Personalized Genetic Test for Cardiology Patient: John Doe DOB: 8/21/1955 Accession #: 997123456 Gender: Male Collection Date: 7/10/2013 Received Date: 7/10/2013 Ordered By: 7/10/2013 Report Generated: 4/15/2014 Indications for Testing: None Specified Genetic Test Implications for Current Medications Current Medication List: None Specified Risk Management Thrombophilia Increased Risk of Thrombosis Anticoagulation: asymptomatic individuals with a history of thrombosis, a short course of prophylactic anticoagulation may be considered in high-risk settings such as surgery, pregnancy, or prolonged immobilization. Decisions regarding prophylactic anticoagulation should be based on a risk/benefit assessment. Estrogen-containing preparations: women with a positive history of thrombotic events or with an additional thrombotic risk factor: consider avoiding estrogen contraception and hormone replacement therapy. Women with no history of thrombotic events: consider informing on the risk of estrogen-containing contraceptives; consider alternative forms of contraception and control of menopausal symptoms. Women electing to use oral contraceptives: consider avoiding third-generation formulations because of their higher thrombotic risk. Women who require short-term hormone replacement therapy for severe menopausal symptoms: consider low-dose transdermal preparations. Hyperhomocysteinemia No Increased Risk of Hyperhomocysteinemia MTHFR Enzyme Activity is normal. PersonalizeDx Laboratories Dosing Guidance Cardiovascular Medications Carvedilol (Coreg) Flecainide (Tambocor) Irbesartan (Avapro) Metoprolol (Lopressor) Mexiletine (Mexitil) Nebivolol (Bystolic) Prasugrel (Effient) Propafenone (Rythmol) Propranolol (Inderal) Timolol (Timoptic) Fluvastatin (Lescol) Warfarin (Coumadin) Other Medications Clopidogrel (Plavix) Page 1 of 7
Darifenacin (Enablex) Dexlansoprazole (Dexilant) Esomeprazole (Nexium) Fesoterodine (Toviaz) Lansoprazole (Prevacid) Metoclopramide (Reglan) Mirabegron (Myrbetriq) Omeprazole (Prilosec) Ondansetron (Zofran) Pantoprazole (Protonix) Rabeprazole (Aciphex) Tamsulosin (Flomax) Tolterodine (Detrol) Voriconazole (Vfend) Glimepiride (Amaryl) Glipizide (Glucotrol) Glyburide (Micronase) Tolbutamide (Orinase) Pain Medications Buprenorphine (Butrans, Buprenex) Carisoprodol (Soma) Codeine (Codeine) Cyclobenzaprine (Flexeril, Amrix) Dihydrocodeine (Synalgos-DC) Fentanyl (Actiq) Hydrocodone (Vicodin) Hydromorphone (Dilaudid, Exalgo) Meperidine (Demerol) Morphine (MS Contin) Oxycodone (Percocet) Oxymorphone (Opana, Numorphan) Tapentadol (Nucynta) Tramadol (Ultram) PersonalizeDx Laboratories Celecoxib (Celebrex) Flurbiprofen (Ansaid) Piroxicam (Feldene) Psychotropic Medications Page 2 of 7
Aripiprazole (Abilify) Atomoxetine (Strattera) Citalopram (Celexa) Clozapine (Clozaril) Desipramine (Norpramin) Desvenlafaxine (Pristiq) Diazepam (Valium) Donepezil (Aricept) Duloxetine (Cymbalta) Escitalopram (Lexapro) Gabapentin (Neurontin) Galantamine (Razadyne) Haloperidol (Haldol) Iloperidone (Fanapt) Mirtazapine (Remeron) Nortriptyline (Pamelor) Olanzapine (Zyprexa) Paliperidone (Invega) Paroxetine (Paxil) Perphenazine (Trilafon) Pimozide (Orap) Pregabalin (Lyrica) Risperidone (Risperdal) Thioridazine (Mellaril) Venlafaxine (Effexor) Vortioxetine (Brintellix) Amitriptyline (Elavil) Clobazam (Onfi) Clomipramine (Anafranil) Doxepin (Silenor) Imipramine (Tofranil) Phenytoin (Dilantin) Sertraline (Zoloft) Tetrabenazine (Xenazine) Trimipramine (Surmontil) Page 3 of 7
Test Details Assay Results Phenotype Clinical Consequences CYP2C19 *2/*17 Provisional Intermediate Metabolizer CYP2C9 *2/*2 Poor Metabolizer CYP2D6 *1/*5 Normal Metabolizer CYP3A4 *1/*1 Normal Metabolizer CYP3A5 *9/*9 Unknown Phenotype PersonalizeDx Laboratories Substrates of CYP2C19 may require special attention for this patient. Substrates of CYP2C9 may require special attention for this patient. Substrates of CYP3A5 may require special attention for this patient. CYP2C9 *2/*2 Poor Metabolizer The patient's CYP2C9 and VKORC1 genotype results VKORC1-1639G>A G/G Low Warfarin Sensitivity show a decreased CYP2C9 activity with an average VKORC1 expression. A decreased warfarin dose requirement is expected. Factor II Factor V Leiden 20210G>A GA 1691G>A GG Increased Thrombosis Risk The patient's genotypes for Factor V Leiden and Factor II predicts an increased risk for thrombosis. Consider avoiding estrogen-containing preparations. A short course of prophylactic anticoagulation may be considered in high-risk settings such as surgery. MTHFR MTHFR 1298A>C AC 677C>T CC No Increased Risk of Hyperhomocysteinemia. The patient MTHFR function is slightly reduced and no significant hyperhomocysteinemia is expected. Methodology: Array based assays detect listed alleles, including all common and most rare variants with known clinical significance at analytical sensitivity and specificity >99%. Limitations: These assays do not detect polymorphisms other than those listed. These assays have been developed and performance characteristics determined by PGXL. Rare false positive or false negative results may occur. These assays have not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance is not necessary. These tests are used for clinical purposes and should not be considered as investigational. CYP2C19 *2, *3, *4, *4B, *5, *6, *7, *8, *9, *10, *17; CYP2C9 *2, *3, *4, *5, *6, *11; CYP2D6 *2, *3, *4, *4M, *6, *7, *8, *9, *10, *12, *17, *29, *41, *5 (gene deletion), XN (gene duplication); CYP3A4 *1B, *2, *3, *12, *17; CYP3A5 *1D, *2, *3, *3B, *3C, *6, *7, *8, *9; Factor II 20210G>A; Factor V Leiden 1691G>A; MTHFR 677C>T, 1298A>C; VKORC1-1639G>A, 698C>T, 1173C>T, 1542G>C, 2255C>T, 358C>T, 3730G>A, 5808T>G Approved by: Dr. Nathash Kallichanda, Medical Director, PersonalizeDx Labs Page 4 of 7
Appendix: Dosing Guidance Amitriptyline (Elavil) Moderate Sensitivity to Amitriptyline (CYP2C19 *2/*17 Provisional Intermediate Metabolizer) Amitriptyline should be used with caution in patients with reduced CYP2C19 activity. Consider a lower starting dose and increase dosing over several days until an optimal response is achieved. Celecoxib (Celebrex) High Sensitivity to Celecoxib (CYP2C9 *2/*2 Poor Metabolizer) Consider starting at half the lowest recommended dose and evaluate response the first week. Be alert to gastrointestinal adverse events. Consider alternative medication for the management of Juvenile Rheumatoid Arthritis. Clobazam (Onfi) Possible Sensitivity to Clobazam (CYP2C19 *2/*17 Provisional Intermediate Metabolizer) In CYP2C19 Intermediate metabolizers, plasma levels of the active metabolite N-desmethylclobazam were 2-fold higher than those found in CYP2C19 normal metabolizers. The dose adjustment for intermediate metabolizers is not well established; therefore, the recommendation for poor metabolizers is proposed. 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. Clomipramine (Anafranil) Moderate Sensitivity to Clomipramine (CYP2C19 *2/*17 Provisional Intermediate Metabolizer) Clomipramine should be used with caution in patients with reduced CYP2C19 activity. Consider a lower starting dose and increase dosing over several days until an optimal response is achieved. Clopidogrel (Plavix) Reduced Response to Clopidogrel (CYP2C19 *2/*17 Provisional Intermediate Metabolizer) Consider alternative therapy. Example of alternative drugs: Prasugrel (contraindicated in TIA/Stroke patients); Ticagrelor; Aspirin; Aspirin plus Dipyridamole. Doxepin (Silenor) Moderate Sensitivity to Doxepin (CYP2C19 *2/*17 Provisional Intermediate Metabolizer) Doxepin should be used with caution in patients with reduced CYP2C19 activity. Consider a lower starting dose and increase dosing over several days until an optimal response is achieved. Flurbiprofen (Ansaid) High Sensitivity to Flurbiprofen (CYP2C9 *2/*2 Poor Metabolizer) At standard dosge, plasma concentrations of flurbiprofen are expected to be high resulting in an increased risk of toxicity. Administer flurbiprofen with caution and reduce dose if necessary. Fluvastatin (Lescol) Increased Sensitivity to Fluvastatin (CYP2C9 *2/*2 Poor Metabolizer) Increased fluvastatin plasma concentrations due to reduced CYP2C9 activity may occur, resulting in myotoxicity/hepatotoxicity. Consider monitoring the patient for treatment-related adverse effects and adjust dose as needed. Other adverse events predisposing factors include advanced age ( 65), diabetes, hypothyroidism, renal or hepatic impairments, high statin dose, CYP2C9 inhibitors, ABCG2 inhibitors and female gender. Page 5 of 7
Glimepiride (Amaryl) Possible Sensitivity to Glimepiride (CYP2C9 *2/*2 Poor Metabolizer) Subjects with reduced CYP2C9 activity may have increased glimepiride plasma drug concentrations at standard doses leading to hypoglycemic episodes. Because there is insufficient data to whether such changes have a significant clinical impact, glimepiride can be prescribed according to standard label recommended-dosage and administration with frequent monitoring of glucose plasma levels. Glipizide (Glucotrol) Possible Sensitivity to Glipizide (CYP2C9 *2/*2 Poor Metabolizer) Subjects with reduced CYP2C9 activity may have increased glipizide plasma drug concentrations at standard doses leading to hypoglycemic episodes. Because there is insufficient data to whether such changes have a significant clinical impact, glipizide can be prescribed according to standard label recommended-dosage and administration with frequent monitoring of glucose plasma levels. Glyburide (Micronase) Possible Sensitivity to Glyburide (CYP2C9 *2/*2 Poor Metabolizer) Subjects with reduced CYP2C9 activity may have increased glyburide plasma drug concentrations at standard doses leading to hypoglycemic episodes. Because there is insufficient data to whether such changes have a significant clinical impact, glyburide can be prescribed according to standard label recommended-dosage and administration with frequent monitoring of glucose plasma levels. Imipramine (Tofranil) Moderate Sensitivity to Imipramine (CYP2C19 *2/*17 Provisional Intermediate Metabolizer) Imipramine should be used with caution in patients with reduced CYP2C19 activity. Consider a lower starting dose and increase dosing over several days until an optimal response is achieved. Phenytoin (Dilantin) High Sensitivity to Phenytoin (CYP2C9 *2/*2 Poor Metabolizer) Consider a standard loading dose and reduce maintenance dose by 50%. Evaluate response and serum concentrations after 7-10 days. Be alert to neurological concentration-related adverse events. Piroxicam (Feldene) High Sensitivity to Piroxicam (CYP2C9 *2/*2 Poor Metabolizer) At standard dosge, plasma concentrations of piroxicam are expected to be high resulting in an increased risk of toxicity. Administer piroxicam with caution and reduce dose if necessary. Sertraline (Zoloft) Moderate Sensitivity to Sertraline (CYP2C19 *2/*17 Provisional Intermediate Metabolizer) Sertraline should be used with caution in patients with reduced CYP2C19 activity. Because there is insufficient data to allow calculation of dose adjustment when sertraline is prescribed, consider using a lower than recommended dose and be alert to adverse drug events such as nausea, vomiting or diarrhea. Tetrabenazine (Xenazine) Normal Sensitivity to Tetrabenazine (CYP2D6 *1/*5 Normal Metabolizer) 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. Tolbutamide (Orinase) Possible Sensitivity to Tolbutamide (CYP2C9 *2/*2 Poor Metabolizer) Subjects with reduced CYP2C9 activity may have increased tolbutamide plasma drug concentrations at standard doses leading to hypoglycemic episodes. Because there is insufficient data to whether such changes have a significant clinical impact, tolbutamide can be prescribed according to standard label recommended-dosage and administration with frequent monitoring of glucose plasma levels. Page 6 of 7
Trimipramine (Surmontil) Moderate Sensitivity to Trimipramine (CYP2C19 *2/*17 Provisional Intermediate Metabolizer) Trimipramine should be used with caution in patients with reduced CYP2C19 activity. Consider a lower starting dose and increase dosing over several days until an optimal response is achieved. Warfarin (Coumadin) Mild sensitivity to warfarin (CYP2C9 *2/*2 ) Initiation Therapy: a dose decrease may be required. Consider using the warfarin dose range provided in the FDAapproved label: 3-4 mg/day. Or consider using a personalized dose calculated by a pharmacogenetic algorithm. The estimated time to reach steady state is 8-10 days. Page 7 of 7