Comprehensive Pharmacogenetic Report with DDI

PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Comments: None provided.

Current Patient Medications Paxil, Doxepin, Diazepam, Voltaren, Oxycodone, Abilify, Pravachol, Fluvoxamine, Ondansetron

Pharmacogenetic Interactions

SILENOR Doxepin | EVIDENCE LEVEL 1 Increased Sensitivity to Doxepin (CYP2D6: Poor Metabolizer) Consider an alternative drug or reduce doxepin starting dose by 50%. Adjust maintenance dose according to nordoxepin plasma concentrations.

SILENOR Doxepin | EVIDENCE LEVEL 2 Increased Sensitivity to Doxepin (CYP2C19: Ultra-Rapid Metabolizer) Consider an alternative drug, or consider prescribing doxepin at standard dose and monitor the plasma concentrations of doxepin and desmethyl-doxepin to guide dose adjustments.

PAROXETINE Paxil | EVIDENCE LEVEL 2 Increased Sensitivity to Paroxetine (CYP2D6: Poor Metabolizer) At standard label-recommended dosage, paroxetine levels are expected to be high, and adverse events may occur. Consider an alternative medication. If paroxetine is warranted, consider a 50% decrease of the initial dose and titrate based on the clinical response and tolerability. Some studies show that compared to normal metabolizers, poor metabolizers may experience more sexual dysfunction.

ARIPIPRAZOLE Abilify | EVIDENCE LEVEL 1 Increased Sensitivity to Aripiprazole (CYP2D6: Poor Metabolizer) Poor metabolizers have a significantly reduced capacity to metabolize aripiprazole and its active metabolite, and should receive lower doses. Careful titration is recommended until a favorable response is achieved.

Daily dosing (oral or intramuscular): aripiprazole dose should initially be reduced to one-half (50%) of the usual dose, then adjusted to achieve a favorable clinical response. Reduce the maximum dose to 10 mg/day (67% of the maximum recommended daily dose). The dose of aripiprazole for poor metabolizers who are administered a strong CYP3A4 inhibitor should be reduced to one- quarter (25%) of the usual dose.

Monthly dosing (intramuscular): the starting and maintenance monthly recommended dose is lower than the usually recommended dose, and should be 300 mg. Some patients may benefit from a reduction to 200 mg. Reduce the monthly dose to 200 mg if a CYP3A4 inhibitor is prescribed to CYP2D6 poor metabolizers receiving 300 mg of aripiprazole.

VALIUM Diazepam | EVIDENCE LEVEL 2 Possible Altered Sensitivity to Diazepam (CYP2C19: Ultra-Rapid Metabolizer) CYP2C19 rapid and ultra-rapid metabolizers metabolize diazepam and nordiazepam more rapidly than normal metabolizers. However, there is insufficient data to allow calculation of dose adjustment when diazepam is prescribed. Monitor the patient's response and adjust the dose accordingly.

LUVOX Fluvoxamine | EVIDENCE LEVEL 2 Increased Sensitivity to Fluvoxamine (CYP2D6: Poor Metabolizer)

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 1 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

LUVOX Fluvoxamine | EVIDENCE LEVEL 2 Delayed Response to Fluvoxamine (SLC6A4: Low Serotonin Transporter Expression) The genotype predicts significantly decreased serotonin transporter levels resulting in less efficient transporter function. A longer titration period may be required to achieve maximal antidepressant response. The patient may respond to fluvoxamine more slowly (up to 12 weeks) and may experience more side effects. The patient may benefit from non-selective antidepressants.

ZOFRAN, ZUPLENZ Ondansetron | EVIDENCE LEVEL 2 Lack of Benefit from Ondansetron Treatment in Early Onset Alcoholism (SLC6A4: Low Serotonin Transporter Expression) Ondansetron has been shown to be effective in inhibiting heavy drinking behaviors in patients with early onset alcoholism. This patient carries two short or S alleles of SLC6A4 5-HTTLPR variant. Preliminary studies demonstrate that use of ondansetron may not benefit patients with this genotype. The abstinence rates from alcohol and the number of drinks per drinking day were not significantly different between patients treated with placebo or ondansetron.

PERCOCET, OXYCONTIN Oxycodone | EVIDENCE LEVEL 1 Possible Altered Response to Oxycodone (CYP2D6: Poor Metabolizer) Decreased conversion of oxycodone to the more active metabolite oxymorphone is expected in CYP2D6 poor metabolizers. However, there is insufficient evidence whether poor metabolizers have decreased analgesia when taking oxycodone. Adequate pain relief can be achieved by increasing the dose in response to pain symptoms. Other opioids not metabolized by CYP2D6 may also be considered (i.e., morphine, oxymorphone, buprenorphine, fentanyl, methadone, and hydromorphone).

DICLOFENAC Voltaren | EVIDENCE LEVEL 2 Possible Sensitivity to Diclofenac (CYP2C9: Poor Metabolizer) Diclofenac is extensively metabolized by hydroxylation and direct glucuronidation. About 50% of diclofenac is eliminated as a 4- hydroxymetabolite, a reaction mediated by CYP2C9. Other CYP enzymes including CYP2C8, CYP2C19 and CYP3A4 are also involved in the formation of a 5-hydroxymetabolite. A substantial portion of the drug is also directly glucuronidated by UGT2B7 and UGT2B4. Individuals with decreased CYP2C9 activity (i.e poor metabolizers) should be closely monitored for increased gastrointestinal adverse events when prescribed diclofenac and lower doses may be more appropriate for these patients.

PRAVASTATIN Pravachol | EVIDENCE LEVEL 2 Normal Myopathy Risk (SLCO1B1: Normal Function) Pravastatin plasma concentrations are not expected to increase, and unless other genetic or circumstantial risk factors are present, pravastatin can be prescribed at standard FDA-recommended starting doses and adjusted based on disease-specific guidelines. (Other myopathy predisposing factors include advanced age (≥65), uncontrolled hypothyroidism, renal impairment, high statin dose, comedications, and female gender.)

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 2 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Diazepam & Fluvoxamine SERIOUS

Benzodiazepines that do not undergo extensive Phase I metabolism (lorazepam, oxazepam) may be an alternative in patients receiving fluvoxamine.The US manufacturer of fluvoxamine recommends that fluvoxamine and diazepam not be concurrently administered.If fluvoxamine is concurrently administered with alprazolam, the manufacturer of fluvoxamine recommends that the initial dose of alprazolam be reduced by 50%, followed by titration to the lowest effective dose.If fluvoxamine is started in a patient already receiving a benzodiazepine, monitor closely and anticipate the need to reduce the benzodiazepine dose.Counsel patient to report excess drowsiness, confusion, memory problems including sleep-driving behaviors, or loss of coordination.

Doxepin & Paxil SERIOUS

Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds at the initiation of concurrent therapy with selected SSRIs and SNRIs. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly.If the SSRI or SNRI is discontinued in a patient receiving a tricyclic compound, the dosage of the tricyclic compound may need to be adjusted upward as the effects of enzyme inhibition wane.The effects of fluoxetine on hepatic metabolism may last for up to 5 weeks after fluoxetine discontinuation. A tricyclic compound started after the discontinuation of fluoxetine should be started a lower initial dosage.If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, and fainting.

Fluvoxamine & Doxepin MODERATE

Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds at the initiation of concurrent therapy with selected SSRIs or SNRIs. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly.If the SSRI or SNRI is discontinued in a patient receiving a tricyclic compound, the dosage of the tricyclic compound may need to be adjusted.If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

Fluvoxamine & Voltaren MODERATE

Selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors and NSAIDs should be used concurrently with caution. Patients should be warned about the increased risk of bleeding and be educated about signs and symptoms of bleeding.

Pravachol & Paxil MODERATE

Monitor diabetic patients newly started on this combination for elevated glucose measurements. Consider changing to a different statin or serotonin reuptake inhibitor (SSRI) if needed to maintain control of diabetes.For non-diabetic patients with elevated random glucose measurements, test fasting glucose concentration. If significantly elevated, change to a different statin or SSRI.

Abilify & Paxil MODERATE

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 3 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

NAME: Sample Report Alcala - SPECIMEN TYPE: Buccal Swab Christian Tagwerker, Ph.D. Psychotropic Alcala Testing and Analysis Services --619-450-5870 ACC #: Psychotropic COLLECTION DATE: 1/1/1900 DO NOT DISTRIBUTE DOB: 1/1/1900 RECEIVED DATE: 1/1/1900 3703 Camino del Rio South, 100-A SEX: Female REPORT DATE: 10/4/2016 San Diego, CA 98102 www.alcalalabs.com The US manufacturer of oral aripiprazole states that the dose of aripiprazole should be reduced to one-half of its normal dose when strong CYP2D6 inhibitors such as bupropion, fluoxetine, paroxetine and quinidine are coadministered, unless aripiprazole is being used as adjunctive therapy for Major Depressive Disorder. If the patient is also receiving a strong CYP3A4 inhibitor, the dose of aripiprazole should be reduced to one-fourth its normal dose. When the inhibitor(s) is(are) discontinued, the dose of aripiprazole should be increased.The US manufacturer of aripiprazole extended-release injection recommends the following dose adjustments for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:- if the aripiprazole dose is 400 mg per month and a strong CYP2D6 inhibitor is started, then decrease aripiprazole dose to 300 mg per month.- if the aripiprazole dose is 400 mg per month and patient receives concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, then decrease dose to 200 mg per month. Patients who are CYP2D6 poor metabolizers and receive treatment with a strong CYP3A inhibitor should also receive 200 mg per month.- if the routine aripiprazole dose is 300 mg per month and a strong CYP2D6 inhibitor is started, then decrease aripiprazole dose to 200 mg per month.- If the routine aripiprazole dose is 300 mg per month and patient receives concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, then decrease dose to 160 mg per month. Patients who are CYP2D6 poor metabolizers and receive treatment with a strong CYP3A inhibitor should also receive 160 mg per month.The US manufacturer of aripiprazole lauroxil extended-release injection recommends the following dose adjustments for patients who receive a strong CYP2D6 inhibitor for greater than 14 days:- Reduce the dose of aripiprazole lauroxil to the next lower strength. No dosage adjustment is necessary in patient taking the 441 mg dose, if tolerated.- For patients taking both a strong CYP2D6 and CYP3A4 inhibitor, avoid 662 mg and 882 mg doses. No dose adjustment is necessary in patients taking the 441 mg dose, if it is tolerated.

Doxepin & Paxil MODERATE

Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds when concurrent therapy with fluoxetine or paroxetine is started or if the dosage of either agent is increased. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly.If the fluoxetine or paroxetine is discontinued in a patient receiving a tricyclic compound other than cyclobenzaprine, the dosage of the tricyclic compound may need to be adjusted upward as the effects of enzyme inhibition wane.The effects of fluoxetine on hepatic metabolism may last for 3-5 weeks after fluoxetine discontinuation. A tricyclic compound (other than cyclobenzaprine) started after the discontinuation of fluoxetine should be started a lower initial dosage.Patients receiving fluoxetine or paroxetine and clomipramine, imipramine, or cyclobenzaprine should be monitored for serotonin syndrome. Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus. Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus. Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.When concurrent therapy may be associated with QT prolongation, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

Paxil & Voltaren MODERATE

Unrecognized Medications: None

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 4 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Highly elevated risk for indicated condition or adverse drug reaction. Medication can be prescribed with monitoring; alternative therapy may be needed. PHARMACOGENETIC RESULTS Moderately elevated risk for indicated condition or adverse drug reaction. Medication can be prescribed with monitoring; therapy adjustment may be needed. DRUG-DRUG INTERACTIONS Typical risk for indicated condition or adverse drug reaction. Medication can be prescribed according to standard dosing guidelines.

EVIDENCE Recommendations are suitable for implementation in a clinical setting. Recommendations extracted from evidence based guidelines LEVEL 1 issued by international pharmacogenetic consortia, professional societies or regulatory bodies (CPIC, DPWG, FDA, EMA, CPNDA, ACMG).

EVIDENCE Recommendations are informative and implementation in a clinical setting is optional. The evidence documenting these drug-gene associations may be limited or insufficient and may require further investigation. There are no established evidence based guidelines LEVEL 2 issued by international pharmacogenetic consortia, professional societies or regulatory bodies.

MODERATE Drug interactions of moderate severity. The clinician should assess the patient’s characteristics and take action as needed.

Severe drug interaction or contraindicated drug combination which may produces serious consequences in most patients. This drug SERIOUS combination generally should not be dispensed or administered to the same patient. Action is required to reduce risk of severe adverse interaction.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 5 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Test Details Gene Genotype Phenotype Alleles Tested CYP2C9 *3/*3 Poor Metabolizer *2, *3, *4, *5, *6, *7, *8, *11, *14, *27 CYP2C19 *17/*17 Ultra-Rapid Metabolizer *2, *3, *4, *4B, *5, *6, *7, *8, *9, *10, *12, *14, *15, *17 *2, *31, *33, *4, *4M, *46, *49, *53, *6, *7, *8, *9, *10, *11, CYP2D6 *5/*8 Poor Metabolizer *12, *14A, *14B, *15, *17, *29, *35, *41, *44, *5 (gene deletion), XN (gene duplication) CYP3A5 *3/*3 Poor Metabolizer *1D, *2, *3, *3B, *3C, *4, *6, *7, *8, *9 *2, *4, *5, *8, *11, *12, *13, *16A, *16B, *17, *18A, *18B, *20, CYP3A4 *1/*1 Normal Metabolizer *22 -1639G>A, 1542G>C, 5808T>G, 1173C>T, , , 698C>T, VKORC1 -1639G>A A/A High Warfarin Sensitivity 2255C>T, 3730G>A Normal Metabolizer - Higher CYP1A2 *1F/*1F *1C, *1D, *1E, *1F, *1J, *1B, *1K, *1L, *1V, *1W, *7, *1G Inducibility 388A>G, , , , 467A>G, , -11187G>A, 521T>C, , SLCO1B1 521T>C TT Normal Function 1865+248G>A COMT Val158Met AG Intermediate COMT Activity Val158Met OPRM1 A118G AA Normal OPRM1 Function A118G Homozygous for the C allele HTR2C -759C>T C/C -759C>T, 2565G>C (rs3813929) SLC6A4 S/S Low Serotonin Transporter Expression La, S, Lg ADRA2A C-1291G C/C Homozygous for C Allele C-1291G SLC6A4 463T>G C/A Heterozygous for the C Allele La, S, Lg Heterozygous for the A allele HTR2A rs7997012 A/G -1438G>A, 102C>T, rs7997012 (rs7997012) Homozygous for the C allele HTR2C 2565G>C C/C -759C>T, 2565G>C (rs1414334) HTR2A -1438G>A C/C Homozygous for the C allele (rs6311) -1438G>A, 102C>T, rs7997012 DRD2 -241A>G T/T Homozygous for rs1799978 T Allele -241A>G, rs2283265, 939T>C, 957C>T DRD2 rs2283265 C/C Homozygous for rs2283265 C allele -241A>G, rs2283265, 939T>C, 957C>T 1298A>C CC Unknown Risk of MTHFR 1298A>C, 677C>T, 1305C>T 677C>T TT Hyperhomocysteinemia MTHFR 677C>T TT Reduced MTHFR Activity 1298A>C, 677C>T, 1305C>T Factor II 20210G>A AA Unknown Risk of Thrombosis 20210G>A, 1691G>A Factor V Leiden 1691G>A AA

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 6 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Genomic DNA is extracted from dry buccal swabs using magnetic particle processing. DNA from patient samples are amplified with primers specific for genes such as ABCB1, ABCG2, ADRA2A, DRB1, AGT, CACNA1C, CEP72, CES1, CFTR, COMT, CYP1A2, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP2C9, DPYD, DRD2, DRD3, EDN1, F2, F5, G6PD, GNB3, GRIK4, GSTA1, HTR1A, HTR2A, HTR2C, IFNL3, KCNIP1, LDLR, MTHFR, NAT1, NR1H3, OPRM1, RYR1, SLC6A2, SLC6A4, SLCO1B1, TPMT, UGT1A1, UGT2B7, VKORC1 depending on the selected panel, using Nested Patch PCR (Varley, et. al.), Oligo-directed or Illumina TSCA Extension Ligation protocols and are used to detect alleles and genotypes listed in this report with known clinical significance at analytical sensitivity and specificity >99%. Positive and negative controls are used with each run. Patient samples, positive, and negative controls are sequenced using a MiSeq (Illumina). Sequences are analyzed using alignment and base call algorithms with GATK1.6, Illumina Variantstudio and Kailos Blue Software for the presence or absence of single nucleotide base changes, insertions and deletions. LR-PCR utilized for confirmation of CYP2D6 duplications and deletions. Results and recommendations are compiled as part of a medical report. Genetic testing was performed in the Alcala Testing & Analysis Services facility at 3703 Camino del Rio South #100-A; San Diego, CA. 92108. CLIA#: 05D2027247. Medical Director: Dr. David J. Smith, MD. This report was reviewed and approved for release by the Medical Director: Dr. David J. Smith, MD.

LAB DISCLAIMER

The information presented on this report is provided as supplementary health information. The results presented are intended for use by a physician, pharmacist or other healthcare professional to advise a patient on the use of prescribed medications. This test is not a 510k cleared test, but managed by CMS and FDA under the Clinical Laboratory Improvement Amendment (CLIA) as a LDT. The ordering physician is responsible for the diagnosis and management of disease and decisions based on the data provided. Results are dependent on adequate specimen collection and processing.

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.

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.

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.

The Drug interaction report is provided via a third party agreement with First Data Bank (FDB). FDB is entirely responsible for the accuracy of the drug interaction data. The report is solely intended to be used by a medical professional. The drug interaction report is based on patient reported medications and does not account for other factors such as smoking history, tobacco use, diet and other underlying chronic conditions like diabetes or heart disease. The treating medical professional bears the ultimate responsibility for all the treatment decisions made in regards to a patient and including any decisions based on the drug interaction report.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 7 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

NAME: Sample Report Alcala - SPECIMEN TYPE: Buccal Swab Christian Tagwerker, Ph.D. Psychotropic Alcala Testing and Analysis Services --619-450-5870 ACC #: Psychotropic COLLECTION DATE: 1/1/1900 DO NOT DISTRIBUTE DOB: 1/1/1900 RECEIVED DATE: 1/1/1900 3703 Camino del Rio South, 100-A SEX: Female REPORT DATE: 10/4/2016 San Diego, CA 98102 www.alcalalabs.com Risk Management Hyperhomocysteinemia - Depression Increased Risk of Hyperhomocysteinemia The patient carries two MTHFR C677T mutations (homozygous). MTHFR enzyme activity is severely reduced (30% 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. This patient exhibits significantly reduced MTHFR activity, which is a risk factor for hyperhomocysteinemia. Low MTHFR activity may further exacerbate folate deficiency in patients with depression and may increase the risk of depressive relapse or delay the response to antidepressants. 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, this patient is likely to benefit from methylfolate as an antidepressant-augmenting agent. Testing for homocysteine levels and serum folate levels may be informative for this patient. Although methylfolate may substantially benefit this patient, it should not replace the antidepressant therapy and methylfolate should always be used as an adjuvant to antidepressant medication. Thrombophilia Unknown Risk of Thrombosis The patient carries two Factor V Leiden G1691A mutations (homozygous carrier) and two Factor II G20210A mutations (homozygous carrier). This genotype has never been reported. The patient's thrombotic risk is unknown The patient's thrombosis risk is unknown. This genotype has never been reported. Consult with a genetic counselor for further information. Hyperhomocysteinemia - Thrombosis Unknown Risk of Hyperhomocysteinemia The patient carries two MTHFR C677T mutations and two MTHFR A1298C mutations. This genotype has never been reported. The patient's risk for hyperhomocysteinemia is unknown. The patient's genotype has never been reported. Because the patient's risk for hyperhomocysteinemia is not well documented, consider consulting a genetic counselor for more information.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 8 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

PHARMACOGENETIC RESULTS INTERACTING DRUGS

CLASS DRUG* High Risk 5-Alpha Reductase Dutasteride (Avodart) Inhibitors for Benign Prostatic Finasteride (Proscar) Hyperplasia Alfuzosin (UroXatral) Ondansetron

Doxazosin (Cardura) Alpha-Blockers for Benign Prostatic Silodosin (Rapaflo) Hyperplasia Tamsulosin (Flomax)

Terazosin (Hytrin)

Azilsartan (Edarbi, Edarbyclor) Voltaren

Candesartan (Atacand) Voltaren

Eprosartan (Teveten) Voltaren

Angiotensin II Irbesartan (Avapro) Voltaren Receptor Antagonists Losartan (Cozaar, Hyzaar) Voltaren Olmesartan (Benicar) Voltaren

Telmisartan (Micardis) Voltaren

Valsartan (Diovan, Entresto) Voltaren

Antiaddictives Naltrexone (Vivitrol, Contrave) Oxycodone

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 9 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Doxepin

Amphetamine (Adderall) Fluvoxamine

Paxil

Ondansetron Atomoxetine (Strattera) Paxil

Clonidine (Kapvay) Doxepin

Dexmethylphenidate (Focalin) Doxepin

Anti-ADHD Agents Doxepin

Dextroamphetamine (Dexedrine) Fluvoxamine

Paxil

Guanfacine (Intuniv)

Doxepin

Lisdexamfetamine (Vyvanse) Fluvoxamine

Paxil

Methylphenidate (Ritalin) Doxepin

Antianginal Agents Ranolazine (Ranexa) Ondansetron

Ondansetron Flecainide (Tambocor) Paxil Antiarrhythmics Mexiletine (Mexitil)

Propafenone (Rythmol) Ondansetron

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 10 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Fluvoxamine

Apixaban (Eliquis) Paxil

Voltaren

Fluvoxamine

Dabigatran Etexilate (Pradaxa) Paxil

Voltaren

Fluvoxamine

Edoxaban (Savaysa) Paxil Anticoagulants Voltaren

Fondaparinux (Arixtra) Voltaren

Fluvoxamine

Rivaroxaban (Xarelto) Paxil

Voltaren

Fluvoxamine

Warfarin (Coumadin) Paxil

Voltaren

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 11 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Brivaracetam (Briviact)

Abilify

Carbamazepine (Tegretol, Carbatrol, Epitol) Fluvoxamine

Oxycodone

Eslicarbazepine (Aptiom)

Ethosuximide (Zarontin)

Ezogabine (Potiga) Ondansetron

Felbamate (Felbatol) Ondansetron

Abilify Fosphenytoin (Cerebyx) Oxycodone

Gabapentin (Neurontin)

Lacosamide (Vimpat)

Lamotrigine (Lamictal)

Levetiracetam (Keppra)

Oxcarbazepine (Trileptal, Oxtellar XR)

Anticonvulsants Perampanel (Fycompa)

Abilify

Phenobarbital (Luminal) Diazepam

Oxycodone

Abilify Phenytoin (Dilantin) Oxycodone

Pregabalin (Lyrica)

Abilify

Primidone (Mysoline) Diazepam

Oxycodone

Rufinamide (Banzel)

Tiagabine (Gabitril)

Topiramate (Topamax)

Valproic Acid (Depakote, Depakene)

Vigabatrin (Sabril)

Zonisamide (Zonegran)

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 12 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Donepezil (Aricept) Ondansetron Antidementia Galantamine (Razadyne) Agents Memantine (Namenda)

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 13 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Fluvoxamine Amitriptyline (Elavil) Paxil

Fluvoxamine Amoxapine (Amoxapine) Paxil

Fluvoxamine

Citalopram (Celexa) Ondansetron

Voltaren

Fluvoxamine

Clomipramine (Anafranil) Ondansetron

Paxil

Fluvoxamine

Desipramine (Norpramin) Ondansetron

Paxil

Doxepin Desvenlafaxine (Pristiq) Voltaren

Paxil Doxepin (Silenor) Fluvoxamine

Abilify

Doxepin

Duloxetine (Cymbalta) Fluvoxamine

Paxil

Voltaren

Fluvoxamine

Escitalopram (Lexapro) Ondansetron

Voltaren

Abilify

Diazepam Fluoxetine (Prozac, Sarafem) Doxepin

Voltaren

Diazepam

Antidepressants Fluvoxamine (Luvox) Doxepin

Voltaren

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 14 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Fluvoxamine

Imipramine (Tofranil) Ondansetron

Paxil

Levomilnacipran (Fetzima) Voltaren

Maprotiline (Ludiomil)

Mirtazapine (Remeron) Ondansetron

Abilify

Nefazodone (Serzone) Diazepam

Oxycodone

Fluvoxamine

Nortriptyline (Pamelor) Ondansetron

Paxil

Abilify

Doxepin Paroxetine (Paxil, Brisdelle) Voltaren

Pravachol

Fluvoxamine Protriptyline (Vivactil) Paxil

Doxepin Sertraline (Zoloft) Voltaren

Fluvoxamine

Trimipramine (Surmontil) Ondansetron

Paxil

Doxepin

Venlafaxine (Effexor) Ondansetron

Voltaren

Vilazodone (Viibryd) Voltaren

Paxil Vortioxetine (Trintellix) Voltaren

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 15 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Dolasetron (Anzemet) Ondansetron

Abilify

Metoclopramide (Reglan) Fluvoxamine Antiemetics Paxil

Ondansetron (Zofran, Zuplenz)

Palonosetron (Aloxi)

Antifolates Methotrexate (Trexall) Voltaren

Abilify

Diazepam Antifungals Voriconazole (Vfend) Ondansetron

Oxycodone

Antimalarials Proguanil (Malarone)

Fluvoxamine

Clopidogrel (Plavix) Paxil

Voltaren

Fluvoxamine

Prasugrel (Effient) Paxil Antiplatelets Voltaren

Fluvoxamine

Ticagrelor (Brilinta) Paxil

Voltaren

Vorapaxar (Zontivity) Voltaren

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 16 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Aripiprazole (Abilify) Paxil

Ondansetron Asenapine (Saphris) Paxil

Brexpiprazole (Rexulti) Paxil

Chlorpromazine (Thorazine) Ondansetron

Diazepam

Fluvoxamine Clozapine (Clozaril) Ondansetron

Paxil

Fluphenazine (Prolixin)

Fluvoxamine Haloperidol (Haldol) Ondansetron

Ondansetron Iloperidone (Fanapt) Paxil

Loxapine (Loxitane, Adasuve)

Lurasidone (Latuda)

Fluvoxamine Olanzapine (Zyprexa) Ondansetron

Paliperidone (Invega) Ondansetron

Perphenazine (Trilafon) Antipsychotics Pimavanserin (Nuplazid)

Doxepin

Fluvoxamine Pimozide (Orap) Ondansetron

Paxil

Quetiapine (Seroquel) Ondansetron

Ondansetron Risperidone (Risperdal) Paxil

Ondansetron Tetrabenazine (Xenazine) Paxil

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 17 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Doxepin

Fluvoxamine Thioridazine (Mellaril) Ondansetron

Paxil

Thiothixene (Navane)

Fluvoxamine

Trazodone (Oleptro) Ondansetron

Paxil

Trifluoperazine (Stelazine)

Ziprasidone (Geodon) Ondansetron

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 18 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Darifenacin (Enablex)

Fesoterodine (Toviaz)

Mirabegron (Myrbetriq) Antispasmodics for Oxybutynin (Ditropan) Overactive Bladder Solifenacin (Vesicare)

Tolterodine (Detrol)

Trospium (Sanctura)

Alprazolam (Xanax) Fluvoxamine

Clobazam (Onfi) Fluvoxamine Benzodiazepines Clonazepam (Klonopin)

Diazepam (Valium) Fluvoxamine

Carvedilol (Coreg)

Labetalol (Normodyne, Trandate)

Metoprolol (Lopressor) Paxil Beta Blockers Nebivolol (Bystolic)

Propranolol (Inderal)

Timolol (Timoptic)

Diuretics Torsemide (Demadex) Voltaren

Fibromyalgia Agents Milnacipran (Savella) Voltaren

Apremilast (Otezla)

Immunomodulators Leflunomide (Arava)

Tofacitinib (Xeljanz)

Ondansetron Immunosupressants Tacrolimus (Prograf) Voltaren

Nateglinide (Starlix) Meglitinides Repaglinide (Prandin, Prandimet)

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 19 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Carisoprodol (Soma)

Fluvoxamine Cyclobenzaprine (Flexeril, Amrix) Paxil

Muscle Relaxants Metaxalone (Skelaxin)

Methocarbamol (Robaxin)

Fluvoxamine Tizanidine (Zanaflex) Ondansetron

Fluvoxamine Celecoxib (Celebrex) Paxil

Fluvoxamine Diclofenac (Voltaren) Paxil

Fluvoxamine Flurbiprofen (Ansaid) Paxil

Fluvoxamine Ibuprofen (Advil, Motrin) Paxil

Fluvoxamine Indomethacin (Indocin) Paxil

Fluvoxamine Ketoprofen (Orudis) Paxil

NSAIDs Fluvoxamine

Ketorolac (Toradol) Paxil

Voltaren

Fluvoxamine Meloxicam (Mobic) Paxil

Fluvoxamine Nabumetone (Relafen) Paxil

Fluvoxamine Naproxen (Aleve) Paxil

Fluvoxamine Piroxicam (Feldene) Paxil

Fluvoxamine Sulindac (Clinoril) Paxil

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 20 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Alfentanil (Alfenta)

Diazepam Buprenorphine (Butrans, Buprenex) Oxycodone

Codeine (Codeine; Fioricet with Codeine) Paxil

Dihydrocodeine (Synalgos-DC)

Fluvoxamine Fentanyl (Actiq) Paxil

Hydrocodone (Vicodin)

Hydromorphone (Dilaudid, Exalgo)

Levorphanol (Levo Dromoran)

Fluvoxamine Meperidine (Demerol) Paxil Opioids Morphine (MS Contin)

Oxycodone (Percocet, Oxycontin)

Oxymorphone (Opana, Numorphan)

Sufentanil (Sufenta)

Doxepin

Tapentadol (Nucynta) Fluvoxamine

Paxil

Abilify

Doxepin

Tramadol (Ultram) Fluvoxamine

Ondansetron

Paxil

Abilify

Doxepin Other Neurological Dextromethorphan / Quinidine (Nuedexta) Ondansetron Agents Paxil

Flibanserin (Addyi) Fluvoxamine

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 21 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

CLASS DRUG* High Risk

Avanafil (Stendra)

Phosphodiesterase Sildenafil (Viagra) Inhibitors for Erectile Dysfunction Tadalafil (Cialis) Vardenafil (Levitra) Ondansetron

Dexlansoprazole (Dexilant, Kapidex)

Esomeprazole (Nexium)

Proton Pump Lansoprazole (Prevacid) Inhibitors Omeprazole (Prilosec)

Pantoprazole (Protonix)

Rabeprazole (Aciphex)

Atorvastatin (Lipitor)

Fluvastatin (Lescol)

Lovastatin (Mevacor, Altoprev, Advicor)

Statins Pitavastatin (Livalo)

Pravastatin (Pravachol) Paxil

Rosuvastatin (Crestor)

Simvastatin (Zocor)

Chlorpropamide (Diabenese)

Glimepiride (Amaryl)

Sulfonylureas Glipizide (Glucotrol)

Glyburide (Micronase)

Tolbutamide (Orinase) *Current patient medications are listed in bold whereas italicized drug names indicate drugs with no pharmacogenetic guidance

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 22 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Amitriptyline Increased Sensitivity to Amitriptyline (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Elavil Select an alternative drug, or consider prescribing amitriptyline at a reduced dose (50% reduction) with monitoring of plasma concentrations of amitriptyline and nortriptyline.

Amitriptyline Increased Sensitivity to Amitriptyline (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Elavil Consider an alternative drug, or consider prescribing amitriptyline at standard dose and monitor the plasma concentrations of amitriptyline and nortriptyline to guide dose adjustments.

Citalopram Insufficient Response to Citalopram (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 1 Celexa At standard label-recommended dosage, citalopram plasma concentrations levels are expected to be low which may result in a loss of efficacy. Consider an alternative medication. If citalopram is warranted, consider increasing the dose to a maximum of 150% and titrate based on the clinical response and tolerability.

Clomipramine Increased Sensitivity to Clomipramine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Anafranil Consider an alternative drug, or prescribe clomipramine at 50% of the recommended standard starting dose. Monitor plasma concentrations of clomipramine and desmethylclomipramine, and titrate accordingly until a favorable response is achieved.

Clomipramine Increased Sensitivity to Clomipramine (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Anafranil Consider an alternative drug, or consider prescribing clomipramine at standard dose and monitor the plasma concentrations of clomipramine and desmethyl-clomipramine to guide dose adjustments.

Codeine Non-Response to Codeine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Codeine; Fioricet with Greatly reduced morphine levels are expected, and the patient may not experience adequate pain relief when taking Codeine codeine. Avoid prescribing codeine, and consider alternative opioids other than tramadol, or a non-opioid analgesic such as a NSAID or a COX-2 inhibitor. Unless contraindicated, available alternative opioids not sensitive to CYP2D6 function include: fentanyl, morphine, hydromorphone, oxymorphone, and tapentadol.

Desipramine Increased Sensitivity to Desipramine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Norpramin Consider an alternative drug, or prescribe desipramine at 50% of recommended standard starting dose. Monitor plasma concentrations of desipramine and metabolites and titrate accordingly until a favorable response is achieved.

Doxepin Increased Sensitivity to Doxepin (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Silenor Consider an alternative drug or reduce doxepin starting dose by 50%. Adjust maintenance dose according to nordoxepin plasma concentrations.

Doxepin Increased Sensitivity to Doxepin (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Silenor Consider an alternative drug, or consider prescribing doxepin at standard dose and monitor the plasma concentrations of doxepin and desmethyl-doxepin to guide dose adjustments.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 23 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Haloperidol Increased Sensitivity to Haloperidol (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Haldol Haloperidol is metabolized by CYP2D6, CYP3A4, and other enzymes. Decreased CYP2D6 activity results in higher haloperidol concentrations, potentially leading to more adverse events. Consider an alternative drug, or prescribe haloperidol at 50% of the usual starting dose, then adjust dosage to achieve a favorable clinical response.

Imipramine Increased Sensitivity to Imipramine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Tofranil Consider an alternative drug, or consider a 50% reduction of the imipramine recommended starting dose, then titrate in response to imipramine and desipramine plasma concentrations.

Imipramine Increased Sensitivity to Imipramine (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Tofranil Consider an alternative drug, or consider prescribing imipramine at the standard dose and monitor the plasma concentrations of imipramine and desipramine to guide dose adjustments.

Metoprolol Significantly Increased Sensitivity to Metoprolol (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Lopressor Based on the genotype result, this patient is at risk of excessive beta-blockade when taking metoprolol at standard dosage. Heart Failure: Consider alternative beta-blockers such as bisoprolol or carvedilol, or prescribe metoprolol at a lower dose. When compared to a normal metabolizer, a poor metabolizer may require a 75% dose reduction. Other indications: Consider alternative beta-blockers such as bisoprolol or atenolol, or prescribe metoprolol at a lower dose. When compared to a normal metabolizer, a poor metabolizer may require a 75% dose reduction. If metoprolol is prescribed, be alert to adverse events (e.g., bradycardia or cold extremities).

Nortriptyline Increased Sensitivity to Nortriptyline (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Pamelor Select an alternative drug, or consider prescribing nortriptyline at a reduced dose (50% reduction) with monitoring of plasma concentrations of nortriptyline and metabolites.

Paroxetine Increased Sensitivity to Paroxetine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Paxil, Brisdelle At standard label-recommended dosage, paroxetine levels are expected to be high, and adverse events may occur. Consider an alternative medication. If paroxetine is warranted, consider a 50% decrease of the initial dose and titrate based on the clinical response and tolerability. Some studies show that compared to normal metabolizers, poor metabolizers may experience more sexual dysfunction.

Protriptyline Increased Sensitivity to Protriptyline (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Vivactil Consider alternative or prescribe protriptyline at 50% of recommended standard starting dose. Monitor plasma concentrations of protriptyline and metabolites and titrate accordingly until a favorable response is achieved.

Risperidone Significantly Increased Sensitivity to Risperidone (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Risperdal Consider an alternative drug, OR prescribe risperidone at a reduced dose, be extra alert of adverse events, and adjust dosage in response to clinical response and tolerability.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 24 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Tramadol Non-Response to Tramadol (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Ultram The patient will not experience adequate pain relief when taking tramadol. Avoid prescribing tramadol, and consider alternative opioids other than codeine or a non-opioid analgesic such as a NSAID or a COX-2 inhibitor. Unless contraindicated, available alternative opioids not sensitive to CYP2D6 function include: fentanyl, morphine, hydromorphone, oxymorphone, and tapentadol.

Trimipramine Increased Sensitivity to Trimipramine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Surmontil Consider an alternative drug, or consider a 50% reduction of the trimipramine recommended starting dose, then titrate in response to trimipramine plasma concentrations.

Trimipramine Increased Sensitivity to Trimipramine (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Surmontil Consider an alternative drug, or consider prescribing trimipramine at standard dose and monitor the plasma concentrations of trimipramine and desmethyl-trimipramine to guide dose adjustments.

Venlafaxine Significantly Increased Sensitivity to Venlafaxine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Effexor The patient has an increased risk of side effects when taking standard doses of venlafaxine. Consider an alternative drug, OR prescribe venlafaxine, be extra alert of adverse events, and adjust dosage in response to clinical response and tolerability. Monitor O-desmethylvenlafaxine plasma concentrations.

Aripiprazole Increased Sensitivity to Aripiprazole (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Abilify Poor metabolizers have a significantly reduced capacity to metabolize aripiprazole and its active metabolite, and should receive lower doses. Careful titration is recommended until a favorable response is achieved.

Amoxapine Possible Sensitivity to Amoxapine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Amoxapine Like other tricyclic and tetracyclic antidepressants, amoxapine is metabolized by CYP2D6. However, the overall contribution of this enzyme in the metabolism of this drug is not well documented. Decreased CYP2D6 activity may result in higher amoxapine concentrations potentially leading to higher adverse events. There are no established dosing adjustments for patients with decreased CYP2D6 function; therapy must be initiated cautiously and adjusted according to the patient's response.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 25 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Brexpiprazole Increased Sensitivity to Brexpiprazole (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Rexulti The exposure to brexpiprazole in CYP2D6 poor metabolizers is 120% higher than the exposure in CYP2D6 normal metabolizers. Because the incidence of akathisia is dose-related in patients suffering from schizophrenia or major depressive disorders, it is recommended to prescribe half of the usual doses of brexpiprazole to CYP2D6 poor metabolizers. Careful titration is recommended until a favorable response is achieved.

Adjunctive Treatment of Major Depression Disorder: the recommended starting doses should be reduced by half (0.25 mg or 0.5 mg once daily). The daily maintenance doses and maximum recommended dose are 0.5-1 mg and 1.5 mg, respectively. Schizophrenia: the recommended starting dose is 0.5 mg once daily. The daily maintenance doses and maximum recommended dose are 1-2 mg and 2 mg, respectively.

Dose adjustments with comedications: Administer a quarter of the usual dose if a strong/moderate CYP3A4 inhibitor is coadministered. Double usual dose over 1 to 2 weeks if a strong CYP3A4 inducer is coadministered.

Carisoprodol Altered Sensitivity to Carisoprodol (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Soma There is insufficient data to allow calculation of dose adjustment. If carisoprodol is prescribed, it is recommended to use a lower dose, and to carefully monitor the patient for side effects.

Carvedilol Moderate Sensitivity to Carvedilol (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Coreg Carvedilol can be prescribed at standard label-recommended dosage and administration. CYP2D6 poor metabolizers may experience dizziness during up-titration. Careful titration is recommended with monitoring until a favorable response is achieved.

Celecoxib High Sensitivity to Celecoxib (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 1 Celebrex 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.

Chlorpromazine Increased Sensitivity to Chlorpromazine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Thorazine Chlorpromazine is metabolized by CYP2D6, CYP3A4 and flavin-containing monooxygenases. Decreased CYP2D6 activity results in higher chlorpromazine concentrations potentially leading to higher adverse events. Consider prescribing chlorpromazine at a lower starting dose and then adjust dosage to achieve a favorable clinical response.

Chlorpropamide Possible Sensitivity to Chlorpropamide (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 2 Diabenese Subjects with reduced CYP2C9 activity may have increased chlorpropamide plasma drug concentrations at standard doses, leading to hypoglycemic episodes. Because there is insufficient data to whether such changes have a significant clinical impact, chlorpropamide can be prescribed according to standard label-recommended dosage and administration, with frequent monitoring of plasma glucose levels.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 26 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Clozapine Unfavorable Response to Clozapine (HTR2A: Homozygous for the C allele (rs6311)) EVIDENCE LEVEL 2 Clozaril The patient does not carry the HTR2A variant rs6311. Preliminary studies suggest that this genotype may be associated with an unfavorable response to clozapine in patients with European ancestry.

Clozapine Risk of Metabolic Syndrome with Clozapine (HTR2C: Homozygous for the C allele EVIDENCE LEVEL 2 (rs1414334)) Clozaril Genetic variations in the Serotonin 2C Receptor (HTR2C) gene in known to be partially involved in the adverse effects to atypical antipsychotic medications. The patient is homozygous for C allele of HTR2C variant rs1414334. The patient may have an increased risk of developing metabolic syndrome when treated with clozapine.

Clozapine Non-Response to Clozapine (CYP1A2: Normal Metabolizer - Higher Inducibility) EVIDENCE LEVEL 2 Clozaril 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.

Darifenacin Possible Sensitivity to Darifenacin (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Enablex Darifenacin exposure is increased 30% in CYP2D6 poor metabolizers. Although dose adjustment may not be needed in these patients, monitor patients for increased side effects when darifenacin is prescribed at standard label-recommended dosage and administration.

Dexlansoprazole Insufficient Response to Dexlansoprazole (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Dexilant, Kapidex • Helicobacter pylori eradication: increase dose by 200% and be alert to insufficient response. • Other: be extra alert to insufficient response and consider dose increase of 200%.

Dexmethylphenid Unfavorable Response to Dexmethylphenidate (ADRA2A: Homozygous for C Allele) EVIDENCE LEVEL 2 ate Focalin The patient carries two C alleles of the ADRA2A –1291 C>G polymorphism. Preliminary studies suggest that this genotype may be associated with an unfavorable response to dexmethylphenidate in children and adolescents with the attention- deficit and hyperactivity disorder of inattentive type.

Dexmethylphenid Decreased Response to Dexmethylphenidate (COMT: Intermediate COMT Activity) EVIDENCE LEVEL 2 ate Focalin 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 Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 27 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Diazepam Possible Altered Sensitivity to Diazepam (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Valium CYP2C19 rapid and ultra-rapid metabolizers metabolize diazepam and nordiazepam more rapidly than normal metabolizers. However, there is insufficient data to allow calculation of dose adjustment when diazepam is prescribed. Monitor the patient's response and adjust the dose accordingly.

Donepezil Possible Altered Response to Donepezil (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Aricept When compared to a normal metabolizer, a poor metabolizer has a 30% decrease in donepezil clearance. The clinical significance of this decrease is not well documented. Consider using a standard dosing regimen, be alert for adverse events, and adjust dosage in response to clinical response and tolerability.

Duloxetine Possible Sensitivity to Duloxetine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Cymbalta Limited data suggest that duloxetine plasma concentrations might be increased in CYP2D6 poor metabolizers. Therefore, duloxetine can be prescribed at standard label-recommended dosage, and careful titration is recommended until a favorable response is achieved.

Esomeprazole Insufficient Response to Esomeprazole (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Nexium • Helicobacter pylori eradication: increase dose by 50-100% and be alert to insufficient response. • Other: be extra alert to insufficient response and consider dose increase of 50-100%.

Flecainide Significantly Increased Sensitivity to Flecainide (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Tambocor Consider prescribing a lower flecainide dose. When compared to a CYP2D6 normal metabolizer, a poor metabolizer may require a 50% dose reduction. Careful titration with ECG recording and monitoring of flecainide plasma concentrations are recommended until a favorable clinical response is achieved.

Fluphenazine Increased Sensitivity to Fluphenazine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Prolixin Fluphenazine is metabolized by CYP2D6, CYP1A2 and other enzymes. Decreased CYP2D6 activity may result in higher fluphenazine concentrations potentially leading to higher adverse events such as extrapyramidal symptoms. There are no established dosing adjustments for patients lacking CYP2D6 function therefore, therapy must be initiated cautiously with oral or parenteral fluphenazine hydrochloride. When the pharmacological effects and an appropriate dosage are apparent, an equivalent dose of fluphenazine decanoate (IM or SC) may be administered and subsequent dosage adjustments may be necessary.

Flurbiprofen Increased Sensitivity to Flurbiprofen (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 1 Ansaid At standard dosage, plasma concentrations of flurbiprofen are expected to be high, resulting in an increased risk of gastrointestinal toxicity. Administer flurbiprofen with caution and reduce dose if necessary.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 28 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Fluvoxamine Increased Sensitivity to Fluvoxamine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Luvox At standard label-recommended dosage, fluvoxamine levels are expected to be high and adverse events may occur. Consider a 25-50% reduction of recommended starting dose to help prevent concentration-dependent adverse events and titrate based on the clinical response and tolerability. An alternative medication may also be considered.

Fluvoxamine Delayed Response to Fluvoxamine (SLC6A4: Low Serotonin Transporter Expression) EVIDENCE LEVEL 2 Luvox The genotype predicts significantly decreased serotonin transporter levels resulting in less efficient transporter function. A longer titration period may be required to achieve maximal antidepressant response. The patient may respond to fluvoxamine more slowly (up to 12 weeks) and may experience more side effects. The patient may benefit from non- selective antidepressants.

Fosphenytoin High Sensitivity to Fosphenytoin (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 1 Cerebyx In CYP2C9 poor metabolizers, the plasma concentrations of phenytoin are expected to increase, resulting in an increased risk of severe neurological toxicity. This risk increases further in individuals who are also CYP2C19 poor metabolizers. Consider a standard loading dose, and reduce the maintenance dose by 50%. Evaluate response and serum concentrations after 7-10 days. Be alert to neurological concentration-related adverse events.

Galantamine Possible Sensitivity to Galantamine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Razadyne A CYP2D6 poor metabolizer has a drug exposure that is approximately 50% higher than the exposure in a normal metabolizer. Although dosage adjustment is not necessary in a patient identified as a CYP2D6 poor metabolizer as the dose of drug is individually titrated to tolerability, a slower titration can be considered as it may improve tolerability.

Glimepiride Possible Sensitivity to Glimepiride (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 1 Amaryl 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 plasma glucose levels.

Glipizide Possible Sensitivity to Glipizide (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 2 Glucotrol 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 Possible Sensitivity to Glyburide (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 1 Micronase 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.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 29 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Ibuprofen Possible Sensitivity to Ibuprofen (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 2 Advil, Motrin Ibuprofen is extensively metabolized into hydroxylate or carboxylate metabolites by CYP2C8 and CYP2C9. Diminished ibuprofen clearance has been found in CYP2C9 poor metabolizers and those with decreased CYP2C8 activity. This change in clearance may result in elevated concentrations of the drug inadvertently leading to adverse events. Although, dosage adjustment is not necessary in a patient identified as a CYP2C9 poor metabolizer, a lower dose and a closer monitoring for increased gastrointestinal adverse events may be considered.

Iloperidone Increased Sensitivity to Iloperidone (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Fanapt Iloperidone dose should be reduced by one-half and titrated slowly to avoid orthostatic hypotension. Because iloperidone is associated with QTc prolongation, caution is warranted when prescribing the drug in patients with reduced CYP2D6 activity. If patients taking iloperidone experience symptoms that could indicate the occurrence of cardiac arrhythmias (e.g., dizziness, palpitations, or syncope), the prescriber should initiate further evaluation, including cardiac monitoring.

Indomethacin Possible Sensitivity to Indomethacin (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 2 Indocin Indomethacin is metabolized mainly by O-demethylation to its inactive metabolite O-desmethylindomethacin, a reaction catalyzed by CYP2C9. At standard dosage, plasma concentrations of indomethacin are expected to be high resulting in an increased risk of gatrointestinal toxicity. To minimize the potential risk for an adverse event, the lowest effective dose should be used for the shortest possible duration.

Lansoprazole Insufficient Response to Lansoprazole (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Prevacid • Helicobacter pylori eradication: increase dose by 200% and be alert to insufficient response. • Other: be extra alert to insufficient response and consider dose increase of 200%.

Losartan Possible Decreased Response to Losartan (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 2 Cozaar, Hyzaar Losartan is metabolized to its active metabolite by CYP2C9 and CYP3A4. The patient's genotype predicts a reduced exposure to losartan's active metabolite and a possible reduced hypotensive effect. Losartan can be prescribed at label- recommended dosage and administration with additional monitoring of the patient's response.

Maprotiline Increased Sensitivity to Maprotiline (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Ludiomil Like other tricyclic and tetracyclic antidepressants, maprotiline is metabolized by CYP2D6 as well as CYP1A2. Compared to CYP2D6 normal metabolizers, CYP2D6 poor metabolizers have higher exposure to maprotiline at therapeutic doses which may increase the risk of concentration-dependent toxicities. There are no established dosing adjustments for patients with decreased CYP2D6 function however, it is recommended to initiate maprotiline therapy at a low dosage and gradually adjust the dosing according to the patient's response. The lowest effective dosage should always be considered during maintenance therapy.

Meloxicam Increased sensitivity to Meloxicam (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 2 Mobic CYP2C9 poor metabolizers have a higher risk of experiencing gastrointestinal toxicities when taking meloxicam at standard doses. To minimize the potential risk of adverse events in these patients, the lowest effective dose should be used for the shortest possible duration.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 30 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Methylphenidate Unfavorable Response to Methylphenidate (ADRA2A: Homozygous for C Allele) EVIDENCE LEVEL 2 Ritalin The patient carries two C alleles of the ADRA2A –1291 C>G polymorphism. Preliminary studies suggest that this genotype may be associated with an unfavorable response to methylphenidate in children and adolescents with the attention- deficit and hyperactivity disorder of inattentive type.

Methylphenidate Decreased Response to Methylphenidate (COMT: Intermediate COMT Activity) EVIDENCE LEVEL 2 Ritalin 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.

Metoclopramide Increased Sensitivity to Metoclopramide (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Reglan Metoclopramide is metabolized at a slower rate in CYP2D6 poor metabolizers which results in significantly higher serum concentrations of the drug. Considering the CNS and extrapyramidal adverse effects of metoclopramide, close monitoring for toxicity and eventually a dose decrease are recommended. Patients with renal disease at increased risk.

Mexiletine Significantly Increased Sensitivity to Mexiletine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Mexitil Consider prescribing a lower mexiletine dose. A slow titration with ECG recording and monitoring of mexiletine plasma concentrations are recommended until a favorable clinical response is achieved.

Naltrexone Altered Response to Naltrexone (OPRM1: Normal OPRM1 Function) EVIDENCE LEVEL 2 Vivitrol, Contrave Treatment of alcohol 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.

Nateglinide Possible Sensitivity to Nateglinide (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 2 Starlix The patient's genotype predicts a reduced CYP2C9 activity, which may result in a slightly increased risk for hypoglycemia. Nateglinide can be prescribed at label-recommended dosage and administration with additional monitoring of the patient's response.

Nefazodone Possible Sensitivity to Nefazodone (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Serzone Nefazodone is metabolized by CYP3A4 to its active metabolite m-chlorophenylpiperazine and other metabolites. The m- chlorophenylpiperazine metabolite which may contribute to adverse events, is further metabolized by CYP2D6. Individuals lacking CYP2D6 activity have higher levels of m-chlorophenylpiperazine metabolite and may experience more moderate and transient side effects when starting therapy. Consider prescribing nefazodone at a lower dose and adjust dose according to the patient's tolerability and clinical response.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 31 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Olanzapine Non-Response to Olanzapine (CYP1A2: Normal Metabolizer - Higher Inducibility) EVIDENCE LEVEL 2 Zyprexa 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.

Omeprazole Insufficient Response to Omeprazole (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 1 Prilosec • Helicobacter pylori eradication: increase dose by 100-200% and be alert to insufficient response. • Other: be extra alert to insufficient response and consider dose increase of 100-200%.

Ondansetron Lack of Benefit from Ondansetron Treatment in Early Onset Alcoholism (SLC6A4: Low EVIDENCE LEVEL 2 Serotonin Transporter Expression) Zofran, Zuplenz Ondansetron has been shown to be effective in inhibiting heavy drinking behaviors in patients with early onset alcoholism. This patient carries two short or S alleles of SLC6A4 5-HTTLPR variant. Preliminary studies demonstrate that use of ondansetron may not benefit patients with this genotype. The abstinence rates from alcohol and the number of drinks per drinking day were not significantly different between patients treated with placebo or ondansetron.

Oxycodone Possible Altered Response to Oxycodone (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Percocet, Oxycontin Decreased conversion of oxycodone to the more active metabolite oxymorphone is expected in CYP2D6 poor metabolizers. However, there is insufficient evidence whether poor metabolizers have decreased analgesia when taking oxycodone. Adequate pain relief can be achieved by increasing the dose in response to pain symptoms. Other opioids not metabolized by CYP2D6 may also be considered (i.e., morphine, oxymorphone, buprenorphine, fentanyl, methadone, and hydromorphone).

Pantoprazole Insufficient Response to Pantoprazole (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 1 Protonix • Helicobacter pylori eradication: increase dose by 400% and be alert to insufficient response. • Other: be extra alert to insufficient response and consider dose increase of 400%.

Perphenazine Increased Sensitivity to Perphenazine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Trilafon Patients with a decreased CYP2D6 function will eliminate perphenazine more slowly, which can result in higher drug concentrations and possibly more adverse events (extrapyramidal symptoms). Consider close monitoring and dose reduction to avoid toxicity.

Phenytoin High Sensitivity to Phenytoin (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 1 Dilantin In CYP2C9 poor metabolizers, the plasma concentrations of phenytoin are expected to increase, resulting in an increased risk of severe neurological toxicity. This risk increases further in individuals who are also CYP2C19 poor metabolizers. Consider a standard loading dose, and reduce the maintenance dose by 50%. Evaluate response and serum concentrations after 7-10 days. Be alert to neurological concentration-related adverse events.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 32 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Piroxicam Increased Sensitivity to Piroxicam (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 1 Feldene At standard dosage, plasma concentrations of piroxicam are expected to be high, resulting in an increased risk of gastrointestinal toxicity. Administer piroxicam with caution and reduce dose if necessary.

Propafenone Increased Sensitivity to Propafenone (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Rythmol Consider reducing the propafenone dose, and monitor ECG. Compared to normal metabolizers, poor metabolizers may require a 70% dose reduction. Consider monitoring for plasma concentrations.

Ranolazine Increased Sensitivity to Ranolazine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Ranexa Ranolazine is metabolized mainly by CYP3A4, and to a lesser extent by CYP2D6. At 500 mg twice daily, subjects lacking CYP2D6 activity (poor metabolizers) had 62% higher ranolazine exposure than subjects with normal CYP2D6 activity. The corresponding difference at 1000 mg twice daily dose was 25%.

The risk for increased exposure leading to adverse events is higher in patients lacking CYP2D6 activity (i.e., poor metabolizers). The recommended initial oral dose is 375 mg twice daily. A slower up titration and additional monitoring is recommended in these patients. Exposure related side effects might include nausea, vomiting, syncope, and dizziness. If a patient experiences treatment-related adverse events, down titration of the dose to 500 mg or 375 mg twice daily may be required. If symptoms do not resolve after dose reduction, treatment should be discontinued.

Ranolazine is a QTc prolonging drug. Caution should be observed when treating: 1- patients with a history of congenital or a family history of long QT syndrome, 2- patients with known acquired QT interval prolongation, and 3- patients treated with drugs affecting the QTc interval. Administration of CYP3A4 inhibitors increases the exposure of ranolazine significantly. As a consequence, the QTc prolongation by ranolazine in the presence of potent CYP3A inhibitors is significantly elevated relative to when the drug is administered alone.

Sertraline Possible Reduced Response to Sertraline (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 2 Zoloft Sertraline can be prescribed at standard label-recommended dosage and administration. If patient does not respond to recommended maintenance dosing, consider an alternative medication.

Tamsulosin Increased Sensitivity to Tamsulosin (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Flomax Tamsulosin is metabolized at a slower rate in CYP2D6 poor metabolizers, which results in significantly higher serum concentrations of tamsulosin. Therefore, this drug should be used with caution in patients known to be CYP2D6 poor metabolizers, particularly at a daily dose higher than 0.4 mg.

Tetrabenazine Increased Sensitivity to Tetrabenazine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 1 Xenazine 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 poor metabolizers is 50 mg with a maximum single dose of 25 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.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 33 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Tizanidine Possible Non-Response to Tizanidine (CYP1A2: Normal Metabolizer - Higher EVIDENCE LEVEL 2 Inducibility) Zanaflex 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.

Tolbutamide Possible Sensitivity to Tolbutamide (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 1 Orinase 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.

Tolterodine Possible Sensitivity to Tolterodine (CYP2D6: Poor Metabolizer) EVIDENCE LEVEL 2 Detrol Tolterodine is metabolized at a slower rate in CYP2D6 poor metabolizers, which results in significantly higher serum concentrations of tolterodine and negligible concentrations of its active metabolite (5-hydroxymethytolterodine). Considering the antimuscarinic potency of tolterodine and its active metabolite, and the protein binding of these compounds, tolterodine accounts for the major part of the clinical effect in poor metabolizers, and the same dosage can be applied irrespective of phenotype status.

Patients with congenital or acquired QT prolongation: the effect of tolterodine on the QT interval prolongation is greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day, and is more pronounced in CYP2D6 poor metabolizers than normal metabolizers. This should be considered when tolterodine is prescribed to patients with a known history of QT prolongation, or patients who are taking Class IA or Class III antiarrhythmics.

Torsemide Possible Sensitivity to Torsemide (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 2 Demadex The patient's genotype predicts a reduced CYP2C9 function, which may result in reduced torsemide clearance. There is insufficient data to whether such change has a significant clinical impact and whether the diuretic effects are more pronounced in patients with this phenotye. Torsemide can be prescribed at label-recommended dosage and administration with additional monitoring of the patient's response.

Diclofenac Possible Sensitivity to Diclofenac (CYP2C9: Poor Metabolizer) EVIDENCE LEVEL 2 Voltaren Diclofenac is extensively metabolized by hydroxylation and direct glucuronidation. About 50% of diclofenac is eliminated as a 4-hydroxymetabolite, a reaction mediated by CYP2C9. Other CYP enzymes including CYP2C8, CYP2C19 and CYP3A4 are also involved in the formation of a 5-hydroxymetabolite. A substantial portion of the drug is also directly glucuronidated by UGT2B7 and UGT2B4. Individuals with decreased CYP2C9 activity (i.e poor metabolizers) should be closely monitored for increased gastrointestinal adverse events when prescribed diclofenac and lower doses may be more appropriate for these patients.

Voriconazole Non-response to Voriconazole (CYP2C19: Ultra-Rapid Metabolizer) EVIDENCE LEVEL 1 Vfend Voriconazole plasma concentrations may be low when standard dosage is used, increasing the risk of loss of response and effectiveness. Closely monitor voriconazole plasma concentrations, and adjust the dose accordingly.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 34 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

Warfarin Very High Sensitivity to Warfarin (CYP2C9 *3/*3 VKORC1 -1639G>A A/A) EVIDENCE LEVEL 1 Coumadin Initiation Therapy: the expected therapeutic dose is substantially lower than the usual one. Consider using the following warfarin dose range provided in the FDA-approved label: 0.5-2 mg/day. OR consider using a personalized dose calculated by a pharmacogenetic algorithm. The estimated time to reach steady state is more than 2-4 weeks. Frequent INR monitoring is recommended.

Genetic Test Results For Sample Report Alcala - Psychotropic Lab Director: Dr. David J. Smith, MD | CLIA: 05D2027247 | 3703 Camino del Rio South, 100-A, San Diego CA 98102 | www.alcalalabs.com | 619-450-5870 Page 35 of 36 PATIENT INFORMATION SPECIMEN DETAILS ORDERED BY

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: Sample Report Alcala - VKORC1 -1639G>A A/A High Warfarin Sensitivity Psychotropic DOB: 1/1/1900 OPRM1 A118G AA Normal OPRM1 Function ACC #: Psychotropic Low Serotonin Transporter SLC6A4 S/S Expression Pharmacogenetic Test Summary SLC6A4 463T>G C/A Heterozygous for the C Allele CYP2C19 *17/*17 Ultra-Rapid Metabolizer 1298A>C CC Unknown Risk of CYP2C9 *3/*3 Poor Metabolizer MTHFR 677C>T TT Hyperhomocysteinemia CYP2D6 *5/*8 Poor Metabolizer MTHFR 677C>T TT Reduced MTHFR Activity CYP3A4 *1/*1 Normal Metabolizer Factor II 20210G>A AA CYP3A5 *3/*3 Poor Metabolizer Factor V Unknown Risk of Thrombosis 1691G>A AA Leiden

For a complete report contact Alcala Testing and Analysis Services -- DO NOT DISTRIBUTE www.alcalalabs.com