Case 1:20-cv-01580-LPS Document 34 Filed 02/26/21 Page 1 of 27 PageID #: 6971
`Case 1:20-cv-01580-LPS Document 34 Filed 02/26/21 Page 1 of 27 PageID #: 6971
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`GUARDANT HEALTH, INC.,
`Plaintiff,
`
`)
`;
`i C. A. No. 20-cv-01580-LPS
`V.
`FOUNDATION MEDICINE, INC., 3
`Defendant.
`;
`
`DECLARATION OF AMEET MALIK
`
`I, Ameet Malik, hereby declare:
`
`l. I am employed by Novartis Pharmaceuticals Corporation
`(“Novartis”) and am Executive Vice President and Head, US
`Oncology.
`
`2. I understand that Guardant Health, Inc. (“Guardant”) has
`filed a motion for a preliminary injunction, by which it seeks to
`prevent Foundation Medicine, Inc. (“FMI”) from continuing to
`use or sell its FDA-approved FoundationOne® Liquid CDX test
`in the United States.
`
`3. I am providing this Declaration to provide information
`regarding the impact on Novartis and on patient access to
`PIQRAY® if FMI’s test is removed from the market in the United
`States.
`
`4. Novartis manufactures and sells the drug PIQRAY®
`(alpelisib).
`PIQRAY® is a kinase inhibitor that FDA approved
`for use in combination with fulvestrant for the treatment of
`postmenopausal women, and men, with hormone receptor (HR)-
`positive, human epidermal growth factor receptor 2 (HER2)-
`negative, PIK3CA-mutated, advanced or metastatic breast
`cancer as detected by an FDA-approved test
`following
`progression on or after an endocrine-based regimen.
`[PIQRAY®
`Label at 1, “Indications and Usage”].
`
`5. Clinicians determine if a patient may benefit from
`treatment with PIQRAY® through an FDA-approved companion
`diagnostic, also referred to as CDx.
`
`

`

`Case 1:20-cv-01580-LPS Document 34 Filed 02/26/21 Page 2 of 27 PageID #: 6972
`Casellfiopatfiéfilai;LfifiiefitXiWififiHR—WiOétZH/ERZWMW PageID #: 6972
`advanced or metastatic breast cancer are selected for treatment
`with PIQRAY® based on the presence of one or more PIK3CA-
`mutations. The presence of such mutations is determined by
`testing tumor tissue or plasma specimens taken from the patient
`using a diagnostic test.
`PIQRA ”s prescribing information
`states: “Select patients for the treatment of HR—positive, HERZ-
`negative advanced or metastatic breast cancer with PIQRAY“,
`based on the presence of one or more PIK3CA mutations in
`tumor tissue or plasma specimens. If no mutation is detected in a
`plasma specimen,
`test
`tumor tissue.” [PIQRAY ® Label, at
`Section 2.1].
`
`7. Novartis directs potential prescribers to information on
`FDA-approved tests for the detection of PIK3CA mutations in
`breast
`cancer
`that
`is
`available
`at:
`http://www.fda,gov/CompanionDiagnostics. See id.
`
`8. FoundationOne® Liquid CDX is the only comprehensive
`genomic profiling (CGP) liquid test approved by FDA for use to
`identify patients who may benefit
`from PIQRAY®.
`If
`FoundationOne® Liquid CDX were not available in the U.S., then
`there would be no approved liquid CGP test available to identify
`patients in the U.S. who could benefit from PIQRAY ®. This
`could result
`in many fewer patients being identified by
`physicians in the U.S. as patients who would benefit from
`treatment with PIQRAY®.
`
`9. Novartis collaborated with FMI during the FDA
`application process for a companion diagnostic for PIQRAY?
`Developing its drug therapies alongside a companion diagnostic
`test allows Novartis to identify which patients may benefit from
`treatment with our therapies. Novartis has collaborated with
`FMI in development, regulatory, and commercial activities in
`support of pre—market approval and post-market delivery of
`PIQRAY®to patients, healthcare providers, and payers.
`
`10. Novartis and FMI are also awaiting FDA approval of a
`companion diagnostic test
`for TABRECTA® (capmatinib).
`TABRECTA® is a kinase inhibitor approved by FDA for the
`treatment of adult patients with metastatic non-small cell lung
`cancer (NSCLC) whose tumors have a mutation that leads to
`mesenchymal—epithelial transition (MET) exon 14 skipping as
`detected by an FDA-approved test.
`
`11. If FDA approves FoundationOne® Liquid CDX as a
`companion
`diagnostic
`test
`for
`TABRECTA",
`then
`FoundationOne® Liquid CDX will be the only liquid test, CGP or
`
`

`

`Case 1:20-cv-01580-LPS Document 34 Filed 02/26/21 Page 3 of 27 PageID #: 6973
`otfié‘raisé,0a¥p%%%9r L635 qumentaé taiaaaagelaatiameam 27 PageID #: 6973
`may benefit from TABRECTA®. There are currently no other
`FDA—approved liquid tests to identify patients eligible for
`treatment with TABRECTA?
`FDA approval of a liquid
`companion diagnostic test will make TABRECTA® available in
`the US. to a patient population that previously did not have
`access to this drug because the patient did not have sufficient
`tissue available for testing.
`
`12. FMI and Novartis have worked together to obtain FDA
`approval
`for FoundationOne® Liquid CDX as a companion
`diagnostic test for use with TABRECTA®.
`
`I declare under penalty of perjury under the laws of the
`United States that
`the foregoing and the content of my
`Declaration are true and correct to the best of my knowledge.
`
`Executed
`this
`£231
`day
`of February
`2021,
`in
`MaéISo/x, New 3253,“!
`
`.
`
`Xmeet Malik /
`
`

`

`Case 1:20-cv-01580-LPS Document 34 Filed 02/26/21 Page 4 of 27 PageID #: 6974
`Case 1:20-cv-01580-LPS Document 34 Filed 02/26/21 Page 4 of 27 PageID #: 6974
`
`EXHIBIT A
`
`EXHIBIT A
`
`

`

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`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`PIQRAY safely and effectively. See full prescribing information for
`PIQRAY.
`PIQRAY® (alpelisib) tablets, for oral use
`Initial U.S. Approval: 2019
`----------------------------RECENT MAJOR CHANGES--------------------------
`Warnings and Precautions, Severe Cutaneous
`9/2020
`Adverse Reactions (5.2)
`-----------------------------INDICATIONS AND USAGE--------------------------
`PIQRAY is a kinase inhibitor indicated in combination with fulvestrant for the
`treatment of postmenopausal women, and men, with hormone receptor (HR)-
`positive, human epidermal growth factor receptor 2 (HER2)-negative,
`PIK3CA-mutated, advanced or metastatic breast cancer as detected by an
`FDA-approved test following progression on or after an endocrine-based
`regimen. (1)
`----------------------DOSAGE AND ADMINISTRATION------------------------
` Recommended Dose: 300 mg (two 150 mg tablets) taken orally once daily
`with food. (2.2)
` For adverse reactions, consider dose interruption, dose reduction, or
`discontinuation. (2.3)
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`Tablets: 50 mg, 150 mg, and 200 mg (3)
`-------------------------------CONTRAINDICATIONS-----------------------------
`Severe hypersensitivity to PIQRAY or to any of its components. (4)
`-----------------------WARNINGS AND PRECAUTIONS-----------------------
` Severe Hypersensitivity: Permanently discontinue PIQRAY. Promptly
`initiate appropriate treatment. (5.1)
` Severe Cutaneous Adverse Reactions (SCARs): PIQRAY can cause
`SCARs, including Stevens-Johnson syndrome (SJS), erythema multiforme
`(EM), toxic epidermal necrolysis (TEN), and drug reaction with
`eosinophilia and systemic symptoms (DRESS). Interrupt PIQRAY for
`signs or symptoms of SCARs. Permanently discontinue PIQRAY if SCARs
`are confirmed. (5.2)
` Hyperglycemia: PIQRAY can cause severe hyperglycemia, including
`ketoacidosis. The safety of PIQRAY in patients with Type 1 or
`uncontrolled Type 2 diabetes has not been established. Before initiating
`treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and
`optimize blood glucose. After initiating treatment, monitor periodically.
`Initiate or optimize anti-hyperglycemic medications as clinically indicated.
`Interrupt, reduce dose, or discontinue PIQRAY if severe hyperglycemia
`occurs. (2.3, 5.3)
`
` Pneumonitis: PIQRAY can cause severe pneumonitis and interstitial lung
`disease. Monitor for clinical symptoms or radiological changes. Interrupt or
`discontinue PIQRAY if severe pneumonitis occurs. (2.3, 5.4)
` Diarrhea: PIQRAY can cause severe cases of diarrhea, including
`dehydration and acute kidney injury. Most patients experience diarrhea
`(Grade ≤ 2) during treatment with PIQRAY. Advise patients to start
`antidiarrheal treatment, increase oral fluids, and notify their healthcare
`provider if diarrhea occurs. Interrupt, reduce dose, or discontinue PIQRAY
`if severe diarrhea occurs. (2.3, 5.5)
` Embryo-Fetal Toxicity: PIQRAY can cause fetal harm. Advise patients of
`potential risk to a fetus and to use effective contraception. (5.6, 8.1, 8.3)
`Refer to the Full Prescribing Information of fulvestrant for pregnancy and
`contraception information.
`------------------------------ADVERSE REACTIONS------------------------------
`Most common adverse reactions, including laboratory abnormalities (all
`grades, incidence ≥ 20%) were glucose increased, creatinine increased,
`diarrhea, rash, lymphocyte count decreased, gamma glutamyl transferase
`(GGT) increased, nausea, alanine aminotransferase (ALT) increased, fatigue,
`hemoglobin decreased, lipase increased, decreased appetite, stomatitis,
`vomiting, weight decreased, calcium decreased, glucose decreased, activated
`partial thromboplastin time (aPTT) prolonged, and alopecia. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-
`1088 or www.fda.gov/medwatch.
`------------------------------DRUG INTERACTIONS------------------------------
` CYP3A4 Inducers: Avoid coadministration of PIQRAY with a strong
`CYP3A4 inducer. (7.1)
` Breast Cancer Resistance Protein (BCRP) Inhibitors: Avoid the use of
`BCRP inhibitors in patients treated with PIQRAY. If unable to use
`alternative drugs, closely monitor for increased adverse reactions. (7.1)
` CYP2C9 Substrates: Closely monitor when PIQRAY is coadministered
`with CYP2C9 substrates where decreases in the plasma concentration of
`these drugs may reduce activity. (7.2)
`----------------------------USE IN SPECIFIC POPULATIONS------------------
`Lactation: Advise not to breastfeed. (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 9/2020
`
`3
`4
`5
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Patient Selection
`2.2
`Dosage and Administration
`2.3
`Dose Modifications for Adverse Reactions
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Severe Hypersensitivity
`5.2
`Severe Cutaneous Adverse Reactions
`5.3
`Hyperglycemia
`5.4
`Pneumonitis
`5.5
`Diarrhea
`5.6
`Embryo-Fetal Toxicity
`ADVERSE REACTIONS
`6.1
`Clinical Trial Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`7.1
`Effect of Other Drugs on PIQRAY
`7.2
`Effect of PIQRAY on Other Drugs
`USE IN SPECIFIC POPULATIONS
`
`6
`
`7
`
`8
`
`10
`11
`12
`
`Pregnancy
`8.1
`Lactation
`8.2
`Females and Males of Reproductive Potential
`8.3
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`Renal Impairment
`8.6
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1
`Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`14
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`PATIENT COUNSELING INFORMATION
`17
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`13
`
`

`

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`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`PIQRAY is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men,
`with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-
`mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or
`after an endocrine-based regimen.
`
`DOSAGE AND ADMINISTRATION
`2
`Patient Selection
`2.1
`Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with
`PIQRAY, based on the presence of one or more PIK3CA mutations in tumor tissue or plasma specimens [see
`Clinical Studies (14)]. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-
`approved tests for the detection of PIK3CA mutations in breast cancer is available at:
`http://www.fda.gov/CompanionDiagnostics.
`2.2
`Dosage and Administration
`The recommended dose of PIQRAY is 300 mg (two 150 mg film-coated tablets) taken orally, once daily, with
`food [see Clinical Pharmacology (12.3)].
`Continue treatment until disease progression or unacceptable toxicity occurs [see Dosage and Administration
`(2.3)].
`Patients should take their dose of PIQRAY at approximately the same time each day.
`Swallow PIQRAY tablets whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet
`should be ingested if it is broken, cracked, or otherwise not intact.
`If a dose of PIQRAY is missed, it can be taken with food within 9 hours after the time it is usually taken. After
`more than 9 hours, skip the dose for that day. The next day, take PIQRAY at the usual time.
`If the patient vomits after taking the dose, advise the patient not to take an additional dose on that day, and to
`resume the dosing schedule the next day at the usual time.
`When given with PIQRAY, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and
`29, and once monthly thereafter. Refer to the Full Prescribing Information for fulvestrant.
`2.3
`Dose Modifications for Adverse Reactions
`The recommended dose modifications for adverse reactions (ARs) are listed in Table 1.
`Table 1: PIQRAY Dose Reduction Guidelines for Adverse Reactions1
`PIQRAY Dose Level
`Dose and Schedule
`Number and Strength of Tablets
`Starting dose
`300 mg once daily
`Two 150 mg tablets
`First-dose reduction
`250 mg once daily
`One 200 mg tablet and one 50 mg tablet
`Second-dose reduction
`200 mg once daily2
`One 200 mg tablet
`1Only one dose reduction is permitted for pancreatitis.
`2If further dose reduction below 200 mg once daily is required, discontinue PIQRAY.
`Tables 2, 3, 4, and 5 summarize recommendations for dose interruption, reduction, or discontinuation of
`PIQRAY in the management of specific ARs.
`
`

`

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`
`Cutaneous Adverse Reactions
`If a severe cutaneous adverse reaction (SCAR) is confirmed, permanently discontinue PIQRAY. Do not
`reintroduce PIQRAY in patients who have experienced previous SCAR during PIQRAY treatment [see
`Warnings and Precautions (5.2)].
`Table 2: Dose Modification and Management for Rash and Severe Cutaneous Adverse Reactions (SCARs)
`[see Warnings and Precautions (5.1, 5.2)]
`Grade1,2
`Recommendation3
`Grade 1
`No PIQRAY dose adjustment required.
`(< 10% body surface area
`Initiate topical corticosteroid treatment.
`(BSA) with active skin
`Consider adding oral antihistamine to manage symptoms.
`toxicity)
`If the etiology is SCAR, permanently discontinue PIQRAY.
`
`Grade 2
`(10%-30% BSA with active
`skin toxicity)
`
`Grade 3 (e.g., severe rash not
`responsive to medical
`management)
`(> 30% BSA with active skin
`toxicity)
`
`No PIQRAY dose adjustment required.
`Initiate or intensify topical corticosteroid and oral antihistamine treatment.
`Consider low dose systemic corticosteroid treatment.
`If the etiology is SCAR, permanently discontinue PIQRAY.
`Interrupt PIQRAY.
`Initiate or intensify topical/systemic corticosteroid and oral antihistamine treatment.
`If the etiology is SCAR, permanently discontinue PIQRAY.
`If the etiology is not a SCAR, interrupt dose until recovery to Grade ≤ 1, then resume PIQRAY
`at same dose level for first occurrence of rash, or at next lower dose level in case of second
`occurrence.
`Permanently discontinue PIQRAY.
`
`Grade 4 (e.g., severe bullous,
`blistering or exfoliating skin
`conditions)
`(any % BSA associated with
`extensive superinfection, with
`IV antibiotics indicated; life-
`threatening consequences)
`1Grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
`2For all grades of rash, consider consultation with a dermatologist.
`3Antihistamines administered prior to rash onset may decrease incidence and severity of rash based on the SOLAR-1 trial.
`Hyperglycemia
`Table 3: Dose Modification and Management for Hyperglycemia
`[see Warnings and Precautions (5.3)]
`Fasting Plasma Glucose
`Recommendation
`(FPG)/Fasting Blood
`Glucose Values1
`
`Dose modifications and management should only be based on fasting glucose values (FPG or fasting blood glucose).
`Grade 1
`No PIQRAY dose adjustment required.
`Fasting glucose > ULN -160
`Initiate or intensify anti-diabetic treatment2.
`mg/dL or > ULN -8.9 mmol/L
`
`

`

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`
`Grade 2
`Fasting glucose > 160-250
`mg/dL or > 8.9-13.9 mmol/L
`
`Grade 3
`> 250-500 mg/dL
`or > 13.9-27.8 mmol/L
`
`No PIQRAY dose adjustment required.
`Initiate or further intensify anti-diabetic treatment2.
`If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 21 days under
`appropriate anti-diabetic treatment, reduce PIQRAY dose by 1 dose level and follow fasting
`glucose value specific recommendations.
`Interrupt PIQRAY.
`Initiate or intensify oral anti-diabetic treatment2 and consider additional anti-diabetic medications3
`for 1-2 days until hyperglycemia improves.
`Administer intravenous hydration and consider appropriate treatment (e.g., intervention for
`electrolyte/ketoacidosis/hyperosmolar disturbances).
`If fasting glucose decreases to ≤ 160 mg/dL or 8.9 mmol/L within 3 to 5 days under appropriate
`anti-diabetic treatment, resume PIQRAY at 1 lower dose level.
`If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 3 to 5 days under
`appropriate anti-diabetic treatment, consultation with a physician with expertise in the treatment
`of hyperglycemia is recommended.
`If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 21 days following
`appropriate anti-diabetic treatment2, permanently discontinue PIQRAY treatment.
`Interrupt PIQRAY.
`Initiate or intensify appropriate anti-diabetic treatment2 (administer intravenous hydration and
`consider appropriate treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar
`disturbances)), re-check fasting glucose within 24 hours and as clinically indicated.
`If fasting glucose decreases to ≤ 500 mg/dL or 27.8 mmol/L, follow fasting glucose value specific
`recommendations for Grade 3.
`If fasting glucose is confirmed at > 500 mg/dL or 27.8 mmol/L, permanently discontinue
`PIQRAY treatment.
`Abbreviation: ULN, upper limit of normal.
`1FPG/Fasting Blood Glucose/Grade levels reflect hyperglycemia grading according to Common Terminology Criteria for Adverse Events
`(CTCAE) Version 4.03.
`2Initiate applicable anti-diabetic medications, including metformin and insulin sensitizers (such as thiazolidinediones or dipeptidyl peptidase-4
`inhibitors), and review respective prescribing information for dosing and dose titration recommendations, including local diabetic treatment
`guidelines. Metformin was recommended in the SOLAR-1 trial with the following guidance: Initiate metformin 500 mg once daily. Based on
`tolerability, metformin dose may be increased to 500 mg twice daily, followed by 500 mg with breakfast, and 1000 mg with dinner, followed by
`further increase to 1000 mg twice daily if needed [see Warnings and Precautions (5.3)].
`3As recommended in the SOLAR-1 trial, insulin may be used for 1-2 days until hyperglycemia resolves. However, this may not be necessary in
`the majority of PIQRAY-induced hyperglycemia, given the short half-life of PIQRAY and the expectation of glucose levels normalizing after
`interruption of PIQRAY.
`
`Grade 4
`> 500 mg/dL
`or ≥ 27.8 mmol/L
`
`

`

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`
`Diarrhea
`
`Table 4: Dose Modification and Management for Diarrhea
`[see Warnings and Precautions (5.5)]
`Grade1
`Recommendation
`No PIQRAY dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically
`indicated.
`
`Grade 1
`
`Grade 2
`
`Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Interrupt PIQRAY dose
`until recovery to Grade ≤ 1, then resume PIQRAY at same dose level.
`
`Grade 3 and 4
`
`Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Interrupt PIQRAY dose
`until recovery to Grade ≤ 1, then resume PIQRAY at the next lower dose level.
`
`1Grading according to CTCAE Version 5.0.
`
`Other Toxicities
`Table 5: Dose Modification and Management for Other Toxicities (Excluding Hyperglycemia, Rash, and
`Diarrhea)
`Grade1
`Grade 1 or 2
`
`Recommendation
`No PIQRAY dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically
`indicated2,3.
`Interrupt PIQRAY dose until recovery to Grade ≤ 1, then resume PIQRAY at the next lower dose level.
`Grade 3
`Permanently discontinue PIQRAY.
`Grade 4
`1Grading according to CTCAE Version 5.0.
`2For Grade 2 and 3 pancreatitis, interrupt PIQRAY dose until recovery to Grade < 2 and resume at next lower-dose level. Only one dose
`reduction is permitted. If toxicity reoccurs, permanently discontinue PIQRAY treatment.
`3For Grade 2 total bilirubin elevation, interrupt PIQRAY dose until recovery to Grade ≤ 1 and resume at the same dose if resolved in ≤ 14 days
`or resume at the next lower dose level if resolved in > 14 days.
`
`Refer to the Full Prescribing Information of fulvestrant for dose modification guidelines in the event of toxicity
`and for other relevant safety information.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Tablets: 50 mg, 150 mg, and 200 mg alpelisib
`50 mg: Light pink, unscored, round and curved with beveled edges film-coated tablet, imprinted with “L7” on
`one side and “NVR” on the other side.
`150 mg: Pale red, unscored, ovaloid and curved with beveled edges film-coated tablet, imprinted with “UL7” on
`one side and “NVR” on the other side.
`200 mg: Light red, unscored, ovaloid and curved with beveled edges film-coated tablet, imprinted with “YL7”
`on one side and “NVR” on the other side.
`
`CONTRAINDICATIONS
`4
`PIQRAY is contraindicated in patients with severe hypersensitivity to it or any of its components [see Warnings
`and Precautions (5.1)].
`
`

`

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`
`WARNINGS AND PRECAUTIONS
`5
`Severe Hypersensitivity
`5.1
`Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, can occur in patients treated
`with PIQRAY. Severe hypersensitivity reactions were manifested by symptoms including, but not limited to,
`dyspnea, flushing, rash, fever, or tachycardia.
`The incidence of Grade 3 and 4 hypersensitivity reactions was 0.7% [see Adverse Reactions (6)].
`Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue
`PIQRAY in the event of severe hypersensitivity.
`5.2
`Severe Cutaneous Adverse Reactions
`Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome (SJS), erythema multiforme
`(EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)
`can occur in patients treated with PIQRAY.
`In the SOLAR-1 study, SJS and EM were reported in 0.4% and 1.1% of the patients, respectively [see Adverse
`Reactions (6.1)]. Drug reaction with eosinophilia and systemic symptoms (DRESS) was reported in patients
`treated with PIQRAY in the postmarketing setting [see Adverse Reactions (6.2)].
`If signs or symptoms of SCARs occur, interrupt PIQRAY until the etiology of the reaction has been determined.
`Consultation with a dermatologist is recommended.
`If a SCAR is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have
`experienced previous severe cutaneous adverse reactions during PIQRAY treatment.
`If a SCAR is not confirmed, PIQRAY may require dose modifications, topical corticosteroids, or oral
`antihistamine treatment as described in Table 2 [see Dosage and Administration (2.3)].
`Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal
`lesions, progressive skin rash, or lymphadenopathy).
`5.3
`Hyperglycemia
`Severe hyperglycemia, including ketoacidosis, can occur in patients treated with PIQRAY. Hyperglycemia was
`reported in 65% of patients treated with PIQRAY. Grade 3 (FPG > 250 to 500 mg/dL) and Grade 4 (FPG > 500
`mg/dL) hyperglycemia was reported in 33% and 3.9% of patients, respectively. Ketoacidosis was reported in
`0.7% of patients (n = 2) treated with PIQRAY.
`Among the patients who experienced Grade ≥ 2 (FPG 160 to 250 mg/dL) hyperglycemia, the median time to
`first occurrence of hyperglycemia was 15 days (range, 5 to 517 days).
`In the 187 patients with hyperglycemia, 87% (163/187) were managed with anti-diabetic medication, and 76%
`(142/187) reported use of metformin as single agent or in combination with other anti-diabetic medication
`[i.e., insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas]. In patients with Grade ≥ 2
`hyperglycemia with at least 1 grade improvement (n = 153), median time to improvement from the first event
`was 8 days (range, 2 to 65 days).
`In all patients with elevated FPG who continued fulvestrant treatment after discontinuing PIQRAY (n = 54),
`96% (n = 52) of patients had FPG levels that returned to baseline.
`Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood
`glucose. After initiating treatment with PIQRAY, monitor fasting glucose (FPG or fasting blood glucose) at
`least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated.
`Monitor HbA1c every 3 months and as clinically indicated.
`
`

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`If a patient experiences hyperglycemia after initiating treatment with PIQRAY, monitor fasting glucose as
`clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment
`with anti-diabetic medication, continue monitoring fasting glucose at least once a week for 8 weeks, followed
`by once every 2 weeks and as clinically indicated. Consider consultation with a healthcare practitioner with
`expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.
`The safety of PIQRAY in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as
`these patients were excluded from the SOLAR-1 trial. Patients with a medical history of Type 2 diabetes were
`included. Patients with a history of diabetes mellitus may require intensified diabetic treatment. Closely monitor
`patients with diabetes.
`Based on the severity of the hyperglycemia, PIQRAY may require dose interruption, reduction, or
`discontinuation as described in Table 3 [see Dosage and Administration (2.3)].
`Advise patients of the signs and symptoms of hyperglycemia (e.g., excessive thirst, urinating more often than
`usual or higher amount of urine than usual, or increased appetite with weight loss).
`5.4
`Pneumonitis
`Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, can occur in patients
`treated with PIQRAY.
`Pneumonitis was reported in 1.8% of patients treated with PIQRAY.
`In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis,
`interrupt PIQRAY immediately and evaluate the patient for pneumonitis. Consider a diagnosis of non-infectious
`pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, cough,
`dyspnea, or interstitial infiltrates on radiologic exams and in whom infectious, neoplastic, and other causes have
`been excluded by means of appropriate investigations.
`Permanently discontinue PIQRAY in all patients with confirmed pneumonitis.
`Advise patients to immediately report new or worsening respiratory symptoms.
`5.5
`Diarrhea
`Severe diarrhea, including dehydration and acute kidney injury, can occur in patients treated with PIQRAY.
`Most patients (58%) experienced diarrhea during treatment with PIQRAY. Grade 3 diarrhea occurred in 7%
`(n = 19) of patients. Among patients with Grade 2 or 3 diarrhea (n = 71), the median time to onset was 46 days
`(range, 1 to 442 days).
`Dose reductions of PIQRAY were required in 6% of patients and 2.8% of patients permanently discontinued
`PIQRAY due to diarrhea. In the 164 patients that experienced diarrhea, anti-diarrheal medications
`(e.g., loperamide) were required to manage symptoms in 63% (104/164) of these patients.
`Based on the severity of the diarrhea, PIQRAY may require dose interruption, reduction, or discontinuation as
`described in Table 4 [see Dosage and Administration (2.3)].
`Advise patients to start anti-diarrheal treatment, increase oral fluids, and notify their healthcare provider if
`diarrhea occurs while taking PIQRAY.
`5.6
`Embryo-Fetal Toxicity
`Based on findings in animals and its mechanism of action, PIQRAY can cause fetal harm when administered to
`a pregnant woman. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits
`during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-
`implantation loss), reduced fetal weights, and increased incidences of fetal malformations at maternal exposures
`based on area under the curve (AUC) that were ≥ 0.8 times the exposure in humans at the recommended dose of
`300 mg/day. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
`Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for
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`1 week after the last dose. Advise male patients with female partners of reproductive potential to use condoms
`and effective contraception during treatment with PIQRAY and for 1 week after the last dose [see Use in
`Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
`Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.
`
`ADVERSE REACTIONS
`6
`The following adverse reactions are discussed in greater detail in other sections of the labeling:
` Severe Hypersensitivity [see Warnings and Precautions (5.1)]
` Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
` Hyperglycemia [see Warnings and Precautions (5.3)]
` Pneumonitis [see Warnings and Precautions (5.4)]
` Diarrhea [see Warnings and Precautions (5.5)]
`6.1
`Clinical Trial 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 PIQRAY was evaluated in a randomized, double-blind, placebo-controlled trial (SOLAR-1) in
`571 patients with HR-positive, HER2-negative, advanced or metastatic breast cancer enrolled into two cohorts,
`with or without a PIK3CA mutation [see Clinical Studies (14)].
`Patients received either PIQRAY 300 mg plus fulvestrant (n = 284) or placebo plus fulvestrant (n = 287).
`Fulvestrant 500 mg was administered intramuscularly on Cycle 1, Day 1 and 15, and then at Day 1 of each
`28-day cycle during treatment phase.
`Two patients (0.7%) died while on treatment with PIQRAY plus fulvestrant due to causes other than the
`underlying malignancy. Causes of death included one cardio-respiratory arrest and one second primary
`malignancy. Neither was suspected to be related to study treatment.
`Serious adverse reactions occurred in 35% of patients receiving PIQRAY plus fulvestrant. Serious adverse
`reactions in > 2% of patients receiving PIQRAY plus fulvestrant included hyperglycemia (10%), rash (3.5%),
`diarrhea (2.8%), acute kidney injury (2.5%), abdominal pain (2.1%), and anemia (2.1%).
`Osteonecrosis of the jaw (ONJ) was reported in 4.2% of patients (12/284) in the PIQRAY plus fulvestrant arm
`compared to 1.4% of patients (4/287) in the placebo arm. All patients experiencing ONJ had prior or
`concomitant bisphosphonates or RANK-ligand inhibitor administration.
`Among patients receiving PIQRAY plus fulvestrant, 4.6% permanently discontinued both PIQRAY and
`fulvestrant and 21% permanently discontinued PIQRAY alone, due to ARs. The most frequent ARs leading to
`treatment discontinuation of PIQRAY in > 2% patients receiving PIQRAY plus fulvestrant were hyperglycemia
`(6%), rash (4.2%), diarrhea (2.8%), and fatigue (2.5%).
`Dose reductions due to ARs occurred in 55% of patients