`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
` TECHNIVIE safely and effectively. See full prescribing information for
`
` TECHNIVIE.
`
` TECHNIVIE (ombitasvir, paritaprevir and ritonavir) tablets, for oral use
`
` Initial U.S. Approval: 2015
`
`
`• Patients with moderate to severe hepatic impairment. (4, 5.2, 8.6, 12.3)
`
`
`• Co-administration with drugs that are: highly dependent on CYP3A for
`
`
`
`
`
`clearance; moderate and strong inducers of CYP3A. (4)
`
`
`• Known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis,
`
`
`Stevens-Johnson syndrome). (4)
`
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`• Risk of Hepatitis B Virus Reactivation:
`
`
`
`Test all patients for evidence of current or prior HBV infection before
`
`
`initiation of HCV treatment. Monitor HCV/HBV coinfected patients for
`
`
`
`
`
`HBV reactivation and hepatitis flare during HCV treatment and post­
`
`
`
`treatment follow-up. Initiate appropriate patient management for HBV
`
`infection as clinically indicated. (5.1)
`
`
`
`• Hepatic Decompensation and Hepatic Failure in Patient with Cirrhosis:
`
`
`
`Hepatic decompensation and hepatic failure, including liver transplantation
`
`
`
`
`or fatal outcomes, have been reported mostly in patients with advanced
`
`
`
`cirrhosis. Discontinue treatment in patients who develop evidence of
`
`
`
`
`hepatic decompensation. (5.2)
`
`
`• ALT Elevations: Discontinue ethinyl estradiol-containing medications prior
`
`
`
`
`to starting TECHNIVIE (alternative contraceptive methods are
`
`
`recommended). Perform hepatic laboratory testing on all patients during the
`
`
`
`first 4 weeks of treatment. For ALT elevations on TECHNIVIE, monitor
`
`
`closely and follow recommendations in full prescribing information. (5.3)
`
`
`
`• Risks Associated With Ribavirin Combination Treatment: The warnings
`
`
`
`and precautions for ribavirin also apply to this combination regimen. (5.4)
`
`
`
`
`• Drug Interactions: The concomitant use of TECHNIVIE and certain other
`
`
`
`
`drugs may result in known or potentially significant drug interactions, some
`
`
`
`of which may lead to loss of therapeutic effect of TECHNIVIE. (5.5)
`
`
`
`
`ADVERSE REACTIONS
`
`
`The most commonly reported adverse reactions (incidence greater than 10%
`
`of subjects, all grades) observed with treatment with ombitasvir, paritaprevir
`
`
`
`and ritonavir with ribavirin for 12 weeks were asthenia, fatigue, nausea and
`
`
`
`insomnia. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
`
`at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`
`
`DRUG INTERACTIONS
`
`
`Co-administration of TECHNIVIE can alter the plasma concentrations of
`
`some drugs and some drugs may alter the plasma concentrations of
`
`
`TECHNIVIE. The potential for drug-drug interactions must be considered
`
`
`
`before and during treatment. Consult the full prescribing information prior to
`
`
`
`
`
`and during treatment for potential drug interactions. (4, 5.5, 7, 12.3)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide.
`
`
`
`Revised: 2/2017
`
`
`
`WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
`PATIENTS COINFECTED WITH HCV AND HBV
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`Hepatitis B virus (HBV) reactivation has been reported, in some cases
`
`
`
`
`
`resulting in fulminant hepatitis, hepatic failure, and death. (5.1)
`
`
`
`
`
`
`
`
`
`
` RECENT MAJOR CHANGES
`
`
`Boxed Warning
`Dosage and Administration (2.1)
`
`
`Contraindications (4)
`
`Warnings and Precautions (5.1)
`
`
`
`2/2017
`
`2/2017
`
`5/2016
`
`2/2017
`
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
`
` TECHNIVIE is a fixed-dose combination of ombitasvir, a hepatitis C virus
`
` NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor,
`
` and ritonavir, a CYP3A inhibitor and is indicated in combination with
`
`
`
`
` ribavirin for the treatment of patients with genotype 4 chronic hepatitis C
`
`
`
` virus (HCV) infection without cirrhosis. (1)
`
`
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`Testing Prior to the Initiation of Therapy:
`
`
`
`
`
`• Test all patients for HBV infection by measuring HBsAg and anti-HBc.
`
`
`
`
`(2.1)
`
`• Assess baseline hepatic laboratory and clinical parameters. (2.1)
`
`
`
`
`Recommended dosage: Two tablets taken orally once daily (in the morning)
`
`
`with a meal without regard to fat or calorie content. TECHNIVIE is
`
`
`recommended to be used in combination with ribavirin. (2.2)
`
`
`
`
`
`
`
`Duration
`Treatment
`Patient Population
`
`
`
`Genotype 4 without cirrhosis
`
`12 weeks
`TECHNIVIE + ribavirin*
`
`
`
`*TECHNIVIE administered without ribavirin for 12 weeks may be considered
`
`
`
` for treatment-naïve patients who cannot take or tolerate ribavirin [see
`Microbiology (12.4) and Clinical Studies (14)].
`
`
`
`
`
`
`
`
` DOSAGE FORMS AND STRENGTHS
` Tablets: 12.5 mg ombitasvir, 75 mg paritaprevir, 50 mg ritonavir. (3)
`
`
`CONTRAINDICATIONS
`
`
`• The contraindications to ribavirin also apply to this combination regimen.
`
`
`
`(4)
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN
`PATIENTS COINFECTED WITH HCV AND HBV
`
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Testing Prior to the Initiation of Therapy
`
`
`
`2.2 Recommended Dosage in Adults
`
`
`2.3 Dosage in Patients with Hepatic Impairment
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV
`
`
`
`and HBV
`
`5.2 Risk of Hepatic Decompensation and Hepatic Failure in Patients with
`
`
`
`Cirrhosis
`
`5.3 Increased Risk of ALT Elevations
`
`
`5.4 Risks Associated With Ribavirin Combination Treatment
`
`
`
`5.5 Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug
`
`
`
`
`Interactions
`
`5.6 Risk of HIV-1 Protease Inhibitor Drug Resistance in HCV/HIV-1 Co­
`
`
`
`infected Patients
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`
`
`6.2 Post-Marketing Experience
`
`7 DRUG INTERACTIONS
`
`7.1 Potential for TECHNIVIE to Affect Other Drugs
`
`7.2 Potential for Other Drugs to Affect One or More Components of
`
`
`
`
`TECHNIVIE
`
`
`7.3 Established and Other Potential Drug Interactions
`
`
`7.4 Drugs without Clinically Significant Interactions with TECHNIVIE
`
`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
`
`
`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
`
`
`
`
`Reference ID: 4055837
`
`
`
`
`Page 1 of 35
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`

`

`
`
` 14 CLINICAL STUDIES
`
` 14.1 Clinical Trial Results in Adults with Chronic GT4 HCV Infection
`
` without Cirrhosis
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`
` *Sections or subsections omitted from the full prescribing information are not
`
` listed.
`
`
`
`
`
`
`Reference ID: 4055837
`
`
`
`
`Page 2 of 35
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`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
` WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS
`
`
`
`
` COINFECTED WITH HCV AND HBV
`
`
`
`
`
`Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before
`initiating treatment with TECHNIVIE. HBV reactivation has been reported in
`
`
`
` HCV/HBV coinfected patients who were undergoing or had completed treatment with
` HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases
`
`
` have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV
` coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and
`
` post-treatment follow-up. Initiate appropriate patient management for HBV infection as
`
`
`
` clinically indicated [see Warnings and Precautions (5.1)].
`
`
`
`
`
` 1 INDICATIONS AND USAGE
`
` TECHNIVIE is indicated in combination with ribavirin for the treatment of patients with
`
`genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis.
`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
` 2.1 Testing Prior to the Initiation of Therapy
`
`
`
`
`
`
` • Test all patients for evidence of current or prior HBV infection by measuring hepatitis B
`
`
`
` surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV
`
`
`
` treatment with TECHNIVIE [see Warnings and Precautions (5.1)].
`
`
`
` • Prior to initiation of TECHNIVIE, assess baseline hepatic laboratory and clinical
`
`
`
` parameters [see Contraindications (4) and Warnings and Precautions (5.2 and 5.3)].
`
`
`
`
`
`
` 2.2 Recommended Dosage in Adults
`
`TECHNIVIE is ombitasvir, paritaprevir and ritonavir fixed dose combination tablets.
`
`
`
` The recommended dosage of TECHNIVIE is two tablets taken orally once daily (in the
`morning). Take TECHNIVIE with a meal without regard to fat or calorie content [see Clinical
`Pharmacology (12.3)].
`
`TECHNIVIE is used in combination with ribavirin (RBV). When administered with
`
`
`TECHNIVIE, the recommended dosage of RBV is based on weight: 1000 mg per day for
`
`subjects less than 75 kg and 1200 mg per day for those weighing at least 75 kg, divided and
`
`administered twice-daily with food. For ribavirin dosage modifications, refer to the ribavirin
`
`prescribing information.
`
`
`Table 1 shows the recommended TECHNIVIE treatment regimen and duration for HCV
`
`genotype 4 patients without cirrhosis.
`
`
`
`
`
`Reference ID: 4055837
`
`
`
`
`
`
` Page 3 of 35
`
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`PGR2019-00048
`Corcept Ex. 2032, Page 3
`
`

`

`Table 1. Treatment Regimen and Duration for Patients with HCV Genotype 4 without
`
`Cirrhosis
`
`
`
`Duration
`Treatment
`Patient Population
`
`
`
`
`
`12 weeks
`TECHNIVIE + ribavirin*
`Genotype 4 without cirrhosis
`
`
`*TECHNIVIE administered without RBV for 12 weeks may be considered for treatment-naïve
` patients who cannot take or tolerate ribavirin [see Microbiology (12.4) and Clinical Studies
`
`
`
`
`(14)].
`
`
`
`
`
`
` 2.3 Dosage in Patients with Hepatic Impairment
`
`TECHNIVIE is contraindicated in patients with moderate to severe hepatic impairment (Child-
`
`
`
`
` Pugh B and C) [see Contraindications (4), Warnings and Precautions (5.2), Use in Specific
`
` Populations (8.6), and Clinical Pharmacology (12.3)].
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`TECHNIVIE is a pink-colored, film-coated, oblong, biconvex-shaped tablet debossed “AV1” on
`
`
` one side. Each tablet contains 12.5 mg ombitasvir, 75 mg paritaprevir and 50 mg ritonavir.
`
`
`
` 4 CONTRAINDICATIONS
`
` • The contraindications to ribavirin also apply to this combination regimen. Refer to the
`
`
`
`
` ribavirin prescribing information for a list of contraindications for ribavirin.
`
`
`• TECHNIVIE is contraindicated:
`
`
` ◦ In patients with moderate to severe hepatic impairment (Child-Pugh B and C) due to risk
`
` of potential toxicity [see Warnings and Precautions (5.2), Use in Specific Populations
`
`
`
`
` (8.6) and Clinical Pharmacology (12.3)].
`
` ◦ 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.
`
`
`◦ With drugs that are moderate or strong inducers of CYP3A and may lead to reduced
`
`
` efficacy of TECHNIVIE.
` ◦ In patients with known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis
`
`(TEN) or Stevens-Johnson syndrome).
`
`Table 2 lists drugs that are contraindicated with TECHNIVIE [see Drug Interactions (7)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Table 2. Drugs that are Contraindicated with TECHNIVIE
`Drug(s) within Class
`
`
` that are
`Contraindicated
`
`
`Alfuzosin HCl
`
`
`
` Clinical Comments
`
`
`Potential for hypotension.
`
`Drug Class
`
`
`
`Alpha1-adrenoreceptor
`
`antagonist
`
`Anti-gout
`
`
`Colchicine
`
`
`Potential for serious and/or life-threatening
`
`reactions in patients with renal and/or hepatic
`
`Reference ID: 4055837
`
`
`
`
`Page 4 of 35
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`PGR2019-00048
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`

`
`
` Anti-anginal
`
`
`
` Ranolazine
`
`
`
` Antiarrhythmic
`
`
`
` Dronedarone
`
`
`
` Anticonvulsants
`
`
`
` Antimycobacterial
`
`
` Carbamazepine,
`
`phenytoin,
`
` phenobarbital
`
` Rifampin
`
`
`
` Antipsychotic
`
`
`
` Lurasidone
`
` Pimozide
`
`
`
`
`
` Ergot derivatives
`
`Ergotamine,
`dihydroergotamine,
`methylergonovine
`
`
`Ethinyl estradiol­
` containing products
`
`
`
`
` GI Motility Agent
`
`
`
`
`
` Herbal Product
`
`HMG-CoA Reductase
`
` Inhibitors
`Non-nucleoside reverse
`
` transcriptase inhibitor
`
`Phosphodiesterase-5
`
` (PDE5) inhibitor
`
`
`
` Sedatives/hypnotics
`
`Ethinyl estradiol­
`
` containing medications
`
` such as combined oral
`
` contraceptives
`
` Cisapride
`
`
`
` St. John’s Wort
` (Hypericum
`
`
` perforatum)
`
` Lovastatin,
`
` simvastatin
`
` Efavirenz
`
`Sildenafil when dosed
`as Revatio for the
` treatment of pulmonary
`
`arterial hypertension
`
`(PAH)
` Triazolam
`
` Orally administered
`
` midazolam
`
`
`
`
`
`
`
` impairment.
`
` Potential for serious and/or life-threatening
`
` reactions.
`
` Potential for serious and/or life-threatening
` reactions such as cardiac arrhythmias.
`
`
`
` Ombitasvir, paritaprevir and ritonavir exposures
`
` may decrease leading to a potential loss of
`
` therapeutic activity of TECHNIVIE.
`
`
` Ombitasvir, paritaprevir and ritonavir exposures
`
`
` may decrease leading to a potential loss of
`
` therapeutic activity of TECHNIVIE.
`
`
` Potential for serious and/or life-threatening
`
`
` reactions.
`
`Potential for serious and/or life-threatening
`
`
`
` reactions such as cardiac arrhythmias.
` Acute ergot toxicity characterized by
`
`vasospasm and tissue ischemia has been
`associated with co-administration of ritonavir
`
`and ergonovine, ergotamine,
`dihydroergotamine, or methylergonovine.
`
`
`
` Potential for ALT elevations [see Warnings and
`
` Precautions (5.3)].
`
`
`
`
`
`
`
`
` Potential for serious and/or life threatening
` reactions such as cardiac arrhythmias
`
`
`
` Ombitasvir, paritaprevir and ritonavir exposures
`
` may decrease leading to a potential loss of
`
` therapeutic activity of TECHNIVIE.
`
`
` Potential for myopathy including
`
`
` rhabdomyolysis.
` Co-administration of efavirenz based regimens
`
`with paritaprevir, ritonavir was poorly tolerated
`
`and resulted in liver enzyme elevations.
`There is increased potential for sildenafil­
`
` associated adverse events such as visual
`disturbances, hypotension, priapism, and
`
`syncope.
`
`Triazolam and orally administered midazolam
`
` are extensively metabolized by CYP3A4.
`
` Coadministration of triazolam or orally
`
`Reference ID: 4055837
`
`
`
`
`
`
` Page 5 of 35
`
`
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2032, Page 5
`
`

`

` administered midazolam with TECHNIVIE
`
`
`
` may cause large increases in the concentration
`
` of these benzodiazepines. The potential exists
` for serious and/or life threatening events such as
`
` prolonged or increased sedation or respiratory
`
`depression.
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
`
`
`
` 5.1 Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
`
` Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who
`
`
` were undergoing or had completed treatment with HCV direct acting antivirals, and who were
`
`
` not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic
`
`
` failure and death. Cases have been reported in patients who are HBsAg positive and also in
`
` patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc
`
`
` positive). HBV reactivation has also been reported in patients receiving certain
`
`
`
` immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with
`
` treatment with HCV direct-acting antivirals may be increased in these patients.
`
`
` HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a
`
`
`
` rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance
`
`
` of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e.,
`
` increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver
`
`
`
`
` failure, and death can occur.
`Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti-
`
`
` HBc before initiating HCV treatment with TECHNIVIE. In patients with serologic evidence of
`
` HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation
`
` during HCV treatment with TECHNIVIE and during post-treatment follow-up. Initiate
`
` appropriate patient management for HBV infection as clinically indicated.
`
`
`
`
`
` 5.2 Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
`
`
` TECHNIVIE is not indicated in patients with cirrhosis.
`Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes,
`
`
` have been reported postmarketing in patients treated with ombitasvir, paritaprevir, ritonavir with
`
` and without dasabuvir and with and without ribavirin. Most patients with these severe outcomes
`
` had evidence of advanced cirrhosis prior to initiating therapy. Reported cases typically occurred
`
` within one to four weeks of initiating therapy and were characterized by the acute onset of rising
`
`
`
`
` direct serum bilirubin levels without ALT elevations in association with clinical signs and
`
`
` symptoms of hepatic decompensation. Because these events are reported voluntarily from a
`
` population of uncertain size, it is not always possible to reliably estimate their frequency or
`
`
` establish a causal relationship to drug exposure. Discontinue treatment in patients who develop
`
` evidence of hepatic decompensation.
`
`
`Reference ID: 4055837
`
`
`
`
`Page 6 of 35
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2032, Page 6
`
`

`

`TECHNIVIE is contraindicated in patients with moderate to severe hepatic impairment (Child-
`
`
`Pugh B and C) [see Contraindications (4), Adverse Reactions (6.2), Use in Specific Populations
`
`
`
`(8.6), and Clinical Pharmacology (12.3)].
`
`
`
`
`5.3 Increased Risk of ALT Elevations
`
`During clinical trials with ombitasvir, paritaprevir and ritonavir with or without dasabuvir and
`
`with or without ribavirin, elevations of ALT to greater than 5 times the upper limit of normal
`(ULN) occurred in approximately 1% of subjects [see Adverse Reactions (6.1)]. ALT elevations
`
`
`
`
`were typically asymptomatic, occurred during the first 4 weeks of treatment, and declined within
`
`two to eight weeks of onset with continued dosing.
`
`
`These ALT elevations were significantly more frequent in female subjects who were using
`
`ethinyl estradiol-containing medications such as combined oral contraceptives, contraceptive
`
`
`
`patches or contraceptive vaginal rings. Ethinyl estradiol-containing medications must be
`discontinued prior to starting therapy with TECHNIVIE [see Contraindications (4)]. Alternative
`
`
`
`
`methods of contraception (e.g., progestin only contraception or non-hormonal methods) are
`recommended during TECHNIVIE therapy. Ethinyl estradiol-containing medications can be
`
`
`restarted approximately 2 weeks following completion of treatment with TECHNIVIE.
`
`
`
`Women using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens
`
`
`used in hormone replacement therapy had a rate of ALT elevation similar to those not receiving
`
`
`any estrogens. Due to the limited number of subjects taking these other estrogens in clinical
`
`studies, caution is warranted for co-administration with TECHNIVIE [see Adverse Reactions
`
`(6.1)].
`
`
`
`Hepatic laboratory testing should be performed during the first 4 weeks of starting treatment and
`
`as clinically indicated thereafter. If ALT is found to be elevated above baseline levels, it should
`
`be repeated and monitored closely:
`
`
`
`• Patients should be instructed to consult their health care professional without delay if they
`
`
`
`
`have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or
`
`
`discolored feces.
`
`
`
`• Consider discontinuing TECHNIVIE if ALT levels remain persistently greater than 10 times
`
`
`the ULN.
`
`• Discontinue TECHNIVIE if ALT elevation is accompanied by signs or symptoms of liver
`
`
`
`
`inflammation or increasing direct bilirubin, alkaline phosphatase, or INR.
`
`
`
`
`5.4 Risks Associated With Ribavirin Combination Treatment
`
`
`The warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, apply
`
`
`
`to this combination regimen. Refer to the ribavirin prescribing information for a full list of the
`
`
`warnings and precautions for ribavirin.
`
`
`5.5 Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions
`
`
`The concomitant use of TECHNIVIE and certain other drugs may result in known or potentially
`
`
`
`significant drug interactions, some of which may lead to:
`
`
`• Loss of therapeutic effect of TECHNIVIE and possible development of resistance
`
`
`
`
`Reference ID: 4055837
`
`
`
`
`Page 7 of 35
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2032, Page 7
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`
`
`
`
`
`
` • Possible clinically significant adverse reactions from greater exposures of concomitant drugs
`
` or components of TECHNIVIE.
`
`See Table 4 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 TECHNIVIE therapy; review concomitant
`
`
`
`medications during TECHNIVIE therapy; and monitor for the adverse reactions associated with
`the concomitant drugs [see Contraindications (4) and Drug Interactions (7)].
`
`
`
`
`
`
`
`5.6 Risk of HIV-1 Protease Inhibitor Drug Resistance in HCV/HIV-1 Co-infected Patients
`
`
`The ritonavir component of TECHNIVIE is also an HIV-1 protease inhibitor and can select for
`
`
`HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected
`
`
`patients treated with TECHNIVIE should also be on a suppressive antiretroviral drug regimen to
`reduce the risk of HIV-1 protease inhibitor drug resistance.
`
`
`6 ADVERSE REACTIONS
`
`TECHNIVIE should be administered with ribavirin (RBV). Refer to the prescribing information
`
`for ribavirin for a list of ribavirin-associated adverse reactions.
`
`
`The following adverse reaction is described below and elsewhere in the labeling:
`
`
`• Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis [see
`
`
`
`
`Warnings and Precautions (5.2)]
`
`
`• Increased Risk of ALT Elevations [see Warnings and Precautions (5.3)]
`
`
`
`
`
`
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
`
`observed in clinical trials of ombitasvir, paritaprevir and ritonavir cannot be directly compared to
`
`rates in the clinical trials of another drug and may not reflect the rates observed in practice.
`
`
`
`
`The safety assessment of TECHNIVIE is based on data from a clinical study that included 135
`
`
`
`
`HCV genotype 4-infected subjects without cirrhosis, 91 who received ombitasvir 25 mg,
`paritaprevir 150 mg and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three
`
`
`paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily with ribavirin for 12
`weeks and 44 subjects without cirrhosis who received ombitasvir 25 mg, paritaprevir 150 mg,
`and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg
`
`tablets and one ritonavir 100 mg capsule) once daily without ribavirin for 12 weeks (PEARL-I).
`
`
`Adverse reactions that occurred in subjects treated with ombitasvir, paritaprevir and ritonavir
`
`
`with or without ribavirin for 12 weeks are listed in Table 3. The majority of adverse reactions in
`
`PEARL-I were mild in severity. None of the subjects who received ombitasvir, paritaprevir and
`
`ritonavir with ribavirin experienced a serious adverse reaction. None of the subjects receiving
`
`ombitasvir, paritaprevir and ritonavir with or without ribavirin discontinued treatment due to an
`
`adverse reaction.
`
`
`
`
`
`
`Reference ID: 4055837
`
`
`
`
`Page 8 of 35
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2032, Page 8
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`
`
` Adverse Reaction
`
`
`
` Table 3. Selected Adverse Reactions (All Grades) with ≥5% Frequency Reported in
`
`
`
` Subjects Treated with Ombitasvir, Paritaprevir and Ritonavir with or without Ribavirin
`
` for 12 Weeks
`PEARL-I
`
`
`
`Ombitasvir, paritaprevir,
`Ombitasvir, paritaprevir,
`
` ritonavir + RBV
`
` ritonavir
`
` 12 Weeks
`
` 12 Weeks
`
` N = 91
`
`
` N = 44
`%
`%
`
`
`
`
`
`29
`25
`Asthenia
`
`
`
`15
`7
`Fatigue
`
`
`
`14
`9
`Nausea
`
`
`
`13
`5
`Insomnia
`
`
`
`7
`5
`Pruritus*
`Skin reactions$,#
`
`
`
`7
`5
`
`
`
`*Grouped term ‘pruritus’ includes the preferred terms pruritus and pruritus generalized.
` $Grouped term ‘skin reactions’ includes the preferred terms rash, erythema, eczema, rash
`
`
`maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash
`erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash,
`
`
`photosensitivity reaction, psoriasis, skin reaction, ulcer and urticaria.
`
`
`#The majority of events were graded as mild in severity. There were no serious events or severe
`
`cutaneous reactions, such as Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis
`
`(TEN), erythema multiforme (EM) or drug rash with eosinophilia and systemic symptoms
`
`
`
`(DRESS).
`
`
`
`
`
`
` Laboratory Abnormalities
`Serum ALT Elevations
`
`
`None of the 135 HCV GT4 infected subjects treated with TECHNIVIE experienced post-
`
`baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) after
`
`starting treatment [see Warnings and Precautions (5.3)].
`
`Serum Bilirubin Elevations
`
`
`
`Post-baseline elevations in bilirubin at least 2 times ULN were observed in 5% (7/134) of
`
`subjects receiving TECHNIVIE; all of whom were also receiving RBV. These bilirubin
`
`increases were predominately indirect and related to the inhibition of the bilirubin
`
`
`transporters OATP1B1/1B3 by paritaprevir and possibly ribavirin-induced hemolysis.
`Bilirubin elevations occurred early after initiation of treatment, peaked by study Week 1, and
`
`
`generally resolved with ongoing therapy. Bilirubin elevations were generally not associated
`
`with serum ALT elevations.
`Anemia/Decreased Hemoglobin
`
`
`The mean change from baseline in hemoglobin levels in subjects treated with TECHNIVIE
`
`
`
`in combination with ribavirin was -2.1 g/dL and the mean change in subjects treated with
`
`
`TECHNIVIE alone was -0.4 g/dL. Decreases in hemoglobin levels occurred early in
`
`Reference ID: 4055837
`
`
`
`
`Page 9 of 35
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`
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2032, Page 9
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`

`

`treatment (Week 1-2) with further reductions through Week 3. Hemoglobin values remained
`
`low during the remainder of treatment and returned towards baseline levels by post-treatment
`
`
`Week 4. One subject treated with TECHNIVIE with ribavirin had a single hemoglobin level
`decrease to less than 8 g/dL during treatment. Four percent (4/91) of subjects treated with
`
`TECHNIVIE with ribavirin underwent ribavirin dose reductions to manage anemia/decreased
`
`hemoglobin levels; none received a blood transfusion or erythropoietin. No subjects treated
`
`
`with TECHNIVIE alone had a hemoglobin level less than 8 g/dL.
`
`
`6.2 Post-Marketing Experience
`
`
`
`The following adverse reactions have been identified during post approval use of TECHNIVIE.
`
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`
`
`
`
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`
`exposure.
`
`
`Immune System Disorders: Hypersensitivity reactions (including angioedema).
`Hepatobiliary Disorders: Hepatic decompensation, hepatic failure [see Warnings and
`
`
`Precautions (5.2)].
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Potential for TECHNIVIE to Affect Other Drugs
`
`
`Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir and ritonavir are
`
`
`inhibitors of BCRP and P-gp. Ritonavir is an inhibitor of CYP3A4. Co-administration of
`
`TECHNIVIE with drugs that are substrates of CYP3A, P-gp, BCRP, OATP1B1 or OATP1B3
`
`may result in increased plasma concentrations of such drugs [see also Contraindications (4),
`
`
`Warnings and Precautions (5.5), and Clinical Pharmacology (12.3)].
`
`
`
`7.2 Potential for Other Drugs to Affect One or More Components of TECHNIVIE
`
`Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes. Co-administration of
`
`TECHNIVIE with strong inhibitors of CYP3A may increase paritaprevir and ritonavir
`
`
`concentrations. Ombitasvir is primarily metabolized via amide hydrolysis while CYP enzymes
`
`
`play a minor role in its metabolism. Ombitasvir, paritaprevir and ritonavir are substrates of P-gp.
`
`
`
`Paritaprevir is a substrate of BCRP, OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP,
`OATP1B1 or OATP1B3 may increase the plasma concentrations of the various components of
`
`
`TECHNIVIE.
`
`
`7.3 Established and Other Potential Drug Interactions
`
`
`If dosage adjustments of concomitant medications are made due to treatment with TECHNIVIE,
`
`
`dosages should be re-adjusted after administration of TECHNIVIE is completed. Dosage
`
`
`adjustment is not required for TECHNIVIE.
`
`Table 4 provides the effect of co-administration of TECHNIVIE on concentrations of
`
`
`
`concomitant drugs and the effect of concomitant drugs on the various components of
`
`
`TECHNIVIE. See Contraindications (4) for drugs that are contraindicated with TECHNIVIE.
`
`
`
`Reference ID: 4055837
`
`
`
`
`Page 10 of 35
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2032, Page 10
`
`

`

`
`
` Refer to the ritonavir prescribing information for other potentially significant drug interactions
`
`with ritonavir.
`
`
`
`
`
`
`
`Table 4. Established Drug Interactions Based on Drug Interaction Trials
`
`Concomitant Drug Class:
`Effect on
`
`
`
` Clinical Comments
`Drug Name
`Concentration
`
`
`ANGIOTENSIN RECEPTOR BLOCKERS e.g.
`
`Decrease the dose of the angiotensin receptor
`valsartan*,
`↑ angiotensin
`
`
`blockers and monitor patients for signs and
`losartan*,
`receptor blockers
`
`
`
`symptoms of hypotension and/or worsening
`candesartan*
`
`
`renal function. If such events occur, consider
`
`further dose reduction of the angiotensin
`
`
`receptor blocker or switching to an
`alternative to the angiotensin receptor
`
`blocker.
`
`
`ANTIARRHYTHMICS
`
`digoxin
`
`
`↑ digoxin
`
`
`amiodarone*,
`
`bepridil*,
`
`
`disopyramide*,
`
`flecainide*,
`
`lidocaine (systemic)*,
`
`mexiletine*,
`
`propafenone*,
`quinidine*
`
`ANTIDIABETIC DRUGS
`
`metformin
`
`
`↑ antiarrhythmics
`
`
`
`↔ metformin
`
`
`
`ANTIFUNGALS
`
`ketoconazole
`
`
`↑ ketoconazole
`
`
`voriconazole*
`
`
`↓ voriconazole
`
`
`Decrease digoxin dose by 30-50%.
`
`Appropriate monitoring of serum digoxin
`
`levels is recommended.
`
`Therapeutic monitoring (if available) is
`
`recommended for antiarrhythmics when co­
`administered with TECHNIVIE.
`
`
`Monitor for signs of onset of lactic acidosis
`
`such as respiratory distress, somnolence, and
`
` non-specific abdominal distress or worsening
`
`renal function. Concomitant metformin use in
`patients with renal insufficiency or hepatic
`
`impairment is not recommended. Refer to the
`
`prescribing information of metformin for
`
`further guidance.
`
`
`When TECHNIVIE is co-administered with
`
`ketoconazole, the maximum daily dose of
`
`ketoconazole should be limited to 200 mg per
`
`day.
`
`Co-administration of TECHNIVIE with
`
`voriconazole is not recommended unless an
`assessment of the benefit-to-risk ratio
`
`
`Reference ID: 40558