HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use VIRACEPT
`
`
`
`
`safely and effectively. See full prescribing information for VIRACEPT.
`
`
`
`
`
`VIRACEPT® (nelfinavir mesylate) Tablets, for oral use
`
`
`
`
` VIRACEPT® (nelfinavir mesylate) Oral Powder, for oral use
`
`Initial U.S. Approval: 1997
`
`
`
`----------------------------------RECENT MAJOR CHANGES--------------------------­
`
`Contraindications (4)
`9/2016
`
`
`
`-------------------------------INDICATIONS AND USAGE------------------------------­
`
`VIRACEPT is a protease inhibitor indicated for the treatment of HIV-1 infection in
`
`
`
`
`
`
`
`
`combination with other antiretroviral agents. (1)
`
`
`
`
`
`------------------------------DOSAGE AND ADMINISTRATION----------------------­
`
`• See full prescribing information for administration instructions (2)
`
`
`
`• Adults and adolescents 13 years and older (tablets): 1250 mg twice daily or 750
`
`
`
`
`
`
`
`mg three times daily with a meal (2.1)
`
`
`
`• Children 2 to less than 13 years (oral powder or 250 mg tablets): 45 to 55
`
`
`
`
`
`
`
`
`mg/kg twice daily or 25 to 35 mg/kg three times daily with a meal. Refer to
`
`
`
`
`
`
`
`
`
`
`Tables 1 and 2 of the full prescribing information for specific dosing guidelines
`
`based on age and body weight (2.2)
`
`
`
`
`-----------------------------DOSAGE FORMS AND STRENGTHS-----------------------------
` • Tablet: 250 mg, 625 mg nelfinavir free base (3)
`
`
`
`
` • Oral Powder: 50 mg/g nelfinavir free base (3)
`
`
`
`
`
`------------------------------------------CONTRAINDICATIONS------------------------------------­
`
`• Coadministration with drugs that are highly dependent on CYP3A for clearance
`
`
`
`
`
`and which elevated concentrations are associated with serious and/or life-
`
`
`threatening events (4)
`
`
`------------------------------WARNINGS AND PRECAUTIONS-----------------------­
`ALERT: Find out about medicines that should not be taken with VIRACEPT.
`
`
`
`
`• The concomitant use of VIRACEPT 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)
`
`
`• Hepatic impairment: should not be used in patients with either moderate or
`
`
`
`
`
`
`
`severe hepatic impairment (2.4, 5.2)
`
`
`• Phenylketonuria: the oral powder contains 11.2 mg phenylalanine per gram of
`
`
`
`
`
`
`
`
`powder (5.3)
`
`
`
`
`______________________________________________________________________________________________________________________________________
`
`
`• Diabetes mellitus/hyperglycemia: new onset or exacerbation of pre-
`
`
`
`
`
`existing diabetes mellitus and hyperglycemia reported with protease
`
`
`
`
`inhibitors. In some cases after treatment discontinuation, hyperglycemia
`
`
`
`
`persisted (5.4)
`
`
`
`• Hemophilia: increased bleeding, including spontaneous skin hematomas
`
`
`
`and hemarthrosis reported with protease inhibitors. In more than half of
`
`
`
`
`the cases, protease inhibitors was continued or reintroduced (5.5)
`
`
`
`• Fat redistribution: observed with antiretroviral therapy (5.6)
`
`
`
`
`
`Immune reconstitution syndrome: reported with combination
`
`
`
`•
`antiretroviral therapy, including VIRACEPT. Patients may develop an
`
`inflammatory response to indolent or residual opportunistic infections
`
`
`(5.7)
`
`
`----------------------------------ADVERSE REACTIONS-----------------------------------­
` • Most common adverse reactions (≥2%) of moderate or severe intensity in
`
`
`
`
` adults and adolescents (13 years and older) are diarrhea, nausea, rash, and
`
`
`
`
` flatulence (6.1).
`
` • Most common adverse reactions in pediatric patients (2 to less than 13
`
`
`
`
`
`
`
` years) are diarrhea, leukopenia/neutropenia, rash, anorexia, and abdominal
`
`
` pain. (6.2)
`
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at
`
`
`
`
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`
`-----------------------------------DRUG INTERACTIONS----------------------------------­
`
`
`• Co-administration of VIRACEPT with other drugs (CYP3A substrates)
`
`
`
`
`
`can alter the concentration of these other drugs, and other drugs
`
`
`
`
`
`
`
`(inhibitors and/or inducers of CYP3A or CYP2C19) may alter the
`
`
`
`
`
`concentrations of nelfinavir. The potential drug-drug concentrations must
`
`be considered prior to and during therapy (4, 7, 12.3)
`
`
`
`
`
`• VIRACEPT should be given with food one hour after or more than 2
`
`
`
`
`
`hours before didanosine (7)
`
`
`
`-------------------------------USE IN SPECIFIC POPULATIONS----------------------­
`
`
`
`
`
`• Use during pregnancy if the potential benefit justifies the potential risk to
`
`
`
`the fetus (8.1)
`
`
`
`• Nursing mothers: should not breast-feed their infants (8.3)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA­
`
`approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 9/2016
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`7.3 Established and Potentially Significant Drug Interactions
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`1
`INDICATIONS AND USAGE
`
`
`8.1 Pregnancy
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`8.3 Nursing Mothers
`
`
`
`
`
`2.1 Adults and Adolescents (13 years and older)
`
`
`8.4 Pediatric Use
`
`
`
`2.2 Pediatric Patients (2 to less than 13 years)
`
`
`8.5 Geriatric Use
`
`
`
`2.3 Method of administration
`
`
`8.6 Hepatic Impairment
`
`
`2.4 Hepatic Impairment
`
`
`8.7 Renal Impairment
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`10 OVERDOSAGE
`
`
`
`4 CONTRAINDICATIONS
`
`
`11 DESCRIPTION
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`
`5.1 Risk of Serious Adverse Reactions Due to Drug Interactions
`
`
`12.1 Mechanism of Action
`
`
`5.2 Hepatic Impairment
`
`
`12.2 Pharmacodynamics
`
`
`5.3 Phenylketonurics
`
`
`12.3 Pharmacokinetics
`
`
`5.4 Diabetes Mellitus/Hyperglycemia
`
`
`12.4 Microbiology
`
`
`5.5 Hemophilia
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`5.6 Fat Redistribution
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`5.7
`Immune Reconstitution Syndrome
`
`
`14 CLINICAL STUDIES
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`
`14.1 Studies in Antiretroviral Treatment Naïve Adult Patients
`
`
`
`
`
`
`
`6.1 Clinical Trials Experience: Adults and Adolescents (13 years and older)
`
`
`
`
`14.2 Studies in Antiretroviral Treatment Experienced Adult Patients
`
`
`
`
`
`6.2 Clinical Trials Experience: Pediatrics (2 to less than 13 years of age)
`
`14.3 Studies in Pediatric Patients
`
`
`6.3 Postmarketing Experience
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`7 DRUG INTERACTIONS
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`7.1 Potential for VIRACEPT to Affect Other Drugs
`
`
`
`*Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`7.2 Potential for Other Drugs to Affect VIRACEPT
`___________________________________________________________________________________________________________________________________
`
`
`
`
`Reference ID: 3986049
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2031, Page 1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`1
`
`
`VIRACEPT in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection.
`
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Adults and Adolescents (13 years and older)
`
`
`
`
`The recommended dose is 1250 mg (five 250 mg tablets or two 625 mg tablets) twice daily or 750 mg (three 250 mg tablets) three
`times daily. VIRACEPT should be taken with a meal. Patients unable to swallow the 250 or 625 mg tablets may dissolve the tablets in
`
`
`
`
`a small amount of water [see Dosage and Administration (2.3)].
`
`
`
`
`2.2 Pediatric Patients (2 to less than 13 years)
`
`
`
`
`In children 2 years of age and older, the recommended oral dose of VIRACEPT Oral Powder or 250 mg tablets is 45 to 55 mg/kg
`
`
`twice daily or 25 to 35 mg/kg three times daily. All doses should be taken with a meal. Doses higher than the adult maximum dose of
`
`
`
`
`
`
`2500 mg per day have not been studied in children.
`
`
`For children unable to swallow tablets, VIRACEPT 250 mg tablet(s) may be dissolved in a small amount of water or, VIRACEPT
`
`
`
`
`
`Oral Powder may be administered [see Dosage and Administration (2.3)].
`
`
`
`
`
`The healthcare provider should assess appropriate formulation and dosage for each patient. Tables 1 and 2 provide dosing guidelines
`
`for VIRACEPT tablets and powder based on age and body weight.
`
`Table 1:
`
`
`Dosing Table for Children 2 to less than 13 years of age (tablets)
`
`
`
`
`
` Twice daily (BID)
` Three times daily (TID)
`
`
`
` 45 – 55 mg/kg
`
`
` 25 – 35 mg/kg
` ≥2 years
`
` ≥2 years
`
`
` Number of tablets
`
` (250 mg)
`
`
`
`
`
`
` Body weight
`
`
`
`
`
`
`
`
`
`
`
`
` Number of tablets
`
` (250 mg)
`
`
`
` 1
`
`2
`
`
`2
`
`
`
`
` 3†
`
`
`
` Kg
`
`
`
`
`
` 10 – 12
`
`13 – 18
`
`
`
`19 – 20
`
`
`
`
`
` 2
`
`3
`
`
`4
`
`
`4 – 5*
`≥21
`
`
`
`
` * For BID dosing, the maximum dose per day is 5 tablets BID
`
`
`
`
` † For TID dosing, the maximum dose per day is 3 tablets TID
`
`
`
`
`
`Reference ID: 3986049
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2031, Page 2
`
`

`

`
`Body weight
`
`
`Table 2:
`
`
`
`Dosing Table for Children 2 to less than 13 years of age (powder)
`
`
`
`
`
`
`Twice daily (BID)
`Three times daily (TID)
`
`
`45 – 55 mg/kg
`25 – 35 mg/kg
`
`
`
`
`
`
`
`
`
`
` Kg
`
`
`
` 9.0 to <10.5
`
`
`10.5 to <12
`
`
`12 to <14
`
`
`14 to <16
`
`
`
` Scoops of
`
` powder
` (50 mg/1 g)
`
`
`
`
`
` 10
`
`
`11
`
`
`13
`
`
`15
`
`
` Teaspoons* of
`
` powder
`
`
`
` 2½
`
`
`2¾
`
`
`3¼
`
`
`3¾
`
`
`16 to <18
`
`Not
`recommended†
`
`
`Not
`recommended†
`
`
`18 to <23
`
`
`Not
`recommended†
`
`
`Not
`recommended†
`
`
`
`
` Scoops of
`
` powder
` (50 mg/1 g)
`
`
`
`
`
` 6
`
`
`7
`
`
`8
`
`
`9
`
`
`10
`
`
`12
`
`
` Teaspoons* of
`
` powder
`
`
`
` 1½
`
`
`1¾
`
`
`2
`
`
`2¼
`
`
`2½
`
`
`3
`
`
`≥23
`
`
`15
`
`
`3¾
`
`Not
`Not
`recommended†
`recommended†
`
`
` If a teaspoon is used to measure VIRACEPT oral powder, 1 level teaspoon contains 200 mg of
`
`
` VIRACEPT (4 level scoops equals 1 level teaspoon)
` † Use VIRACEPT 250 mg tablet
`
`
`
`
`
`
`
` *
`
`
`
`
`
`2.3 Method of Administration
`
`
`For Patients Unable to Swallow Viracept Tablets
`
`• Place VIRACEPT tablet(s) in small amount of water.
`
`
`
`• Once dissolved, mix the cloudy liquid well, and consume it immediately.
`
`
`
`
`• The glass should be rinsed with water and the rinse swallowed to ensure the entire dose is consumed.
`
`
`
`
`
`
`
`Viracept Oral Powder
`
`• Mix VIRACEPT Oral Powder with a small amount of water, milk, formula, soy formula, soy milk, or dietary supplements
`
`
`
`
`
`
`
`
`
`• Once mixed, the entire contents must be consumed in order to obtain the full dose.
`
`
`
`
`If the mixture is not consumed immediately, it must be stored under refrigeration, but storage must not exceed 6 hours.
`
`
`
`•
`• Acidic food or juice (e.g., orange juice, apple juice, or apple sauce) are not recommended for mixing VIRACEPT Oral
`
`
`
`
`Powder because the combination may result in a bitter taste.
`
`
`• VIRACEPT Oral Powder should not be reconstituted with water in its original container.
`
`
`
`
`
`2.4 Hepatic Impairment
`
`
`VIRACEPT can be used in patients with mild hepatic impairment without any dose adjustment. VIRACEPT should not be used in
`
`
`
`
`
`patients with either moderate or severe hepatic impairment [see Warnings and Precautions (5.2), Use in Specific Populations (8.6),
`
`
`
`
`and Clinical Pharmacology (12.3)].
`
`
`
`
`Reference ID: 3986049
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2031, Page 3
`
`

`

`3 DOSAGE FORMS AND STRENGTHS
`
`
`VIRACEPT 250 mg Tablet: Light-blue, capsule-shaped tablets with a clear film coating engraved with “VIRACEPT” on one side and
`
`
`
`
`
`
`“250 mg” on the other.
`
`
`VIRACEPT 625 mg Tablet: White oval tablet with a clear film coating engraved with "V" on one side and "625" on the other.
`
`
`
`
`
`
`VIRACEPT Oral Powder: Off-white powder containing 50 mg (as nelfinavir-free base) in each level scoopful (1 gram).
`
`
`
`
`4 CONTRAINDICATIONS
`
`
`Coadministration of VIRACEPT 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 events. These drugs and other contraindicated drugs
`
`
`
`
`
`(which may lead to reduced efficacy of nelfinavir) are listed in Table 3 [also see Drug Interactions (7), Table 6].
`
`
`
`
`Table 3:
`
`
`Drugs That Are Contraindicated With VIRACEPT
`
`
`Drugs Within Class That Are
`Clinical Comment
`
`
`
`Contraindicated With VIRACEPT
`
`
`
`Drug Class
`
`Alpha 1-adrenoreceptor
`
`
`antagonist
`
`
`Alfuzosin
`
`
`Antiarrhythmics
`
`
`Amiodarone, quinidine
`
`
`
`
`Antimycobacterial Agents Rifampin
`
`Antipsychotics
`
`
`Lurasidone
`
`
`Pimozide
`
`
`
`Ergot Derivatives
`
`
`Dihydroergotamine, ergotamine,
`
`
`
`methylergonovine
`
`
`
`GI Motility Agent
`
`
`Cisapride
`
`Herbal products
`
`
`St. John's wort (Hypericum
`
`
`perforatum)
`
`
`Potentially increased alfuzosin concentrations can result in
`
`hypotension.
`
`
`Potential for serious and/or life-threatening cardiac
`arrhythmia.
`
`
`
`Plasma concentrations of nelfinavir can be reduced by
`
`
`concomitant use of rifampin. This may lead to loss of
`
`
`
`
`therapeutic effect and possible development of resistance to
`
`
`
`VIRACEPT or other coadministered antiretroviral agents.
`
`Potential for serious and/or life-threatening reactions.
`
`
`
`Potential for serious and/or life threatening reactions such as
`
`
`cardiac arrhythmias.
`
`
`Potential for serious and/or life threatening reactions such as
`
`
`
`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.
`
`Plasma concentrations of nelfinavir can be reduced by
`
`
`
`concomitant use of the herbal preparation St. John’s wort.
`
`
`
`This may lead to loss of therapeutic effect and possible
`
`
`
`development of resistance to VIRACEPT or other
`
`
`coadministered antiretroviral agents.
`
`
`
`
`
`
`Potential for serious reactions such as myopathy including
`
`rhabdomyolysis.
`
`
`HMG-CoA Reductase
`
`Inhibitors
`
`
`
`PDE5 Inhibitors
`
`
`
`Reference ID: 3986049
`
`
`Lovastatin, Simvastatin
`
`
` Sildenafil (Revatio®) [for treatment
`
`
` of pulmonary arterial hypertension]a
`
` A safe and effective dose has not been established when used
`
`
`
`
`
` with nelfinavir. There is increased potential for sildenafil­
` associated adverse events (which include visual disturbances,
`
`
`
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2031, Page 4
`
`

`

`hypotension, prolonged erection, and syncope).
`
`Sedative/Hypnotics
`
`
`
`Triazolam, oral midazolam
`
`Potential for serious and/or life threatening reactions such as
`prolonged or increased sedation or respiratory depression.
`a See Drug Interactions, Table 6 for coadministration of sildenafil and tadalafil when dosed for erectile dysfunction.
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`ALERT: Find out about medicines that should not be taken with VIRACEPT. This statement is included on the product’s bottle
`
`
`
`
`label.
`5.1 Risk of Serious Adverse Reactions Due to Drug Interactions
`
`
`
`Initiation of VIRACEPT, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications
`
`
`
`
`metabolized by CYP3A in patients already receiving VIRACEPT, may increase plasma concentrations of medications metabolized by
`
`
`
`
`CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of VIRACEPT, 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 VIRACEPT.
`
`
`
`• Loss of therapeutic effect of VIRACEPT and possible development of resistance.
`
`
`
`
`See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations
`
`
`
`
`[see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during VIRACEPT therapy; review concomitant
`
`
`medications during VIRACEPT therapy; and monitor for the adverse reactions associated with the concomitant medications
`
`
`
`[see Contraindications (4) and Drug Interactions (7)].
`
`
`5.2 Hepatic Impairment
`
`
`VIRACEPT should not be used in patients with either moderate or severe hepatic impairment (Child-Pugh B or C, score greater than
`
`
`
`
`or equal to 7) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
`
`
`
`
`5.3 Phenylketonurics
`
`
`Viracept Oral Powder contains phenylalanine, a component of aspartame. Each gram of VIRACEPT powder contains 11.2 mg
`
`
`
`
`phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.
`
`
`
`5.4 Diabetes Mellitus/Hyperglycemia
`
`
`
`New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-
`
`
`marketing surveillance in HIV-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.
`
`
`
`5.5 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 has not been established.
`
`
`
`
`5.6 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.
`
`
`
`5.7
`Immune Reconstitution Syndrome
`
`
`Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIRACEPT.
`
`
`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.
`
`
`
`
`
`
`Reference ID: 3986049
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2031, Page 5
`
`

`

`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.
`
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug
`
`
`
`cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
`
`
`
`6.1 Clinical Trials Experience: Adults and Adolescents (13 years and older)
`
`
`
`
`
`The safety of VIRACEPT was studied in over 5000 patients who received drug either alone or in combination with nucleoside
`
`
`analogues. The majority of adverse events were of mild intensity. The most frequently reported adverse event among patients
`
`
`
`
`
`receiving VIRACEPT was diarrhea, which was generally of mild to moderate intensity.
`
`
`
`
`
`
`Drug-related clinical adverse experiences of moderate or severe intensity in ≥2% of patients treated with VIRACEPT coadministered
`
`
`
`
`
`with d4T and 3TC (Study 542) for up to 48 weeks, or with ZDV plus 3TC (Study 511) for up to 24 weeks are presented in Table 4.
`
`
`
`
`
`Table 4:
`
`
`
`Percentage of Patients with Treatment-Emergent* Adverse Events of Moderate or Severe
`
`
`
`
`
`
`
`
`Intensity Reported in ≥ 2% of Adult and Adolescent Patients
`
`Study 511
`
`
` Study 542
`
` 24 weeks
`
` 48 weeks
`
`
`
`
`
`
`
`
`
`
`Adverse Events
`
`
`Placebo
`
`+ ZDV/3TC
`
`(n=101)
`
`
`
`
`
`
`750 mg TID
`
`VIRACEPT +
`d4T/3TC
`
`(n=210)
`
`
`15%
`
`3%
`
`1%
`
`
`1%
`
`
`500 mg TID
`
`750 mg TID
`
`1250 mg BID
`
`VIRACEPT +
`VIRACEPT +
`VIRACEPT +
`ZDV/3TC
`
`ZDV/3TC
`
`d4T/3TC
`
`(n=97)
`
`(n=100)
`
`(n=344)
`
`Digestive System
`
`
`
`
`
`20%
`20%
`14%
`3%
`Diarrhea
`
`
`
`
`
`3%
`7%
`3%
`4%
`Nausea
`
`
`
`
`
`1%
`2%
`5%
`0
`Flatulence
`
`
`
`
`
`Skin/Appendages
`
`
`
`
`
`2%
`3%
`1%
`1%
`Rash
`
`
`
`
`
` * Includes those adverse events at least possibly, probably or definitely related to study drug or of unknown
`
`
`relationship and excludes concurrent HIV conditions
`
`
`Adverse events occurring in less than 2% of patients receiving VIRACEPT in all phase 2 and 3 clinical trials and considered at least
`
`
`
`possibly related or of unknown relationship to treatment and of at least moderate severity are listed below.
`
`
`Body as a Whole: abdominal pain, accidental injury, allergic reaction, asthenia, back pain, fever, headache, malaise, pain, and
`
`
`
`
`
`redistribution/accumulation of body fat [see Warnings and Precautions (5.7)].
`
`
`
`Digestive System: anorexia, dyspepsia, epigastric pain, gastrointestinal bleeding, hepatitis, mouth ulceration, pancreatitis, and
`
`
`
`
`
`vomiting.
`
`
`Hemic/Lymphatic System: anemia, leukopenia, and thrombocytopenia.
`
`
`Metabolic/Nutritional System: increases in alkaline phosphatase, amylase, creatine phosphokinase, lactic dehydrogenase, SGOT,
`
`
`SGPT, and gamma-glutamyl transpeptidase; hyperlipemia, hyperuricemia, hyperglycemia, hypoglycemia, dehydration, and liver
`
`
`
`
`function tests abnormal.
`
`
`Musculoskeletal System: arthralgia, arthritis, cramps, myalgia, myasthenia, and myopathy.
`
`
`
`
`Nervous System: anxiety, depression, dizziness, emotional lability, hyperkinesia, insomnia, migraine, paresthesia, seizures, sleep
`
`
`
`disorder, somnolence, and suicide ideation.
`
`
`Respiratory System: dyspnea, pharyngitis, rhinitis, and sinusitis.
`
`
`
`Skin/Appendages: dermatitis, folliculitis, fungal dermatitis, maculopapular rash, pruritus, sweating, and urticaria.
`
`
`
`
`
`
`Reference ID: 3986049
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2031, Page 6
`
`

`

`Special Senses: acute iritis and eye disorder.
`
`
`Urogenital System: kidney calculus, sexual dysfunction, and urine abnormality.
`
`
`Laboratory Abnormalities
`
`
`
`The percentage of patients with marked laboratory abnormalities in Studies 542 and 511 are presented in Table 5. Marked laboratory
`
`
`
`
`
`abnormalities are defined as a Grade 3 or 4 abnormality in a patient with a normal baseline value, or a Grade 4 abnormality in a patient
`
`
`with a Grade 1 abnormality at baseline.
`
`
`
`
`
`
`
`
`
`Table 5:
`
`
`
`Percentage of Patients by Treatment Group with Marked Laboratory Abnormalities* in >2% of Patients
`
`
`
`
`
`
`
` Study 511
` Study 542
`
`
`
`
`
`
`Placebo
`
`500 mg TID
`
`750 mg TID
`
`1250 mg BID
`
`750 mg TID
`
`+
`VIRACEPT +
`VIRACEPT +
`VIRACEPT
`
`VIRACEPT
`
`ZDV/3TC
`
`ZDV/3TC
`
`ZDV/3TC
`
`+ d4T/3TC
`
`+ d4T/3TC
`
`(n=101)
`
`(n=97)
`
`(n=100)
`
`(n=344)
`
`(n=210)
`
`Hematology
`
`
`
`
`
`
`0
`0
`2%
`3%
`6%
`Hemoglobin
`
`
`
`
`
`
`1%
`2%
`5%
`3%
`4%
`Neutrophils
`
`
`
`
`
`
`0
`1%
`1%
`6%
`1%
`Lymphocytes
`
`
`
`
`
`
`Chemistry
`
`
`
`
`
`
`1%
`2%
`1%
`1%
`6%
`ALT (SGPT)
`
`
`
`
`
`
`1%
`2%
`0
`1%
`4%
`AST (SGOT)
`
`
`
`
`
`
`
`NA
`NA
`2%
`2%
`7%
`Creatine Kinase
`
`
`
`
`
`
` * Marked laboratory abnormalities are defined as a shift from Grade 0 at baseline to at least Grade 3 or from Grade 1 to
`
`
`Grade 4
`
`
`
`
`
`6.2 Clinical Trials Experience: Pediatrics (2 to less than 13 years of age)
`
`
`
`
`VIRACEPT has been studied in approximately 400 pediatric patients in clinical trials from birth to 13 years of age. The adverse event
`
`
`profile seen during pediatric clinical trials was similar to that for adults.
`
`
`
`The most commonly reported drug-related, treatment-emergent adverse events reported in the pediatric studies included: diarrhea,
`
`leukopenia/neutropenia, rash, anorexia, and abdominal pain. Diarrhea, regardless of assigned relationship to study drug, was reported
`
`
`in 39% to 47% of pediatric patients receiving VIRACEPT in 2 of the larger treatment trials. Leukopenia/neutropenia was the
`
`
`laboratory abnormality most commonly reported as a significant event across the pediatric studies.
`
`
`6.3 Postmarketing Experience
`
`
`
`
`The following adverse reactions have been identified during post-approval use of VIRACEPT. 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.
`Body as a Whole: hypersensitivity reactions (including bronchospasm, moderate to severe rash, fever, and edema).
`
`
`
`
`
`Cardiovascular System: QTc prolongation, torsades de pointes.
`
`
`
`Digestive System: jaundice.
`
`
`
`
`Metabolic/Nutritional System: bilirubinemia, metabolic acidosis.
`
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Potential for VIRACEPT to Affect Other Drugs
`
`
`
`
`Nelfinavir is an inhibitor of CYP3A. Coadministration of VIRACEPT and drugs primarily metabolized by CYP3A (e.g.,
`
`
`
`dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and PDE5 inhibitors) may result in
`
`
`
`Reference ID: 3986049
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2031, Page 7
`
`

`

`increased plasma concentrations of such drugs that could increase or prolong both its therapeutic and adverse effects (see Tables 3 and
`
`
`
`
`
`
`6).
`
`
`7.2 Potential for Other Drugs to Affect VIRACEPT
`
`
`Nelfinavir is metabolized by CYP3A and CYP2C19. Coadministration of VIRACEPT and drugs that induce CYP3A or CYP2C19,
`
`
`
`
`such as rifampin, may decrease nelfinavir plasma concentrations and reduce its therapeutic effect. Coadministration of VIRACEPT
`
`
`
`and drugs that inhibit CYP3A or CYP2C19 may increase nelfinavir plasma concentrations.
`
`
`
`7.3 Established and Other Potentially Significant Drug Interactions
`
`
`Table 6 provides the effect on concentrations of VIRACEPT or concomitant drug as a result of coadministration with VIRACEPT.
`
`
`
`
`These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of
`
`
`interaction and potential for serious adverse events or loss of efficacy.
`
`
`
`
`
` Table 6:
`
` Established and Other Potentially Significant Drug Interactions:
`
` Alteration in Dose or Regimen May Be Recommended Based on
`
`
`
`
`
`Drug Interaction Studies
`
` [see Clinical Pharmacology (12.3) (Tables 12 and 13) for magnitude of interaction]
`
` Clinical Comment
`
`
` Effect on
` Concentration
`
`
`
`
`
`
`
`
`
`
` ↓ nelfinavir (C min )
`
`
`
`
`
` ↔ nelfinavir
`
`
`
`
` ↑ nelfinavir
`
` ↑ indinavir
`
`
`
`
`
`
` ↑ nelfinavir
`
` ↔ ritonavir
`
`
`
`
` ↑ nelfinavir
`
` ↑ saquinavir
`
`
`
`
`
` Warfarin
`
`
`
`
`
`
`
`
`
`
`
`
` Concomitant
`
` Drug Class:
`
` Drug Name
`
`
`
` Delavirdine
`
`
`
` Nevirapine
`
`
`
` Didanosine
`
`
`
` Indinavir
`
`
`
` Ritonavir
`
`
`
` Saquinavir
`
`
`
` Warfarin
`
`Carbamazepine
`
` Phenobarbital
`
` Phenytoin
`
`
` HIV Antiviral Agents: Reverse Transcriptase Inhibitors
` Concentrations of nelfinavir were increased while concentrations
`
`
`
`
`
` ↑ nelfinavir (Cmin )
`
` of delavirdine were decreased when the two agents were
`
` ↓ delavirdine
`
` coadministered. Appropriate doses of the combination, with
`
`
`
` respect to safety and efficacy, have not been established.
`
`
`
` Concentrations of nelfinavir were decreased when coadministered
`
`
` with nevirapine. An appropriate dose of nelfinavir with respect to
`
`
` safety and efficacy has not been established.
`
`
`
`
`
` There was no change in nelfinavir concentration when
`
` coadministered with didanosine. However, it is recommended that
`
` didanosine be administered on an empty stomach; therefore,
`
`
` didanosine should be given one hour before or two hours after
`
`
` VIRACEPT (given with food).
` HIV Antiviral Agents: Protease Inhibitors
`
`
`
` Concentrations of both indinavir and nelfinavir were increased
` when the two agents were coadministered. Appropriate doses for
`
`
`
`
` these combinations, with respect to safety and efficacy, have not
`
`
`
` been established.
` Concentrations of nelfinavir were increased when coadministered
`
`
`
`
`
`
` with ritonavir. An appropriate dose of nelfinavir for this
` combination, with respect to safety and efficacy, has not been
`
`
`
` established.
`
`
` Concentrations of both saquinavir and nelfinavir were increased
` when the two agents were coadministered. Appropriate doses for
`
`
`
`
` these combinations, with respect to safety and efficacy, have not
`
`
` been established.
` ANTICOAGULANT
`
`
`
`
` Coadministration of warfarin and VIRACEPT may affect
`
`
`
` concentrations of warfarin. It is recommended that the INR
` (international normalized ratio) be monitored carefully during
`
`
`
` treatment with VIRACEPT, especially when commencing therapy.
` ANTICONVULSANTS
`
`
`
`
` Concentrations of nelfinavir may be decreased. VIRACEPT may
` not be effective due to decreased nelfinavir plasma concentrations
`
`
`
` in patients taking these agents concomitantly.
`
`
` Phenytoin plasma/serum concentrations should be monitored;
`
` phenytoin dose may require adjustment to compensate for altered
`
` phenytoin concentration.
`
`
`
`
` ↓ nelfinavir
`
` ↓ phenytoin
`
`
`
`
`
`
`
`
`
`Reference ID: 3986049
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2031, Page 8
`
`

`

`
`
` Trazodone
`
`
`
` Colchicine
`
`Rifabutin
`
`
`
`
` Bosentan
`
` Atorvastatin
`
`Rosuvastatin
`
`
`
`
` Cyclosporine
`
` Tacrolimus
`
` Sirolimus
`
`
`
` Salmeterol
`
`
`
` Fluticasone
`
`
`
`
`
` ↑ trazodone
`
`
`
`
`
` ↑ colchicines
`
`
`
`
`
`
`
`
`
`
`
`
`
` ANTIDEPRESSANT
`
` Concomitant use of trazodone and VIRACEPT may increase
`
`
`
` plasma concentrations of trazodone. Adverse events of nausea,
` dizziness, hypotension and syncope have been observed following
`
`
`
` coadministration of trazodone and ritonavir. If trazodone is used
` with a CYP3A4 inhibitor such as VIRACEPT, the combination
`
`should be used with caution and a lower dose of trazodone should
`
` be considered.
`
` ANTIGOUT
`
`
` Patients with renal or hepatic impairment should not be given
`
` colchicine with VIRACEPT due to the risk of colchicine toxicity.
`
`
`
` Treatment of gout flares –
`
`
`
` co- administration of colchicine in patients on VIRACEPT:
`
` 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour
`
` later. Dose to be repeated no earlier than 3 days.
`
` Prophylaxis of gout-flares –
`
`
`
` coadministration of colchicine in patients on VIRACEPT:
`
`If the original colchicine regimen was 0.6 mg twice a day, the
`
`
`regimen should be adjusted to 0.3 mg once a day.
`
`If the original colchicine regimen was 0.6 mg once a day, the
`
`
`regimen should be adjusted to 0.3 mg once every other day.
`
`
`Treatment of familial Mediterranean fever (FMF)–
`
`
`coadministration of colchicine in patients on VIRACEPT:
`
`
`Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a
`
`
` day).
` ANTIMYCOBACTERIAL
`
`It is recommended that the dose of rifabutin be reduced to one-half
`
`
`
` the usual dose when administered with VIRACEPT; 1250 mg BID
` is the preferred dose of VIRACEPT when coadministe