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Home , Hydroxybupropion, Levomilnacipran

PATIENT INFORMATION SPECIMEN DETAILS

NAME: SPECIMEN TYPE: DOB: ORDERED BY: SEX: REPORT DATE: ACC #: mygeneRx Report Current Patient Medications , , , , , Bromazepam, ,

Amitriptyline Moderate Sensitivity to Amitriptyline (CYP2C19: Intermediate Metabolizer) ACTIONABLE 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.

Bupropion Possibly Decreased Response to Bupropion (CYP2B6: Intermediate Metabolizer) INFORMATIVE Bupropion is metabolized to its by CYP2B6. This metabolite contributes to the therapeutic effects of bupropion when used as a agent or as an . Individuals who are CYP2B6 intermediate metabolizers may or may not have lower blood levels of hydroxybupropion which may or may not result in a reduced response to bupropion treatment. 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.

Quetiapine Normal Response to Quetiapine INFORMATIVE Pharmacogenetic guidance: Quetiapine is predominantly metabolized to several metabolites by CYP3A4. CYP3A5 and CYP2D6 are also responsible for quetiapine but their role in the overall metabolism of this drug is minor compared to CYP3A4. N-desalkylquetiapine, a pharmacologically active metabolite (responsible of the antidepressant effect) is further metabolized by CYP2D6 and CYP3A4. Preliminary studies have shown that genetic polymorphisms of CYP3A4, CYP2D6 and CYP3A5 may be responsible in variable exposures to quetiapine and to its active metabolite N-desalkylquetiapine. However, the clinical significance of these changes is not established yet and no genetically guided drug selection or dosing recommendations are available. Quetiapine dose should be titrated based on the clinical response and tolerability of the individual patient. Polypharmacy guidance: Quetiapine dose should be reduced to one sixth of original dose when co-medicated with a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, indinavir, ritonavir, ). When the CYP3A4 inhibitor is discontinued, the dose should be increased by 6 fold. Quetiapine dose should be increased up to 5 fold of the original dose when used in combination with a chronic treatment (e.g. > 7-14 days) of a potent CYP3A4 inducer (e.g., phenytoin, carbamazepine, rifampin, St. John’s wort etc.). When the CYP3A4 inducer is discontinued, the dose should be reduced to the original level within 7-14 days.

Sertraline Normal Sensitivity to Sertraline (CYP2C19: Intermediate Metabolizer) ACTIONABLE

Sertraline can be prescribed at standard label-recommended dosage and administration.

Trazodone Normal Response to Trazodone INFORMATIVE Pharmacogenetic guidance: Trazodone is metabolized to its active metabolite m-chlorophenylpiperazine by CYP3A4. This metabolite which may contribute to adverse events, is further metabolized by CYP2D6. The impact of genetic polymorphisms of this on the clinical response to trazodone is not well documented. No genetically guided drug selection or dosing recommendations are available. Polypharmacy guidance: It is likely that CYP3A4 inhibitors may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, the risk of cardiac arrhythmia may be increased. Therefore coadministration of trazodone with drugs that are inhibit CYP3A4 should be approached with caution.

Venlafaxine Normal Sensitivity to Venlafaxine (CYP2D6: Normal Metabolizer) ACTIONABLE Venlafaxine can be prescribed at standard label-recommended dosage and administration. Careful titration is recommended until a favorable response is achieved.

Medications outside the scope of the report: Recognized drugs: Bromazepam Unrecognized drugs: Hypericum Perforatum

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 1 of 15 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 --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 2 of 15 Risk Management -Induced Tardive Dyskinesia Increased Risk of Antipsychotic-Induced Tardive Dyskinesia The patient does not carry the Taq1A variant (homozygous for the A2 allele). The genotype results predict that the patient has normal receptor DRD2 density and hypodopaminergic functioning. The patient has increased risk for tardive dyskinesia when treated with . Closely monitor the patient for signs of tardive dyskinesia.

Antipsychotic-Induced Hyperprolactinemia Normal Risk of Antipsychotic-Induced Hyperprolactinemia The patient does not carry the Taq1A variant (homozygous for the A2 allele). The genotype results predict that the patient has normal dopamine receptor DRD2 density and hypodopaminergic functioning. The patient has normal risk of hyperprolactinemia when treated with antipsychotics. Monitor the patients closely for any signs of hyperprolactinemia.

Antipsychotic-Induced Weight Gain Low Risk of Antipsychotic-Induced Weight Gain The patient does not carry the Taq1A variant (homozygous for the A2 allele). The genotype results predict that the patient has normal dopamine receptor DRD2 density and hypodopaminergic functioning. The patient has a normal risk for weight gain when treated with antipsychotics. Monitor the patients closely for signs weight gain.

Hyperlipidemia/Atherosclerotic Cardiovascular Disease No increased risk of hyperlipidemia/atherosclerotic vascular disease The patient is negative for the APOE 388 T>C (Arg112Cys) and 526 C>T (Cys158Arg) mutations. The patient's genotype is wild-type, which is the most common genotype in the general population (frequency: >60%). A patient with wild-type genotype does not have a defect in the apolipoprotein E (APOE), which is an integral structure of lipoprotein particles that have critical roles in blood lipid metabolism and transport. Defects in APOE can increase a person's risk for developing atherosclerosis and cardiovascular disease. No action is needed when a patient is normolipidemic.

Hyperhomocysteinemia - Depression No Increased Risk of Hyperhomocysteinemia The patient does not carry the MTHFR C677T variant. MTHFR enzyme activity is normal. 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. With a normal MTHFR activity, this patient can process folate normally and is unlikely to have elevated plasma levels of homocysteine. Patients diagnosed with depression: as lower folate levels are associated with poorer antidepressant response, and baseline levels of folate within the normal range predict antidepressant response, testing for homocysteine levels and serum folate levels is recommended for this patient before prescribing methylfolate as an antidepressant-augmenting agent.

Thrombophilia No Increased Risk of Thrombosis The patient does not carry the Factor V Leiden G1691A mutation or Factor II G20210A mutation (wild-type). 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. Unless other genetic and/or circumstantial risk factors are present (e.g., smoking or obesity…), estrogen-containing contraceptive and hormone replacement therapy can be used by the patient.

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 3 of 15 Hyperhomocysteinemia - Thrombosis No Increased Risk of Hyperhomocysteinemia The patient carries two MTHFR A1298C mutations (homozygous) and no MTHFR C677T mutation. MTHFR enzyme activity is reduced (60% of normal activity). The patient's reduced MTHFR activity is a 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). The patient's MTHFR activity is slightly reduced.

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 4 of 15 Potentially Impacted Medications

CATEGORY DRUG CLASS STANDARD PRECAUTIONS USE WITH CAUTION CONSIDER ALTERNATIVES

Anticancer Agents Antifolates Methotrexate

Azilsartan Candesartan Eprosartan Angiotensin II Receptor Irbesartan Antagonists Losartan Olmesartan Telmisartan Valsartan

Antianginal Agents Ranolazine

Flecainide Antiarrhythmics Mexiletine Propafenone

Apixaban Dabigatran Etexilate Anticoagulants Edoxaban Warfarin Fondaparinux Cardiovascular Rivaroxaban

Prasugrel Antiplatelets Ticagrelor Clopidogrel Vorapaxar

Carvedilol Labetalol Metoprolol Beta Blockers Nebivolol Timolol

Diuretics Torsemide

Atorvastatin Lovastatin Fluvastatin Statins Pitavastatin Rosuvastatin Pravastatin Simvastatin

Nateglinide Meglitinides Repaglinide

Chlorpropamide Diabetes Glimepiride Sulfonylureas Glipizide Glyburide Tolbutamide

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 5 of 15 CATEGORY DRUG CLASS STANDARD PRECAUTIONS USE WITH CAUTION CONSIDER ALTERNATIVES

Dolasetron Antiemetics

Gastrointestinal Dexlansoprazole Esomeprazole Lansoprazole Proton Pump Inhibitors Omeprazole Pantoprazole Rabeprazole

Antifungals Voriconazole Infections Antimalarials Proguanil

Fibromyalgia Agents

Carisoprodol Muscle Relaxants Tizanidine Metaxalone Methocarbamol

Celecoxib Diclofenac Flurbiprofen Ibuprofen Indomethacin Ketoprofen NSAIDs Ketorolac Meloxicam Nabumetone Naproxen Pain Piroxicam Sulindac

Alfentanil Codeine Fentanyl Hydrocodone Meperidine Oxycodone Oxymorphone Sufentanil

Bupropion Antiaddictives

Amphetamine Anti-ADHD Agents

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 6 of 15 CATEGORY DRUG CLASS STANDARD PRECAUTIONS USE WITH CAUTION CONSIDER ALTERNATIVES

Brivaracetam Carbamazepine Eslicarbazepine Ethosuximide Ezogabine Fosphenytoin Gabapentin Lacosamide Lamotrigine Anticonvulsants Primidone Levetiracetam Zonisamide Oxcarbazepine Phenytoin Pregabalin Rufinamide Tiagabine Valproic Acid Vigabatrin

Donepezil Antidementia Agents

Amoxapine Psychotropic Amitriptyline Nefazodone Sertraline Venlafaxine

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 7 of 15 CATEGORY DRUG CLASS STANDARD PRECAUTIONS USE WITH CAUTION CONSIDER ALTERNATIVES

Aripiprazole Fluphenazine Antipsychotics Quetiapine Thiothixene Trazodone

Alprazolam Clobazam Clonazepam

Mood Stabilizers

Other Neurological / Quinidine Agents

Anti-Gout Agents Allopurinol

Rheumatology Apremilast Immunomodulators Leflunomide Tofacitinib

Transplantation Immunosupressants Tacrolimus

5-Alpha Reductase Dutasteride Inhibitors for Benign Finasteride Prostatic Hyperplasia

Alfuzosin Alpha-Blockers for Doxazosin Benign Prostatic Silodosin Hyperplasia Tamsulosin Terazosin

Darifenacin Urologicals Fesoterodine Mirabegron Antispasmodics for Oxybutynin Overactive Bladder Solifenacin Tolterodine Trospium

Avanafil Phosphodiesterase Sildenafil Inhibitors for Erectile Tadalafil Dysfunction Vardenafil

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 8 of 15 Dosing Guidance

Clopidogrel Reduced Response to Clopidogrel (CYP2C19: Intermediate Metabolizer) ACTIONABLE Consider alternative therapy. Examples of alternative drugs: prasugrel (contraindicated in TIA/Stroke patients), ticagrelor, aspirin, aspirin plus dipyridamole.

Allopurinol Decreased Response to Allopurinol (ABCG2: Intermediate Transporter Function) INFORMATIVE The patient carries one copy of rs2231142 A allele. Preliminary studies suggest that the patient's genotype may be associated with a poor response to allopurinol for the treatment of gout. Carefully monitor the patient's responsiveness or consider an alternative therapy. This genotype result cannot be used to identify patients at risk for severe cutaneous adverse reactions.

Amitriptyline Moderate Sensitivity to Amitriptyline (CYP2C19: Intermediate Metabolizer) ACTIONABLE 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.

Bupropion Possibly Decreased Response to Bupropion (CYP2B6: Intermediate Metabolizer) INFORMATIVE Bupropion is metabolized to its active metabolite hydroxybupropion by CYP2B6. This metabolite contributes to the therapeutic effects of bupropion when used as a smoking cessation agent or as an antidepressant. Individuals who are CYP2B6 intermediate metabolizers may or may not have lower blood levels of hydroxybupropion which may or may not result in a reduced response to bupropion treatment. 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.

Clobazam Possible Sensitivity to Clobazam (CYP2C19: Intermediate Metabolizer) ACTIONABLE 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, and 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 Moderate Sensitivity to Clomipramine (CYP2C19: Intermediate Metabolizer) ACTIONABLE 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.

Clozapine Non-Response to Clozapine (CYP1A2: Normal Metabolizer - Higher Inducibility) INFORMATIVE Smokers have a high risk for non-response at standard doses and may require higher doses. There is an association between high clozapine doses and the risk of seizures, and therefore careful monitoring is recommended during dosing adjustment. Smoking cessation will increase plasma drug levels, leading to adverse events. Therefore, therapeutic drug monitoring accompanied by dose reduction is recommended in patients who have quit smoking.

Dexmethylphenid Decreased Response to Dexmethylphenidate (COMT: Intermediate COMT Activity) INFORMATIVE ate The patient's genotype result predicts a less optimal response to dexmethylphenidate. Dosage should be individualized according to the needs and response of the patient. Therapy should be initiated in small doses, with gradual weekly increments.

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 9 of 15 Doxepin Moderate Sensitivity to Doxepin (CYP2C19: Intermediate Metabolizer) ACTIONABLE 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.

Fluvastatin Increased Myotoxicty/Hepatotoxicty Risk (ABCG2: Intermediate Transporter Function) INFORMATIVE Carriers of the ABCG2 421C>A variant are at greater risk of developing adverse events to fluvastatin therapy compared to noncarriers of this mutation. Increased fluvastatin plasma concentrations due to reduced ABCG2 transport activity may occur in these patients. Monitor the patient for treatment-related adverse effects, and adjust dose as needed. Other myotoxicity/hepatotoxicity predisposing factors include advanced age (≥65), diabetes, hypothyroidism, renal or hepatic impairments, high statin dose, CYP2C9 inhibitors, ABCG2 inhibitors, and female gender.

Imipramine Moderate Sensitivity to Imipramine (CYP2C19: Intermediate Metabolizer) ACTIONABLE 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.

Leflunomide Increased Sensitivity to Leflunomide (CYP2C19: Intermediate Metabolizer) INFORMATIVE 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.

Lorazepam Possible Altered Response to Lorazepam (UGT2B15: Poor Metabolizer) INFORMATIVE Lorazepam clearance is reduced in this patient. However, there is insufficient evidence whether this change results in a significant clinical effect. Consider monitoring the patient for increased sedation and adjust dosing accordingly.

Methadone Possible Sensitivity to Methadone (CYP2B6: Intermediate Metabolizer) INFORMATIVE Based on currently available evidence, S-methadone plasma concentrations may increase, resulting in higher risk of cardiac arrhythmias and QTc prolongation. Consider lower starting doses of methadone, and adjust dosing based on the clinical response.

Methylphenidate Decreased Response to Methylphenidate (COMT: Intermediate COMT Activity) INFORMATIVE The patient's genotype result predicts a less optimal response to methylphenidate. Dosage should be individualized according to the needs and response of the patient. Therapy should be initiated in small doses, with gradual weekly increments.

Naltrexone Altered Response to Naltrexone (OPRM1: Normal OPRM1 Function) INFORMATIVE Treatment of dependence: the patient has the wild-type genotype for OPRM1 that is associated with a poorer outcome with naltrexone therapy. Naltrexone-treated patients not carrying the 118A> G mutation are less likely to respond to this drug, and may have higher relapse rates than those who are carriers of this mutation.

Olanzapine Non-Response to Olanzapine (CYP1A2: Normal Metabolizer - Higher Inducibility) INFORMATIVE There is little evidence regarding the impact of CYP1A2 genetic variants on olanzapine response. Smokers may be at risk for non-response at standard doses. Careful monitoring is recommended during dosing adjustment. Smoking cessation may increase plasma drug levels, leading to adverse events. Therefore, therapeutic drug monitoring accompanied by dose reduction may be needed in patients who have quit smoking.

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 10 of 15 Oxazepam Possible Altered Response to Oxazepam (UGT2B15: Poor Metabolizer) INFORMATIVE Oxazepam clearance is reduced in this patient. However, there is insufficient evidence whether this change results in a significant clinical effect. Consider monitoring the patient for increased sedation and adjust dosing accordingly.

Phenobarbital Possible Sensitivity to Phenobarbital (CYP2C19: Intermediate Metabolizer) INFORMATIVE CYP2C19 is partly involved in the metabolism of phenobarbital, and although CYP2C19 intermediate metabolizers have a 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.

Primidone Possible Sensitivity to Primidone (CYP2C19: Intermediate Metabolizer) INFORMATIVE CYP2C19 is partly involved in the metabolism of primidone, and although CYP2C19 intermediate metabolizers have a 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.

Rosuvastatin Increased Myopathy Risk (SLCO1B1 521T>C TT ABCG2 421C>A AC) INFORMATIVE The patient carries a polymorphism in the ABCG2 gene that is associated with a higher rosuvastatin plasma exposure. This may result in improved lipid-lowering response but an increased risk of adverse events. The patient does not carry a polymorphism in the SLCO1B1 gene that is associated with an increased risk of myopathy. However, because this test cannot find all of the inherited or circumstantial reasons for myopathy, other factors may affect this risk assessment. Examples of such factors include: uncontrolled hypothyroidism, renal impairment, diabetes, and comedications with ABCG2 or SLCO1B1 inhibitors. For patient age 20-60 or > 60 years, the maximum recommended dose range to reduce the risk of high statin exposure: 20 mg/day. Start with usual doses 10-20 mg/day or 5 mg/day in Asian patients.

Tetrabenazine Normal Sensitivity to Tetrabenazine (CYP2D6: Normal Metabolizer) ACTIONABLE 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.

Tizanidine Possible Non-Response to Tizanidine (CYP1A2: Normal Metabolizer - Higher INFORMATIVE Inducibility) There is little evidence regarding the impact of CYP1A2 genetic variants on tizanidine response. Smokers may be at risk for non-response and may require higher doses. There is an association between high tizanidine plasma concentrations and the risk of hypotension and excessive sedation. Therefore, careful monitoring is recommended during dosing adjustment. Smoking cessation may increase plasma drug levels, leading to excessive hypotension and sedation. Careful monitoring accompanied by dose reduction may be needed in patients who have quit smoking.

Trimipramine Moderate Sensitivity to Trimipramine (CYP2C19: Intermediate Metabolizer) ACTIONABLE 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.

Voriconazole Moderate Sensitivity to Voriconazole (CYP2C19: Intermediate Metabolizer) ACTIONABLE Voriconazole should be used with caution in patients with reduced CYP2C19 activity. Monitor closely voriconazole plasma concentrations, and adjust the dose accordingly.

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 11 of 15 Warfarin Moderate Sensitivity to Warfarin (CYP2C9 *1/*1 VKORC1 -1639G>A A/A) ACTIONABLE Initiation Therapy: a dose decrease may be required. Consider using the following warfarin dose range provided in the FDA-approved label: 3-4 mg/day. OR consider using a personalized dose calculated by a pharmacogenetic algorithm. The estimated time to reach steady state is 4-5 days.

Zonisamide Possible Sensitivity to Zonisamide (CYP2C19: Intermediate Metabolizer) INFORMATIVE CYP2C19 is partly involved in the metabolism of zonisamide, and although preliminary studies show that CYP2C19 intermediate metabolizers have a slightly lower (15%) 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.

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 12 of 15 Test Details

Gene Genotype Phenotype Clinical Consequences CYP2C9 *1/*1 Normal Metabolizer Consistent with a typical CYP2C9 activity. This test did not identify risks for side effects or loss of efficacy with drug substrates. CYP2C19 *1/*2 Intermediate Metabolizer Consistent with a moderate deficiency in CYP2C19 activity. Potential risk for side effects or loss of efficacy with drug substrates. CYP2D6 *1/*17 Normal Metabolizer Consistent with a typical CYP2D6 activity. This test did not identify risks for side effects or loss of efficacy with drug substrates. CYP3A5 *3/*3 Poor Metabolizer Consistent with a poor CYP3A5 activity. This phenotype is the most common in the general population. Caution is advised when prescribing narrow therapeutic index drugs. Alternative drugs or dose adjustment may be required if CYP3A inhibitors or inducers are co-prescribed. CYP3A4 *1/*1 Normal Metabolizer Consistent with a typical CYP3A4 activity. Caution is advised when prescribing narrow therapeutic index drugs. Alternative drugs or dose adjustment may be required if CYP3A inhibitors or inducers are co-prescribed. VKORC1 -1639G>A A/A High Warfarin Sensitivity VKORC1 is the site of action of warfarin. The patient may require a substantial decrease in warfarin dose. Apolipoprotein E ε3/ε3 No Increased Risk of No Increased Risk of Cardiovascular Disease Hyperlipidemia/Atheroscleroti c Vascular Disease CYP2B6 *1/*6 Intermediate Metabolizer Consistent with a moderate deficiency in CYP2B6 activity. Potential risk for side effects or loss of efficacy with drug substrates. CYP1A2 *1F/*1F Normal Metabolizer - Higher Consistent with a typical CYP1A2 activity in absence of inducing substances. Inducibility Rapid Metabolism occurs in presence of inducers such as , cruciferous vegetables, carbamazepine, rifampin and smoking. SLCO1B1 521T>C TT Normal Transporter Function Consistent with a typical SLCO1B1 transporter function. The patient's risk for statin-induced myopathy is not increased. COMT Val158Met AG Intermediate COMT Activity Consistent with a reduced catechol O-methyltransferase (COMT) function. ANKK1/DRD2 DRD2:Taq1A GG Unaltered DRD2 function Consistent with a normal dopamine receptor D2 function. OPRM1 A118G AA Normal OPRM1 Function Consistent with a normal OPRM1 receptor signaling efficiency induced by exogenous opioids. This is associated with a good analgesia following standard doses and a poor response to naltrexone. UGT2B15 *2/*2 Poor Metabolizer Consistent with a decreased UGT2B15 glucuronidation function. Potential risk for side effects with drug substrates. ABCG2 421C>A AC Intermediate Transporter Consistent with a decreased ABCG2 transporter function. The patient's risk for Function statin-induced adverse events is intermediate. ADRA2A C-1291G G/G Homozygous for G Allele Carriers of the G allele of ADRA2A C-1291G variant, show greater reduction of inattentive symptoms when administered Methylphenidate or Dexmethylphenidate. BDNF 434C>T C/T Heterozygous for rs6265 T Consistent with reduced activity-dependent secretion of BDNF from neurons Allele and impaired BDNF signaling. MTHFR 1298A>C CC No Increased Risk of

The patient's reduced MTHFR activity is a not a risk factor for 677C>T CC Hyperhomocysteinemia hyperhomocysteinemia. Unless other risk factors are present, the patient is not expected to have an increased risk for venous thromboembolism (VTE). 

Factor II 20210G>A GG No Increased Risk of

The patient's risk of thrombosis is not increased (average risk of clotting is Factor V Leiden 1691G>A GG Thrombosis 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.

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 13 of 15 Alleles Tested: ABCG2 421C>A; ADRA2A C-1291G; ANKK1/DRD2 DRD2:Taq1A; Apolipoprotein E ε2, ε4, (ε3 is reference); BDNF 434C>T; COMT Val158Met; CYP1A2 *1F, *1K; CYP2B6 *6, *9, *11, *18; CYP2C19 *2, *3, *4, *4B, *6, *7, *8, *9, *10, *17; CYP2C9 *2, *3, *4, *5, *6, *8, *11, *27; CYP2D6 *2, *3, *4, *4M, *6, *7, *8, *9, *10, *12, *14A, *14B, *17, *29, *35, *41; CYP3A4 *3, *12, *17, *22; CYP3A5 *3, *3C, *6, *7; Factor II 20210G>A; Factor V Leiden 1691G>A; MTHFR 1298A>C, 677C>T; OPRM1 A118G; SLCO1B1 521T>C; UGT2B15 *2; VKORC1 -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%.

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. DNAlysis Biotechnology developed this test and its performance characteristics. This test has not been cleared or approved by the U.S. Food and Drug Administration. 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.

The pharmacogenetic assay involves non-FDA approved interpretational software and genotype-phenotype associations performed by Translational Software. A qualified designee within DNAlysis Biotechnology uses Translational Software to generate and subsequently review the report.

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 14 of 15 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: DOB: ACC #:

Pharmacogenetic Test Summary Intermediate Transporter ABCG2 421C>A AC Function ADRA2A C-1291G G/G Homozygous for G Allele ANKK1/DRD2 DRD2:Taq1A GG Unaltered DRD2 function No Increased Risk of Apolipoprotein E ε3/ε3 Hyperlipidemia/Atherosclerotic Vascular Disease BDNF 434C>T C/T Heterozygous for rs6265 T Allele COMT Val158Met AG Intermediate COMT Activity Normal Metabolizer - Higher CYP1A2 *1F/*1F Inducibility CYP2B6 *1/*6 Intermediate Metabolizer CYP2C19 *1/*2 Intermediate Metabolizer CYP2C9 *1/*1 Normal Metabolizer CYP2D6 *1/*17 Normal Metabolizer CYP3A4 *1/*1 Normal Metabolizer CYP3A5 *3/*3 Poor Metabolizer Factor II 20210G>A GG Normal Thrombosis Risk Factor V Leiden 1691G>A GG Normal Thrombosis Risk MTHFR 1298A>C CC Reduced MTHFR Activity MTHFR 677C>T CC Normal MTHFR Activity OPRM1 A118G AA Normal OPRM1 Function SLCO1B1 521T>C TT Normal Transporter Function UGT2B15 *2/*2 Poor Metabolizer VKORC1 -1639G>A A/A High Warfarin Sensitivity

For a complete report contact DNAlysis Biotechnology DO NOT DISTRIBUTE www.dnalysis.co.za

Genetic Test Results For --- Lab Director: Thenusha Naidoo | 204 Oxford Rd, Illovo, 2095 | www.dnalysis.co.za | +27 11 268 0268 Page 15 of 15