-------------------------------CONTRAINDICATIONS--------------------------­
`
`Contraindications to peginterferon alfa and ribavirin also apply to
`•
`
`
`INCIVEK combination treatment. (4)
`
`
`
`• Women who are or may become pregnant and men whose female
`
`partners are pregnant: Because ribavirin may cause birth defects and
`
`
`
`
`fetal death, telaprevir in combination with peginterferon alfa and
`
`ribavirin is contraindicated in pregnant women and in men whose
`
`
`
`female partners are pregnant. (4, 5.3, 8.1)
`
`
`Co-administration with drugs that:
`
`
`are highly dependent on CYP3A for clearance and for which
`•
`
`
`elevated plasma concentrations are associated with serious and/or
`
`
`
`life-threatening events. (4)
`
`strongly induce CYP3A which may lead to lower exposure and
`
`
`
`loss of efficacy of INCIVEK. (4)
`
`
`•
`
`
`•
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS---------------------­
`
`Serious Skin Reactions/Rash: Fatal and non-fatal serious skin reactions
`•
`
`
`
`
`
`(including SJS, DRESS, and TEN) have been reported. Patients with
`
`
`
`
`
`mild to moderate rash should be monitored for progression. If rash
`
`
`
`progresses and becomes severe, INCIVEK should be discontinued. For
`
`
`
`
`serious skin reactions, including rash with systemic symptoms or a
`
`
`
`
`progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin
`
`
`must be discontinued immediately. Consider discontinuing other
`
`
`
`medications known to be associated with serious skin reactions. (5.1)
`
`
`
`
`
`
`
`Anemia: Monitor hemoglobin prior to and at regular intervals during
`
`
`
`
`INCIVEK combination treatment. Follow dose modifications for
`
`ribavirin; discontinue INCIVEK if required. (5.2)
`
`
`Pregnancy: 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 initiating therapy, use at least 2
`
`
`
`
`effective methods of contraception, and undergo monthly pregnancy
`
`
`tests. (5.3, 8.1)
`
`
`•
`
`
`•
`
`
`
`------------------------------ADVERSE REACTIONS----------------------------­
`
`The most common adverse drug reactions to INCIVEK (incidence at least
`
`
`
`
`5% higher with INCIVEK than in controls) were rash, pruritus, anemia,
`
`
`
`
`
`
`nausea, hemorrhoids, diarrhea, anorectal discomfort, dysgeusia, fatigue,
`
`vomiting, and anal pruritus. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Vertex
`
`
`Pharmaceuticals Incorporated at 877-824-4281 or FDA at 1-800-FDA­
`
`
`
`1088 or www.fda.gov/medwatch.
`
`
`
`------------------------------DRUG INTERACTIONS----------------------------­
`
`Co-administration of INCIVEK combination treatment with other
`•
`
`
`
`drugs can alter the concentration of other drugs and other drugs may
`
`
`
`alter the concentrations of telaprevir. Consult the full prescribing
`
`
`information prior to and during treatment for potential drug-drug
`
`
`
`interactions. (4, 7, 12.3)
`
`
`-------------------------USE IN SPECIFIC POPULATIONS-------------------­
`
`Hepatic Impairment: INCIVEK is not recommended for use in
`•
`
`
`
`patients with Child-Pugh score greater than or equal to 7 (class B and
`
`
`
`
`C). (5.7, 8.6)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`
`
`
`
`Revised: 10/2013
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use INCIVEK
` safely and effectively. See full prescribing information for INCIVEK.
`
`
`
`
`INCIVEK® (telaprevir) tablets, for oral use
`
`
`
`
`Initial U.S. Approval: 2011
`
`
`
`
`WARNING: SERIOUS SKIN REACTIONS
`
`See full prescribing information for complete boxed warning.
`
`
`
`• Fatal and non-fatal serious skin reactions, including Stevens Johnson
`
`
`Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms
`
`(DRESS), and Toxic Epidermal Necrolysis (TEN), have been reported in
`
`
`
`patients treated with INCIVEK combination treatment. Fatal cases have
`
`
`
`
`
`been reported in patients with progressive rash and systemic symptoms
`
`
`who continued to receive INCIVEK combination treatment after a serious
`
`
`
`skin reaction was identified. (5.1)
`
`
`
`• For serious skin reactions, including rash with systemic symptoms or a
`
`
`progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must
`
`
`be discontinued immediately. Discontinuing other medications known to be
`
`
`
`associated with serious skin reactions should be considered. Patients should
`
`be promptly referred for urgent medical care. (5.1)
`
`
`
`
`
`
`-----------------------------RECENT MAJOR CHANGES-----------------------­
`
`Boxed Warning
`12/2012
`•
`
`
`
`
`
`Dosage and Administration (2.1)
`10/2013
`•
`
`
`
`
`10/2013
`Contraindications (4)
`•
`
`
`
`
`
`• Warnings and Precautions (5.1, 5.2)
`12/2012
`
`
`
`
`
`• Warnings and Precautions (5.5)
`04/2013
`
`
`
`
`
`
`•
`
`
`•
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`INCIVEK is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated, in
`
`
`
`combination with peginterferon alfa and ribavirin, for the treatment of genotype
`
`
`1 chronic hepatitis C (CHC) in adult patients with compensated liver disease,
`
`
`
`
`including cirrhosis, who are treatment-naïve or who have been previously
`
`
`treated with interferon-based treatment, including prior null responders, partial
`
`
`
`
`responders, and relapsers. (1.1)
`
`INCIVEK must not be used as monotherapy and must only be used in
`•
`
`
`
`
`
`combination with peginterferon alfa and ribavirin. (5.6)
`
`
`A high proportion of previous null responders (particularly those with
`
`
`
`
`cirrhosis) did not achieve Sustained Virologic Response (SVR) and had
`
`
`telaprevir resistance-associated substitutions emerge on treatment with
`
`INCIVEK. (12.4, 14.3)
`
`
`INCIVEK efficacy has not been established for patients who have
`
`previously failed therapy with a treatment regimen that includes INCIVEK
`
`
`
`
`or other HCV NS3/4A protease inhibitors. (12.4)
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`Reference ID: 3397093
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`1125 mg taken twice daily (10-14 hours apart) with food (not low fat).
`•
`
`
`
`
`
`
`
`(2.1, 12.3)
`INCIVEK must be administered with both peginterferon alfa and ribavirin
`
`
`
`for all patients for 12 weeks, followed by a response-guided regimen of
`
`either 12 or 36 additional weeks of peginterferon alfa and ribavirin
`
`
`depending on viral response and prior response status. (2.1)
`
`For specific dosage instructions for peginterferon alfa and ribavirin, refer
`
`to their respective prescribing information. (2.1)
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS-------------------­
`375 mg tablets (3)
`
`
`
`
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2024, Page 1
`
`

`

`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: SERIOUS SKIN REACTIONS
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Chronic Hepatitis C
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment
`
`2.1
`
`
`
`2.2 Dose Reduction
`
`
`
`
`2.3 Discontinuation of Dosing
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Serious Skin Reactions/Rash
`
`
`
`
`5.2 Anemia
`
`
`
`5.3 Pregnancy: Use with Ribavirin and Peginterferon Alfa
`
`
`
`
`
`
`5.4 Drug Interactions
`
`
`
`5.5 Laboratory Tests
`
`
`
`5.6 General
`
`
`
`5.7 Hepatic Impairment
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Post-marketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Potential for INCIVEK to Affect Other Drugs
`
`
`
`7.2 Potential for Other Drugs to Affect INCIVEK
`
`
`
`
`7.3 Established and Other Potentially 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 Hepatic Impairment
`
`
`
`8.7 Renal Impairment
`
`
`
`8.8 Liver 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
`
`
`14.1 Description of Adult Clinical Trials
`
`
`
`14.2 Treatment-Naïve Adults
`
`
`
`14.3 Previously Treated Adults
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`
`Reference ID: 3397093
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2024, Page 2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`WARNING: SERIOUS SKIN REACTIONS
`• Fatal and non-fatal serious skin reactions, including Stevens Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),
`
`
`
`and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with INCIVEK combination treatment. Fatal cases have been reported in
`
`
`
`
`patients with progressive rash and systemic symptoms who continued to receive INCIVEK combination treatment after a serious skin reaction was identified
`
`
`
`
`
`
`[see Warnings and Precautions (5.1)].
`
`
`
`• For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must be
`
`
`
`
`discontinued immediately. Discontinuing other medications known to be associated with serious skin reactions should be considered. Patients should be
`
`
`
`
`
`promptly referred for urgent medical care [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`1
`
`
`
`•
`
`
`•
`
`INDICATIONS AND USAGE
`
`1.1 Chronic Hepatitis C
`
`
`INCIVEK® (telaprevir), in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype 1 chronic hepatitis C in adult patients
`
`
`
`
`
`
`
`
`with compensated liver disease, including cirrhosis, who are treatment-naïve or who have previously been treated with interferon-based treatment, including
`
`
`
`
`prior null responders, partial responders, and relapsers [see Clinical Studies (14.2 and 14.3), including definitions of these terms].
`
`
`
`
`
`
`
`
`
`
`
`The following points should be considered when initiating treatment with INCIVEK:
`
`INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin [see Warnings and
`
`
`
`
`
`
`
`•
`Precautions (5.6)].
`
`A high proportion of previous null responders (particularly those with cirrhosis) did not achieve a Sustained Virologic Response (SVR) and had
`
`
`
`
`telaprevir resistance-associated substitutions emerge on treatment with INCIVEK combination treatment [see Microbiology (12.4) and Clinical
`
`
`
`
`
`
`Studies (14.3)].
`
`INCIVEK efficacy has not been established for patients who have previously failed therapy with a treatment regimen that includes INCIVEK or
`
`
`other HCV NS3/4A protease inhibitors [see Microbiology (12.4)].
`
`
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 INCIVEK/Peginterferon Alfa/Ribavirin Combination Treatment
`
`
`
`The recommended dose of INCIVEK tablets is 1125 mg (three 375-mg tablets) taken orally twice daily (10-14 hours apart) with food (not low fat) [see
`
`
`
`
`
`
`
`
`
`
`Clinical Pharmacology (12.3)].
`
`
`For specific dosage instructions for peginterferon alfa and ribavirin, refer to their respective prescribing information.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Duration of Treatment
`
`
`The recommended duration of treatment with INCIVEK is 12 weeks in combination with peginterferon alfa and ribavirin. HCV RNA levels should be
`
`
`
`
`monitored at weeks 4 and 12 to determine combination treatment duration and assess for treatment futility (Tables 1 and 2).
`
`
`
`
`
`
`
`
`
`Table 1: Recommended Treatment Duration (See also Table 2 for Treatment Futility Rules)
`
`
`
`
`Treatment-Naïve and Prior Relapse Patients
`
`
`
`
`HCV RNAa
`
` Undetectable (Target Not Detected) at
`
`
`
` Weeks 4 and 12
`Detectable (1000 IU/mL or less) at
`
`Weeks 4 and/or 12
`
`
`
`
` Triple Therapy
`
`
` INCIVEK,
` peginterferon alfa and ribavirin
`
` First 12 weeks
`
`
`
`
`
` Dual Therapy
`
` peginterferon alfa and ribavirin
`
`
` Additional 12 weeks
`
`
`
`First 12 weeks
`
`
`Additional 36 weeks
`
`
`
`Prior Partial and Null Responder Patients
`
`
`
`
`All Patients
`
`
` Triple Therapy
`
`
` INCIVEK,
` peginterferon alfa and ribavirin
`First 12 weeks
`
`
`
`
`
`
` Dual Therapy
`
`
`peginterferon alfa and ribavirin
`Additional 36 weeks
`
`
`
` Total
`
`Treatment
`
` Duration
`
` 24 weeks
`
`48 weeks
`
`
`
`Total
`Treatment
`
` Duration
`48 weeks
`
`
` aIn clinical trials, HCV RNA in plasma was measured using a COBAS® TaqMan® assay with a lower limit of quantification of 25 IU/mL and a limit of
`
`
`
`
`
`
`
`
`
` detection of 10 IU/mL. See Laboratory Tests (5.5) for a description of HCV RNA assay recommendations.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`For the purpose of assessing response-guided therapy eligibility at weeks 4 and 12 (see Table 1), an “undetectable” HCV RNA (Target Not Detected) result
`
`
`
`
`
`
`
`
`
`
`is required; a confirmed “detectable but below limit of quantification” HCV RNA result should not be considered equivalent to an “undetectable” HCV RNA
`(Target Not Detected) result [see Laboratory Tests (5.5)].
`
`
`
`
`
`
`
`
`
`
`Treatment-naïve patients with cirrhosis who have undetectable HCV RNA (Target Not Detected) at weeks 4 and 12 of INCIVEK combination treatment
`
`
`may benefit from an additional 36 weeks of peginterferon alfa and ribavirin (48 weeks total) [see Clinical Studies (14.2)].
`
`
`
`
`
`2.2 Dose Reduction
`
`
`
`
`To prevent treatment failure, the dose of INCIVEK must not be reduced or interrupted. Refer to the respective prescribing information for dose modification
`of peginterferon alfa and ribavirin [see Warnings and Precautions (5.6)].
`
`
`
`
`
`
` 3 of 28
`
`
`
`Reference ID: 3397093
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2024, Page 3
`
`

`

`
`
`2.3 Discontinuation of Dosing
`
`Patients with inadequate viral response are unlikely to achieve SVR, and may develop treatment-emergent resistance substitutions [see Microbiology (12.4)].
`
`
`
`
`
`
`
`Discontinuation of therapy is recommended in all patients with (1) HCV RNA levels of greater than 1000 IU/mL at Treatment Week 4 or 12; or (2)
`
`
`confirmed detectable HCV RNA levels at Treatment Week 24 (see Table 2).
`
`
`
`Table 2: Treatment Futility Rules: All Patients
`
`
`HCV RNA
` Week 4 or Week 12: Greater than 1000 IU/mL
`
`
`
`
`
`
`
`
`
`
`
`
` Action
`
` Discontinue INCIVEK and peginterferon alfa and ribavirin (INCIVEK treatment complete at 12
`
` weeks)
`
`
`Discontinue peginterferon alfa and ribavirin
`
`
`
`
`
`
`
`
`
`Week 24: Detectable
`
`I
`
`If peginterferon alfa or ribavirin is discontinued for any reason, INCIVEK must also be discontinued.
`
`
`
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`Each tablet contains 375 mg of telaprevir. Tablets are available as purple, film-coated, capsule-shaped tablets debossed with the characters “V 375” on one
`
`
`
`
`side.
`
`
`
`
`
`4 CONTRAINDICATIONS
`
`
`Contraindications to peginterferon alfa and ribavirin also apply to INCIVEK combination treatment.
`
`
`
`
`INCIVEK combination treatment is contraindicated in:
`
`
`women who are or may become pregnant. Ribavirin may cause fetal harm when administered to a pregnant woman. If this drug is used during
`
`
`
`
`
`
`•
`pregnancy, or if the patient becomes pregnant while taking this drug treatment, the patient should be apprised of the potential hazard to a fetus [see
`
`
`
`
`
`
`
`
`Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
`
`
`
`
`• men whose female partners are pregnant.
`
`
`
`INCIVEK is a strong inhibitor of CYP3A. INCIVEK is contraindicated when combined with drugs that are highly dependent on CYP3A for clearance and
`
`
`
`
`
`
`for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). INCIVEK is contraindicated
`
`
`
`
`
`when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of INCIVEK. Contraindicated drugs are
`
`
`
`
`
`listed below in Table 3 [also see Drug Interactions (7), Table 5 and Clinical Pharmacology (12.3), Tables 6 and 7].
`
`
`
`
`
`
`
`
`
`
`
`
`
` Clinical Comments
`
`Table 3: Drugs that are Contraindicated with INCIVEK
`
`
`
`
` Drugs within Class that are Contraindicated with
`
`
`Drug Class
`
`
` INCIVEK
` Alpha 1-adrenoreceptor antagonist
`
` Alfuzosin
`
` Anticonvulsants
` Carbamazepine, phenobarbital, phenytoin
`
`
`
`
`
`
`
` Antimycobacterials
`
`
` Ergot derivatives
`
` GI motility agent
`
`
`
` Herbal products
`
`
`
` Rifampin
`
` Dihydroergotamine, ergonovine, ergotamine,
`
` methylergonovine
`
` Cisapride
`
`
`
` St. John's wort (Hypericum perforatum)
`
`
`
`
`
`
` HMG-CoA reductase inhibitors
`
` Neuroleptic
`
`
`
`
`
` Lovastatin, simvastatin
`
` Pimozide
`
`
`
` PDE5 inhibitor
`
`Sildenafil (Revatio®) or tadalafil (Adcirca®) [for
`treatment of pulmonary arterial hypertension]a
`
`
`
`
`
`
` Potential for hypotension or cardiac arrhythmia
`
`
`
` Potential for lower exposure and loss of efficacy of
`
` INCIVEK
` Rifampin significantly reduces telaprevir plasma
`
` concentrations.
`
` Potential for acute ergot toxicity characterized by
`
` peripheral vasospasm or ischemia
`
`
` Potential for cardiac arrhythmias
` Plasma concentrations of telaprevir can be reduced
`
`
`
`
` by concomitant use of the herbal preparation St.
`
` John’s wort.
`
` Potential for myopathy including rhabdomyolysis
`
` Potential for serious and/or life-threatening adverse
`
` reactions such as cardiac arrhythmias
`
`Potential for PDE5 inhibitor-associated adverse
`
` events, including visual abnormalities, hypotension,
` prolonged erection, and syncope
`
` Prolonged or increased sedation or respiratory
` Orally administered midazolamb, triazolam
`
` Sedatives/hypnotics
`
`
` depression
`
` a See Drug Interactions, Table 5 for co-administration of sildenafil and tadalafil when dosed for erectile dysfunction.
`
`
`b See Drug Interactions, Table 5 for parenterally administered midazolam.
`
`
`
`
`
`
`
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`
`5.1 Serious Skin Reactions/Rash
`
`
`
`
`
`
`Fatal and non-fatal serious skin reactions, including Stevens Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),
`
`
`
`
`
`
`
`and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with INCIVEK combination treatment. Fatal cases have been reported in
`
`
`
`
`
`patients with progressive rash and systemic symptoms who continued to receive INCIVEK combination treatment after a serious skin reaction was
`
`identified.
`
`
`
`
`
`For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must
`
`
`
`
`be discontinued immediately. Discontinuing other medications known to be associated with serious skin reactions should be considered. Patients
`
`
`should be promptly referred for urgent medical care.
`
`
`
`
`
`In clinical trials, serious skin reactions, including DRESS and SJS were reported in less than 1% of subjects who received INCIVEK combination treatment
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`compared to none who received peginterferon alfa and ribavirin alone. These serious skin reactions required hospitalization, and all subjects recovered. The
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`presenting signs of DRESS may include rash, fever, facial edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). Eosinophilia may or
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`may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips).
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`Reference ID: 3397093
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`5
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2024, Page 4
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` TEN and Erythema Multiforme (EM) have been observed in post-marketing experience [see also Boxed Warning and Adverse Reactions (6.2)].
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`Rash events (all grades) developed in 56% of subjects who received INCIVEK combination treatment [see Adverse Reactions (6.1)] and in 34% of subjects
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`who received peginterferon alfa and ribavirin. Rash most frequently began during the first 4 weeks, but could occur at any time during INCIVEK
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`combination treatment. Rash events led to discontinuation of INCIVEK alone in 6% of subjects and discontinuation of INCIVEK combination treatment in
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`1% of subjects. Severe rash (e.g., a generalized rash or rash with vesicles or bullae or ulcerations other than SJS) was reported in 4% of subjects who
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`received INCIVEK combination treatment compared to less than 1% who received peginterferon alfa and ribavirin alone. The severe rash may have a
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`prominent eczematous component.
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`Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes
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`severe, INCIVEK should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of INCIVEK
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`discontinuation, sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa should be considered. If medically indicated,
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`earlier interruption or discontinuation of ribavirin and peginterferon alfa should be considered [see also Boxed Warning]. Patients should be monitored until
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`the rash has resolved. INCIVEK must not be reduced or restarted if discontinued due to rash. Treatment of rash with oral antihistamines and/or topical
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`corticosteroids may provide symptomatic relief but effectiveness of these measures has not been established. Treatment of rash with systemic corticosteroids
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`is not recommended [see Drug Interactions (7)].
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`5.2 Anemia
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`Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of INCIVEK to peginterferon alfa and ribavirin is associated with an
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`additional decrease in hemoglobin concentrations. A decrease in hemoglobin levels occurred during the first 4 weeks of treatment, with lowest values
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`reached at the end of INCIVEK dosing. Hemoglobin values gradually returned to levels observed with peginterferon alfa and ribavirin after INCIVEK
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`dosing was completed. Hemoglobin values less than or equal to 10 g per dL were observed in 36% of subjects who received INCIVEK combination
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`treatment compared to 17% of subjects who received peginterferon alfa and ribavirin. In clinical trials, the median time to onset of hemoglobin less than or
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`equal to 10 g per dL was faster among subjects treated with INCIVEK combination treatment compared to those who received peginterferon alfa and
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`ribavirin: 56 days (range 8-365 days) versus 63 days (range 13-341 days), respectively. Hemoglobin values less than 8.5 g per dL were observed in 14% of
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`subjects who received INCIVEK combination treatment compared to 5% of subjects receiving peginterferon alfa and ribavirin.
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`In subjects receiving INCIVEK combination treatment, 32% underwent a ribavirin dose modification (reduction, interruption or discontinuation) due to
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`anemia, 6% received a blood transfusion, 4% discontinued INCIVEK, and 1% discontinued INCIVEK combination treatment. In subjects treated with
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`peginterferon alfa and ribavirin alone, 12% underwent ribavirin dose modification due to anemia, 1% received a blood transfusion, and fewer than 1%
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`discontinued treatment. Anemia requiring ribavirin dose reduction, blood transfusion, and/or erythropoiesis stimulating agent (ESA) has been reported to
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`occur as soon as 10 days following initiation of INCIVEK combination treatment.
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`Hemoglobin should be monitored prior to and at least at weeks 2, 4, 8 and 12 during INCIVEK combination treatment and as clinically appropriate. Earlier
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`and more frequent monitoring for some patients should be considered. For the management of anemia, ribavirin dose reductions should be used (refer to the
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`prescribing information for ribavirin for its dose reduction guidelines). If ribavirin dose reductions are inadequate, discontinuation of INCIVEK should be
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`considered. If ribavirin is permanently discontinued for the management of anemia, INCIVEK must also be permanently discontinued. Ribavirin may be
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`restarted per the dosing modification guidelines for ribavirin. The dose of INCIVEK must not be reduced and INCIVEK must not be restarted if
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`discontinued.
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`5.3 Pregnancy: Use with Ribavirin and Peginterferon Alfa
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`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
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`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
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`therapy.
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`Because INCIVEK must be used in combination with peginterferon alfa and ribavirin, the contraindications and warnings applicable to those drugs are
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`applicable to combination therapy. Female patients of childbearing potential and their male partners as well as male patients and their female partners must
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`use 2 effective contraceptive methods during treatment and for 6 months after all treatment has ended. Female patients should have monthly pregnancy tests
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`during treatment and during the 6-month period after stopping treatment. Extreme care must be taken to avoid pregnancy in female patients and in female
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`partners of male patients as significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin [see
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`Contraindications (4) and Use in Specific Populations (8.1)]. Refer also to the prescribing information for ribavirin.
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`Female Patients
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`Hormonal contraceptives may be continued but may not be reliable during INCIVEK dosing and for up to 2 weeks following cessation of INCIVEK [see
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`Drug Interactions (7)]. During this time, female patients of childbearing potential should use 2 effective non-hormonal methods of contraception. Examples
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`may include barrier methods or intrauterine devices (IUDs) [see also Use in Specific Populations (8.1)]. Two weeks after completion of INCIVEK
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`treatment, hormonal contraceptives are again appropriate as one of the 2 required effective methods of birth control; however, specific prescribing
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`information recommendations should be followed for the contraceptives.
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`5.4 Drug Interactions
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`See Table 3 for a listing of drugs that are contraindicated for use with INCIVEK due to potentially life-threatening adverse events or potential loss of
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`therapeutic effect to INCIVEK [see Contraindications (4)]. Refer to Table 5 for established and other potentially significant drug-drug interactions [see
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`Drug Interactions (7)].
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`5.5 Laboratory Tests
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`HCV RNA levels should be monitored at weeks 4 and 12 and as clinically indicated. Use of a sensitive real-time RT-PCR assay for monitoring HCV RNA
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`levels during treatment is recommended. The assay should have a lower limit of HCV RNA quantification equal to or less than 25 IU per mL and a limit of
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`HCV RNA detection of approximately 10-15 IU per mL. For the purpose of assessing response-guided therapy eligibility, an “undetectable” HCV RNA
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`(Target Not Detected) result is required; a confirmed “detectable but below limit of quantification” HCV RNA result should not be considered equivalent to
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`an “undetectable” HCV RNA result (reported as "Target Not Detected" or "HCV RNA Not Detected").
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`Hematology evaluations (including hemoglobin, white cell differential, and platelet count) are recommended prior to and at weeks 2, 4, 8 and 12 and as
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`clinically appropriate. Chemistry evaluations (including electrolytes, serum creatinine, uric acid, hepatic enzymes, bilirubin, and TSH) are recommended as
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`frequently as hematology evaluations or as clinically appropriate [see Adverse Reactions (6.1)].
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`Refer to the prescribing information for peginterferon alfa and ribavirin, including pregnancy testing requirements.
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` 5 of 28
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`Reference ID: 3397093
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2024, Page 5
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`5.6 General
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`INCIVEK must not be administered as monotherapy and must only be prescribed with both peginterferon alfa and ribavirin. Therefore, the prescribing
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`information for peginterferon alfa and ribavirin must be consulted before starting treatment with INCIVEK.
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`There are no clinical data on re-treating patients who have failed an HCV NS3/4A protease inhibitor-based treatment, nor are there data on repeated courses
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`of INCIVEK [see Microbiology (12.4)].
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`5.7 Hepatic Impairment
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`INCIVEK is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) or patients with
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`decompensated liver disease. Refer to prescribing information for peginterferon alfa and ribavirin which must be co-administered with INCIVEK [see Use in
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`Specific Populations (8.6)].
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`ADVERSE REACTIONS
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`The following adverse reactions are discussed in greater detail in other sections of the label:
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`Serious Skin Reactions/Rash [see Boxed Warning and Warnings and Precautions (5.1)]
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`•
`Anemia [see Warnings and Precautions (5.2)]
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`•
`Pregnancy: Use with Ribavirin and Peginterferon alfa [see Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations
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`•
`(8.1)]
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`INCIVEK must be administered with peginterferon alfa and ribavirin. Refer to their respective prescribing information for their associated adverse reactions.
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`6.1 Clinical Trials Experience
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`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly
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`compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
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`The safety assessment is based on data from pooled adequate and well-controlled clinical trials including 1797 subjects who received INCIVEK combination
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`treatment and 493 who received peginterferon alfa and ribavirin.
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`Serious adverse drug reactions occurred in 3% of subjects who received INCIVEK combination treatment compared to none of the subjects treated with
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`peginterferon alfa and ribavirin. The most frequent serious adverse events in subjects treated with INCIVEK combination treatment were skin disorders (rash
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`and/or pruritus) and anemia [see Warnings and Precautions (5.1 and 5.2)]. Fourteen percent of subjects discontinued INCIVEK due to adverse drug
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`reactions. Rash, anemia, fatigue, pruritus, nausea, and vomiting were the most frequent adverse drug reactions leading to discontinuation of INCIVEK.
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`INCIVEK was administered in combination with peginterferon alfa and ribavirin. The following table lists adverse drug reactions that occurred in subjects
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`treated with INCIVEK with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone (Table 4).
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`Table 4: Clinical Adverse Drug Reactions Reported with at Least 5% Higher Frequency Among Subjects Receiving INCIVEK
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` INCIVEK, peginterferon alfa, and ribavirin
` Peginterferon alfa and ribavirin
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` Combination Treatment
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` N=493
` N=1797
` Rash*
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` 56%
` 34%
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` Fatigue
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` 56%
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` 50%
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` Pruritus
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` 47%
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` 28%
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` Nausea
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` 39%
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` 28%
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`Anemia*
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` 36%
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` 17%
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