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Table of Pharmacogenomic Biomarkers in Drug Labeling

Inclusion criteria: germline or somatic gene variants (polymorphisms, mutations), functional deficiencies with a genetic etiology, gene expression differences, chromosomal abnormalities; selected proteins that are used for treatment selection are also included;

Exclusion criteria: non-human genetic factors (e.g., viral or bacterial), biomarkers used for disease diagnostic purposes that are not used to determine dosing or treatment selection within the diagnosed disease, and biomarkers that are related to a drug other than the referenced drug (e.g., influences the effect of the referenced drug as a perpetrator of an interaction with another drug)

NDA/ANDA/BLA Number, Label Version Date Drug Therapeutic Area* Biomarker† Labeling Sections Labeling Text‡
020977, 03/20/2017 Abacavir Infectious Diseases HLA-B Boxed Warning, Dosage and Administration, Contraindications, Warnings and Precautions BOXED WARNING WARNING: HYPERSENSITIVITY REACTIONS, and LACTIC ACIDOSIS, AND SEVERE HEPATOMEGALY Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with ZIAGEN® (abacavir). Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele [see Warnings and Precautions (5.1)]. ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see Contraindications (4), Warnings and Precautions (5.1)]. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN or reinitiation of therapy with ZIAGEN, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue ZIAGEN immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see Contraindications (4), Warnings and Precautions (5.1)]. Following a hypersensitivity reaction to ZIAGEN, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see Warnings and Precautions (5.1)]. (…) 2 DOSAGE AND ADMINISTRATION 2.1 Screening for HLA-B*5701 Allele Prior to Starting ZIAGEN Screen for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN [see Boxed Warning, Warnings and Precautions (5.1)]. 4 CONTRAINDICATIONS ZIAGEN is contraindicated in patients: • who have the HLA-B*5701 allele [see Warnings and Precautions (5.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions have occurred with ZIAGEN (abacavir). These hypersensitivity reactions have included multi- organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with ZIAGEN (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see Adverse Reactions (6.1)]. Patients who carry the HLA B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with ZIAGEN: • All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN or reinitiation of therapy with ZIAGEN, unless patients have a previously documented HLA-B*5701 allele assessment. • ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. • Before starting ZIAGEN, review medical history for prior exposure to any abacavir containing product. NEVER restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status. • To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue ZIAGEN immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). • If a hypersensitivity reaction cannot be ruled out, do not restart ZIAGEN or any other abacavir-containing products because more severe symptoms which may include life-threatening hypotension and death, can occur within hours. • If a hypersensitivity reaction is ruled out, patients may restart ZIAGEN. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of ZIAGEN or any other abacavir containing product is recommended only if medical care can be readily accessed. • A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.

* Therapeutic areas do not necessarily reflect the CDER review division.

† Representative biomarkers are listed based on standard nomenclature as per the Human Genome Organization (HUGO) symbol and/or simplified descriptors using other common conventions. Listed biomarkers do not necessarily reflect the terminology used in labeling. The term “Nonspecific” is provided when labeling does not explicitly identify the specific biomarker(s) or when the biomarker is represented by a molecular phenotype or gene signature, and in some cases the biomarker was inferred based on the labeling language.

‡ Referenced figures and tables may be found in the labeling available at Drugs@FDA. Blue text represents the most recent addtions and/or changes since last posted version.

Table of Pharmacogenomic Biomarkers in Drug Labeling

NDA/ANDA/BLA Number, Label Version Date Drug Therapeutic Area* Biomarker† Labeling Sections Labeling Text‡
125427, 07/25/2016 Ado-Trastuzumab Emtansine Oncology ERBB2 (HER2) Indications and Usage, Warnings and Precautions, Adverse Reactions, Clinical Pharmacology, Clinical Studies 1 INDICATIONS AND USAGE KADCYLA®, as a single agent, is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination.

Patients should have either: • Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of completing adjuvant therapy. 5 WARNINGS AND PRECAUTIONS 5.9 HER2 Testing Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2- positive metastatic breast cancer. (…) (…) Hepatic failure has been observed in two patients (0.2%) with HER2-positive metastatic breast cancer in clinical trials (n=884) with KADCYLA as single-agent. 12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics Elimination (…) Based on population pharmacokinetic analysis (n=671), body weight, sum of longest diameter of target lesions by RECIST, HER2 extracellular domain (ECD) concentrations, AST, albumin, and baseline trastuzumab concentrations were identified as statistically significant covariates for adotrastuzumab emtansine clearance.(…) Effect of Hepatic Impairment (…) The liver is a primary organ for eliminating DM1 and DM1-containing catabolites. The pharmacokinetics of trastuzumab emtasine and DM1- containing catabolites were evaluated after the administration of 3.6 mg/kg of KADCYLA to metastatic HER2-positive breast cancer patients with normal hepatic function (n=10), mild (Child Pugh A; n=10) and moderate (ChildPugh B; n=8) hepatic impairment. 12.6 Cardiac Electrophysiology The effect of multiple doses of KADCYLA (3.6 mg/kg every 3 weeks) on the QTc interval was evaluated in an open label, single arm study in 51 patients with HER2-positive metastatic breast cancer. No large changes in the mean QT interval (i.e., > 20 ms) were detected in the study. 14 CLINICAL STUDIES 14.1 Metastatic Breast Cancer The efficacy of KADCYLA was evaluated in a randomized, multicenter, open-label trial of 991 patients with HER2 positive, unresectable locally advanced or metastatic breast cancer. Prior taxane and trastuzumab-based therapy was required before trial enrollment. Patients with only prior adjuvant therapy were required to have disease recurrence during or within six months of completing adjuvant therapy. Breast tumor samples were required to show HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 determined at a central laboratory.
201292, 10/04/2016 Afatinib Oncology EGFR Indications and Usage, Dosage and Administration, Adverse Reactions, Clinical Studies 1 INDICATIONS AND USAGE KADCYLA®, as a single agent, is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination.

Patients should have either: • Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of completing adjuvant therapy. 5 WARNINGS AND PRECAUTIONS 5.9 HER2 Testing Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2- positive metastatic breast cancer. (…) (…) Hepatic failure has been observed in two patients (0.2%) with HER2-positive metastatic breast cancer in clinical trials (n=884) with KADCYLA as single-agent. 12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics Elimination (…) Based on population pharmacokinetic analysis (n=671), body weight, sum of longest diameter of target lesions by RECIST, HER2 extracellular domain (ECD) concentrations, AST, albumin, and baseline trastuzumab concentrations were identified as statistically significant covariates for adotrastuzumab emtansine clearance.(…) Effect of Hepatic Impairment (…) The liver is a primary organ for eliminating DM1 and DM1-containing catabolites. The pharmacokinetics of trastuzumab emtasine and DM1- containing catabolites were evaluated after the administration of 3.6 mg/kg of KADCYLA to metastatic HER2-positive breast cancer patients with normal hepatic function (n=10), mild (Child Pugh A; n=10) and moderate (ChildPugh B; n=8) hepatic impairment. 12.6 Cardiac Electrophysiology The effect of multiple doses of KADCYLA (3.6 mg/kg every 3 weeks) on the QTc interval was evaluated in an open label, single arm study in 51 patients with HER2-positive metastatic breast cancer. No large changes in the mean QT interval (i.e., > 20 ms) were detected in the study. 14 CLINICAL STUDIES 14.1 Metastatic Breast Cancer The efficacy of KADCYLA was evaluated in a randomized, multicenter, open-label trial of 991 patients with HER2 positive, unresectable locally advanced or metastatic breast cancer. Prior taxane and trastuzumab-based therapy was required before trial enrollment. Patients with only prior adjuvant therapy were required to have disease recurrence during or within six months of completing adjuvant therapy. Breast tumor samples were required to show HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 determined at a central laboratory.

* Therapeutic areas do not necessarily reflect the CDER review division.

† Representative biomarkers are listed based on standard nomenclature as per the Human Genome Organization (HUGO) symbol and/or simplified descriptors using other common conventions. Listed biomarkers do not necessarily reflect the terminology used in labeling. The term “Nonspecific” is provided when labeling does not explicitly identify the specific biomarker(s) or when the biomarker is represented by a molecular phenotype or gene signature, and in some cases the biomarker was inferred based on the labeling language.

‡ Referenced figures and tables may be found in the labeling available at Drugs@FDA. Blue text represents the most recent addtions and/or changes since last posted version.

Table of Pharmacogenomic Biomarkers in Drug Labeling

NDA/ANDA/BLA Number, Label Version Date Drug Therapeutic Area* Biomarker† Labeling Sections Labeling Text‡
208434, 11/04/2016 Alectinib Oncology ALK Indications and Usage, Adverse Reactions, Clinical Pharmacology, Clinical Studies EGFR mutation-positive, metastatic NSCLC, and in Study 2, a randomized, active controlled trial in patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.(…) EGFR Mutation-Positive, Metastatic NSCLC

The data in Tables 1 and 2 below reflect the exposure of 229 EGFR-tyrosine kinase inhibitor-naïve, GILOTRIF-treated patients with EGFR mutation- positive, metastatic, non-squamous NSCLC enrolled in a randomized, multicenter, open-label trial (Study 1). (…) 14 CLINICAL STUDIES 14.1 EGFR Mutation-Positive Non-Small Cell Lung Cancer The efficacy and safety of GILOTRIF in the first-line treatment of 345 patients with EGFR mutation-positive, metastatic [Stage IV and Stage IIIb with pleural and/or pericardial effusion as classified by the American Joint Commission on Cancer (AJCC, 6th edition)] non-small cell lung cancer (NSCLC) were established in a randomized, multicenter, open-label trial (Study 1). Patients were randomized (2:1) to receive GILOTRIF 40 mg orally once daily (n=230) or up to 6 cycles of pemetrexed/cisplatin (n=115). Randomization was stratified according to EGFR mutation status (exon 19 deletion vs exon 21 L858R vs other) and race (Asian vs non-Asian). The major efficacy outcome was progression-free survival (PFS) as assessed by an independent review committee (IRC). Other efficacy outcomes included overall response rate (ORR) and overall survival (OS). EGFR mutation status was prospectively determined for screening and enrollment of patients by a clinical trial assay (CTA). Tumor samples from 264 patients (178 randomized to GILOTRIF and 86 patients randomized to chemotherapy) were tested retrospectively by the companion diagnostic therascreen® EGFR RGQ PCR Kit, which is FDA- approved for selection of patients for GILOTRIF treatment. Among the patients randomized, 65% were female, median age was 61 years, baseline ECOG performance status was 0 (39%) or 1 (61%), 26% were Caucasian and 72% were Asian. The majority of the patients had a tumor sample with an EGFR mutation categorized by the CTA as either exon 19 deletion (49%) or exon 21 L858R substitution (40%), while the remaining 11% had other mutations. Subgroup analyses were conducted based on the stratification factor of EGFR mutation status (Del19, L858R, other) and mutation category (common [Del19, L858R] vs uncommon [other]). (See Figure 2) (…) There were 26 GILOTRIF-treated patients in the “other” (uncommon) EGFR mutations subgroup with nine unique mutation patterns. None of these 26 patients achieved a complete response, while four achieved a partial response (see Table 6). No responses were seen in GILOTRIF treated patients with the following mutations: T790M alone (n=2), deletion 19 and T790M (n=3), G719X and T790M (n=1), exon 20 insertion (n=6), and L861Q alone (n=3). There were 11 chemotherapy-treated patients in the “other” uncommon EGFR mutation subgroup; of these, four (36%) achieved a partial response. (See Table 6).
208434, 11/04/2016 Alectinib Oncology ALK Indications and Usage, Adverse Reactions, Clinical Pharmacology, Clinical Studies 1 INDICATIONS AND USAGE ALECENSA is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ALECENSA was evaluated in 253 patients with ALK-positive non-small cell lung cancer (NSCLC) treated with ALECENSA 600 mg orally twice daily in two clinical trials, Studies 1 and 2. (…) 12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics The pharmacokinetics of alectinib and its major active metabolite M4 have been characterized in patients with ALK-positive NSCLC and healthy subjects. In patients with ALK-positive NSCLC, the geometric mean (coefficient of variation %) steady-state maximal concentration (Cmax,ss) for alectinib was 665 ng/mL (44%) and for M4 was 246 ng/mL (45%) with peak to trough concentration ratio of 1.2. (…) Absorption Alectinib reached maximal concentrations at 4 hours following administration of ALECENSA 600 mg twice daily under fed conditions in patients with ALK- positive NSCLC. (…) Distribution The apparent volume of distribution is 4,016 L for alectinib and 10,093 L for M4. Alectinib and M4 are bound to human plasma proteins greater than 99%, independent of drug concentration. Alectinib concentrations in the cerebrospinal fluid in patients with ALK-positive NSCLC approximate estimated alectinib free concentrations in the plasma. (…) Elimination The apparent clearance (CL/F) is 81.9 L/hour for alectinib and 217 L/hour for M4. The geometric mean elimination half-life is 33 hours for alectinib and 31 hours for M4 in patients with ALK-positive NSCLC. 14 CLINICAL STUDIES The safety and efficacy of ALECENSA were established in two single-arm, multicenter clinical trials (Studies 1 and 2). Patients with locally advanced or metastatic ALK-positive NSCLC, who have progressed on crizotinib, with documented ALK positive NSCLC based on an FDA-approved test, and ECOG PS of 0-2 were enrolled in both studies.
085971, Amitriptyline Psychiatry CYP2D6 Precautions PRECAUTIONS

* Therapeutic areas do not necessarily reflect the CDER review division.

† Representative biomarkers are listed based on standard nomenclature as per the Human Genome Organization (HUGO) symbol and/or simplified descriptors using other common conventions. Listed biomarkers do not necessarily reflect the terminology used in labeling. The term “Nonspecific” is provided when labeling does not explicitly identify the specific biomarker(s) or when the biomarker is represented by a molecular phenotype or gene signature, and in some cases the biomarker was inferred based on the labeling language.

‡ Referenced figures and tables may be found in the labeling available at Drugs@FDA. Blue text represents the most recent addtions and/or changes since last posted version.

Table of Pharmacogenomic Biomarkers in Drug Labeling

NDA/ANDA/BLA Number, Label Version Date Drug Therapeutic Area* Biomarker† Labeling Sections Labeling Text‡
07/17/2014 Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7 to 10% of Caucasians are so called “poor metabolizers”);

reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers.
020541, 05/02/2014 Anastrozole Oncology ESR, PGR (Hormone Receptor) Indications and Usage, Adverse Reactions, Drug Interactions, Clinical Studies 1 INDICATIONS AND USAGE 1.1 Adjuvant Treatment ARIMIDEX is indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. 1.2 First-Line Treatment

ARIMIDEX is indicated for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer. 1.3 Second-Line Treatment ARIMIDEX is indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to ARIMIDEX. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience A post-marketing trial assessed the combined effects of ARIMIDEX and the bisphosphonate risedronate on changes from baseline in BMD and markers of bone resorption and formation in postmenopausal women with hormone receptor-positive early breast cancer. All patients received calcium and vitamin D supplementation. At 12 months, small reductions in lumbar spine bone mineral density were noted in patients not receiving bisphosphonates. Bisphosphonate treatment preserved bone density in most patients at risk of fracture. (…) 7 DRUG INTERACTIONS 7.1 Tamoxifen Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the co- administration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of ARIMIDEX and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial [see Clinical Studies (14.1)]. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole. (…) 14 CLINICAL STUDIES 14.1 Adjuvant Treatment of Breast Cancer in Postmenopausal Women At a median follow-up of 33 months, the combination of ARIMIDEX and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor-positive subpopulation. (…) Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127] in the ARIMIDEX arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 84% of the trial patients, disease- free survival was also statistically significantly improved (HR = 0.83, 95% CI: 0.73, 0.94, p=0.0049) in the ARIMIDEX arm compared to the tamoxifen arm. (See Figure 2) (…) The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 8. (see Table 8) A summary of the study efficacy results is provided in Table 9. (See Table 9, 10, and Figure 4) (…) 14.2 First-Line Therapy in Postmenopausal Women with Advanced Breast Cancer Two double-blind, controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of ARIMIDEX compared with tamoxifen as first-line therapy for hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women. (See Table 11) (…) 14.3 Second-Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy Anastrozole was studied in two controlled clinical trials (0004, a North American study; 0005, a predominately European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER-positive; a smaller fraction were ER-unknown or ER negative; the ER- negative patients were eligible only if they had had a positive response to tamoxifen.
021912, 02/27/2014 Arformoterol (1) Pulmonary UGT1A1 Clinical Pharmacology 12 CLINICAL PHARMACOLOGY 12.5 Pharmacogenomics Arformoterol is eliminated through the action of multiple drug metabolizing enzymes. Direct glucuronidation of arformoterol is mediated by several UGT enzymes and is the primary elimination route. O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. In otherwise healthy subjects with reduced CYP2D6 and/or UGT1A1 enzyme activity, there was no impact on systemic exposure to arformoterol compared to subjects with normal CYP2D6 and/or UGT1A1 enzyme activities

* Therapeutic areas do not necessarily reflect the CDER review division.

† Representative biomarkers are listed based on standard nomenclature as per the Human Genome Organization (HUGO) symbol and/or simplified descriptors using other common conventions. Listed biomarkers do not necessarily reflect the terminology used in labeling. The term “Nonspecific” is provided when labeling does not explicitly identify the specific biomarker(s) or when the biomarker is represented by a molecular phenotype or gene signature, and in some cases the biomarker was inferred based on the labeling language.

‡ Referenced figures and tables may be found in the labeling available at Drugs@FDA. Blue text represents the most recent addtions and/or changes since last posted version.

Table of Pharmacogenomic Biomarkers in Drug Labeling

NDA/ANDA/BLA Number, Label Version Date Drug Therapeutic Area* Biomarker† Labeling Sections Labeling Text‡
021912,02/27/2014 Arformoterol (2) Pulmonary CYP2D6 Clinical Pharmacology 12 CLINICAL PHARMACOLOGY 12.5 Pharmacogenomics

Arformoterol is eliminated through the action of multiple drug metabolizing enzymes. Direct glucuronidation of arformoterol is mediated by several UGT enzymes and is the primary elimination route. O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. In otherwise healthy subjects with reduced CYP2D6 and/or UGT1A1 enzyme activity, there was no impact on systemic exposure to arformoterol compared to subjects with normal CYP2D6 and/or UGT1A1 enzyme activities
021436,08/18/2016 Aripiprazole Psychiatry CYP2D6 Dosage and Administration, Use in Specific Populations, Clinical Pharmacology 2 DOSAGE AND ADMINISTRATION 2.7 Dosage Adjustments for Cytochrome P450 Considerations Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or

CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 2). When the coadministered drug is withdrawn from the combination therapy, ABILIFY dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, ABILIFY dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response. (See Table 2) 8 USE IN SPECIFIC POPULATIONS 8.6 CYP2D6 Poor Metabolizers Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see DOSAGE AND ADMINISTRATION (2.7) and CLINICAL PHARMACOLOGY (12.3)]. 12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics (…) For CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours. Drug Interaction Studies Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 1 and Figure 2, respectively. Based on simulation, a 4.5-fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors. (…) Studies in Specific Populations Exposures of aripiprazole and dehydro-aripiprazole in specific populations are summarized in Figure 4 and Figure 5, respectively. In addition, in pediatric patients (10 to 17 years of age) administered with Abilify (20 mg to 30 mg), the body weight corrected aripiprazole clearance was similar to the adults. (See Figure 4 and 5)
207533, 08/18/2016 Aripiprazole Lauroxil Psychiatry CYP2D6 Dosage and Administration, Use in Specific Populations, Clinical Pharmacology 2 DOSAGE AND ADMINISTRATION 2.4 Dose Adjustments for CYP450 Considerations

Refer to the prescribing information for oral aripiprazole for recommendations regarding dosage adjustments due to drug interactions, for the first 21 days when the patient is taking oral aripiprazole concomitantly with the first dose of ARISTADA. Once stabilized on ARISTADA, refer to the dosing recommendations below for patients taking CYP 2D6 inhibitors , CYP 3A4 inhibitors , or CYP 3A4 inducers: • No dosage changes recommended for ARISTADA, if CYP 450 modulators are added for less than 2 weeks. • Make dose changes to ARISTADA if CYP 450 modulators are added for greater than 2 weeks. (See Table 4) 8 USE IN SPECIFIC POPULATIONS 8.6 CYP2D6 Poo r Metabolizers Dosage adjustment is recommended in known CYP 2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. 12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics Metabolism and Elimination (…) Elimination of aripiprazole is mainly through hepatic metabolism involving CYP 3A4 and CYP 2D6. Dosage adjustments are recommended in CYP 2D6 poor metabolizers due to high aripiprazole concentrations [see Dosage and Administration (2.4)]. (…) Drug Interaction Studies No specific drug interaction studies have been performed with ARISTADA. The drug interaction data provided below is obtained from studies with oral aripiprazole. Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 1 and Figure 2, respectively. Based on simulation, a 4.5-fold increase in mean Cm ax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP 2D6 and CYP 3A4 inhibitors. After oral administration, a 3-fold increase in mean Cm ax and AUC values at steady-state is expected

* Therapeutic areas do not necessarily reflect the CDER review division.

† Representative biomarkers are listed based on standard nomenclature as per the Human Genome Organization (HUGO) symbol and/or simplified descriptors using other common conventions. Listed biomarkers do not necessarily reflect the terminology used in labeling. The term “Nonspecific” is provided when labeling does not explicitly identify the specific biomarker(s) or when the biomarker is represented by a molecular phenotype or gene signature, and in some cases the biomarker was inferred based on the labeling language.

‡ Referenced figures and tables may be found in the labeling available at Drugs@FDA. Blue text represents the most recent addtions and/or changes since last posted version.

Table of Pharmacogenomic Biomarkers in Drug Labeling

NDA/ANDA/BLA Number, Label Version Date Drug Therapeutic Area* Biomarker† Labeling Sections Labeling Text‡
in poor metabolizers of CYP 2D6 administered with strong CYP 3A4 inhibitors. (See Figure 1, 2, and 3) Specific Population Studies

A population pharmacokinetic analysis showed no effect of sex, race or smoking on ARISTADA pharmacokinetics [see Use in Specific Populations (8.8)]. Exposures of aripiprazole and dehydro-aripiprazole using oral aripiprazole in specific populations are summarized in Figure 4 and Figure 5, respectively. (See Figure 4 and 5)
021248,02/20/2015 Arsenic Trioxide Oncology PML-RARA Indications and Usage 1 INDICATIONS AND USAGE TRISENOX is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or

have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR- alpha gene expression.
761034,05/18/2016 Atezolizumab Oncology CD274 (PD-L1) Adverse Reactions, Clinical Pharmacology, Clinical Studies 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience

NSCLC The safety of TECENTRIQ was evaluated in Study 3, a multi-center, international, randomized, open label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression [see Clinical Studies (14.2)]. (…) 12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics Specific Populations Age (21–89 years), body weight, gender, positive anti-therapeutic antibody (ATA) status, albumin levels, tumor burden, region or race, mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin < 1.0 to 1.5 × ULN and any AST), level of PD-L1 expression, or ECOG status had no clinically significant effect on the systemic exposure of atezolizumab. (…) 14 CLINICAL STUDIES 14.1 Urothelial Carcinoma (…) Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 310 patients, 32% were classified as having PD-L1 expression of ≥ 5% (defined as PD-L1 stained tumorinfiltrating immune cells [IC] covering ≥ 5% of the tumor area). The remaining, 68% of patients, were classified as having PD-L1 expression of < 5% of the tumor area). Confirmed ORR in all patients and the two PD-L1 subgroups are summarized in Table 5. The median follow-up time for this cohort was 14.4 months. In 59 patients with disease progression following neoadjuvant or adjuvant therapy, the ORR was 22.0% (95% CI: 12.3%, 34.7%). (See Table 5) (…) 14.2 Metastatic Non-Small Cell Lung Cancer Previously Treated Metastatic NSCLC The efficacy of TECENTRIQ was investigated in two multi-center, international, randomized, open-label trials in patients with metastatic NSCLC who progressed during or following a platinumcontaining regimen. Study 2 was a trial in 1225 patients with the primary analysis population consisting of the first 850 randomized patients and Study 3 was a trial in 287 patients. In both studies, eligible patients were stratified by PD-L1 expression status in tumor- infiltrating immune cells (IC), by the number of prior chemotherapy regimens, and by histology. (…) (…) Tumor assessments were conducted every 6 weeks for the first 36 weeks, and every 9 weeks thereafter. In Study 2, tumor specimens were evaluated prospectively for PD-L1 expression on tumor cells (TC) and IC using the VENTANA PD-L1 (SP142) Assay and the results were used to define the PD-L1 expression subgroups for the analyses described below. (See Table 6) (…) (…) Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define the PD-L1 expression subgroups for pre-specified analyses. Of the 850 patients, 16% were classified as having high PD-L1 expression, defined as having PD-L1 expression on ≥ 50% of TC or ≥ 10% of IC. In an exploratory efficacy subgroup analysis of OS based on PD-L1 expression, the hazard ratio was 0.41 (95% CI: 0.27, 0.64) in the high PD-L1 expression subgroup and 0.82 (95% CI: 0.68, 0.98) in patients who did not have high PD-L1 expression. Results of an updated survival analysis in Study 3 with a median follow-up of 22 months are provided for all randomized patients (Table 7 and Figure 2).
021411, 05/26/2015 Atomoxetine Psychiatry CYP2D6 Dosage and Administration, Warnings and Precautions, Adverse Reactions, Drug Interactions, Clinical Pharmacology 2 DOSAGE AND ADMINISTRATION 2.4 Dosing in Specific Populations

Dosing adjustment for use with a strong CYP2D6 inhibitor or in patients who are known to be CYP2D6 PMs. In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, or in patients who are known to be CYP2D6 PMs, STRATTERA should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. 5 WARNINGS AND PRECAUTIONS 5.12 Laboratory Tests Routine laboratory tests are not required. CYP2D6 metabolism- Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of STRATTERA compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of STRATTERA [see Adverse Reactions (6.1)]. 5.13 Concomitant Use of Potent CYP2D6 Inhibitors or Use in patients who are known to be CYP2D6 PMs

* Therapeutic areas do not necessarily reflect the CDER review division.

† Representative biomarkers are listed based on standard nomenclature as per the Human Genome Organization (HUGO) symbol and/or simplified descriptors using other common conventions. Listed biomarkers do not necessarily reflect the terminology used in labeling. The term “Nonspecific” is provided when labeling does not explicitly identify the specific biomarker(s) or when the biomarker is represented by a molecular phenotype or gene signature, and in some cases the biomarker was inferred based on the labeling language.

‡ Referenced figures and tables may be found in the labeling available at Drugs@FDA. Blue text represents the most recent addtions and/or changes since last posted version.

Table of Pharmacogenomic Biomarkers in Drug Labeling

NDA/ANDA/BLA Number, Label Version Date Drug Therapeutic Area* Biomarker† Labeling Sections Labeling Text‡
Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4 hydroxyatomoxetine. Dosage adjustment of STRATTERA may be necessary when coadministered with potent CYP2D6 inhibitors

(e.g., paroxetine, fluoxetine, and quinidine) or when administered to CYP2D6 PMs. [See Dosage and Administration (2.4) and Drug Interactions (7.2)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Child and Adolescent Clinical Trials (…) The following adverse reactions occurred in at least 2% of child and adolescent CYP2D6 PM patients and were statistically significantly more frequent in PM patients compared with CYP2D6 EM patients: insomnia (11% of PMs, 6% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); middle insomnia (3% of PMs, 1% of EMs); conjunctivitis (3% of PMs, 1% of EMs); syncope (3% of PMs, 1% of EMs); early morning awakening (2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs); sedation (4% of PMs, 2% of EMs). (…) Adult Clinical Trials (…) The following adverse events occurred in at least 2% of adult CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metaboliser (EM) patients: vision blurred (4% of PMs, 1% of EMs); dry mouth (35% of PMs, 17% of EMs); constipation (11% of PMs, 7% of EMs); feeling jittery (5% of PMs, 2% of EMs); decreased appetite (23% of PMs, 15% of EMs); tremor (5% of PMs, 1% of EMs); insomnia (19% of PMs, 11% of EMs); sleep disorder (7% of PMs, 3% of EMs); middle insomnia (5% of PMs, 3% of EMs); terminal insomnia (3% of PMs, 1% of EMs); urinary retention (6% of PMs, 1% of EMs); erectile dysfunction (21% of PMs, 9% of EMs); ejaculation disorder (6% of PMs, 2% of EMs); hyperhidrosis (15% of PMs, 7% of EMs); peripheral coldness (3% of PMs, 1% of EMs). (…) 7 DRUG INTERACTIONS 7.2 Effect of CYP2D6 Inhibitors on Atomoxetine In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css, max is about 3- to 4-fold greater than atomoxetine alone. In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of STRATTERA on QTc prolongation was evaluated in a randomized, double-blinded, positive-(moxifloxacin 400 mg) and placebo-controlled, cross-over study in healthy male CYP2D6 poor metabolizers. A total of 120 healthy subjects were administered STRATTERA (20 mg and 60 mg) twice daily for 7 days. No large changes in QTc interval (i.e., increases >60 msec from baseline, absolute QTc >480 msec) were observed in the study. However, small changes in QTc interval cannot be excluded from the current study, because the study failed to demonstrate assay sensitivity. There was a slight increase in QTc interval with increased atomoxetine concentration. 12.3 Pharmacokinetics Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about 5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with normal activity [extensive metabolizers (EMs)]. (…) Absorption and distribution Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in EMs and 94% in PMs. Maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing. (…) Metabolism and elimination Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC of atomoxetine is approximately 10-fold and Css, max is about 5-fold greater than EMs. Laboratory tests are available to identify CYP2D6 PMs. Coadministration of STRATTERA with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary [see Warnings and Precautions (5.13)]. Atomoxetine did not inhibit or induce the CYP2D6 pathway. The major oxidative metabolite formed, regardless of CYP2D6 status, is 4-hydroxyatomoxetine, which is glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates in plasma at lower concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs). Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs, AUC of atomoxetine is approximately 10-fold and Css, max is about 5-fold greater than EMs. The elimination half-life of 4-hydroxyatomoxetine is similar to that of N- desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours).

* Therapeutic areas do not necessarily reflect the CDER review division.

† Representative biomarkers are listed based on standard nomenclature as per the Human Genome Organization (HUGO) symbol and/or simplified descriptors using other common conventions. Listed biomarkers do not necessarily reflect the terminology used in labeling. The term “Nonspecific” is provided when labeling does not explicitly identify the specific biomarker(s) or when the biomarker is represented by a molecular phenotype or gene signature, and in some cases the biomarker was inferred based on the labeling language.

‡ Referenced figures and tables may be found in the labeling available at Drugs@FDA. Blue text represents the most recent addtions and/or changes since last posted version.

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