HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`These highlights do not include all the information needed to use
`
`
`
`
`
`
`
`
`VICTRELIS safely and effectively. See full prescribing information
`
`
`
`
`
`
`for VICTRELIS.
`
`
`VICTRELIS® (boceprevir) capsules, for oral use
`
`
`
`
`
`
`
`Initial U.S. Approval: 2011
`
`
`
`
`-------------------------- RECENT MAJOR CHANGES -------------------------
`
`
`
`
`
`Contraindications (4)
`01/2017
`
`
`
`
`
`---------------------------INDICATIONS AND USAGE----------------------------­
`
`
`
`
`
`
`
`
`VICTRELIS is a hepatitis C virus (HCV) NS3/4A protease inhibitor
`indicated for the treatment of chronic hepatitis C (CHC) genotype 1
`
`
`
`infection, in combination with peginterferon alfa and ribavirin, in adult
`
`
`
`patients with compensated liver disease, including cirrhosis, who are
`
`
`
`
`
`previously untreated or who have failed previous interferon and
`
`
`
`
`
`
`ribavirin therapy, including prior null responders, partial responders,
`
`and relapsers. (1)
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`VICTRELIS must not be used as a monotherapy and should only
`
`
`
`be used in combination with peginterferon alfa and ribavirin. (1)
`
`The efficacy of VICTRELIS has not been studied in patients who
`
`
`have previously failed therapy with a treatment regimen that
`
`
`includes VICTRELIS or other HCV NS3/4A protease inhibitors. (1)
`
`
`
`
`
`----------------------- DOSAGE AND ADMINISTRATION ----------------------­
`
`
`800 mg administered orally three times daily (every 7 to 9 hours)
`•
`
`
`
`
`
`
`with food (a meal or light snack). (2)
`
`
`in combination with
`VICTRELIS must be administered
`
`
`
`
`peginterferon alfa and ribavirin. Initiate therapy with peginterferon
`
`
`for 4 weeks,
`then add VICTRELIS
`to
`alfa and ribavirin
`
`
`
`peginterferon alfa and ribavirin regimen. The duration of treatment
`
`
`
`
`
`is based on viral response, prior response status and presence of
`
`
`cirrhosis. (2)
`
`
`
`Refer to the prescribing information for peginterferon alfa and
`
`
`ribavirin for specific dosing instructions. (2)
`
`
`
`
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS-------------------­
`
`
`Capsules: 200 mg (3)
`
`
`
`-----------------------------CONTRAINDICATIONS--------------------------------­
`
`All contraindications to peginterferon alfa and ribavirin also
`
`•
`
`
`
`apply since VICTRELIS must be administered with
`
`peginterferon alfa and ribavirin. (4)
`
`
`
`
`
`Because ribavirin may cause birth defects and fetal death,
`
`
`boceprevir in combination with peginterferon alfa and ribavirin is
`
`
`contraindicated in pregnant women and in men whose female
`
`
`partners are pregnant. (4)
`
`
`Contraindicated in patients with a history of a hypersensitivity
`
`
`reaction to boceprevir. (4)
`
`
`that are highly dependent on
`Coadministration with drugs
`
`
`
`
`for which elevated plasma
`for clearance, and
`CYP3A4/5
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4048649
`
`
`concentrations are associated with serious and/or life-threatening
`
`
`events is contraindicated. (4)
`
`
`
`inducers where
`Coadministration with potent CYP3A4/5
`
`
`
`significantly reduced boceprevir plasma concentrations may be
`
`
`associated with reduced efficacy is contraindicated. (4)
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`Use of VICTRELIS with Ribavirin and Peginterferon alfa:
`Embryofetal Toxicity (Use with Ribavirin and Peginterferon
`
`
`
`
`
`•
`Alfa): Ribavirin may cause birth defects and fetal death;
`
`
`avoid pregnancy in female patients and female partners of
`
`male patients. Patients must have a negative pregnancy test
`
`
`
`
`
`prior to therapy; use two or more forms of contraception, and
`
`
`
`
`
`
`
`have monthly pregnancy tests. (5.1)
`
`
`Anemia - The addition of VICTRELIS to peginterferon alfa and
`
`
`ribavirin is associated with an additional decrease in hemoglobin
`
`
`concentrations compared with peginterferon alfa and ribavirin
`
`
`alone. (5.2)
`
`Neutropenia - The addition of VICTRELIS to peginterferon alfa
`
`and ribavirin may result in worsening of neutropenia associated
`
`
`with peginterferon alfa and ribavirin therapy alone. (5.3)
`
`Hypersensitivity – Serious acute hypersensitivity reactions (e.g.,
`
`
`
`
`urticaria, angioedema) have been observed during combination
`
`therapy with VICTRELIS, peginterferon alfa and ribavirin. (5.5)
`
`
`
`
`
`
`-------------------------------ADVERSE REACTIONS-----------------------------­
`
`
`
`The most commonly reported adverse reactions (greater than 35% of
`
`
`
`subjects) in clinical trials in adult subjects receiving the combination of
`
`
`
`
`
`
`VICTRELIS with PegIntron and REBETOL were fatigue, anemia,
`
`nausea, headache and dysgeusia. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­
`
`
`
`
`
`
`
`
`
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`-------------------------------DRUG INTERACTIONS-----------------------------­
`
`VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly
`
`
`
`
`
`•
`metabolized by CYP3A4/5. The potential
`for drug-drug
`
`
`
`
`interactions must be considered prior to and during therapy. (4, 7,
`
`
`
`
`
`
`12.3)
`
`
`
`--------------------------USE IN SPECIFIC POPULATIONS--------------------­
`
`Safety and efficacy have not been studied in the following
`
`
`
`
`
`
`
`•
`populations:
`
`o
`Patients with decompensated cirrhosis (8.7); and
`
`
`
`
`o Organ transplant recipients (8.8)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`
`
`Guide.
`
`
`Revised: 01/2017
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2026, Page 1
`
`

`

`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 VICTRELIS/Peginterferon alfa/Ribavirin Combination
`
`
`
`Therapy: Patients Without Cirrhosis Who Are Previously
`
`
`
`Untreated or Who Previously Failed Interferon and Ribavirin
`
`
`
`
`Therapy
`
`2.2 VICTRELIS/Peginterferon alfa/Ribavirin Combination
`
`
`
`
`
`Therapy: Patients with Cirrhosis
`
`
`
`2.3 Dose Modification
`
`
`2.4 Discontinuation of Dosing Based on Treatment Futility
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Embryofetal Toxicity (Use with Ribavirin and Peginterferon
`
`
`
`
`Alfa)
`
`5.2 Anemia (Use with Ribavirin and Peginterferon Alfa)
`
`
`
`5.3 Neutropenia (Use with Ribavirin and Peginterferon Alfa)
`
`
`
`5.4 Pancytopenia (Use with Ribavirin and Peginterferon Alfa)
`
`
`
`5.5 Hypersensitivity
`
`
`5.6 Drug Interactions
`
`
`5.7
`Laboratory Tests
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Potential for VICTRELIS to Affect Other Drugs
`
`
`
`
`
`
`
`7.2 Potential for Other Drugs to Affect VICTRELIS
`
`
`
`
`7.3 Established and Other Potential Significant Drug Interactions
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`8.8 Organ Transplantation
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`12.4 Microbiology
`
`
`12.5 Pharmacogenomics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16.1 How Supplied
`
`
`16.2 Storage and Handling
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` INDICATIONS AND USAGE
` 1
`VICTRELIS® (boceprevir) is indicated for the treatment of chronic hepatitis C genotype 1 infection, in
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease,
`
`
`
`
`including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin
`
`
`
`
`therapy, including prior null responders, partial responders, and relapsers [see Clinical Studies (14)].
`
`
`
`The following points should be considered when initiating VICTRELIS for treatment of chronic hepatitis
`
`C infection:
`
`
`
`
`
`
`
`
`• VICTRELIS must not be used as monotherapy and should only be used in combination with
`
`peginterferon alfa and ribavirin.
`
`
`
`
`
`
`
`
`
`• The efficacy of VICTRELIS has not been studied in patients who have previously failed therapy with a
`
`
`
`treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
`
`
`
`
`
`• Poorly interferon responsive patients who were treated with VICTRELIS in combination with
`peginterferon alfa and ribavirin have a lower likelihood of achieving a sustained virologic response
`
`(SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure,
`
`
`compared to patients with a greater response to peginterferon alfa and ribavirin [see Microbiology
`
`
`
`(12.4) and Clinical Studies (14)].
`
`
`
`2
`
`
`DOSAGE AND ADMINISTRATION
`
`VICTRELIS must be administered in combination with peginterferon alfa and ribavirin. The dose of
`
`
`
`
`
`
`
`
`
`
`
`
`VICTRELIS is 800 mg (four 200-mg capsules) three times daily (every 7 to 9 hours) with food [a meal or
`
`
`
`
`light snack] (see Table 1). Refer to the prescribing information for peginterferon alfa and ribavirin for
`
`instructions on dosing.
`
`The following dosing recommendations differ for some subgroups from the dosing studied in the
`
`
`
`
`Phase 3 trials [see Clinical Studies (14)]. Response-Guided Therapy (RGT) is recommended for most
`
`
`
`
`
`individuals, but longer dosing is recommended in targeted subgroups (e.g., patients with cirrhosis).
`
`
`
`
`Reference ID: 4048649
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2026, Page 2
`
`

`

`
`
`
`
` 2.1 VICTRELIS/Peginterferon alfa/Ribavirin Combination Therapy: Patients Without Cirrhosis
`
` Who Are Previously Untreated or Who Previously Failed Interferon and Ribavirin Therapy
`
`
`
`
`
`
`
`
` Initiate therapy with peginterferon alfa and ribavirin for 4 weeks (Treatment Weeks 1-4).
`
`
`
`
`•
`
`
`
`
`
` • Add VICTRELIS 800 mg (four 200-mg capsules) orally three times daily (every 7 to 9 hours) to
`
` peginterferon alfa and ribavirin regimen after 4 weeks of treatment. Based on the patient's HCV-RNA
`
` levels at Treatment Week (TW) 8, TW12 and TW24, use the following guidelines to determine
`
`
` duration of treatment (see Table 1).
`
`
`
`
`
`
`
`
`
`
` Table 1
`
`
` Duration of Therapy in Patients Without Cirrhosis Who Are Previously Untreated or Who Previously Failed Interferon and
`
`
` Ribavirin Therapy
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Previously
`
` Untreated
`Patients
`
`
`Previous
`
`Partial
`
`Responders
`or Relapsers‡
`
`
` ASSESSMENT*
`
`
` (HCV-RNA Results†)
` At Treatment
`
` At Treatment
`
`
` Week 24
`
` Week 8
`
`
`
`
`
` RECOMMENDATION
`
`
`
` Not Detected
`
`
`Not Detected
`
`
`
`
` Complete three-medicine regimen at TW28.
`
`Detected
`
`
`
`Not Detected
`
`1. Continue all three medicines and finish through TW36; and then
`
`
`
`2. Administer peginterferon alfa and ribavirin and finish through
`
`TW48.
`
`
`Not Detected
`
`
`
`Not Detected
`
`Complete three-medicine regimen at TW36.
`
`
`
`
`Detected
`
`
`Not Detected
`
`
`
`
`1. Continue all three medicines and finish through TW36; and then
`
`2. Administer peginterferon alfa and ribavirin and finish through
`
`TW48.
`
`Previous Null
`
`Responders‡
`
`
`
`
`Detected or
`
`Not Detected
`
`
`Not Detected
`
`
`
`
`
`
`Continue all three medicines and finish through TW48.
`
`
` *TREATMENT FUTILITY
`
`
`
`
`
`
`
`
` If the patient has HCV-RNA results greater than or equal to 1000 IU/mL at TW8, then discontinue three-medicine regimen.
`
`
`
`
` If the patient has HCV-RNA results greater than or equal to 100 IU/mL at TW12, then discontinue three-medicine regimen.
`
`
`
` If the patient has confirmed, detectable HCV-RNA at TW24, then discontinue three-medicine regimen.
`
`
`
`
`†“Not Detected” refers to HCV-RNA assay results reported as “Target Not Detected” or “HCV-RNA Not Detected”. In clinical
`
`
`
`
`
`trials, HCV-RNA in plasma was measured using a Roche COBAS® TaqMan® assay with a lower limit of quantification of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`25 IU/mL and a limit of detection of 9.3 IU/mL. See Warnings and Precautions (5.7) for a description of HCV-RNA assay
`
`recommendations.
` ‡ See Clinical Studies (14) for definitions of previous response to interferon and ribavirin therapy.
`
`
`
`
`
`
`
`
`
`
`
`Consideration should be given to treating previously untreated patients who are poorly interferon
`
`
`
`
`responsive (as determined at TW4) with 4 weeks peginterferon alfa and ribavirin followed by 44 weeks of
`
`
`VICTRELIS 800 mg orally three times daily (every 7 to 9 hours) in combination with peginterferon alfa and
`
`
`ribavirin in order to maximize rates of SVR.
`
`
`2.2 VICTRELIS/Peginterferon alfa/Ribavirin Combination Therapy: Patients with Cirrhosis
`
`
`
`
`Prior to initiating therapy in patients with compensated cirrhosis, see Use in Specific Populations (8.7)
`
`
`for additional information.
`
`
`Patients with compensated cirrhosis should receive 4 weeks peginterferon alfa and ribavirin followed
`
`
`
`
`
`
`by 44 weeks VICTRELIS 800 mg (four 200-mg capsules) three times daily (every 7 to 9 hours) in
`
`
`
`combination with peginterferon alfa and ribavirin.
`
`
`
`
`
`
`Reference ID: 4048649
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2026, Page 3
`
`

`

`
` 2.3 Dose Modification
`
`
` Dose reduction of VICTRELIS is not recommended.
`
`
`
`
`
`
`
`
`
` If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the
`
`
` peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to the prescribing
`
`
`
` information for peginterferon alfa and ribavirin for additional information about how to reduce and/or
`
`
`
` discontinue the peginterferon alfa and/or ribavirin dose. VICTRELIS must not be administered in the
`
`
` absence of peginterferon alfa and ribavirin. If peginterferon alfa or ribavirin is permanently discontinued,
`
`
`
`
`
`
` VICTRELIS must also be discontinued.
`
`
`
`
` 2.4 Discontinuation of Dosing Based on Treatment Futility
`
`
`
`
`
`
` Discontinuation of therapy is recommended in all patients with 1) HCV-RNA levels of greater than or
`
`
`
`
`
`
` equal to 1000 IU per mL at TW8; or 2) HCV-RNA levels of greater than or equal to 100 IU per mL at
`
`
`
`
`
` TW12; or 3) confirmed detectable HCV-RNA levels at TW24.
`
`
`
`
`
`
`
` 3
`
` DOSAGE FORMS AND STRENGTHS
`
`
`VICTRELIS 200 mg Capsules, red-colored cap with the Merck logo printed in yellow ink, and a yellow-
`
`
`colored body with “314” printed in red ink.
`
`
`CONTRAINDICATIONS
`4
`
`
`
`
`
`
`
`Contraindications to peginterferon alfa and ribavirin also apply to VICTRELIS combination treatment.
`
`
`
`Refer to the respective prescribing information for a list of the contraindications for peginterferon alfa and
`
`ribavirin.
`
`
`
`
`
`VICTRELIS in combination with peginterferon alfa and ribavirin is contraindicated in:
`
`
`
`
`
`
`• Pregnant women and men whose female partners are pregnant because of the risks for birth
`
`
`defects and fetal death associated with ribavirin [see Warnings and Precautions (5.1) and Use in
`
`
`
`
`Specific Populations (8.1)].
`
`
`
`
`• Patients with a history of a hypersensitivity reaction to boceprevir [see Warnings and Precautions
`
`
`(5.5)].
`
`Coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which
`
`
`
`
`
`
`elevated plasma concentrations are associated with serious and/or life-threatening events, including
`
`
`
`those in Table 2, is contraindicated [see Drug Interactions (7)].
`
`
`
`
`
`
`
`Coadministration with potent CYP3A4/5 inducers, where significantly reduced boceprevir plasma
`
`
`
`concentrations may be associated with reduced efficacy, including those in Table 2, is contraindicated
`
`[see Drug Interactions (7)].
`
`
`Drug Class
` Alpha 1-Adrenoreceptor antagonists
`
`
`
`
`
` Anticonvulsants
`
`
`
` Antimycobacterial Agents
`
`
`
` Antipsychotics
`
`
`
`
` Carbamazepine, phenobarbital,
`
` phenytoin
`
` Rifampin
`
`
`
` Lurasidone
`
`
` Pimozide
`
`
`
`
`
`
`
`
`
` Table 2
`
`
`
` Drugs that are contraindicated with VICTRELIS
`
`
`Drugs Within Class that are
` Contraindicated With VICTRELIS
`
`
`
` Alfuzosin, doxazosin, silodosin,
` tamsulosin
`
`
` Clinical Comments
`
`
`
` Potential for alpha 1-adrenoreceptor
` antagonist-associated adverse events,
`
`
`
` such as hypotension and
` priapism
`
` May lead to loss of virologic response to
`
` VICTRELIS
` May lead to loss of virologic response to
`
` VICTRELIS.
` Potential for serious and/or life-
`
` threatening reactions.
`
`
` Potential for cardiac arrhythmias.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4048649
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2026, Page 4
`
`

`

`
`
`
`
` Ergot Derivatives
`
`
` GI Motility Agent
`
` Herbal Products
`
`
` Dihydroergotamine, ergonovine,
`
` ergotamine, methylergonovine
`
`
`
`
`
`
`
`
`
` HMG-CoA Reductase Inhibitors
`
`
`
` Lovastatin, simvastatin
`
` Oral Contraceptives
`
`
` PDE5 enzyme Inhibitor
`
`
`
`
` Sedative/Hypnotics
`
`Drospirenone
`
`
` REVATIO® (sildenafil) or ADCIRCA®
`
`
` (tadalafil) when used for the treatment of
`
` pulmonary arterial hypertension*
`
`
`
`
`
`
` Potential for acute ergot toxicity
`
`
`
` characterized by peripheral vasospasm
`
`and ischemia of the extremities and
`
`
` other tissues.
` Potential for cardiac arrhythmias.
`
`
` Cisapride
`
`
` St. John’s wort (Hypericum perforatum) May lead to loss of virologic response to
`
` VICTRELIS.
` Potential for myopathy, including
`
` rhabdomyolysis.
`
`
` Potential for hyperkalemia.
`
`
` Potential for PDE5 inhibitor-associated
` adverse events, including visual
`
` abnormalities, hypotension, prolonged
`
`
`
` erection, and syncope.
` Prolonged or increased sedation or
`
` Triazolam; orally administered
`
` midazolam†
`
` respiratory depression.
`
`
`
` * See Drug Interactions, Table 5 for coadministration of sildenafil and tadalafil when dosed for erectile dysfunction.
`
`† See Drug Interactions, Table 5 for parenterally administered midazolam.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Embryofetal Toxicity (Use with Ribavirin and Peginterferon Alfa)
`
`
`
`
`Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to
`
`
`
`
`
`
`
`
`avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not
`
`
`
`
`
`
`
`be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of
`
`
`
`
`
`therapy. Refer to the prescribing information for ribavirin for additional information.
`
`
`
`Women of childbearing potential and men must use at least two forms of effective contraception during
`
`
`
`treatment and for at least 6 months after treatment has concluded. One of these forms of contraception
`
`
`
`
`
`
`
`
`
`
`
`
`
`can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral
`
`
`
`
`contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have
`
`
`
`
`
`
`
`
`not been studied or are contraindicated. Routine monthly pregnancy tests must be performed during this
`
`
`
`
`
`
`
`
`time [see Contraindications (4) and Drug Interactions (7)].
`
`
`
`
`5.2 Anemia (Use with Ribavirin and Peginterferon Alfa)
`
`
`
`Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of VICTRELIS to
`
`
`
`
`peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations.
`
`
`
`
`Complete blood counts (with white blood cell differential counts) should be obtained pretreatment, and at
`
`
`
`
`
`
`
`Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically
`
`
`
`appropriate. If hemoglobin is less than 10 g per dL, a decrease in dosage of ribavirin is recommended;
`
`
`
`
`
`
`
`
`and if hemoglobin is less than 8.5 g per dL, discontinuation of ribavirin is recommended [see Adverse
`
`
`Reactions (6.1) and Clinical Studies (14)]. If ribavirin is permanently discontinued for management of
`
`
`
`
`anemia, then peginterferon alfa and VICTRELIS must also be discontinued [see Dosage and
`
`
`Administration (2.3)].
`
`Refer to the prescribing information for ribavirin for additional information regarding dose reduction
`
`
`
`
`
`and/or discontinuation.
`
`
`In clinical trials with VICTRELIS, the proportion of subjects who experienced hemoglobin values less
`
`
`
`
`
`
`
`than 10 g per dL and less than 8.5 g per dL was higher in subjects treated with the combination of
`
`
`
`
`
`VICTRELIS with PegIntron®/REBETOL® than in those treated with PegIntron/REBETOL alone (see Table
`
`
`
`
`4). W ith the interventions used for anemia management in the clinical trials, the average additional
`
`
`
`decrease of hemoglobin was approximately 1 g per dL.
`
`
`
`In clinical trials, the median time to onset of hemoglobin less than 10 g per dL from the initiation of
`
`
`
`therapy was similar among subjects treated with the combination of VICTRELIS and PegIntron/REBETOL
`
`
`
`
`(71 days with a range of 15-337 days), compared to those who received PegIntron/REBETOL (71 days
`
`
`
`with a range of 8-337 days). Certain adverse reactions consistent with symptoms of anemia, such as
`
`
`
`dyspnea, exertional dyspnea, dizziness and syncope were reported more frequently in subjects who
`
`
`
`
`received the combination of VICTRELIS with PegIntron/REBETOL than
`in those treated with
`
`PegIntron/REBETOL alone [see Adverse Reactions (6.1)].
`
`
`
`
`Reference ID: 4048649
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2026, Page 5
`
`

`

`
`In clinical trials with VICTRELIS, dose modifications (generally of PegIntron/REBETOL) due to anemia
`
`
`
`
`occurred twice as often in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL
`
`
`
`
`
`
`(26%) compared to PegIntron/REBETOL (13%). The proportion of subjects who discontinued study drug
`
`
`
`
`
`
`due to anemia was 1% in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL
`
`
`
`
`and 1% in subjects who received PegIntron/REBETOL. The use of erythropoiesis stimulating agents
`
`
`
`(ESAs) was permitted for management of anemia, at the investigator’s discretion, with or without ribavirin
`
`
`
`
`
`
`
`dose reduction in the Phase 2 and 3 clinical trials. The proportion of subjects who received an ESA was
`
`
`
`
`
`
`
`
`
`43% in those treated with the combination of VICTRELIS with PegIntron/REBETOL compared to 24% in
`
`
`
`
`
`those treated with PegIntron/REBETOL alone. The proportion of subjects who received a transfusion for
`
`
`
`
`
`
`
`
`
`
`
`the management of anemia was 3% of subjects treated with the combination of VICTRELIS with
`
`
`PegIntron/REBETOL compared to less than 1% in subjects who received PegIntron/REBETOL alone.
`
`
`
`
`
`
`
`
`
`
`Thromboembolic events have been associated with ESA use in other disease states; and have also
`
`
`
`
`
`
`been reported with peginterferon alfa use in hepatitis C patients. Thromboembolic events were reported
`
`
`
`in clinical trials with VICTRELIS among subjects receiving the combination of VICTRELIS with
`
`
`
`PegIntron/REBETOL, and among those receiving PegIntron/REBETOL alone, regardless of ESA use. No
`
`
`definite causality assessment or benefit risk assessment could be made for these events due to the
`
`
`
`presence of confounding factors and lack of randomization of ESA use.
`
`
`
`
`
`
`
`A randomized, parallel-arm, open-label clinical trial was conducted in previously untreated CHC
`
`
`
`
`subjects with genotype 1 infection to compare use of an ESA versus ribavirin dose reduction for initial
`
`
`
`management of anemia during therapy with VICTRELIS in combination with peginterferon alfa-2b and
`
`ribavirin. Similar SVR rates were reported in subjects who were randomized to receive ribavirin dose
`
`
`
`
`
`
`
`
`
`reduction compared to subjects who were randomized to receive an ESA. In this trial, use of ESAs was
`
`
`
`
`
`
`
`associated with an increased risk of thromboembolic events including pulmonary embolism, acute
`
`
`
`
`myocardial infarction, cerebrovascular accident, and deep vein thrombosis compared to ribavirin dose
`
`
`
`
`
`reduction alone. The treatment discontinuation rate due to anemia was similar in subjects randomized to
`
`receive ribavirin dose reduction compared to subjects randomized to receive ESA (2% in each group).
`The transfusion rate was 4% in subjects randomized to receive ribavirin dose reduction and 2% in
`
`subjects randomized to receive ESA.
`
`
`Ribavirin dose reduction is recommended for the initial management of anemia.
`
`
`
`5.3 Neutropenia (Use with Ribavirin and Peginterferon Alfa)
`
`
`In Phase 2 and 3 clinical trials, seven percent of subjects receiving the combination of VICTRELIS with
`PegIntron/REBETOL had neutrophil counts of less than 0.5 x 109 per L compared to 4% of subjects
`
`
`
`
`receiving PegIntron/REBETOL alone (see Table 4). Three subjects experienced severe or life-threatening
`
`
`infections associated with neutropenia, and two subjects experienced life-threatening neutropenia while
`
`
`receiving the combination of VICTRELIS with PegIntron/REBETOL. Complete blood counts (with white
`
`blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and
`
`
`
`
`
`
`
`
`
`
`
`
`12, and should be monitored closely at other time points, as clinically appropriate. Decreases in
`
`
`
`
`
`
`
`
`
`neutrophil counts may require dose reduction or discontinuation of peginterferon alfa and ribavirin. If
`
`
`
`peginterferon alfa and ribavirin are permanently discontinued, then VICTRELIS must also be discontinued
`
`
`[see Dosage and Administration (2.3)].
`Refer to the prescribing information for peginterferon alfa and ribavirin for additional information
`
`
`regarding dose reduction or discontinuation.
`
`
`5.4 Pancytopenia (Use with Ribavirin and Peginterferon Alfa)
`
`
`
`
`Serious cases of pancytopenia have been reported postmarketing in patients receiving VICTRELIS in
`
`
`
`
`
`
`
`combination with peginterferon alfa and ribavirin. Complete blood counts (with white blood cell differential
`
`
`counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be
`
`
`
`
`
`
`monitored closely at other time points, as clinically appropriate.
`
`
`
`the prescribing
`for ribavirin and peginterferon alfa
`Refer
`information
`to
`
`
`
`
`
`
`discontinuation of therapy based on laboratory parameters.
`
`
`
`
`for guidelines
`
`
`
`for
`
`
`
`
`
`
`Reference ID: 4048649
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2026, Page 6
`
`

`

`
`
`
`5.5 Hypersensitivity
`
`Serious acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during
`
`
`
`
`
`
`
`combination therapy with VICTRELIS, peginterferon alfa and ribavirin. If such an acute reaction occurs,
`
`
`
`
`combination therapy should be discontinued and appropriate medical therapy immediately instituted [see
`
`
`Contraindications (4) and Adverse Reactions (6.2)].
`
`
`
`5.6 Drug Interactions
`
`
`
`
`
`
`
`See Table 2 for a listing of drugs that are contraindicated for use with VICTRELIS due to potentially
`
`
`
`
`
`life-threatening adverse events, significant drug
`interactions or
`loss of virologic activity
`
`[see
`
`Contraindications (4)]. Please refer to Table 5 for established and other potentially significant drug
`
`
`interactions [see Drug Interactions (7.3)].
`
`
`
`
`5.7 Laboratory Tests
`
`
`
`
`
`
`
`
`
`
`
`
`
`HCV-RNA levels should be monitored at Treatment Weeks 4, 8, 12, and 24, at the end of treatment,
`
`
`
`
`
`
`
`
`
`during treatment follow-up, and for other time points as clinically indicated. Use of a sensitive real-time
`
`
`
`
`reverse-transcription polymerase chain reaction (RT-PCR) assay for monitoring HCV-RNA levels during
`
`treatment is recommended. The assay should have a lower limit of HCV-RNA quantification of equal to or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`less than 25 IU per mL, and a limit of HCV-RNA detection of approximately 10 to 15 IU per mL. For the
`
`
`
`
`
`
`
`
`purposes of assessing Response-Guided Therapy milestones, a confirmed “detectable but below limit of
`
`quantification” HCV-RNA result should not be considered equivalent to an “undetectable” HCV-RNA
`
`
`
`result (reported as “Target Not Detected” or “HCV-RNA Not Detected”).
`
`
`
`Complete blood count (with white blood cell differential counts) should be obtained at pretreatment,
`
`
`
`
`
`
`
`and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as
`
`clinically appropriate.
`
`
`
`
`
`
`
`Refer to the prescribing information for peginterferon alfa and ribavirin for pre-treatment, on-treatment
`
`
`and post-treatment laboratory testing recommendations including hematology, biochemistry (including
`
`hepatic function tests), and pregnancy testing requirements.
`
`
`6
`
`
`ADVERSE REACTIONS
`
`
`
`
`
`See the peginterferon alfa and ribavirin prescribing information for description of adverse reactions
`
`associated with their use.
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
`
`
`
`
`
`
`
`
`
`in clinical trials of VICTRELIS cannot be directly compared to rates in the clinical trials of another drug
`
`and may not reflect the rates observed in practice.
`
`
`
`
`
`The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail
`
`
`in another section of the labeling:
`
`
`• Anemia [see Warnings and Precautions (5.2)]
`
`
`• Neutropenia [see Warnings and Precautions (5.3)]
`
`
`• Pancytopenia [see Warnings and Precautions (5.4)]
`
`
`
`
`• Hypersensitivity [see Contraindications (4) and Warnings and Precautions (5.5)]
`
`
`
`
`The most commonly reported adverse reactions (more than 35% of subjects regardless of
`
`investigator's causality assessment) in adult subjects were fatigue, anemia, nausea, headache, and
`
`
`
`dysgeusia when VICTRELIS was used in combination with PegIntron and REBETOL.
`
`
`
`
`
`
`
`
`The safety of the combination of VICTRELIS 800 mg three times daily with PegIntron/REBETOL was
`
`
`
`assessed in 2095 subjects with chronic hepatitis C in one Phase 2, open-label trial and two Phase 3,
`
`
`randomized, double-blind, placebo-controlled clinical trials. SPRINT-1 (subjects who were previously
`
`untreated) evaluated the use of VICTRELIS in combination with PegIntron/REBETOL with or without a
`four-week lead-in period with PegIntron/REBETOL compared to PegIntron/REBETOL alone. SPRINT-2
`
`
`(subjects who were previously untreated) and RESPOND-2 (subjects who had failed previous therapy)
`
`
`
`
`
`
`
`
`
`evaluated the use of VICTRELIS 800 mg three times daily in combination with PegIntron/REBETOL with
`
`a four-week lead-in period with PegIntron/REBETOL compared to PegIntron/REBETOL alone [see
`
`
`
`Reference ID: 4048649
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2026, Page 7
`
`

`

`
`
`Table 3
`
`
`
`
`
`
`
`
`
`
`
`Adverse Events Reported in ≥10% of Subjects Receiving the Combination of VICTRELIS with PegIntron/REBETOL and
`
`
`
`
`
`
`
`Reported at a Rate of ≥5% than PegIntron/REBETOL alone
`
`
` Previously Untreated
`
`
`
` (SPRINT-1 and SPRINT-2)
`
` Percentage of Subjects Reporting Adverse
`
` Events
`
`
`
` Previous Treatment Failures
`
` (RESPOND-2)
`
` Percentage of Subjects Reporting Adverse
`
` Events
`
`
`
`
`
`
` Clinical Studies (14)]. The population studied had a mean age of 49 years (3% of subjects were older
`
`
`
` than 65 years of age), 39% were female, 82% were white and 15% were black.
`During the four week lead-in period with PegIntron/REBETOL in subjects treated with the combination
`
`
`
`
`
`
`
`
`
` of VICTRELIS with PegIntron/REBETOL, 28/1263 (2%