`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
` TYBOST safely and effectively. See full prescribing information
`
`
`
`
`
` for TYBOST.
`
`
`TYBOST® (cobicistat) tablets, for oral use
`
`
`
`
`
`Initial U.S. Approval: 2012
`--------------------------RECENT MAJOR CHANGES----------------------------
`
`
`
`
`
`Contraindications (4)
`06/2016
`
`
`
`
`Warnings and Precautions (5.4)
`06/2016
`
`
`---------------------------INDICATIONS AND USAGE---------------------------­
`
`
`TYBOST is a CYP3A inhibitor indicated to increase systemic exposure
`
`
`
`of atazanavir or darunavir (once daily dosing regimen) in combination
`
`
`
`with other antiretroviral agents in the treatment of HIV-1 infection. (1)
`
`
`Limitations of Use:
`
`
`
`
`
`
`• TYBOST is not interchangeable with ritonavir to increase systemic
`
`
`exposure of darunavir 600 mg twice daily, fosamprenavir,
`
`
`
`saquinavir, or tipranavir due to lack of exposure data. The use of
`
`
`
`TYBOST is not recommended with darunavir 600 mg twice daily,
`
`
`fosamprenavir, saquinavir, or tipranavir. (5.4).
`
`
`• Complex or unknown mechanisms of drug interactions preclude
`
`
`extrapolation of ritonavir drug interactions to certain TYBOST
`
`interactions. TYBOST and ritonavir when administered with either
`
`atazanavir or darunavir may result in different drug interactions
`
`
`
`
`when used with concomitant medications. (5.3, 7, 12.3).
`
`
`------------------------DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
`
`
`
`• TYBOST must be coadministered with atazanavir or darunavir at the
`
`
`
`
`same time, with food, and in combination with other HIV-1
`
`
`antiretroviral agents. (2.1)
`
`
`
`• Recommended dosage: (2.1)
`
`
`Coadministered Agent
`TYBOST
`
`
`Dosage
`Dosage
`
`atazanavir 300 mg
`
`orally once daily
`
`
`150 mg orally
`
`once daily
`
`
`
`darunavir 800 mg orally
`
`once daily
`
`
`Patient
`
`Populations
`
`Treatment-naïve or
`
`experienced
`
`Treatment-naïve
`Treatment-experienced
`
`with no darunavir
`resistance associated
`
`substitutions
`
`
`
`
`
`• Prior to starting TYBOST, assess estimated creatinine clearance.
`
`(2.2)
`
`
`
`
`• Coadministration with tenofovir DF: assess estimated creatinine
`
`clearance, urine glucose, and urine protein at baseline. (2.2)
`
`
`• TYBOST coadministered with tenofovir DF is not recommended in
`
`patients who have an estimated creatinine clearance below
`
`
`
`70 mL/min because dose adjustment of tenofovir DF is required
`
`below 50 mL/min and such dose adjustments have not been
`
`
`established for coadministration with TYBOST. (2.3)
`
`
`
`
`
`
`-----------------------DOSAGE FORMS AND STRENGTHS-------------------­
`
`
`Tablets: 150 mg. (3)
`
`
`--------------------------------CONTRAINDICATIONS-----------------------------­
`Coadministration with certain drugs for which altered plasma
`
`
`concentrations are associated with serious and/or life-threatening
`
`events or loss of therapeutic effect. (4)
`
`-------------------------WARNINGS AND PRECAUTIONS----------------------
`
`
`
`
`• Assess creatinine clearance (CLcr) before initiating treatment. (5.1)
`
`
`
`
`• When TYBOST is used in combination with a tenofovir disoproxil
`
`
`fumarate (tenofovir DF) containing regimen, cases of acute renal
`
`
`failure and Fanconi syndrome have been reported. (5.2)
`
`
`
`• Use with tenofovir DF: Assess urine glucose and urine protein at
`
`
`baseline and monitor CLcr, urine glucose, and urine protein. Monitor
`
`
`
`
`serum phosphorus in patients with or at risk for renal impairment.
`
`(5.2)
`
`
`
`
`• TYBOST in combination with more than one antiretroviral that
`
`
`
`
`requires pharmacokinetic enhancement (i.e., two protease inhibitors
`
`
`
`or elvitegravir in combination with a protease inhibitor) is not
`
`recommended. (5.4)
`
`
`
`
`• Use with HIV-1 protease inhibitors other than atazanavir or
`
`
`
`
`darunavir administered once daily is not recommended. (5.4)
`
`
`
`
`
`• Coadministration with drugs or regimens containing ritonavir is not
`
`recommended. (5.4)
`
`--------------------------------ADVERSE REACTIONS----------------------------­
`
`
`
`The most common adverse drug reactions observed with TYBOST in
`
`
`combination with atazanavir (incidence greater than 5%, Grades 2-4)
`
`
`
`
`are jaundice and rash. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Gilead
`
`Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`---------------------------------DRUG INTERACTIONS----------------------------­
`
`
`
`TYBOST, in combination with atazanavir or darunavir, can alter the
`
`
`
`concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that
`
`
`
`
`induce CYP3A can alter the concentrations of TYBOST, atazanavir
`
`and darunavir. Consult the full prescribing information prior to and
`
`
`
`during treatment for potential drug interactions. (4, 5.3, 7, 12.3)
`---------------------------USE IN SPECIFIC POPULATIONS-------------------­
`
`
`• Pregnancy: Use during pregnancy only if the potential benefit
`
`
`
`justifies the potential risk. (8.1)
`
`
`
`
`
`• Lactation: Women infected with HIV should be instructed not to
`
`
`
`breastfeed due to the potential for HIV transmission. (8.2)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
`
`
`
`
`
`
`
`
`
`Revised: 06/2016
`
`
`
`
`7.3 Established and Other Potentially Significant Interactions
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`12.4 Microbiology
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`* Sections or subsections omitted from the full prescribing information
`
`
`are not listed.
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1 INDICATIONS AND USAGE
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`
`2.2 Testing Prior to Initiation of TYBOST
`
`
`2.3 Renal Impairment
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Effects on Serum Creatinine
`
`
`
`
`
`
`5.2 New Onset or Worsening Renal Impairment When Used with
`
`Tenofovir Disoproxil Fumarate
`
`
`
`
`5.3 Risk of Serious Adverse Reactions or Loss of Virologic
`
`Response Due to Drug Interactions
`
`
`
`5.4 Antiretrovirals that are Not Recommended in Combination
`
`
`with TYBOST
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`
`7.1 Potential Effect of Cobicistat (Coadministered with
`
`
`
`Atazanavir or Darunavir) on the Pharmacokinetics of
`
`Concomitant Drugs
`
`
`
`
`7.2 Potential Effect of Concomitant Drugs on the
`
`Pharmacokinetics of Cobicistat (Coadministered with
`
`
`Atazanavir or Darunavir)
`
`
`Reference ID: 3947777
`
`
`
`
`1
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2027, Page 1
`
`

`

`
` FULL PRESCRIBING INFORMATION
` INDICATIONS AND USAGE
`
`
`
` 1
`
`
`
`
`
`TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or
`
`
`
`
`darunavir (once daily dosing regimen) in combination with other antiretroviral agents in
`
`the treatment of HIV-1 infection [see Dosage and Administration (2.1)].
`
`Limitations of Use:
`
`
`• TYBOST is not interchangeable with ritonavir to increase systemic exposure of
`
`
`
`
`darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack
`
`
`of exposure data. The use of TYBOST is not recommended with darunavir 600
`
`
`
`
`
`
`mg twice daily, fosamprenavir, saquinavir, or tipranavir [see Warnings and
`
`
`
`
`
`
`
`Precautions (5.4)].
`
`• Complex or unknown mechanisms of drug interactions preclude extrapolation of
`
`
`ritonavir drug interactions to certain TYBOST interactions. TYBOST and ritonavir
`
`
`when administered with either atazanavir or darunavir may result in different drug
`
`
`
`
`
`interactions when used with concomitant medications [see Warnings and
`
`
`
`
`Precautions (5.3), Drug Interactions (7), and Clinical Pharmacology (12.3)].
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`
`2.1 Recommended Dosage
`
`
`Administer TYBOST in conjunction with atazanavir or darunavir and other antiretroviral
`
`
`
`agents in the treatment of adults with HIV-1 infection. The recommended dosages of
`
`
`
`TYBOST and atazanavir or darunavir given with food are presented in Table 1.
`
`
`
`TYBOST must be coadministered at the same time as atazanavir or darunavir [see
`
`
`
`
`
`Drug Interactions (7)]. Consult the prescribing information for atazanavir or darunavir.
`
`
`
`
`
`Recommended Dosing Regimens
`Table 1
`
`
`
` Coadministered Agent Dosage
`
`
`
` TYBOST Dosage
`
`
`
`
`atazanavir 300 mg orally once daily
`
`
`150 mg orally once
`
`daily
`
`
`
`darunavir 800 mg orally once daily
`
`
`
`
`
`2.2 Testing Prior to Initiation of TYBOST
`
`
`
` Patient Populations
`
`
`
`
`Treatment-naïve or experienced
`
`
`
`Treatment-naïve
`Treatment-experienced with no
`darunavir resistance associated
`
`substitutions
`
`
`
`Reference ID: 3947777
`
`
`
` 2
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2027, Page 2
`
`

`

`
`
`
`
`
`
` Prior to starting TYBOST, assess estimated creatinine clearance because TYBOST
`
`
` decreases estimated creatinine clearance due to inhibition of tubular secretion of
`creatinine without affecting actual renal glomerular function [see Warnings and
`Precautions (5.1)]. When coadministering TYBOST with tenofovir disoproxil fumarate
`
`
`
`(tenofovir DF), assess estimated creatinine clearance, urine glucose, and urine protein
`
`at baseline [see Warnings and Precautions 5.2].
`
`
`
`
` 2.3 Renal Impairment
`
`
`
`
`TYBOST coadministered with tenofovir DF is not recommended in patients who have an
`
`
`estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir
`DF is required below 50 mL/min and such dose adjustments have not been established
`
` for coadministration with TYBOST [see Warnings and Precautions (5.2) and Adverse
`
`
`
`
`
` Reactions (6.1)].
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`Orange, round, biconvex, film-coated tablets debossed with “GSI” on one side and plain
`
`
`faced on the other side providing 150 mg of cobicistat.
`
`
`
`CONTRAINDICATIONS
`4
`
`
`
`
`
`
`The concomitant use of TYBOST with atazanavir or darunavir and the following drugs
`
`
`
`
`(see Table 2) is contraindicated due to the potential for serious and/or life-threatening
`
`
`
`events or loss of therapeutic effect [see Drug Interactions (7.1, 7.2)].
`
`
`
`Table 2
`
`
`
` Drug Class
`
`
`Alpha 1-Adrenoreceptor
`Antagonist
`
`
`Antianginal
`
`
`ranolazine
`
`
`Antiarrhythmic
`
`Anticonvulsants
`
`
`Anti-gout
`
`
`dronedarone
`
`carbamazepine,
`
`phenobarbital,
`
`phenytoin
`
`colchicine
`
`
`Antimycobacterial
`
`
`rifampin
`
`
`
`
`
`
`Drugs that are Contraindicated with Concomitant use with
`
`
`
`TYBOST and Atazanavir or Darunavir
`
` Drugs within
`Class that are
`
`Contraindicated
`
`alfuzosin
`
`
`Clinical Comment
`
`
`Potential for increased alfuzosin concentrations,
`
`which can result in serious or life-threatening
`
`reactions such as hypotension.
`Potential for serious and/or life-threatening
`
`reactions.
`
`Potential for increased dronedarone concentrations.
`
`Potential for decreased atazanavir or darunavir
`
`plasma concentrations, which may result in loss of
`
`
`therapeutic effect and development of resistance.
`
`Contraindicated in patients with renal and/or hepatic
`
`
`
`
`
`
`
`impairment due to potential for serious and/or life-
`
`
`
`
`
`
`threatening reactions.
`
`
`Rifampin is a potent inducer of CYP metabolism and
`coadministration may cause a significant decrease
`
`
`
`in the plasma concentrations of atazanavir or
` darunavir and result in loss of therapeutic effect and
`
`
`
`Reference ID: 3947777
`
`
`
` 3
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2027, Page 3
`
`

`

`
`
` Antineoplastics
`
`
`
` irinotecan
`
`Antipsychotics
`
`
`Ergot Derivatives
`
`
`
`lurasidone
`
`
`pimozide
`
`
`dihydroergotamine,
`
`ergotamine,
`
`methylergonovine
`
`
`GI Motility Agent
`
`
`
`cisapride
`
`
`Herbal Products
`
`
`
`HMG-CoA Reductase
`Inhibitors
`
`Non-nucleoside
`Reverse Transcriptase
`
`Inhibitor
`
`St. John’s wort
`
`
`(Hypericum
`perforatum)
`
`
`lovastatin,
`
`simvastatin
`
`nevirapine
`
`
`Phosphodiesterase-5
`
`(PDE-5) Inhibitor
`
`
` development of resistance.
`
`
` Contraindicated with TYBOST coadministered
`
`with atazanavir only: Atazanavir inhibits UGT1A1
`
` and may interfere with the metabolism of irinotecan,
` resulting in increased irinotecan toxicity.
`
`Potential for serious and/or life-threatening
`
`reactions.
`
`Potential for serious and/or life-threatening reactions
`
`such as cardiac arrhythmias.
`
`
`Potential for serious and/or life-threatening reactions
`
`
`such as acute ergot toxicity characterized by
`
`peripheral vasospasm and ischemia of the
`extremities and other tissues.
`
`
`Potential for serious and/or life-threatening reactions
`
`
`such as cardiac arrhythmias.
`
`
`Products containing St. John’s wort may result in
`
`
`reduced plasma concentrations of atazanavir or
`
`
`darunavir, which may result in loss of therapeutic
`
`
`effect and development of resistance.
`
`Potential for serious reactions such as myopathy
`
`including rhabdomyolysis.
`
`
`Contraindicated with TYBOST coadministered
`
`
`
`
`with atazanavir only: Nevirapine substantially
`
`
`
`decreases atazanavir exposure which may result in
`
`loss of therapeutic effect and development of
`
`resistance. Potential risk for nevirapine-associated
`adverse reactions due to increased nevirapine
`
`exposures.
`
`Potential for sildenafil-associated adverse reactions
`
`
`(which include visual disturbances, hypotension,
`
`priapism, and syncope).
`
`sildenafila when
`
`
`administered as
`REVATIO® for the
`
`
`treatment of
`
`pulmonary arterial
`
`hypertension
`
`
`indinavir
`
`
`triazolam,
`
`orally administered
`midazolamb
`
`
`
`
`Protease Inhibitor
`
`Sedative/hypnotics
`
`
`
`
`
`
`Contraindicated with TYBOST coadministered
`
`with atazanavir only: Both atazanavir and
`
`
`indinavir are associated with indirect (unconjugated)
`
`hyperbilirubinemia.
`Triazolam and orally administered midazolam are
`
`extensively metabolized by CYP3A4. Co­
`
`administration of triazolam or orally administered
`
`midazolam may cause large increases in the
`
`concentration of these benzodiazepines. The
`potential exists for serious and/or life-threatening
`
`
`benzodiazepine reactions such as prolonged or
`
`increased sedation or respiratory depression.
`
`
`
`
` a. See Drug Interactions (7), Table 6 for sildenafil when dosed as VIAGRA for erectile dysfunction.
`
` b. See Drug Interactions (7), Table 6 for parenterally administered midazolam.
`
`
`
`
`
`Reference ID: 3947777
`
`
`
` 4
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2027, Page 4
`
`

`

`WARNINGS AND PRECAUTIONS
`5
`
`
`
`Effects on Serum Creatinine
`5.1
`
`
`
`TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion
`
`
`
`
`of creatinine without affecting actual renal glomerular function. This effect should be
`
`
`
`considered when interpreting changes in estimated creatinine clearance in patients
`
`initiating TYBOST, particularly in patients with medical conditions or receiving drugs
`
`
`
`needing monitoring with estimated creatinine clearance.
`
`Prior to initiating therapy with TYBOST, assess estimated creatinine clearance [see
`
`
`
`Dosage and Administration (2.2)]. Dosage recommendations are not available for drugs
`
`
`
`
`
`that require dosage adjustments in TYBOST-treated patients with renal impairment [see
`
`
`
`
`Adverse Reactions (6.1), Drug Interactions (7.3), and Clinical Pharmacology (12.2)].
`
`
`Consider alternative medications that do not require dosage adjustments in patients
`
`
`
`
`
`with renal impairment.
`Although TYBOST may cause modest increases in serum creatinine and modest
`
`
`declines in estimated creatinine clearance without affecting renal glomerular function,
`
`
`patients who experience a confirmed increase in serum creatinine of greater than
`
`0.4 mg/dL from baseline should be closely monitored for renal safety.
`
`
`
`5.2 New Onset or Worsening Renal Impairment When Used with Tenofovir
`
`
`
`Disoproxil Fumarate
`
`
`Renal impairment, including cases of acute renal failure and Fanconi syndrome, has
`
`
`
`
`been reported when TYBOST was used in an antiretroviral regimen that contained
`
`
`
`
`
`tenofovir DF.
`
`
`• Coadministration of TYBOST and tenofovir DF is not recommended in patients
`
`
`
`
`
`
`
`who have an estimated creatinine clearance below 70 mL/min because dose
`adjustment of tenofovir DF is required below 50 mL/min and such dose
`adjustments have not been established for coadministration with TYBOST [see
`
`
`Dosage and Administration (2.2, 2.3)].
`
`
`• Document urine glucose and urine protein at baseline [see Dosage and
`
`
`
`
`Administration (2.2)] and perform routine monitoring of estimated creatinine
`
`clearance, urine glucose, and urine protein during treatment when TYBOST is
`
`
`
`used with tenofovir DF. Measure serum phosphorus in patients with or at risk for
`
`
`
`renal impairment when used with tenofovir DF.
`
`
`
`• Coadministration of TYBOST and tenofovir DF in combination with concomitant
`
`
`
`
`
`
`or recent use of a nephrotoxic agent is not recommended.
`
`
`
`
`
`Reference ID: 3947777
`
`
`
` 5
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2027, Page 5
`
`

`

`In a clinical trial of TYBOST over 144 weeks (N=692), 10 (2.9%) subjects treated with
`
`
`
`
`
`
`
`TYBOST coadministered with atazanavir and TRUVADA® and 11 (3.2%) subjects
`
`
`
`
`
`
`
`
`
`
`
`treated with ritonavir coadministered with atazanavir and TRUVADA discontinued study
`
`
`
`drug due to a renal adverse event. Seven of the 10 subjects (2.0% overall) in the
`
`
`
`TYBOST group had laboratory findings consistent with proximal renal tubulopathy
`
`
`
`
`
`leading to study drug discontinuation compared to 7 of 11 subjects (2.0% overall) in the
`
`
`
`
`
`
`ritonavir group. One subject in the TYBOST group had renal impairment at baseline
`
`
`
`
`(i.e., estimated creatinine clearance less than 70 mL/min). The laboratory findings in
`
`
`
`
`
`these 7 subjects with evidence of proximal tubulopathy improved but did not completely
`
`
`
`
`
`resolve in all subjects upon discontinuation of TYBOST coadministered with atazanavir
`
`
`
`
`and TRUVADA. Renal replacement therapy was not required in any subject.
`
`
`
`5.3 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to
`
`Drug Interactions
`
`Initiation of TYBOST, a CYP3A inhibitor, in patients receiving medications metabolized
`
`
`by CYP3A, or initiation of medications metabolized by CYP3A in patients already
`
`
`
`
`receiving TYBOST may increase plasma concentrations of medications metabolized by
`
`
`
`
`
`CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase
`
`
`
`or decrease concentrations of TYBOST with atazanavir or darunavir.
`
`
`
`
`Increased concentrations may lead to:
`
`
`
`
`
`• clinically significant adverse reactions, potentially leading to severe, life-
`
`
`
`
`
`threatening, or fatal events from higher exposures of concomitant medications.
`
`
`
`
`
`• clinically significant adverse reactions from higher exposures of TYBOST and
`
`atazanavir or darunavir.
`
`
`
`
`
`Decreased antiretroviral concentrations may lead to:
`
`
`•
`
`
`loss of therapeutic effect of TYBOST with atazanavir or darunavir and possible
`
`development of resistance.
`
`
`
`
`See Table 6 for steps to prevent or manage these possible and known significant drug
`
`
`interactions, including dosing recommendations [see Drug Interactions (7)]. Consider
`
`
`
`the potential for drug interactions prior to and during TYBOST with atazanavir or
`
`
`
`
`
`darunavir therapy; review concomitant medications during TYBOST with atazanavir or
`
`
`
`darunavir therapy; and monitor for the adverse reactions associated with concomitant
`
`
`medications [see Contraindications (4) and Drug Interactions (7)].
`
`
`
`TYBOST or ritonavir when administered with either atazanavir or darunavir may result in
`
`
`
`different drug interactions when used with concomitant medications. Complex or
`
`
`unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug
`
`
`
`interactions to certain TYBOST interactions [see Drug Interactions (7), and Clinical
`
`
`
`Pharmacology (12.3)].
`
`
`
`
`
`5.4 Antiretrovirals that are Not Recommended in Combination with TYBOST
`
`
`Reference ID: 3947777
`
`
`
` 6
`
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`PGR2019-00048
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`

`

`
` The following antiretrovirals are not recommended in combination with TYBOST
` because dosing recommendations for such combinations have not been established
`
`
`
` and coadministration may result in decreased plasma concentrations of the antiretroviral
` agents, leading to loss of therapeutic effect and development of resistance:
`
`
`
`
`
`
`
`
` • More than one antiretroviral that requires pharmacokinetic enhancement (i.e.,
`
`
`
`
`
`
`
` two protease inhibitors or a protease inhibitor in combination with elvitegravir)
`
`
`
` • Darunavir in combination with efavirenz, nevirapine, or etravirine
`
`
`
`
`
` • Atazanavir in combination with etravirine
`
`
`
`
`
`
`
`
`
` • Atazanavir in combination with efavirenz in treatment-experienced patients
`
`
`
`
`
` • Darunavir 600 mg twice daily
`
`
`
`
`
`
`
` • Other HIV-1 protease inhibitors including fosamprenavir, saquinavir, or tipranavir
`
`
`
`
`
`
`
` TYBOST in combination with fixed-dose combination tablets that contain cobicistat is
`not recommended.
`
`
`
`
`
`
`
`
`TYBOST in combination with lopinavir/ritonavir or regimens containing ritonavir is not
`
`
`
`recommended due to similar effects of TYBOST and ritonavir on CYP3A.
`
`
`
`
`ADVERSE REACTIONS
`6
`
`
`The following adverse reaction is described in greater detail in another section of the
`
`
`labeling:
`
`• New Onset or Worsening Renal Impairment When Used with Tenofovir
`
`
`
`
`
`Disoproxil Fumarate [see Warnings and Precautions (5.2)]
`
`
`
`
`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 TYBOST is based on Week 144 data from a Phase 3 trial, Study 114, in
`
`
`
`
`which 692 HIV-1 infected, antiretroviral treatment-naïve subjects received:
`
`
`
`
`• TYBOST coadministered with atazanavir and tenofovir DF/emtricitabine
`
`
`
`
`
`
`(administered as TRUVADA) (N=344) or;
`
`
`
`
`
`•
`
`ritonavir coadministered with atazanavir and tenofovir DF/emtricitabine
`
`
`
`
`
`(administered as TRUVADA) (N=348).
`
`
`
`
`
`Reference ID: 3947777
`
`
`
` 7
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2027, Page 7
`
`

`

` The most common adverse reactions (Grades 2-4) and reported in >5% of subjects in
`
`
`
`
`
`
`
`
` the TYBOST group were jaundice (6%) and rash (5%). The proportion of subjects who
` discontinued study treatment due to adverse events, regardless of severity, was 11% in
`
`
`
`
`
`
` both the TYBOST and ritonavir groups. Table 3 displays the frequency of adverse
` reactions (Grades 2-4) occurring in at least 2% of subjects in the TYBOST group in
`
`
`
`
`
`
` Study 114.
`
`
`
`
`
`
`
` Table 3
`
`Selected Adverse Reactionsa (Grades 2-4) Reported in ≥2% of
`
`
`
`
`
`
`
`HIV-1 Infected Treatment-Naïve Adults in the TYBOST
`
`Coadministered with Atazanavir Group in Study 114 (Week 144
`
`Analysis)
`
`
`
`
`TYBOST Coadministered
`
`Ritonavir Coadministered
`
`with Atazanavir +
`
`with Atazanavir +
`
`TRUVADA
`
`TRUVADA
`
`N=344
`
`N=348
`
`
`
`Jaundice
`3%
`6%
`
`Rashb
`
` 4%
`
` 5%
`2%
`4%
`Ocular icterus
`
`
`
`2%
`2%
`Nausea
`
`
`
`1%
`2%
`Diarrhea
`
`
`
`1%
`2%
`Headache
`
`
`
`
`
`
`
`
`
`
`
` a. Frequencies of adverse reactions are based on Grades 2-4 adverse events attributed to study drugs.
`
`
`
` b. Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis,
`
`
` rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, and urticaria.
`
`
`
`
`
`
` Less Common Adverse Reactions
`
`Selected adverse reactions of at least moderate severity (≥ Grade 2) occurring in less
`
`
`
`
` than 2% of subjects receiving TYBOST coadministered with atazanavir and TRUVADA
`
`
`
` are listed below. These events have been included because of the investigator’s
`
`
`
` assessment of potential causal relationship and were considered serious or have been
`
` reported in more than one subject treated with TYBOST and with greater frequency
`
`
`
`
`
` compared with ritonavir.
` Gastrointestinal Disorders: vomiting, upper abdominal pain
`
`
`
`
`
`
` General Disorders and Administration Site Conditions: fatigue
` Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis
`
` Psychiatric Disorders: depression, abnormal dreams, insomnia
`
`
` Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired,
`
`
` nephrolithiasis
`
` Refer to the prescribing information for atazanavir or darunavir for information regarding
`
` adverse reactions with these drugs.
`
`
`
`
`
`
`Reference ID: 3947777
`
`
`
` 8
`
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2027, Page 8
`
`

`

` Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3-4)
`
`
`
`
`
`
`
`
`
`
` occurring in at least 2% of subjects in the TYBOST group in Study 114 is presented in
`
` Table 4.
`
`
`
`
`
` Laboratory Abnormalities (Grades 3-4) in ≥2% of HIV-1 Infected
`
`
`
`
`
`
` Treatment-Naïve Adults in the TYBOST Coadministered with
` Atazanavir Group in Study 114 (Week 144 Analysis)
`
`
`
`
` TYBOST + Atazanavir +
` Ritonavir + Atazanavir +
`
` TRUVADA
`
`
` TRUVADA
`N=344
`N=348
`
`
`73%
`66%
`
`
`8%
`9%
`
`
`6%
`3%
`
`
`6%
`3%
`
`
`4%
`3%
`
`
`4%
`2%
`
`
`
` 4%
`
` 2%
`
`
`3%
`3%
`
` 3%
`
` 2%
`2%
`2%
`
`
`
`
`
` Table 4
`
`
`
`Laboratory Parameter Abnormality
`
`
`Total Bilirubin (>2.5 × ULN)
`
`Creatine Kinase (≥10.0 × ULN)
`
`
`Urine RBC (Hematuria) (>75 RBC/HPF)
`
`ALT (>5.0 × ULN)
`
`
`AST (>5.0 × ULN)
`
`
`
`GGT (>5.0 × ULN)
`
`
` Serum Amylasea (>2.0 × ULN)
`
`
`
`Urine Glucose (Glycosuria) (≥1000 mg/dL)
`Neutrophils (<750/mm3)
`
`
`Serum Glucose (Hyperglycemia) (>250
`
`mg/dL)
`
` a. For subjects with serum amylase >1.5 x upper limit of normal, lipase test was also performed. The frequency of
`
`
`
`
`
`
`
`
`
` increased lipase (Grades 3-4) occurring in the TYBOST (N=46) and ritonavir (N=35) groups was 7% and 3%,
`
` respectively.
`
`
`
`
` Increase in Serum Creatinine: TYBOST causes increases in serum creatinine and
` decreases in estimated creatinine clearance due to inhibition of tubular secretion of
`
`
`
`
` creatinine without affecting actual renal glomerular function [see Warnings and
`
` Precautions (5.1) and Clinical Pharmacology (12.2)]. In Study 114, increases in serum
`
`
`
`
`
` creatinine and decreases in estimated creatinine clearance occurred early in treatment
`
` with TYBOST, after which they stabilized. The mean (± SD) change in estimated
`
`
` glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of
`
`
`
`
` treatment was –15.1 ± 16.5 mL/min in the TYBOST group and –8.0 ± 16.8 mL/min in the
`
`
`
`
`
`
` ritonavir group.
`
`
`
`
`
` Serum Lipids: Changes from baseline in total cholesterol, HDL-cholesterol, LDL-
`
`
`
`
`cholesterol, and triglycerides are presented in Table 5. In both groups, mean values for
`
`serum lipids remained within the study reference range for each laboratory test. The
`
`
`clinical significance of these changes is unknown.
`
`
`Table 5
`
`
`Lipid Values, Mean Change from Baseline, Reported in HIV-1 Infected
`
`
`
`Treatment-Naïve Adults Receiving TYBOST Coadministered with
`
`
`
`Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir
`
`
`
`
`+ TRUVADA in Study 114 (Week 144 Analysis)
`
`
`Reference ID: 3947777
`
`
`
` 9
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2027, Page 9
`
`

`

`
`
`mg/dL
`
`
`
`
`
`
`
`Ritonavir + Atazanavir +
`TYBOST + Atazanavir +
`
`
`TRUVADA
`TRUVADA
`
`
`
`
`Week 144
`Baseline
`Week 144
`Baseline
`Change from
`
`
`Change from
`baselinea
`baselinea
`
`
` 165
` 163
`
`
`
`
` +11
` +13
`
` [N=227]
` [N=227]
`
` [N=219]
`
` [N=219]
`
`
`
`
`+6
`43
`+7
`43
`
`
`
`
`[N=228]
`[N=228]
`[N=218]
`[N=218]
`
`
`
`
`+16
`104
`+11
`102
`
`
`
`
`[N=228]
`[N=228]
`[N=218]
`[N=218]
`
`
`
`
`+14
`131
`+14
`130
`
`
`
`
`[N=227]
`[N=227]
`[N=219]
`[N=219]
`
` a. The change from baseline is the mean of within-patient changes from baseline for patients with both baseline
`
`
`
`
`
`
`
`
` and Week 144 values. Analysis excludes subjects receiving an HMG-CoA reductase inhibitor drug.
`
`
`mg/dL
`
`
`
`
`
` Total Cholesterol (fasted)
`
`
`HDL-cholesterol (fasted)
`
`
`LDL-cholesterol (fasted)
`
`
`Triglycerides (fasted)
`
` DRUG INTERACTIONS
` 7
`
`
` See also Dosage and Administration (2), Contraindications (4), Warnings and
`
`
` Precautions (5.3, 5.4), and Clinical Pharmacology (12.3).
`
`
`
`
`
` 7.1
`
` Potential Effect of Cobicistat (Coadministered with Atazanavir or Darunavir)
`
`
` on the Pharmacokinetics of Concomitant Drugs
`
` Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat
`
`
`
`
`
` inhibits include p-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3. The plasma
` concentration of drugs that are primarily metabolized by CYP3A or CYP2D6, or are
`
`
`
`
`
`
`
` substrates of P-gp, BCRP, OATP1B1, or OATP1B3 may be increased if those drugs are
`
` coadministered with TYBOST.
`
`
`
`
`
`
`
`
`
`
`
` Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and
`
`
`
`
` based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A
` to a clinically significant extent. The induction effect of cobicistat on CYP2C9,
`
`
` CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro
`
`
`
` induction data.
`
`
`
` Coadministration of TYBOST with atazanavir or darunavir with drugs highly dependent
`
`
`
`
`
`
`
`
` on CYP3A for clearance and for which elevated plasma concentrations are associated
` with serious and/or life-threatening events is contraindicated. Coadministration with
`
`
` other CYP3A substrates may require a dose adjustment or additional monitoring as
`
`
` shown in Table 6.
`
`
`
` 7.2
`
`
`
` Potential Effect of Concomitant Drugs on the Pharmacokinetics of
` Cobicistat (Coadministered with Atazanavir or Darunavir)
`
`
`
` Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Atazanavir and
`
`
`
` darunavir are also metabolized by CYP3A.
`
`
`
`
`
`
`Reference ID: 3947777
`
`
`
` 10
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2027, Page 10
`
`

`

`Coadministration of TYBOST with atazanavir or darunavir in combination with drugs that
`
`
`
`induce CYP3A activity have the potential to decrease plasma concentrations of
`
`
`cobicistat, atazanavir, and darunavir, which may lead to loss of therapeutic effect and
`
`
`
`
`development of resistance (see Table 6).
`
`
`Coadministration of TYBOST with atazanavir or darunavir in combination with other
`
`
`
`
`
`drugs that inhibit CYP3A may further increase the plasma concentrations of cobicistat,
`
`
`
`atazanavir, and darunavir (see Table 6).
`
`
`
`
`7.3 Established and Other Potentially Significant Interactions
`
`
`
`Coadministration of TYBOST with fosamprenavir, saquinavir, or tipranavir is not
`
`
`
`
`
`recommended because pharmacokinetic data are not available to provide appropriate
`
`
`
`dosing recommendations. Use of TYBOST with lopinavir is not recommended because
`
`
`
`
`
`lopinavir is co-formulated with ritonavir.
`
`
`
`Drug interaction trials were not conducted for TYBOST in combination with atazanavir
`
`
`
`
`or darunavir. A