HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
`
` NORVIR safely and effectively. See full prescribing information for
`
`
`
` NORVIR.
`
`
` NORVIR (ritonavir) capsules, soft gelatin for oral use
` Initial U.S. Approval: 1996
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`• The concomitant use of NORVIR and certain other drugs may result in
`
`
`
`known or potentially significant drug interactions. Consult the full
`
`
`
`
`
`prescribing information prior to and during treatment for potential drug
`
`
`
`interactions. (5.1, 7.2)
`
`• Hepatic Reactions: Fatalities have occurred. Monitor liver function before
`
`
`
`
`
`and during therapy, especially in patients with underlying hepatic disease,
`
`
`
`
`including hepatitis B and hepatitis C, or marked transaminase elevations.
`
`
`(5.2, 8.6)
`
`
`• Pancreatitis: Fatalities have occurred; suspend therapy as clinically
`
`
`appropriate. (5.3)
`
`• Allergic Reactions/Hypersensitivity: Allergic reactions have been reported
`
`
`
`
`and include anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson
`
`syndrome, bronchospasm and angioedema. Discontinue treatment if severe
`
`
`
`reactions develop. (5.4, 6.2)
`
`• PR interval prolongation may occur in some patients. Cases of second and
`
`
`
`
`
`
`
`third degree heart block have been reported. Use with caution with patients
`
`
`
`with preexisting conduction system disease, ischemic heart disease,
`
`
`cardiomyopathy, underlying structural heart disease or when administering
`
`
`
`
`
`with other drugs that may prolong the PR interval. (5.5, 12.3)
`
`
`
`
`• Total cholesterol and triglycerides elevations: Monitor prior to therapy and
`
`
`
`periodically thereafter. (5.6)
`
`• Patients may develop new onset or exacerbations of diabetes mellitus,
`
`
`hyperglycemia. (5.7)
`
`
`• Patients may develop immune reconstitution syndrome. (5.8)
`
`
`
`• Patients may develop redistribution/accumulation of body fat. (5.9)
`
`
`
`• Hemophilia: Spontaneous bleeding may occur, and additional factor VIII
`
`
`
`may be required. (5.10)
`
`
`
`
`
`ADVERSE REACTIONS
`
`The most frequently reported adverse drug reactions among patients receiving
`
`NORVIR alone or in combination with other antiretroviral drugs were
`
`
`
`gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper
`
`
`
`
`and lower), neurological disturbances (including paresthesia and oral
`
`
`paresthesia), rash, and fatigue/asthenia (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 NORVIR can alter the concentrations of other drugs.
`
`
`The potential for drug-drug interactions must be considered prior to and
`
`
`
`during therapy. (4, 5.1, 7, 12.3)
`
`
`
`
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`• 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: 12/2016
`
`
`
`
`
`
`
`
`
`5.9 Fat Redistribution
`
`5.10 Patients with Hemophilia
`5.11 Resistance/Cross-resistance
`
`5.12 Laboratory Tests
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trial Experience
`
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`
`
`7.1 Potential for NORVIR to Affect Other Drugs
`
`
`7.2 Established and Other Potentially Significant Drug Interactions
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`
`8.3 Females and Males of Reproductive Potential
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Hepatic Impairment
`10 OVERDOSAGE
`
`
`10.1 Acute Overdosage - Human Overdose Experience
`
`
`
`
` WARNING: DRUG-DRUG INTERACTIONS LEADING TO
`
` POTENTIALLY SERIOUS AND/OR LIFE THREATENING
`
`
` REACTIONS
` See full prescribing information for complete boxed warning
`
`
`
`
` Co-administration of NORVIR with several classes of drugs including
`
`
`
`
` sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may
`
`
`
` result in potentially serious and/or life-threatening adverse events due to
`
`
` possible effects of NORVIR on the hepatic metabolism of certain drugs.
`
`
`
`
` Review medications taken by patients prior to prescribing NORVIR or
`
` when prescribing other medications to patients already taking NORVIR
`
` [see Contraindications (4), Warnings and Precautions (5.1), Drug
`
`
`
` Interactions (7), and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
`
`
` RECENT MAJOR CHANGES
`
`
`
` Contraindications (4)
`
` Warnings and Precautions
`
` Diabetes Mellitus/Hyperglycemia (5.7)
`
`
`
`
`
`
`
` 11/2016
`
`
` 11/2016
`
`
`
`
`
` INDICATIONS AND USAGE
`
`
`
` NORVIR is an HIV protease inhibitor indicated in combination with other
` antiretroviral agents for the treatment of HIV-1 infection. (1)
`
`
`
`
`
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`• Dose modification for NORVIR is necessary when used with other protease
`
`
`
`inhibitors. (2)
`
`
`
`
`
`• Adult patients: 600 mg twice-daily with meals if possible. (2.1)
`
`
`
`• Pediatrics patients: The recommended twice daily dose for children greater
`
`
`
`
`
`than one month of age is based on body surface area and should not exceed
`
`
`
`
`
`600 mg twice daily with meals if possible. (2.2)
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`• Capsule, Soft Gelatin: 100 mg. (3)
`
`
`
`
`
`
`
`
`CONTRAINDICATIONS
`
`
`
`• NORVIR is contraindicated in patients with known hypersensitivity to
`
`
`ritonavir (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) or
`
`
`
`any of its ingredients. (4)
`
`
`
`
`• Co-administration with drugs highly dependent on CYP3A for clearance
`
`
`and for which elevated plasma concentrations may be associated with
`
`serious and/or life-threatening events. (4)
`
`
`
`
`• Co-administration with drugs that significantly reduce ritonavir. (4)
`
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`The following have been observed in patients receiving NORVIR:
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`WARNING: DRUG-DRUG INTERACTIONS LEADING TO
`
`
`POTENTIALLY SERIOUS AND/OR LIFE THREATENING
`REACTIONS
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Adult Patients
`
`2.2 Pediatric Patients
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Risk of Serious Adverse Reactions Due to Drug Interactions
`
`
`5.2 Hepatic Reactions
`
`5.3 Pancreatitis
`
`5.4 Allergic Reactions/Hypersensitivity
`
`5.5 PR Interval Prolongation
`
`5.6 Lipid Disorders
`
`
`5.7 Diabetes Mellitus/Hyperglycemia
`
`5.8 Immune Reconstitution Syndrome
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 1
`
`

`

`
`
`
` 10.2 Management of Overdosage
`
` 11 DESCRIPTION
` 12 CLINICAL PHARMACOLOGY
`
` 12.1 Mechanism of Action
`
` 12.3 Pharmacokinetics
`
` 12.4 Microbiology
`
` 13 NONCLINICAL TOXICOLOGY
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
` 14 CLINICAL STUDIES
`
`
`
`
`
`
`
`
`
` 14.1 Advanced Patients with Prior Antiretroviral Therapy
`
` 14.2 Patients Without Prior Antiretroviral Therapy
`
` 15 REFERENCES
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 17 PATIENT COUNSELING INFORMATION
`
` *Sections or subsections omitted from the full prescribing information are not
`
` listed.
`
`
`
`
`
`
`
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
` WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS
`
` AND/OR LIFE THREATENING REACTIONS
`Co-administration of NORVIR with several classes of drugs including sedative hypnotics,
`
`
` antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or
`life-threatening adverse events due to possible effects of NORVIR on the hepatic
`metabolism of certain drugs. Review medications taken by patients prior to prescribing
`
`NORVIR or when prescribing other medications to patients already taking NORVIR [see
`
`Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Clinical
`
`
`
`
`
`
` Pharmacology (12.3)].
`
`
`
` 1 INDICATIONS AND USAGE
`
` NORVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-1
`
`infection.
`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
` NORVIR is administered orally in combination with other antiretroviral agents. It is
`
` recommended that NORVIR be taken with meals if possible.
`
`
` General Dosing Guidelines
`
`
`
`
`
`Patients should be aware that frequently observed adverse events, such as mild to moderate
`
`
`gastrointestinal disturbances and paraesthesias, may diminish as therapy is continued.
`
`Dose modification for NORVIR
`
`Dose reduction of NORVIR is necessary when used with other protease inhibitors: atazanavir,
`
`darunavir, fosamprenavir, saquinavir, and tipranavir.
`
`
`
`Prescribers should consult the full prescribing information and clinical study information of these
`
`protease inhibitors if they are co-administered with a reduced dose of ritonavir [see Warnings
`
`
`
`
`
`and Precautions (5.1), and Drug Interactions (7)].
`
`
`
`2.1 Adult Patients
`
`Recommended Dosage for treatment of HIV-1
`
`The recommended dosage of ritonavir is 600 mg twice daily by mouth. Use of a dose titration
`schedule may help to reduce treatment-emergent adverse events while maintaining appropriate
`ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and
`
`
`increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice
`
`daily should not be exceeded upon completion of the titration.
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 3
`
`

`

` 2.2 Pediatric Patients
`
`
`
` The recommended dosage of ritonavir in children greater than 1 month is 350 to 400 mg per m2
`
`
`twice daily by mouth and should not exceed 600 mg twice daily. Ritonavir should be started at
`250 mg per m2 twice daily and increased at 2 to 3 day intervals by 50 mg per m2 twice daily. If
`
`
`
`
`
`patients do not tolerate 400 mg per m2 twice daily due to adverse events, the highest tolerated
`
`
`
`dose may be used for maintenance therapy in combination with other antiretroviral agents,
`
`however, alternative therapy should be considered. The use of NORVIR oral solution is
`
`recommended for children greater than 1 month who cannot swallow capsules. Please refer to the
`
`
`NORVIR oral solution full prescribing information for pediatric dosage and administration.
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`• NORVIR (ritonavir) capsules, soft gelatin
`
`
`
`
`White soft gelatin capsules imprinted with the “a” logo, 100 and the code DS, providing 100 mg
`
`
`
`of ritonavir.
`
`
`4 CONTRAINDICATIONS
`
`• When co-administering NORVIR with other protease inhibitors, see the full prescribing
`
`
`
`
`
`
`information for that protease inhibitor including contraindication information.
`
`
`• NORVIR is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal
`
`
`necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.
`
`
`• NORVIR is contraindicated with drugs that are highly dependent on CYP3A for clearance
`
`
`
`and for which elevated plasma concentrations are associated with serious and/or life-
`
`
`threatening reactions.
`
`
`• NORVIR is contraindicated with drugs that are potent CYP3A inducers where significantly
`
`
`reduced lopinavir plasma concentrations may be associated with the potential for loss of
`
`virologic response and possible resistance and cross-resistance.
`
`
`
`
`
`
`
`
` Drug Class
`
`
`
` Table 1. Drugs that are Contraindicated with NORVIR
`
`
`
` Drugs Within Class That
` Clinical Comments
` Are Contraindicated With
`
`
` NORVIR**
`
` Alfuzosin HCL
`
`
`
` Alpha1-adrenoreceptor
`
` antagonist
` Antiarrhythmics
`
`
`
`
`
` Antifungal
`
`Reference ID: 4032051
`
`
`
` Potential for hypotension.
`
`Amiodarone, dronedarone,
`flecainide, propafenone,
`
` quinidine
` Voriconazole
`
`
`Potential for cardiac
`
` arrhythmias.
`
` Voriconazole is contraindicated
` with ritonavir doses of 400 mg
`
`
` every 12 hours or greater due to
` the potential for loss of
`
`
`antifungal response.
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 4
`
`

`

`
`
` Anti-gout
`
`
`
` Colchicinea
`
`
`
` Antipsychotics
`
`
`
` Lurasidone
`
` Pimozide
`
`
`
`
`
` Ergot Derivatives
`
`Dihydroergotamine,
` ergotamine, methylergonovine
`
`
`
`
`
` GI Motility Agent
`
`
`
`
`
` Herbal Products
`
`HMG-CoA Reductase
`
` Inhibitors
`
`
`
` PDE5 inhibitor
`
`
`
` Cisapride
`
`
`
` St. John’s Wort (hypericum
`
` perforatum)
`
`
`
` Lovastatin, simvastatin
`
` Sildenafilb (Revatio®) only
`
` when used for the treatment of
`
`
` pulmonary arterial
` hypertension (PAH)
`
`
`
`
` Sedative/hypnotics
`
`
`
` Oral midazolamc, triazolam
`
`
`
`Potential for serious and/or life-
`
` threatening reactions in patients
`with renal and/or hepatic
`
` impairment.
`
` Potential for serious and/or life ­
`
` threatening reactions.Potential
`
` for serious and/or
` life-threatening reactions such as
`
` cardiac arrhythmias.
`
`
` Potential for acute ergot toxicity
`
`
` characterized by vasospasm and
`
` ischemia of the extremities and
`
`
` other tissues including the
`central nervous system.
`
`Potential for cardiac
`
` arrhythmias.
` May lead to loss of virologic
`
`
` response and possible resistance
`
`
` to NORVIR or to the class of
`
` protease inhibitors.
` Potential for myopathy including
`
` rhabdomyolysis.
`
`
`
`Potential for sildenafil­
`associated adverse events,
`
`including visual abnormalities,
`hypotension, prolonged erection,
`
`and syncope.
`Prolonged or increased sedation
`
`
` or respiratory depression.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` a see Drug Interactions (7), Table 4 for colchicine doses in patients with normal hepatic and renal
`
`
` function.
` b see Drug Interactions (7), Table 4 for co-administration of sildenafil in patients with erectile
`
`
`
` dysfunction.
` c see Drug Interactions (7), Table 4 for parenterally administered midazolam.
`
`
`
`
`
`
`
`
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 5
`
`

`

`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Risk of Serious Adverse Reactions Due to Drug Interactions
`
`
`Initiation of NORVIR, a CYP3A inhibitor, in patients receiving medications metabolized by
`
`
`
`CYP3A or initiation of medications metabolized by CYP3A in patients already receiving
`
`NORVIR, may increase plasma concentrations of medications metabolized by CYP3A. Initiation
`
`
`of medications that inhibit or induce CYP3A may increase or decrease concentrations of
`
`NORVIR, respectively. These interactions may lead to:
`
`
`
`• Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal
`
`
`
`
`events from greater exposures of concomitant medications.
`
`• Clinically significant adverse reactions from greater exposures of NORVIR.
`
`
`
`• Loss of therapeutic effect of NORVIR and possible development of resistance.
`
`
`
`
`When co-administering NORVIR with other protease inhibitors, see the full prescribing
`
`
`
`
`information for that protease inhibitor including important Warnings and Precautions.
`
`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 NORVIR therapy; review concomitant
`
`
`medications during NORVIR therapy, and monitor for the adverse reactions associated with the
`
`
`
`concomitant medications [see Contraindications (4) and Drug Interactions (7)].
`
`
`
`
`
`
`
`5.2 Hepatic Reactions
`
`Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis,
`
`and jaundice have occurred in patients receiving NORVIR alone or in combination with other
`
`
`
`antiretroviral drugs (see Table 3). There may be an increased risk for transaminase elevations in
`
`
`patients with underlying hepatitis B or C. Therefore, caution should be exercised when
`
`
`administering NORVIR to patients with pre-existing liver diseases, liver enzyme abnormalities,
`
`
`or hepatitis. Increased AST/ALT monitoring should be considered in these patients, especially
`
`
`
`during the first three months of NORVIR treatment [see Use In Specific Populations (8.6)].
`
`
`
`There have been postmarketing reports of hepatic dysfunction, including some fatalities. These
`
`
`
`have generally occurred in patients taking multiple concomitant medications and/or with
`
`
`advanced AIDS.
`
`
`5.3 Pancreatitis
`
`Pancreatitis has been observed in patients receiving NORVIR therapy, including those who
`
`developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with
`advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis [see
`
`
`
`Warnings and Precautions (5.8)]. Pancreatitis should be considered if clinical symptoms
`
`
`
`(nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased
`serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit
`
`these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if a
`
`
`diagnosis of pancreatitis is made.
`
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 6
`
`

`

` 5.4 Allergic Reactions/Hypersensitivity
`
`Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have
`
` been reported. Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson
` syndrome have also been reported. Discontinue treatment if severe reactions develop.
`
`
`
` 5.5 PR Interval Prolongation
`
`
`Ritonavir prolongs the PR interval in some patients. Post marketing cases of second or third
`
`
` degree atrioventricular block have been reported in patients.
` NORVIR should be used with caution in patients with underlying structural heart disease,
`
`
` preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these
` patients may be at increased risk for developing cardiac conduction abnormalities.
`
`
`
`
`
` The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the
`PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and
`atazanavir) has not been evaluated. As a result, co-administration of ritonavir with these drugs
`
`
`
`should be undertaken with caution, particularly with those drugs metabolized by CYP3A.
`
`Clinical monitoring is recommended [see Drug Interactions (7), and Clinical Pharmacology
`
`
`
`
`
`(12.3)].
`
`
`
`
`5.6 Lipid Disorders
`
`Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in
`
`substantial increases in the concentration of total cholesterol and triglycerides [see Adverse
`
`
`Reactions (6.1)]. Triglyceride and cholesterol testing should be performed prior to initiating
`
`
`
`NORVIR therapy and at periodic intervals during therapy. Lipid disorders should be managed as
`
`
`
`
`clinically appropriate, taking into account any potential drug-drug interactions with NORVIR
`
`and HMG CoA reductase inhibitors [see Contraindications (4), and Drug Interactions (7)].
`
`
`
`
`
`
`5.7 Diabetes Mellitus/Hyperglycemia
`
`New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia
`
`have been reported during postmarketing surveillance in HIV-1 infected patients receiving
`
`protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin
`or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis
`
`
`has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia
`
`persisted in some cases. Because these events have been reported voluntarily during clinical
`
`
`practice, estimates of frequency cannot be made and a causal relationship between protease
`
`
`
`inhibitor therapy and these events has not been established. Consider monitoring for
`
`
`hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus in patients
`
`treated with NORVIR.
`
`
`5.8 Immune Reconstitution Syndrome
`
`Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with
`
`
`combination antiretroviral therapy, including NORVIR. During the initial phase of combination
`
`antiretroviral treatment, patients whose immune system responds may develop an inflammatory
`
`
`
`response to indolent or residual opportunistic infections (such as Mycobacterium avium
`
`
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 7
`
`

`

`
` infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which
`
`
` may necessitate further evaluation and treatment.
`Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome)
`have also been reported to occur in the setting of immune reconstitution, however, the time to
`onset is more variable, and can occur many months after initiation of treatment.
`
`
`5.9 Fat Redistribution
`
`
`Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement
`
`
`(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid
`appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and
`
`long-term consequences of these events are currently unknown. A causal relationship has not
`
`
`
`been established.
`
`
`5.10 Patients with Hemophilia
`
`There have been reports of increased bleeding, including spontaneous skin hematomas and
`
`hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some
`
`
`patients additional factor VIII was given. In more than half of the reported cases, treatment with
`
`
`
`
`
`protease inhibitors was continued or reintroduced. A causal relationship between protease
`
`inhibitor therapy and these events has not been established.
`
`
`
`5.11 Resistance/Cross-resistance
`
`Varying degrees of cross-resistance among protease inhibitors have been observed. Continued
`
`administration of ritonavir 600 mg twice daily following loss of viral suppression may increase
`
`the likelihood of cross-resistance to other protease inhibitors [see Microbiology (12.4)].
`
`
`
`
`5.12 Laboratory Tests
`
`Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT),
`GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating
`
`NORVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during
`
`
`
`
`therapy.
`
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions are discussed in greater detail in other sections of the labeling.
`
`• Drug Interactions [see Warnings and Precautions (5.1)]
`
`
`
`
`
`• Hepatotoxicity [see Warnings and Precautions (5.2)]
`
`
`
`
`
`• Pancreatitis [see Warnings and Precautions (5.3)]
`
`
`
`
`
`• Allergic Reactions/Hypersensitivity [see Warnings and Precautions (5.4)]
`
`
`
`
`
`
`
`
`
`
`When co-administering NORVIR with other protease inhibitors, see the full prescribing
`
`
`
`
`information for that protease inhibitor including adverse reactions.
`
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 8
`
`

`

`6.1 Clinical Trial Experience
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
` observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`
`
` of another drug and may not reflect the rates observed in clinical practice.
`
`
`
` Adverse Reactions in Adults
`
`The safety of NORVIR alone and in combination with other antiretroviral agents was studied in
`1,755 adult patients. Table 2 lists treatment-emergent Adverse Reactions (with possible or
`
`probable relationship to study drug) occurring in greater than or equal to 1% of adult patients
`
`receiving NORVIR in combined Phase II/IV studies.
`
`
`The most frequently reported adverse drug reactions among patients receiving NORVIR alone or
`
`
`
`in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea,
`vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia
`
`
`and oral paresthesia), rash, and fatigue/asthenia.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` n
`
`
`
` %
`
`
`
` 113
`
`
`
` 6.4
`
` 464
`
`
` 26.4
`
` 1,192 67.9
`
`
` 11.5
`
` 201
`
` 142
`
` 8.1
`
` 2.3
`
` 41
`
` 19
`
` 1.1
` 1,007 57.4
`
`
`
` 31.9
`
` 559
`
`
`
` 811
`
`
`
` 46.2
`
`Table 2. Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship
`to Study Drug) Occurring in greater than or equal to 1% of Adult Patients Receiving
`
`NORVIR in Combined Phase II/IV Studies (N = 1,755)
`
`
`
` Adverse Reactions
` Eye disorders
`
`
` Blurred vision
`
` Gastrointestinal disorders
`
`
` Abdominal Pain (upper and lower)*
`
`
` Diarrhea including severe with electrolyte imbalance*
`
`
` Dyspepsia
`
`
` Flatulence
`
` Gastrointestinal hemorrhage*
`
`
`
` Gastroesophageal reflux disease (GERD)
`
`
` Nausea
`
`
` Vomiting*
` General disorders and administration site conditions
`
`
`
` Fatigue including asthenia*
` Hepatobiliary disorders
`
` Blood bilirubin increased (including jaundice)*
`
`
`
` Hepatitis (including increased AST, ALT, GGT)*
`
` Immune system disorders
`
`
`
` Hypersensitivity including urticatria and face edema*
` Metabolism and nutrition disorders
`
`
`
`
` Edema and peripheral edema*
`
`
`
` 25
`
`
` 153
`
`
` 1.4
`
` 8.7
`
`
`
` 114
`
`
`
` 8.2
`
`
`
` 110
`
`
`
` 6.3
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 9
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` Gout*
`
`
`
` Hypercholesterolemia*
`
`
` Hypertriglyceridemia*
`
` Lipodystrophy acquired*
`
`
` Musculoskeletal and connective tissue disorders
`
`
` Arthralgia and back pain*
`
` Myopathy/creatine phosphokinase increased*
`
`
` Myalgia
` Nervous system disorders
`
`
` Dizziness*
`
` Dysgeusia*
`
`
` Paresthesia (including oral paresthesia)*
` Peripheral neuropathy
`
`
`
`
` Syncope*
`
` Psychiatric disorders
`
`
` Confusion*
`
`
` Disturbance in attention
` Renal and urinary disorders
`
`
` Increased urination*
`
`
` Respiratory, thoracic and mediastinal disorders
`
`
` Coughing*
`
`
` Oropharyngeal Pain*
` Skin and subcutaneous tissue disorders
`
`
`
` Acne*
`
`
` Pruritus*
` Rash (includes erythematous and maculopapular)*
`
`
` Vascular disorders
`
` Flushing, feeling hot*
`
`
`
` Hypertension*
` Hypotension including orthostatic hypotension*
`
`
`
` Peripheral coldness*
` * Represents a medical concept including several similar MedDRA PTs
`
` Laboratory Abnormalities in Adults
`Table 3 shows the percentage of adult patients who developed marked laboratory abnormalities.
`
`
` 24
`
` 52
`
` 158
`
` 51
`
`
` 326
`
` 66
` 156
`
`
`
` 274
`
` 285
`
` 889
`
` 178
`
` 58
`
`
` 52
`
` 44
`
`
`
` 74
`
`
` 380
`
` 279
`
` 67
`
`
` 214
`
` 475
`
`
` 232
`
` 58
`
` 30
`
` 21
`
`
` 1.4
`
` 3.0
`
` 9.0
`
` 2.9
`
`
` 18.6
`
` 3.8
`
` 8.9
`
`
` 15.6
`
` 16.2
`
` 50.7
`
` 10.1
`
` 3.3
`
`
` 3.0
`
` 2.5
`
`
`
` 4.2
`
`
` 21.7
`
` 15.9
`
` 3.8
`
`
` 12.2
`
` 27.1
`
`
` 13.2
`
` 3.3
`
` 1.7
`
` 1.2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 3. Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 10
`
`

`

` Hematology Abnormalities
`
` Occurring in greater than 3% of Patients Receiving NORVIR
`
`
`
` Study 245
`
` Naive Patients
`
`
` Study 247
`
` Advanced Patients
`
`
`
`
` Study 462
`
` PI-Naive
`
` Patients
` NORVIR ZDV NORVIR Placebo NORVIR plus
`
` Saquinavir
`
`
`
`
`
`
`
` Variable
`
`
`
` Limit
`
`
` Chemistry
`
` Cholesterol
`
`
`
` CPK
`
`
`
` GGT
`
`
`
` SGOT (AST)
`
`
`
` SGPT (ALT)
`
` Triglycerides
`
`NORVIR
`
` plus
`
` ZDV
`
`
`
`
`
` 9.6
`
`
`
` 1.8
`
`
`
` 5.3
`
`
`
` 5.3
`
` 9.6
`
`
`
`
`
`
`
`
`
`
`
`
`
` 30.7
`
`
`
` 44.8
`
`
`
` 9.3
`
`
`
` 36.5
`
`
`
` 8.0
`
`
`
` 6.3
`
`
`
` 12.1
`
`
`
` 11.0
`
`
`
` 9.1
`
`
`
` 5.2
`
`
`
` 9.5
`
`
`
` 7.8
`
`
`
` 17.2
`
`
`
` 1.7
`
`
`
` 2.5
`
`
`
` 3.4
`
`
`
` 3.4
`
`
`
` 19.6
`
`
`
` 11.3
`
`
`
` 6.4
`
`
`
` 8.5
`
`
`
` 33.6
`
`
`
` 7.0
`
`
`
` 4.4
`
`
`
` 9.4
`
`
`
` 65.2
`
`
`
` 9.9
`
`
`
` 9.2
`
`
`
` 7.8
`
`
`
` 9.2
`
`
`
` 23.4
`
` High
`
`> 240
`
` mg/dL
`> 1000
`
` IU/L
`> 300
`
` IU/L
`> 180
`
` IU/L
`> 215
`
` IU/L
`> 800
`
` mg/dL
`> 1500
`
` mg/dL
`> 1500
`
` mg/dL
`> 12
`
` mg/dL
`
` Low
` < 30%
`
`< 8.0
`
` g/dL
` ≤ 0.5 x
`
`
`109/L
`
`
` < 3.0 x
`1012/L
`
`
` < 2.5 x
`109/L
`
` Indicates no events reported.
`
`
`
`
`
` Triglycerides
`
`
` Triglycerides
`
` Fasting
` Uric Acid
`
`
`
` Hematology
`
` Hematocrit
` Hemoglobin
`
`
`
`
` Neutrophils
`
`
`
` RBC
`
`
`
` WBC
`
`
`
`
`
`
`
` 1.8
`
`
`
` 1.5
`
`
`
` -
`
`
` 2.6
`
` 0.9
`
`
`
` -
`
`
`
` 1.8
`
`
`
` -
`
`
`
` 2.6
`
`
`
` 1.3
`
`
`
` -
`
`
` -
`
` -
`
`
`
` -
`
`
`
` -
`
`
`
` 0.9
`
`
`
` -
`
`
`
` -
`
`
`
` -
`
` 0.8
`
`
` -
`
`
`
` -
`
`
`
` 5.9
`
`
`
` 6.8
`
`
`
` 12.6
`
`
`
` 9.9
`
`
`
` 3.8
`
` 17.3
`
`
` 3.8
`
`
`
` 6.0
`
`
`
` 18.6
`
`
`
` 36.9
`
`
`
` 0.4
`
`
`
` 0.3
`
`
`
` 0.2
`
` 22.0
`
`
` 3.9
`
`
`
` 8.3
`
`
`
` 24.4
`
`
`
` 59.4
`
`
`
` 11.3
`
`
`
` -
`
`
`
` 1.4
`
`
` 0.7
`
` -
`
`
`
` -
`
`
`
` -
`
`
`
` 3.5
`
`
`
` -
`
`
`
`
`
`
`
`
`
` Adverse Reactions in Pediatric Patients
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 11
`
`

`

`
`
` NORVIR has been studied in 265 pediatric patients greater than 1 month to 21 years of age. The
`
`
` adverse event profile observed during pediatric clinical trials was similar to that for adult
` patients.
`
` Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of
`
`
`
`
`moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled
`in NORVIR clinical trials.
`
`
`Laboratory Abnormalities in Pediatric Patients
`
`The following Grade 3-4 laboratory abnormalities occurred in greater than 3% of pediatric
`
`
`
`patients who received treatment with NORVIR either alone or in combination with reverse
`
`
`transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%),
`
`anemia (4%), and elevated AST (3%).
`
`
`
`6.2 Postmarketing Experience
`
`The following adverse events have been reported during post-marketing use of NORVIR.
`
`Because these reactions are reported voluntarily from a population of unknown size, it is not
`
`possible to reliably estimate their frequency or establish a causal relationship to NORVIR
`
`exposure.
`
`Body as a Whole
`
`Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in
`
`
`hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic
`
`hypotension, and renal insufficiency have also been reported without known dehydration.
`
`Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with
`
`acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues
`
`including the central nervous system.
`
`Cardiovascular System
`
`First-degree AV block, second-degree AV block, third-degree AV block, right bundle branch
`block have been reported [see Warnings and Precautions (5.5)].
`
`
`
`
`Cardiac and neurologic events have been reported when ritonavir has been co-administered with
`
`disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug
`
`interaction cannot be excluded.
`
`Endocrine System
`
`
`Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co­
`administered with fluticasone propionate or budesonide.
`
`Nervous System
`
`There have been postmarketing reports of seizure. Also, see Cardiovascular System.
`
`Skin and subcutaneous tissue disorders
`
`Toxic epidermal necrolysis (TEN) has been reported.
`
`
`
`
`
`Reference ID: 4032051
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2039, Page 12
`
`

`

`
` 7 DRUG INTERACTIONS
` See also Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmaco