity have a higher risk of developing gastrointestinal side effects and hepatotoxicity. There is insufficient data to calculate dose adjustment. If leflunomide is prescribed at standard dosing, monitor closely the patient's response and be alert to increased side effects. Full blood cell count (CBC) and function parameters should be checked no more than 6 months before beginning treatment, and every month for the initial 6 months of therapy. should be checked before beginning treatment and periodically thereafter. • Wiese MD, Schnabl M, O'Doherty C, Spargo LD, Sorich MJ, Cleland LG, Proudman SM. Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis. Arthritis Res Ther 2012 Jul;14(4):R163. • Bohanec Grabar P, Grabnar I, Rozman B, Logar D, Tomsic M, Suput D, Trdan T, Peterlin Masic L, Mrhar A, Dolzan V. Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide- treated patients with rheumatoid arthritis. Drug Metab Dispos 2009 Oct;37(10):2061-8.

Methadone Unknown Sensitivity to Methadone (CYP2B6: Unknown Phenotype) INFORMATIVE Dolophine®

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 11 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

Until additional information is available, prescribe methadone with careful monitoring. If a genotype effect is suspected based on patient response, adjust dosage accordingly, or prescribe an alternative medication. • Dobrinas M, Crettol S, Oneda B, Lahyani R, Rotger M, Choong E, Lubomirov R, Csajka C, Eap CB. Contribution of CYP2B6 alleles in explaining extreme (S)- methadone plasma levels: a CYP2B6 gene resequencing study. Pharmacogenet Genomics 2013 Feb;23(2):84-93. • Kharasch ED, Regina KJ, Blood J, Friedel C. Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism. Anesthesiology 2015 Nov;123(5):1142-53. • Kringen MK, Chalabianloo F, Bernard JP, Bramness JG, Molden E, Høiseth G. Combined Effect of CYP2B6 Genotype and Other Candidate Genes on a Steady- State Serum Concentration of Methadone in Maintenance Treatment. Ther Drug Monit 2017 10;39(5):550-555.

Methotrexate Increased Risk for Methotrexate Toxicity (MTHFR: Reduced MTHFR Activity) INFORMATIVE Trexall® The patient carries one copy of the MTHFR c.665C>T variant resulting in a reduced MTHFR activity. Malignancy: Leukemia or lymphoma patients who are treated with methotrexate standard regimens might have an increased likelihood of treatment interruptions due to methotrexate toxicity. Monitor the patient closely for increased side effects and adjust the dose accordingly. Other genetic and clinical factors may also influence the patient's risk for toxicity and response to methotrexate treatment. Nonmalignant conditions: a limited number of studies found an association between individuals carrying the MTHFR c.665C>T variant and methotrexate-induced toxicity in rheumatoid arthritis patients. However, there is insufficient data to calculate dose adjustment. Monitor patient closely for increased side effects and adjust the dose accordingly. Other genetic and clinical factors may also influence the patient's risk for toxicity and response to methotrexate treatment. • De Mattia E, Toffoli G. C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. Eur J Cancer 2009 May;45(8):1333-51. • Choi YJ, Park H, Lee JS, Lee JY, Kim S, Kim TW, Park JS, Kim JE, Yoon DH, Suh C. Methotrexate elimination and toxicity: MTHFR 677C>T polymorphism in patients with primary CNS lymphoma treated with high-dose methotrexate. Hematol Oncol 2017 Dec;35(4):504-509. • Zhao M, Liang L, Ji L, Chen D, Zhang Y, Zhu Y, Ongaro A. MTHFR gene polymorphisms and methotrexate toxicity in adult patients with hematological malignancies: a meta-analysis. Pharmacogenomics 2016 06;17(9):1005-17.

Morphine Altered Response to Morphine (COMT: High/Normal COMT Activity) INFORMATIVE MS Contin® The patient does not carry the COMT Val158Met variant. The patient may require higher doses of morphine for adequate pain control. The dosing regimen needs to be individualized for each patient, taking into account the patient's prior analgesic treatment experience. • Rakvåg TT, Ross JR, Sato H, Skorpen F, Kaasa S, Klepstad P. Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Mol Pain 2008 Dec;4():64. • Rakvåg TT, Klepstad P, Baar C, Kvam TM, Dale O, Kaasa S, Krokan HE, Skorpen F. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 2005 Jul;116(1-2):73-8. • Matic M, Simons SH, van Lingen RA, van Rosmalen J, Elens L, de Wildt SN, Tibboel D, van Schaik RH. Rescue morphine in mechanically ventilated newborns associated with combined OPRM1 and COMT genotype. Pharmacogenomics 2014 Jul;15(10):1287-95.

Phenobarbital Possible Sensitivity to Phenobarbital (CYP2C19: Poor Metabolizer) INFORMATIVE Luminal® CYP2C19 is partly involved in the metabolism of phenobarbital, and although CYP2C19 poor metabolizers have a 20% lower clearance of phenobarbital than normal metabolizers, no significant changes in clinical outcome has been reported with this antiepileptic drug. Therefore, phenobarbital can be prescribed at standard label-recommended dosage and administration with a closer monitoring for adverse events. • Lee SM, Chung JY, Lee YM, Park MS, Namgung R, Park KI, Lee C. Effects of cytochrome P450 (CYP)2C19 polymorphisms on pharmacokinetics of phenobarbital in neonates and infants with seizures. Arch Dis Child 2012 Jun;97(6):569-72. • Mamiya K, Hadama A, Yukawa E, Ieiri I, Otsubo K, Ninomiya H, Tashiro N, Higuchi S. CYP2C19 polymorphism effect on phenobarbitone. Pharmacokinetics in Japanese patients with epilepsy: analysis by population pharmacokinetics. Eur J Clin Pharmacol ;55(11-12):821-5. • Yukawa E, Mamiya K. Effect of CYP2C19 genetic polymorphism on pharmacokinetics of phenytoin and phenobarbital in Japanese epileptic patients using Non -linear Mixed Effects Model approach. J Clin Pharm Ther 2006 Jun;31(3):275-82. • Anderson, Gail D. "Chemisry, Biotransformation, and Pharmacokinetics." Antiepileptic Drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2002. 496-03. Print.

Primidone Possible Sensitivity to Primidone (CYP2C19: Poor Metabolizer) INFORMATIVE Mysoline® CYP2C19 is partly involved in the metabolism of primidone and although CYP2C19 poor metabolizers have a 20% lower clearance of phenobarbital (active metabolite) than normal metabolizers, no significant changes in clinical outcome has been reported with this antiepileptic drug. Therefore, primidone can be prescribed at standard label-recommended dosage and administration with a closer monitoring for adverse events. • Fincham, Richard W., and Dorothy D. Schottelius. "Primidone." Antiepileptic Drugs. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2002. 621-36. Print.

Propofol Unknown Response to Propofol (CYP2B6: Unknown Phenotype) INFORMATIVE Diprivan®

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 12 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

Altrhough the CYP2B6 metabolizer status is not well characterized, this genotype along with other factors such as old age (>65 years) and associated comorbidities may contribute to delayed emergence from anesthesia. There is insufficient data to allow calculation of dose adjustment; careful monitoring during post-surgery is recommended. The dosing regimen needs to be individualized for each patient, considering the patient's prior propofol dose requirements, age and comorbidities. • Mastrogianni O, Gbandi E, Orphanidis A, Raikos N, Goutziomitrou E, Kolibianakis EM, Tarlatzis BC, Goulas A. Association of the CYP2B6 c.516G>T polymorphism with high blood propofol concentrations in women from northern Greece. Drug Metab Pharmacokinet 2014 ;29(2):215-8. • Murayama N, Minoshima M, Shimizu M, Guengerich FP, Yamazaki H. Involvement of human cytochrome P450 2B6 in the omega- and 4-hydroxylation of the anesthetic agent propofol. Xenobiotica 2007 Jul;37(7):717-24. • Court MH, Duan SX, Hesse LM, Venkatakrishnan K, Greenblatt DJ. Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Anesthesiology 2001 Jan;94(1):110-9.

Sertraline Increased Sensitivity to Sertraline (CYP2C19: Poor Metabolizer) INFORMATIVE Zoloft® At standard label-recommended dosage, sertraline levels are expected to be high, and adverse events may occur. Consider a 50% decrease of the initial dose and titrate based on the clinical response and tolerability. An alternative medication may also be considered. • Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, Ji Y, Leckband SG, Leeder JS, Graham RL, Chiulli DL, LLerena A, Skaar TC, Scott SA, Stingl JC, Klein TE, Caudle KE, Gaedigk A, . Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther 2015 Aug;98(2):127-34.

Tacrolimus Insufficient Response to Tacrolimus (CYP3A5: Normal Metabolizer) ACTIONABLE Prograf® The genotype result predicts that the patient expresses the CYP3A5 protein. Therefore, the patient may metabolize tacrolimus more rapidly, resulting in low tacrolimus trough levels. Studies have shown patients with this genotype may be at increased risk for acute transplant rejection while taking a standard dose of tacrolimus. Therefore, increasing starting dose 1.5 to 2 times recommended starting dose with close monitoring is strongly recommended to achieve therapeutic effect. Total starting dose should not exceed 0.3mg/kg/day. • Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, Wang D, Vinks AA, He Y, Swen JJ, Leeder JS, van Schaik R, Thummel KE, Klein TE, Caudle KE, MacPhee IA. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther 2015 Jul;98(1):19-24.

Tetrabenazine Normal Sensitivity to Tetrabenazine (CYP2D6: Normal Metabolizer) ACTIONABLE Xenazine® For treating chorea associated with Huntington’s disease: Individualization of dose with careful weekly titration is required. The first week's starting dose is 12.5 mg daily; second week, 25 mg (12.5 mg twice daily); then slowly titrate at weekly intervals by 12.5 mg to a tolerated dose. The maximum daily dose in CYP2D6 normal metabolizers is 100 mg, with a maximum single dose of 37.5 mg. If serious adverse events occur, titration should be stopped and the dose of tetrabenazine should be reduced. If the adverse event(s) do not resolve, consider withdrawal of tetrabenazine. • Xenazine [package insert]. Deerfield, IL: Lundbeck Inc.; 2011.

Tofacitinib Increased Sensitivity to Tofacitinib when coadministered with CYP3A4 Inhibitors INFORMATIVE (CYP2C19: Poor Metabolizer) Xeljanz® Tofacitinib is metabolized primarily by CYP3A4 with some contribution from CYP2C19. Genetic variations in the CYP2C19 gene do not significantly influence tofacitinib exposure. In absence of coadministered CYP3A4 inhibitors, tofacitinib can be prescribed according to standard label-recommended dosage and administration (i.e 5 mg twice daily). However, tofacitinib dose should be reduced to 5 mg once daily if a patient who is a CYP2C19 poor metabolizer is also prescribed a CYP3A4 inhibitor such as , erythromycin, diltiazem, troleandomycin, nefazodone, fluconazole, verapamil and HIV protease inhibitors. • Xeljanz [package insert]. New York, NY: Pfizer Inc.; 2014.

Zonisamide Possible Sensitivity to Zonisamide (CYP2C19: Poor Metabolizer) INFORMATIVE Zonegran® CYP2C19 is partly involved in the metabolism of zonisamide, and although preliminary studies show that CYP2C19 poor metabolizers have a slightly lower (30%) zonisamide clearance than normal metabolizers, no significant change in the clinical outcome has been reported with this antiepileptic drug. Therefore, zonisamide can be prescribed at standard label-recommended dosage and administration with a closer monitoring for adverse events. • Okada Y, Seo T, Ishitsu T, Wanibuchi A, Hashimoto N, Higa Y, Nakagawa K. Population estimation regarding the effects of cytochrome P450 2C19 and 3A5 polymorphisms on zonisamide clearance. Ther Drug Monit 2008 Aug;30(4):540-3.

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 13 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

Test Details Gene Genotype Phenotype Alleles Tested Apolipoprotein E ε3/ε2 Altered APOE function ε2, ε4, (ε3 is reference) COMT Val158Met G/G High/Normal COMT Activity Val158Met CYP1A2 Indeterminate Unknown Phenotype *1C, *1D, *1E, *1F, *1J, *1K, *1L, *1V, *1W CYP2B6 Indeterminate Unknown Phenotype *5, *7, *16, *18, *22 CYP2C19 *2/*2 Poor Metabolizer *2, *3, *4, *4B, *5, *6, *7, *8, *9, *10, *17 CYP2C9 *1/*1 Normal Metabolizer *2, *3, *4, *5, *6, *11 CYP2D6 *10/*10 Normal Metabolizer *2, *3, *4, *4M, *6, *7, *8, *9, *10, *12, *14A, *14B, *17, *29, *41 CYP3A4 *1/*1 Normal Metabolizer *1B, *2, *3, *12, *17, *22 CYP3A5 *1/*1 Normal Metabolizer *2, *3, *3B, *3C, *6, *7, *8, *9 F2 rs1799963 GG Normal Risk of Thrombosis rs1799963, rs6025 F5 rs6025 CC MTHFR c.665C>T GA Reduced MTHFR Activity c.1286A>C, c.665C>T MTHFR c.1286A>C GT No Increased Risk of c.1286A>C, c.665C>T c.665C>T GA Hyperhomocysteinemia SLCO1B1 521T>C T/T Normal Function 521T>C VKORC1 -1639G>A G/A Intermediate Warfarin Sensitivity -1639G>A

Limitation: This test will not detect all the known alleles that result in altered or inactive tested genes. This test does not account for all individual variations in the individual tested. Absence of a detectable gene mutation does not rule out the possibility that a patient has different phenotypes due to the presence of an undetected polymorphism or due to other factors such as drug-drug interactions, comorbidities and lifestyle habits.

Methodology: Array based assays detect listed alleles, including all common and most rare variants with known clinical significance at analytical sensitivity and specificity >99%.

Lab Disclaimer: Scientia Diagnostics developed the Genotype test. The performance characteristics of this test were determined by Scientia Diagnostics. It has not been cleared or approved by the U.S. Food and Drug Administration.

Translational Software Disclaimer: The information presented on this report is provided as general educational health information. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Only a physician, pharmacist or other healthcare professional should advise a patient on the use of the medications prescribed.

The pharmacogenetic assay involves use of reporting software and genotype-phenotype associations performed by Translational Software (www.translationalsoftware.com). The software has not been evaluated by the Food and Drug Administration. The software, and the report generated by the software, is not intended to diagnose, treat, cure, or prevent any disease. A qualified designee within the lab uses Translational Software to generate and subsequently review the report. The pharmacogenetic report is one of multiple pieces of information that clinicians should consider in guiding their therapeutic choice for each patient. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to dose guidelines does not necessarily assure a successful medical outcome.

Approved by Randah Al-Kana, MD

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 14 of 15 PATIENT INFORMATION

NAME: Patient TSITest ACC #: TSITest DOB: 1/1/1900 SEX:

Patient Information Card

This is a summary genetic report for your patient to share with other healthcare providers. The card can be cut out along the dashed line and carried with the patient.

REPORT DETAILS Name: Patient TSITest DOB: 1/1/1900 ACC #: TSITest

Pharmacogenetic Test Summary Apolipoprotein ε3/ε2 Altered APOE function E COMT Val158Met G/G High/Normal COMT Activity CYP1A2 Indeterminate Unknown Phenotype CYP2B6 Indeterminate Unknown Phenotype CYP2C19 *2/*2 Poor Metabolizer CYP2C9 *1/*1 Normal Metabolizer CYP2D6 *10/*10 Normal Metabolizer CYP3A4 *1/*1 Normal Metabolizer CYP3A5 *1/*1 Normal Metabolizer Factor II rs1799963 GG Normal Thrombosis Risk Factor V Leiden rs6025 CC Normal Thrombosis Risk MTHFR c.665C>T GA Reduced MTHFR Activity MTHFR c.1286A>C GT Reduced MTHFR Activity SLCO1B1 521T>C T/T Normal Function VKORC1 -1639G>A G/A Intermediate Warfarin Sensitivity

For a complete report contact Scientia Dx www.Your_WebSite.com

Genetic Test Results For Patient TSITest Lab Director: Randah Al-Kana, MD | CLIA: 31D2115446 | 136 Ridge Road, Lyndhurst, NJ 07071 | www.Your_WebSite.com | 201.844.9160 Page 15 of 15

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