HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`INVIRASE safely and effectively. See full prescribing information for
`
`
`
`INVIRASE.
`
`
`INVIRASE® (saquinavir mesylate) capsules and tablets, for oral use
`
`
`
`
`
`
`Initial U.S. Approval: 1995
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`
`
`------------------------DOSAGE AND ADMINISTRATION---------------------­
`
`
`
`
`
`
`
`
`The concomitant use of INVIRASE/ritonavir 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, 7.3)
`
`
`
`QT and PR interval prolongations have been observed in a healthy
`
`
`
`
`volunteer study. Use with caution in patients with preexisting
`
`
`
`
`conduction system abnormalities and certain heart diseases.
`(5.2, 5.3, 12.2)
`
`
`
`
`Dosage and Administration, Recommended Dose (2.1)
`02/2016
`
`
`Patients on INVIRASE therapy may develop new onset or exacerbations
`
`•
`
`
`09/2016
`Contraindications (4)
`
`
`of diabetes mellitus (5.4), hyperglycemia (5.4), elevated cholesterol
`
`
`
`
`
`
`
`
`Warnings and Precautions (5)
`12/2015
`
`
`and/or triglyceride concentrations (5.7), redistribution/accumulation of
`
`
`QT Interval Prolongation (5.3)
`02/2016
`
`body fat (5.9), and immune reconstitution syndrome (5.10). Monitor
`
`
`
`
`cholesterol and triglycerides prior to therapy and periodically thereafter.
`
`
`(5.7)
`
`---------------------------INDICATIONS AND USAGE---------------------------­
`
`
`In patients with underlying hepatitis B or C, cirrhosis, chronic
`
`INVIRASE is an HIV-1 protease inhibitor indicated for the treatment of HIV­
`
`alcoholism and/or other underlying liver abnormalities there have been
`
`
`
`
`1 infection in combination with ritonavir and other antiretroviral agents in
`
`reports of worsening liver disease. (5.5)
`
`adults (over the age of 16 years). (1)
`
`
`Hemophilia: Spontaneous bleeding may occur and additional factor VII
`
`
`may be required. (5.6)
`
`
`Various degrees of cross-resistance have been observed. (5.11)
`
`
`------------------------WARNINGS AND PRECAUTIONS----------------------­
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`INVIRASE must be administered in combination with ritonavir. (2)
`
`
`
`
`
`Adults (over the age of 16 years ): INVIRASE 1000 mg twice daily (5 x
`
`
`200 mg capsules or 2 x 500 mg tablets) in combination with ritonavir
`
`
`100 mg twice daily. (2.1)
`
`
`Treatment-naïve patients initiating treatment with INVIRASE/ritonavir:
`
`
`
`
`
`First 7 days of treatment: INVIRASE 500 mg twice daily with ritonavir
`
`
`
`100 mg twice daily. After 7 days: INVIRASE 1000 mg twice daily with
`
`
`ritonavir 100 mg twice daily. (2.1)
`
`
`See Full Prescribing Information for dosing recommendations for
`
`
`patients switching immediately from treatment with another protease
`
`inhibitor taken with ritonavir or from a non-nucleoside reverse
`
`
`transcriptase inhibitor based regimen, without a wash-out period. (2.1)
`
`
`
`INVIRASE and ritonavir should be taken within 2 hours after a meal.
`
`(2.1)
`
`
`
`-------------------DOSAGE FORMS AND STRENGTHS-------------------­
`
`
`
`
`
`
`200 mg capsules and 500 mg film-coated tablets (3)
`
`
`
`-------------------------------ADVERSE REACTIONS----------------------------­
`
`
`
`The most common adverse reactions are nausea, vomiting, diarrhea, fatigue,
`
`
`
`pneumonia, lipodystrophy and abdominal pain. (6.1)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`
`
`
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`-----------------------------------DRUG INTERACTIONS-----------------------­
`
`
`
`
`•
`
`
`•
`
`
`•
`
`INVIRASE/ritonavir is a potent inhibitor of CYP3A, significantly
`
`
`increasing the exposure of drugs primarily metabolized by CYP3A. (7.1)
`
`
`
`Coadministration of INVIRASE/ritonavir with drugs that induce CYP3A
`
`
`
`may result in decreased plasma concentrations of saquinavir and reduced
`
`
`
`efficacy. (7.2)
`
`Certain drugs or drug classes should not be coadministered with
`
`
`
`
`
`INVIRASE/ritonavir based on drug interaction studies or predicted drug
`
`
`
`
`interactions. (5.1, 7.2, 7.3)
`
`
`
`------------------------------CONTRAINDICATIONS-----------------------------­
`
`
`
`------------------------USE IN SPECIFIC POPULATIONS-------------------­
`
`
`
`Patients with congenital or documented acquired QT prolongation,
`
`
`patients with refractory hypokalemia or hypomagnesemia, or those on
`
`
`
`concomitant therapy with other drugs that prolong the QT interval. (4)
`
`
`
`
`INVIRASE is contraindicated in patients with complete atrioventricular
`
`
`
`
`(AV) block without implanted pacemakers, or patients who are at high
`
`
`risk of complete AV block. (4)
`
`
`
`INVIRASE is contraindicated in patients with clinically significant
`
`
`hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome)
`
`
`
`to saquinavir, saquinavir mesylate, or any of its ingredients. (4)
`
`
`
`INVIRASE when administered with ritonavir is contraindicated in
`
`
`patients with severe hepatic impairment. (4)
`
`
`Coadministration of INVIRASE/ritonavir with CYP3A substrates for
`
`
`
`
`which increased plasma levels may result in serious or life-threatening
`
`reactions. (4)
`
`
`Coadministration of INVIRASE/ritonavir with rifampin due to the risk
`
`
`of severe hepatotoxicity. (4)
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`Pregnancy: Use during pregnancy only if the potential benefit justifies
`
`
`the potential risk to the fetus. (8.1)
`
`
`
`Nursing Mothers: Do not breastfeed if HIV-1-infected mothers are
`
`
`receiving INVIRASE therapy. (8.3)
`
`
`Pediatric Use: Pediatric dose recommendations that are both reliably
`
`
`
`
`effective and below thresholds of concern with respect to QT and PR
`
`
`prolongation could not be determined (8.4)
`
`
`
`Geriatric Use: Caution should be exercised due to greater frequency of
`
`
`
`decreased hepatic, renal or cardiac function in elderly population. (8.5)
`
`Impaired Renal Function: No initial dose adjustment is necessary for
`
`
`
`
`patients with renal impairment. (8.6)
`
`Impaired Hepatic Function: No dose adjustment is necessary for patients
`
`
`
`
`
`with mild or moderate hepatic impairment. (8.7)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide.
`
`
`Revised: 09/2016
`
`
` ____________________________________________________________________________________________________________________________________
`
`
`
`
`Reference ID: 3985957
`
`
`
` 1
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2033, Page 1
`
`

`

`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dose
`
`
`
`2.2 Administration for Patients Unable to Swallow Capsules
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Risk of Serious Adverse Reactions Due to Drug Interactions
`
`
`5.2 PR Interval Prolongation
`
`
`
`5.3 QT Interval Prolongation
`
`
`5.4 Diabetes Mellitus / Hyperglycemia
`
`
`5.5 Hepatotoxicity
`
`
`5.6 Hemophilia
`
`
`5.7 Hyperlipidemia
`
`
`5.8 Lactose Intolerance
`
`
`5.9 Fat Redistribution
`
`
`5.10 Immune Reconstitution Syndrome
`
`
`5.11 Resistance/Cross-resistance
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trial Experience in Adult Subjects
`
`
`
`6.2 Clinical Trial Experience in Pediatric Subjects
`
`
`6.3 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`
`
`7.1 Potential for INVIRASE to Affect Other Drugs
`
`
`7.2 Potential for Other Drugs to Affect INVIRASE
`
`
`
`7.3 Established and Other Potentially Significant Drug Interactions
`
`
`7.4 Drugs without Clinically Significant Interactions with
`
`INVIRASE/ritonavir
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6
`Impaired Renal Function
`
`
`8.7
`Impaired Hepatic Function
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`12.4 Microbiology
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`
`14.1 Description of Clinical Studies in Adults
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
` ____________________________________________________________________________________________________________________________________
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
` Product identification in this document includes: INVIRASE in reference to saquinavir mesylate; saquinavir 200
`mg soft gel capsule formulation1 in reference to saquinavir active base.
`
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`INVIRASE in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV-1 infection
`
`
`in adults (over the age of 16 years).
`
`The following points should be considered when initiating therapy with INVIRASE:
`- The twice daily administration of INVIRASE in combination with ritonavir is supported by safety data
`
`
`
`
`
`from the MaxCmin 1 trial [see Adverse Reactions (6.1)] and pharmacokinetic data [see Clinical
`
`
`Pharmacology (12.3)].
`
`- The efficacy of INVIRASE with ritonavir has not been compared against the efficacy of antiretroviral
`
`
`
`
`
`
`regimens currently considered standard of care.
`- The number of baseline primary protease inhibitor mutations affects the virologic response to
`
`
`
`
`
`INVIRASE/ritonavir.
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`
`
`
`
`
`INVIRASE must be used in combination with ritonavir because ritonavir significantly inhibits saquinavir’s
`
`
`
`
`metabolism to provide increased plasma saquinavir levels.
`
`Cobicistat is not interchangeable with ritonavir to increase systemic exposure of saquinavir [see Warnings and
`
`Precautions (5)].
`
`
`
`
`
` 1 The term “saquinavir soft gel capsules” used in this label refers to the drug product formerly marketed as “Fortovase” (saquinavir
`
`
`
` 200 mg soft gel capsule formulation). This formulation has been withdrawn from the market.
`
`
`
`
`
`
`
`
`
`Reference ID: 3985957
`
`
`
` 2
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2033, Page 2
`
`

`

` Recommended Dose
`
`
` 2.1
` • The standard recommended dose of INVIRASE is 1000-mg twice daily (5 x 200-mg capsules or 2 x 500-mg tablets)
`
`
`
`
` in combination with ritonavir 100-mg twice daily.
`
`
`
`
`
` • For treatment-naïve patients initiating treatment with INVIRASE/ritonavir, the recommended starting dose of
`
`
`
`
`
` INVIRASE is 500-mg twice daily with ritonavir 100-mg twice daily for the first 7 days of treatment. After 7 days, the
`recommended dose of INVIRASE is 1000-mg twice daily with ritonavir 100-mg twice daily [see Warnings and
`
` Precautions (5.3) and Clinical Pharmacology (12.2)].
`
`
`
` • Patients switching immediately (no washout period) from treatment with another ritonavir containing regimen or from
`
`
`
`
`
`
`
`
`
`
`
`a non-nucleoside reverse transcriptase inhibitor based regimen (not including delavirdine, rilpivirine) should initiate
`and continue INVIRASE at the standard recommended dose of 1000-mg twice daily with ritonavir 100-mg twice
`
`
`daily. For patients switching from a regimen containing delavirdine or rilpivirine, the recommended dose is 500-mg
`
`
`twice daily with ritonavir 100-mg twice daily for the first 7 days of treatment [see Warnings and Precautions (5.3)
`
`
`
`
`
`and Drug Interactions (7.3)].
`
`
`
`
`
`
`
`• Ritonavir should be taken at the same time as INVIRASE.
`
`
`•
`
`
`
`
`INVIRASE and ritonavir should be taken within 2 hours after a meal.
`
`
`
`
`
`
`
`
`
`• For patients already taking ritonavir 100-mg twice daily as part of their antiretroviral regimen, no additional ritonavir
`
`is needed.
`
`
`
`
`
`• Pediatric dose recommendations that are both reliably effective and below thresholds of concern for QT and PR
`
`
`interval prolongation could not be determined.
`
`
`
`
`Administration for Patients Unable to Swallow Capsules
`2.2
`
`
`
`
`Open the INVIRASE capsules and place the contents into an empty container. Add 15 mL of either sugar syrup or sorbitol
`syrup (for patients with Type 1 diabetes or glucose intolerance) OR 3 teaspoons of jam to the contents of INVIRASE
`
`
`
`
`
`
`
`
`capsules that are in the container. Stir with a spoon for 30 to 60 seconds. Administer the full amount prepared for each
`
`
`
`dose. Suspensions should be at room temperature before administering.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`Capsules: 200 mg
`
`
`Film-coated tablets: 500 mg
`
`
`CONTRAINDICATIONS
`4
`
`
`
`
`
`QT interval prolongation and torsades de pointes have been reported rarely with INVIRASE/ritonavir use. Do not use in
`
`patients with congenital long QT syndrome, those with refractory hypokalemia or hypomagnesemia, and in combination
`
`with drugs that both increase saquinavir plasma concentrations and prolong the QT interval [see Warnings and
`
`
`
`
`Precautions (5.3) and Clinical Pharmacology (12.2)].
`
`
`
`INVIRASE is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or
`patients who are at high risk of complete AV block [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
`
`INVIRASE is contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-
`
`
`
`
`
`
`Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients.
`
`
`INVIRASE when administered with ritonavir is contraindicated in patients with severe hepatic impairment.
`
`
`
`
`Coadministration of INVIRASE/ritonavir is contraindicated with drugs that are CYP3A substrates for which increased
`
`plasma levels may result in serious or life-threatening reactions. These drugs and potentially related adverse events are
`listed in Table 1.
`
`
`
`Reference ID: 3985957
`
`
`
` 3
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2033, Page 3
`
`

`

` Table 1
`
`
`Drug Class
`
` Drugs That Are Contraindicated With INVIRASE/ritonavir
`
`
`
`
`Drugs Within Class That Are
`Clinical Comment
`Contraindicated With
`
`INVIRASE/ritonavir
`
`Alfuzosin
`
`
`Alpha 1-adrenoreceptor
`
` antagonist
`
`
`
`
`Potentially increased alfuzosin concentrations can result
` in hypotension.
`
`
`
`Antiarrhythmics
`
`Amiodarone, bepridil, dofetilide,
`
` flecainide, lidocaine (systemic),
`
` propafenone, quinidine
`
`
`Potential for serious and/or life-threatening cardiac
`
` arrhythmia.
`
`
`Antidepressant
`
`
`Trazodone
`
`
`
`Increased trazodone concentrations can result in
` potentially life threatening cardiac arrhythmia.
`
`
`
`
`Anti-infectives
`
`Clarithromycin, erythromycin,
`
` halofantrine, pentamidine
`
`
`Potential for serious and/or life-threatening cardiac
`
` arrhythmia.
`
`Antimycobacterial
`
` Agents
`
`
`Rifampin
`
`
`Antipsychotics
`
`
`Lurasidone
` Chlorpromazine, clozapine,
`
`haloperidol, mesoridazine,
`phenothiazines, pimozide,
`sertindole, thioridazine,
`
`ziprasidone
`
`
`
`Ergot Derivatives
`
`Dihydroergotamine, ergonovine,
`
` ergotamine, methylergonovine
`
`
`GI Motility Agent
`
`
`Cisapride
`
`
`Atazanavir
`
`HIV-1 Protease
`
` Inhibitor
`
`HMG-CoA Reductase
`
` Inhibitors
`
`
`Rifampin should not be administered in patients taking
`
` INVIRASE/ritonavir as part of an ART regimen due to
`
`
`
`
` the risk of severe hepatocellular toxicity.
`
`
`
`
`Potential for serious and/or life-threatening reactions.
`
` Potential for serious and/or life threatening reactions
`
` such as cardiac arrhythmias.
`
`
`
`Potential for serious and life threatening reactions such
` as ergot toxicity characterized by peripheral vasospasm
`
`
` and ischemia of the extremities and other tissues.
`
`
`
`Potential for serious and/or life threatening reactions
`
` such as cardiac arrhythmias.
`
`
`Potential for serious and/or life-threatening cardiac
`
` arrhythmia.
`
`
`Lovastatin, Simvastatin
`
`
`
`Potential for myopathy including rhabdomyolysis.
`
`
`Immunosuppressant
`
`
`Tacrolimus
`
`
`PDE5 Inhibitors
`
`Sildenafil (Revatio®)[for
` treatment of pulmonary arterial
`
` hypertension]
`
`
`
`
`Sedative/Hypnotics
`
`
`Triazolam, orally administered
`
` midazolam
`
`
`Reference ID: 3985957
`
`
`Potential for serious and/or life-threatening cardiac
`
` arrhythmia.
`
`
`
`Increased potential for sildenafil-associated adverse
` events (which include visual disturbances, hypotension,
`
` prolonged erection, and syncope). A safe and effective
`
`dose has not been established when used with
`
` INVIRASE/ritonavir.
`
`
`
`
`Potential for serious and/or life threatening reactions
`
` such as prolonged or increased sedation or respiratory
`
` depression.
`Triazolam and orally administered midazolam are
`
`
`
`
`
` 4
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2033, Page 4
`
`

`

`Other drugs that are
`
`
` CYP3A substrates
`
`Dapsone
`
`
` Disopyramide
`Quinine
`
`
`extensively metabolized by CYP3A4. Coadministration
`
`
`
` of triazolam or orally administered midazolam with
` INVIRASE/ritonavir may cause large increases in the
`
`
`
` concentration of these benzodiazepines.
`
`Potential for serious and/or life-threatening cardiac
`
`
` arrhythmia.
`
`
`5
`WARNINGS AND PRECAUTIONS
`
`
`INVIRASE must be used in combination with ritonavir. Please refer to the ritonavir full prescribing information for
`
`
`
`
`additional precautionary measures.
`
`
`INVIRASE is not recommended for use in combination with cobicistat. Dosing recommendations for this
`
`
`
`
`
`
`combination have not been established. Cobicistat is also not recommended in combination with regimens containing
`
`
`
`
`ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Please refer to the cobicistat full prescribing
`
`
`
`
`
`
`information for additional precautionary measures.
`
`
`
`If a serious or severe toxicity occurs during treatment with INVIRASE, INVIRASE should be interrupted until the
`
`
`
`
`
`
`
`
`
`
`
`
`
`etiology of the event is identified or the toxicity resolves. At that time, resumption of treatment with full-dose INVIRASE
`
`
`
`
`may be considered. For antiretroviral agents used in combination with INVIRASE, physicians should refer to the
`
`
`
`complete product information for these drugs for dose adjustment recommendations and for information regarding drug-
`
`
`
`associated adverse reactions.
`
`Risk of Serious Adverse Reactions Due to Drug Interactions
`5.1
`
`
`
`
`Initiation of INVIRASE/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or
`
`
`initiation of medications metabolized by CYP3A in patients already receiving INVIRASE/ritonavir, may increase plasma
`
`
`concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may
`
`
`
`
`
`
`
`
`
`
`
`increase or decrease concentrations of INVIRASE/ritonavir, 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 INVIRASE/ritonavir.
`
`
`
`
`
`• Loss of therapeutic effect of INVIRASE/ritonavir and possible development of resistance.
`
`
`
`
`See Table 3 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
`
`
`
`
`
`
`
`
`
`
`
`INVIRASE/ritonavir therapy; review concomitant medications during INVIRASE/ritonavir therapy; and monitor for the
`
`
`
`
`adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].
`
`
`
`PR Interval Prolongation
`5.2
`
`
`
`Saquinavir/ritonavir prolongs the PR interval in a dose-dependent fashion. Cases of second or third degree atrioventricular
`
`
`
`
`
`block have been reported rarely. Patients with underlying structural heart disease, pre-existing conduction system
`
`
`
`abnormalities, cardiomyopathies and ischemic heart disease may be at increased risk for developing cardiac conduction
`
`
`
`abnormalities. ECG monitoring is recommended in these patients [see Warnings and Precautions (5.3)].
`
`
`
`The impact on the PR interval of co-administration of saquinavir/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 saquinavir/ritonavir with these drugs should be undertaken with caution, particularly with those drugs
`
`metabolized by CYP3A, and clinical monitoring is recommended [see Clinical Pharmacology (12.2)].
`
`
`5.3
`QT Interval Prolongation
`
`
`
`Saquinavir/ritonavir causes dose-dependent QT prolongation. Torsades de pointes have been reported rarely post-
`
`
`
`
`
`
`
`
`
`marketing. Avoid saquinavir/ritonavir in patients with long QT syndrome. ECG monitoring is recommended if therapy is
`
`
`
`
`
`
`
`
`
`
`
`initiated in patients with congestive heart failure, bradyarrhythmias, hepatic impairment and electrolyte abnormalities.
`
`
`Correct hypokalemia or hypomagnesemia prior to initiating saquinavir/ritonavir and monitor these electrolytes
`
`
` 5
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`Reference ID: 3985957
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2033, Page 5
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`

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` periodically during therapy. Do not use in combination with drugs that both increase saquinavir plasma concentrations and
`
`
` prolong the QT interval (see Tables 1 and 3) [see Clinical Pharmacology (12.2)].
`
`
`
`
`
` Patients initiating therapy with INVIRASE/ritonavir:
`
`
`
`An ECG should be performed prior to initiation of treatment. Patients with a QT interval ≥ 450 msec should not initiate
`
`
`
`
`
`
`treatment with INVIRASE/ritonavir.
`
`
`
`
`
`
`
`Treatment-naïve patients initiating treatment with INVIRASE/ritonavir should receive a reduced starting dose of
`
`
`
`
`INVIRASE 500-mg twice daily with ritonavir 100-mg twice daily for the first 7 days of treatment followed by
`
`
`INVIRASE/ritonavir 1000/100 mg twice daily due to potential for an increased risk of PR and QT interval prolongation
`
`
`
`
`
`with the standard 1000/100-mg twice daily dose [see Clinical Pharmacology (12.2)].
`
`
`
`
`For patients with a baseline QT interval < 450 msec, an on-treatment ECG is recommended after approximately 10 days
`
`
`
`
`of therapy.
`
`Patients with a QT interval prolongation over pre-treatment by > 20 msec should discontinue INVIRASE/ritonavir.
`
`
`
`Patients requiring treatment with medications with the potential to increase the QT interval and concomitant
`
`
`
`
`
`
`
`
`
`INVIRASE/ritonavir:
`
`Such combinations should only be used where no alternative therapy is available and the potential benefits outweigh the
`
`
`
`potential risks. An ECG should be performed prior to initiation of the concomitant therapy, and patients with a QT
`
`
`
`
`
`interval > 450 msec should not initiate the concomitant therapy. If baseline QT interval < 450 msec, an on-treatment ECG
`
`
`
`should be performed after 3-4 days of therapy. For patients demonstrating a subsequent increase in QT interval by > 20
`
`
`
`
`msec after commencing concomitant therapy, the physician should use best clinical judgment to discontinue either
`
`
`
`
`
`INVIRASE/ritonavir or the concomitant therapy or both.
`
`
`
`A cardiology consult is recommended if drug discontinuation or interruption is being considered on the basis of ECG
`
`
`
`assessment.
`
`Diabetes Mellitus / Hyperglycemia
`5.4
`
`
`
`New onset diabetes mellitus, exacerbation of preexisting 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 the 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.
`
`
`
`Hepatotoxicity
`5.5
`
`
`In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities,
`
`
`there have been reports of worsening liver disease.
`
`
`Hemophilia
`5.6
`
`
`There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`some patients additional factor VIII was required. In the majority of reported cases treatment with protease inhibitors was
`
`
`continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been
`
`
`
`
`
`
`
`
`
`
`
`established.
`
`Hyperlipidemia
`5.7
`
`
`Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with
`
`
`ritonavir. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis. Cholesterol and
`
`
`
`
`triglyceride levels should be monitored prior to initiating combination dosing regimen of INVIRASE with ritonavir, and at
`
`
`
`
`periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate.
`
`
`5.8
`Lactose Intolerance
`
`
`Each capsule contains lactose (anhydrous) 63.3 mg. This quantity should not induce specific symptoms of intolerance.
`
`
`
`
`
`Reference ID: 3985957
`
`
`
` 6
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2033, Page 6
`
`

`

` Fat Redistribution
` 5.9
`
`
`
`
` Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), facial
`
` wasting, peripheral 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.
`
`
` Immune Reconstitution Syndrome
`
` 5.10
`
` Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including
`
` INVIRASE. 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
`
`
`
`
` 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.
`
`
`5.11
`Resistance/Cross-resistance
`
`
`
`Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. Continued administration of
`
`
`
`
`INVIRASE therapy following loss of viral suppression may increase the likelihood of cross resistance to other protease
`
`
`inhibitors [see Microbiology (12.4)].
`
`
`
`
`ADVERSE REACTIONS
`6
`
`The following adverse reactions are discussed in greater detail in other sections of the labeling:
`• PR Interval Prolongation [see Warnings and Precautions (5.2)]
`
`
`
`• QT Interval Prolongation [see Warnings and Precautions (5.3)]
`
`
`
`
`
`
`
`Clinical Trial Experience in Adult Subjects
`6.1
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`The original INVIRASE safety database consisted of a total of 574 adult subjects who received saquinavir 600 mg alone
`
`
`
`or in combination with ZDV or ddC. Combination dosing with ritonavir is based on 352 HIV-1 infected subjects and 166
`
`
`
`
`
`healthy subjects who received various combinations of either saquinavir (hard gel or soft-gel capsules) with ritonavir.
`
`
`
`
`
`
`The recommended dose of INVIRASE is 1000 mg twice daily co-administered with ritonavir 100 mg twice daily, in
`
`combination with other antiretroviral agents. Table 2 lists grade 2, 3 and 4 adverse events that occurred in ≥2% of
`
`
`
`
`subjects receiving saquinavir soft gel capsules with ritonavir (1000/100 mg bid).
`Grade 2, 3 and 4 Adverse Events (All Causalitya) Reported in ≥2% of Adult Subjects in the
`
`
`
`
`
`
`
`
`
`
`
`
`MaxCmin 1 Study of Saquinavir Soft Gel Capsules in Combination with Ritonavir 1000/100 mg
`
`twice a day
`
`
`Table 2
`
`
`
`
`Adverse Events
`
`
`Endocrine Disorders
`
`Diabetes mellitus/hyperglycemia
`
`Lipodystrophy
`
`Gastrointestinal Disorders
`
`Nausea
`
`Vomiting
`
`Diarrhea
`
`Abdominal Pain
`
`Constipation
`
`
`Reference ID: 3985957
`
`
`Saquinavir soft gel capsules 1000 mg plus
`
`
` Ritonavir 100 mg bid (48 weeks)
`
` N=148
`
`n (%=n/N)
`
`
`4 (3)
`
`8 (5)
`
`
`16 (11)
`
`11 (7)
`
`12 (8)
`
`9 (6)
`
`3 (2)
`
`
`
` 7
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2033, Page 7
`
`

`

`
`
`
`
`
`
` General Disorders and Administration Site Conditions
`
` Fatigue
`
` Fever
` Musculoskeletal Disorders
`
` Back Pain
` Respiratory Disorders
`
` Pneumonia
`
` Bronchitis
` Influenza
`
`
` Sinusitis
` Dermatological Disorders
`
` Rash
` Pruritus
`
` Dry lips/skin
`
` Eczema
`
` aIncludes events with unknown relationship to study drug
`
` Limited experience is available from three trials investigating the pharmacokinetics of the INVIRASE 500 mg film-coated
`
` tablet compared to the INVIRASE 200 mg capsule in healthy volunteers (n=140). In two of these trials saquinavir was
`
`
`
` combined with ritonavir; in the other trial, saquinavir was administered as single drug. The INVIRASE tablet and the
`
`
`
`
`
`
` capsule formulations were similarly tolerated. The most common adverse events were gastrointestinal disorders (such as
`
`
` nausea, vomiting, and diarrhea). Similar bioavailability was demonstrated and no clinically significant differences in
`
`
`
`
`
` saquinavir exposures were seen. Thus, similar safety profiles are expected between the two INVIRASE formulations.
`
` A study investigating the drug-drug interaction of rifampin 600 mg/day daily and INVIRASE 1000 mg/ritonavir 100 mg
`
`
` twice daily enrolled 28 healthy volunteers. Eleven of 17 healthy volunteers (65%) exposed concomitantly to rifampin and
`
`
`
`
`
`
` INVIRASE/ritonavir developed severe hepatocellular toxicity which presented as increased hepatic transaminases. In
`
`
`
`
`
` some subjects, transaminases increased up to >20-fold the upper limit of normal and were associated with gastrointestinal
`
`
` symptoms, including abdominal pain, gastritis, nausea, and vomiting. Following discontinuation of all three drugs, clinical
`
`
`
`
` symptoms abated and the increased hepatic transaminases normalized [see Contraindications (4)].
`
` Additional Adverse Reactions Reported During Clinical Trials with Saquinavir
`
`
`
`
`Blood and lymphatic system disorders: anemia, hemolytic anemia, leukopenia, lymphadenopathy, neutropenia,
`
`
`
`pancytopenia, thrombocytopenia
`
`Cardiac disorders: heart murmur, syncope
`
`
`Ear and labyrinth disorders: tinnitus
`
`
`Eye disorders: visual impairment
`
`
`Gastrointestinal disorders: abdominal discomfort, ascites, dyspepsia, dysphagia, eructati