` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
` KALETRA safely and effectively. See full prescribing information for
`
` KALETRA.
`
`
`
` KALETRA (lopinavir and ritonavir) tablet, for oral use
`
`
`
`
`
` KALETRA (lopinavir and ritonavir) oral solution
` Initial U.S. Approval: 2000
`
`
`
`
`
`
`
`
`
`RECENT MAJOR CHANGES
`
` Contraindications (4)
`
`
`
` Warnings and Precautions
`
` Diabetes Mellitus/Hyperglycemia (5.7)
`
`
`
`
` INDICATIONS AND USAGE
` KALETRA is an HIV-1 protease inhibitor indicated in combination with other
`
` antiretroviral agents for the treatment of HIV-1 infection in adults and
`
`
`
` pediatric patients (14 days and older). (1)
`
`
`
`
` 11/2016
`
` 11/2016
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`Tablets: May be taken with or without food, swallowed whole and not
`
`
`
`chewed, broken, or crushed. (2.1)
`
`
`Oral solution: must be taken with food. (2.1)
`
`
`
`Adults (2.2):
`
`
`
`• Total recommended daily dosage is 800/200 mg given once or twice daily.
`
`
`• KALETRA can be given as once daily or twice daily regimen. See Full
`
`
`
`
`
`Prescribing Information for details.
`
`
`• KALETRA once daily dosing regimen is not recommended in:
`
`
`
`• Adult patients with three or more of the following lopinavir
`
`
`
`resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I,
`
`L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V.
`
`
`(12.4)
`
`• In combination with carbamazepine, phenobarbital, or phenytoin.
`
`
`
`(7.3)
`
`• In combination with efavirenz, nevirapine, or nelfinavir. (12.3)
`
`
`• In pregnant women. (2.4, 8.1, 12.3)
`
`
`Pediatric Patients (14 days and older) (2.3):
`
`
`
`
`
`
`• KALETRA once daily dosing regimen is not recommended in pediatric
`
`
`patients.
`
`
`• Twice daily dose is based on body weight or body surface area.
`
`
`
`Concomitant Therapy in Adults and Pediatric Patients:
`
`• Dose adjustments of KALETRA may be needed when co-administering
`
`
`
`with efavirenz, nevirapine, or nelfinavir. (2.2, 2.3, 7.3)
`
`
`
`
`
`• KALETRA oral solution should not be administered to neonates before a
`
`
`
`
`postmenstrual age (first day of the mother’s last menstrual period to birth
`
`
`
`
`
`plus the time elapsed after birth) of 42 weeks and a postnatal age of at least
`
`
`14 days has been attained (2.3, 5.2)
`
`Pregnancy (2.4):
`
`
`
`
`
`• 400/100 mg twice daily in pregnant patients with no documented lopinavir­
`
`
`associated resistance substitutions.
`
`• There are insufficient data to recommend a KALETRA dose for pregnant
`
`patients with any documented KALETRA-associated resistance
`
`substitutions.
`
`
`
`• No dose adjustment of KALETRA is required for patients during the
`
`
`postpartum period.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`• Tablets: 200 mg lopinavir and 50 mg ritonavir (3)
`
`
`
`
`• Tablets: 100 mg lopinavir and 25 mg ritonavir (3)
`
`
`
`
`
`
`• Oral solution: 80 mg lopinavir and 20 mg ritonavir per milliliter (3)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1 INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General Administration Recommendations
`
`
`2.2 Dosage Recommendations in Adults
`
`
`
`
`2.3 Dosage Recommendations in Pediatric Patients
`
`
`2.4 Dosage Recommendations in Pregnancy
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Reference ID: 4017646
`
`
`
`
`
`CONTRAINDICATIONS
`
`• Hypersensitivity to KALETRA (e.g., toxic epidermal necrolysis, Stevens-
`
`
`Johnson syndrome, erythema multiforme, urticaria, angioedema) or any of
`
`
`its ingredients, including ritonavir. (4)
`
`
`
`
`
`• Co-administration with drugs highly dependent on CYP3A for clearance
`
`and for which elevated plasma levels may result in serious and/or life-
`
`threatening events. (4)
`
`
`• Co-administration with 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. (4)
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`
`The following have been observed in patients receiving KALETRA:
`
`
`
`• The concomitant use of KALETRA 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)
`
`
`
`
`• Toxicity in preterm neonates: KALETRA oral solution should not be used
`
`
`
`in preterm neonates in the immediate postnatal period because of possible
`
`toxicities. A safe and effective dose of KALETRA oral solution in this
`
`
`
`patient population has not been established. (2.3, 5.2).
`
`• Pancreatitis: Fatalities have occurred; suspend therapy as clinically
`
`
`appropriate. (5.3)
`
`• Hepatotoxicity: 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.
`
`(5.4, 8.6)
`
`
`
`• QT interval prolongation and isolated cases of torsade de pointes have been
`
`
`
`
`
`reported although causality could not be established. Avoid use in patients
`
`
`
`with congenital long QT syndrome, those with hypokalemia, and with other
`
`
`drugs that prolong the QT interval. (5.1, 5.5, 12.3)
`
`• PR interval prolongation may occur in some patients. Cases of second and
`
`
`
`
`
`
`
`third degree heart block have been reported. Use with caution in patients
`
`
`
`with pre-existing conduction system disease, ischemic heart disease,
`
`
`cardiomyopathy, underlying structural heart disease or when administering
`
`
`
`with other drugs that may prolong the PR interval. (5.1, 5.6, 12.3)
`
`• Patients may develop new onset or exacerbations of diabetes mellitus,
`
`
`
`hyperglycemia (5.7), immune reconstitution syndrome. (5.8),
`
`
`redistribution/accumulation of body fat. (5.10)
`
`
`
`
`• Total cholesterol and triglycerides elevations. Monitor prior to therapy and
`
`
`periodically thereafter. (5.9)
`
`
`• Hemophilia: Spontaneous bleeding may occur, and additional factor VIII
`
`
`may be required. (5.11)
`
`
`
`ADVERSE REACTIONS
`
`Commonly reported adverse reactions to KALETRA included diarrhea,
`
`
`nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. (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 KALETRA can alter the plasma concentrations of other
`
`
`
`
`drugs and other drugs may alter the plasma concentrations of lopinavir. 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: Breastfeeding not recommended. (8.2)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`Revised: 11/2016
`
`
`
`
`
`5.1 Risk of Serious Adverse Reactions Due to Drug Interactions
`
`5.2 Toxicity in Preterm Neonates
`
`5.3 Pancreatitis
`
`5.4 Hepatotoxicity
`
`
`5.5 QT Interval Prolongation
`
`5.6 PR Interval Prolongation
`
`
`5.7 Diabetes Mellitus/Hyperglycemia
`
`5.8 Immune Reconstitution Syndrome
`
`5.9 Lipid Elevations
`
`5.10 Fat Redistribution
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2030, Page 1
`
`

`

` 5.11 Patients with Hemophilia
`
`
`
` 5.12 Resistance/Cross-resistance
`
` 6 ADVERSE REACTIONS
`
`
`
` 6.1 Clinical Trials Experience
`
`
` 6.2 Postmarketing Experience
`
`
` 7 DRUG INTERACTIONS
` 7.1 Potential for KALETRA to Affect Other Drugs
`
`
`
` 7.2 Potential for Other Drugs to Affect Lopinavir
`
`
` 7.3 Established and Other Potentially Significant Drug Interactions
`
`
` 7.4 Drugs with No Observed or Predicted Interactions with KALETRA
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
` 8.1 Pregnancy
`
`
` 8.2 Lactation
`
`
` 8.4 Pediatric Use
`
`
` 8.5 Geriatric Use
`
`
` 8.6 Hepatic Impairment
`
`
` 10 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 Adult Patients without Prior Antiretroviral Therapy
`
`
`
` 14.2 Adult Patients with Prior Antiretroviral Therapy
`
` 14.3 Other Studies Supporting Approval in Adult Patients
`
`
`
` 14.4 Pediatric Studies
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`
` 16.1 KALETRA Tablets, 200 mg lopinavir and 50 mg ritonavir
`
`
`
` 16.2 KALETRA Tablets, 100 mg lopinavir and 25 mg ritonavir
`
`
`
` 16.3 KALETRA Oral Solution
`
`
` 17 PATIENT COUNSELING INFORMATION
`
` *Sections or subsections omitted from the full prescribing information are not
`
` listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4017646
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2030, Page 2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
` KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV­
`
`1 infection in adults and pediatric patients (14 days and older).
` The following points should be considered when initiating therapy with KALETRA:
`
` • The use of other active agents with KALETRA is associated with a greater likelihood of
`
`
`
`
`
` treatment response [see Microbiology (12.4) and Clinical Studies (14)].
`
`
`
`
`
`
` • Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA
`
`
`
` [see Microbiology (12.4)]. The number of baseline lopinavir resistance-associated
`
`
` substitutions affects the virologic response to KALETRA [see Microbiology (12.4)].
`
`
`
`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
` 2.1 General Administration Recommendations
` KALETRA tablets may be taken with or without food. The tablets should be swallowed whole
`
`
` and not chewed, broken, or crushed. KALETRA oral solution must be taken with food.
`
`
`
`
` 2.2 Dosage Recommendations in Adults
`
` Considerations in Determining KALETRA Once Daily vs. Twice Daily Dosing Regimen:
`
`• KALETRA can be given as once daily or twice daily dosing regimen in patients with less
`
`
`
`
`than three lopinavir resistance-associated substitutions.
`
`
`• KALETRA must be given as twice daily dosing regimen in patients with three or more
`
`
`
`
`resistance-associated substitutions.
`
`
`• Table 1 includes the recommended once daily dosing regimen and Tables 2 and 3 include the
`
`
`recommended twice daily dosing regimen.
`
`
`
`
`
`KALETRA once daily dosing regimen is not recommended in:
`
`• Adult patients with three or more of the following lopinavir resistance-associated
`
`
`
`
`
`
`substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V,
`
`V82A/C/F/S/T, and I84V [see Microbiology (12.4)].
`
`
`
`
`• In combination with carbamazepine, phenobarbital, or phenytoin [see Drug Interactions
`
`
`
`(7.3)].
`
`
`• In combination with efavirenz, nevirapine, or nelfinavir [see Drug Interactions (7.3) and
`
`
`
`
`Clinical Pharmacology (12.3)].
`
`
`• In pregnant women [see Dosage and Administration (2.4), Use in Specific Populations (8.1)
`
`
`and Clinical Pharmacology (12.3)].
`
`
`
`
`
`The dose of KALETRA must be increased when administered in combination with efavirenz,
`
`nevirapine or nelfinavir.
`
`
`Reference ID: 4017646
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2030, Page 3
`
`

`

` Table 3 outlines the dosage recommendations for twice daily dosing when KALETRA is taken in
`
`
`
`combination with efavirenz, nevirapine or nelfinavir.
`
` Table 1. Recommended Dosage in Adults- KALETRA Once Daily Regimen
`
`
`
` KALETRA Dosage Form
` Recommended Dosage
`
` 200 mg/50 mg Tablets
` 800 mg/200 mg (4 tablets) once daily
`
`
`
` 80 mg/20 mg per mL Oral Solution
` 800 mg/200 mg (10 mL) once daily
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 2. Recommended Dosage in Adults - KALETRA Twice Daily Regimen
` Recommended Dosage
`
`
`
` KALETRA Dosage Form
`
` 200 mg/50 mg Tablets
` 400 mg/100 mg (2 tablets) twice daily
`
` 400 mg/100 mg (5 mL) twice daily
` 80 mg/20 mg per mL Oral Solution
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 3. Recommended Dosage in Adults - KALETRA Twice Daily Regimen in
`
`
`
`
` Combination with Efavirenz, Nevirapine, or Nelfinavir
`
`
` Recommended Dosage
`
`
` KALETRA Dosage Form
` 500 mg/125 mg (2 tablets of 200 mg/50 mg
` 200 mg/50 mg Tablets and
`
`
`
`
` + 1 tablet of 100 mg/25 mg) twice daily
` 100 mg/25 mg Tablets
` 80 mg/20 mg per mL Oral Solution
`
`
` 520 mg/130 mg (6.5 mL) twice daily
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.3 Dosage Recommendations in Pediatric Patients
`
`
` KALETRA tablets and oral solution should not be administered once daily in pediatric patients <
`
` 18 years of age. The dose of the oral solution should be administered using a calibrated dosing
`
`
`
` syringe.
`Before prescribing KALETRA 100/25 mg tablets, children should be assessed for the ability to
`
`
`
`
`
` swallow intact tablets. If a child is unable to reliably swallow a KALETRA tablet, the
` KALETRA oral solution formulation should be prescribed.
`
`
` KALETRA oral solution should not be administered to neonates before a postmenstrual age (first
`
` day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks
` and a postnatal age of at least 14 days has been attained [see Warnings and Precautions (5.2)].
`
`
`
` KALETRA oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol.
` Special attention should be given to accurate calculation of the dosage of KALETRA,
`
`
`
` transcription of the medication order, dispensing information and dosing instructions to minimize
`
` the risk for medication errors, and overdose. This is especially important for infants and young
` children. Total amounts of alcohol and propylene glycol from all medicines that are to be given
`
`
`
` to pediatric patients 14 days to 6 months of age should be taken into account in order to avoid
`
` toxicity from these excipients [see Warnings and Precautions (5.2) and Overdosage (10)].
`
`
`
`
`
`
`
`
`
`Reference ID: 4017646
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2030, Page 4
`
`

`

` Pediatric Dosage Calculations
`
` Calculate the appropriate dose of KALETRA for each individual pediatric patient based on body
`
`
`
` weight (kg) or body surface area (BSA) to avoid underdosing or exceeding the recommended
`
` adult dose.
` Body surface area (BSA) can be calculated as follows:
`
`
`
`
`
`
`
`
`
`
`
`
`
`The KALETRA dose can be calculated based on weight or BSA:
`Based on Weight:
`
`
`
`Patient Weight (kg) × Prescribed lopinavir dose (mg/kg) = Administered lopinavir dose (mg)
`Based on BSA:
`
`Patient BSA (m2) × Prescribed lopinavir dose (mg/m2) = Administered lopinavir dose (mg)
`
`
`If KALETRA oral solution is used, the volume (mL) of KALETRA solution can be determined
`
`
`as follows:
`
`
`
`
`Volume of KALETRA solution (mL) = Administered lopinavir dose (mg) ÷ 80 (mg/mL)
`
`
`Dosage Recommendation in Pediatric Patients 14 Days to 6 Months:
`
`
`In pediatric patients 14 days to 6 months of age, the recommended dosage of lopinavir/ritonavir
`using KALETRA oral solution is 16/4 mg/kg or 300/75 mg/m2 twice daily. Prescribers should
`
`
`calculate the appropriate dose based on body weight or body surface area. Table 4 summarizes
`
`
`
`the recommended daily dosing regimen for pediatric patients 14 days to 6 months.
`
`It is recommended that KALETRA not be administered in combination with efavirenz,
`nevirapine, or nelfinavir in patients < 6 months of age.
`
`
`
`
`
`
`
`
`
` Frequency
`
` Given twice daily
`
`
`Table 4. Recommended KALETRA Oral Daily Dosage in Pediatric Patients 14 days to 6
`
`months
`
` Based on Weight (mg/kg) Based on BSA (mg/m2)
`
`Patient Age
`
` 14 days to 6 months
`
`
`
` 16/4
` 300/75
`
`
` Dosage Recommendation in Pediatric Patients > 6 Months to < 18 Years:
`
`
` Without Concomitant Efavirenz, Nevirapine, or Nelfinavir
`
`
` Dosing recommendations using oral solution
`
` In children > 6 months to < 18 years of age, the recommended dosage of lopinavir/ritonavir
`
` using KALETRA oral solution without concomitant efavirenz, nevirapine, or nelfinavir is
`
` 230/57.5 mg/m2 given twice daily, not to exceed the recommended adult dose (400/100 mg [5
`
`mL] twice daily). If weight-based dosing is preferred, the recommended dosage of
`
`
`lopinavir/ritonavir for patients < 15 kg is 12/3 mg/kg given twice daily and the dosage for
`
`
`
`
`
`
`
`Reference ID: 4017646
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2030, Page 5
`
`

`

`
` patients ≥ 15 kg to 40 kg is 10/2.5 mg/kg given twice daily. Table 5 summarizes the
`
`
`
`
`
` recommended daily dosing regimen for pediatric patients > 6 months to < 18 years.
`
`
`
`
`
`
`
` Patient Age
`
`
`
` > 6 months to < 18 years
`
`
`
`
`
` Frequency
`
`
`
`
`
` Given twice daily
`
`Table 5. Recommended KALETRA Oral Daily Dosage in Pediatric Patients > 6 months to
`
`
`
`< 18 years
`
` Based on Weight (mg/kg) Based on BSA (mg/m2)
`
`
`
` <15 kg
` 12/3
` 230/57.5
`
`
` ≥15 kg to 40 kg 10/2.5
`
` Dosing recommendations using tablets
` Table 6 provides the dosing recommendations for pediatric patients > 6 months to < 18 years of
`
`
` age based on body weight or body surface area for KALETRA tablets.
`
`
`
`
`
`
`
`
`
`
`
` Body Weight (kg)
`
`
`
`
`
` Table 6. Pediatric Dosing Recommendations for Patients > 6 Months to < 18 Years of Age
`
`
`
`
`
` Based on Body Weight or Body Surface Area for KALETRA Tablets Without
`
`
` Concomitant Efavirenz, Nevirapine, or Nelfinavir
`
`
` Body Surface Area (m2)*
` Recommended number of
`
` 100/25 mg Tablets Twice Daily
`
`
`2
`
` ≥0.6 to < 0.9
`
` ≥15 to 25
`
`3
`
` ≥0.9 to < 1.4
`
` >25 to 35
` 4 (or two 200/50 mg tablets)
`
`
`
` >35
` ≥1.4
` * KALETRA oral solution is available for children with a BSA less than 0.6 m2 or those who are
`
`
`
` unable to reliably swallow a tablet.
` Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir
`
` Dosing recommendations using oral solution
` A dose increase of KALETRA to 300/75 mg/m2 using KALETRA oral solution is needed when
`
`
`
` co-administered with efavirenz, nevirapine, or nelfinavir in children (both treatment-naïve and
`
` treatment-experienced) > 6 months to < 18 years of age, not to exceed the recommended adult
`
`
`dose (533/133 mg [6.5 mL] twice daily). If weight-based dosing is preferred, the recommended
` dosage for patients <15 kg is 13/3.25 mg/kg given twice daily and the dosage for patients ≥ 15
`
`
`
`
`
`kg to 45 kg is 11/2.75 mg/kg given twice daily.
`Dosing recommendations using tablets
`
`
`
`
`Table 7 provides the dosing recommendations for pediatric patients > 6 months to < 18 years of
`
`age based on body weight or body surface area for KALETRA tablets when given in
`
`combination with efavirenz, nevirapine, or nelfinavir.
`
`
`
`
`
`Reference ID: 4017646
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2030, Page 6
`
`

`

`
`
` Body Weight (kg)
`
`
`
` Table 7. Pediatric Dosing Recommendations for Patients > 6 Months to < 18 Years of Age
`
`
`
`
`
` Based on Body Weight or Body Surface Area for KALETRA Tablets With Concomitant
`
`Efavirenz†, Nevirapine, or Nelfinavir†
`
`
`
` Body Surface Area (m2)*
` Recommended number of
`
` 100/25 mg Tablets Twice Daily
`
`
`2
`
` ≥0.6 to < 0.8
`
` ≥15 to 20
`
`3
`
` ≥0.8 to < 1.2
`
` >20 to 30
` 4 (or two 200/50 mg tablets)
`
` ≥1.2 to <1.7
`
` >30 to 45
`
`
` 5 [see Dosage and Administration (2.2)]
`
`
` >45
` ≥1.7
` * KALETRA oral solution is available for children with a BSA less than 0.6 m2 or those who are
`
`
`
`
`unable to reliably swallow a tablet.
` † Please refer to the individual product labels for appropriate dosing in children.
`
`
`
`
`
`
`
`
`
`
` 2.4 Dosage Recommendations in Pregnancy
`
`
`
` Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented
`lopinavir-associated resistance substitutions. Once daily KALETRA dosing is not recommended
` in pregnancy [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].
`
`
` • There are insufficient data to recommend dosing in pregnant women with any documented
`
`
` lopinavir-associated resistance substitutions.
`
`
` • No dosage adjustment of KALETRA is required for patients during the postpartum period.
`
`
` • Avoid use of KALETRA oral solution in pregnant women [see Use in Specific Populations
`
`
`
` (8.1)].
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
` • Tablets, 200 mg lopinavir, 50 mg ritonavir: Yellow, film-coated, ovaloid, debossed with the
`
`
`
` “a” logo and the code KA providing 200 mg lopinavir and 50 mg ritonavir.
` • Tablets, 100 mg lopinavir, 25 mg ritonavir: Pale yellow, film-coated, ovaloid, debossed with
`
`
`
`
` the “a” logo and the code KC providing 100 mg lopinavir and 25 mg ritonavir.
` • Oral Solution: Light yellow to orange colored liquid containing 400 mg lopinavir and 100
`
`
`
`
`
`mg ritonavir per 5 mL (80 mg lopinavir and 20 mg ritonavir per mL).
`
`
`
`
`
`
`
`4 CONTRAINDICATIONS
`
`• KALETRA is contraindicated in patients with previously demonstrated clinically significant
`
`
`hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema
`
`
`multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir.
`
`
`• KALETRA 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.
`
`
`• KALETRA 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.
`
`Reference ID: 4017646
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2030, Page 7
`
`

`

`
`
`
`
` Drug Class
`
` Alpha 1­
`
`
` Adrenoreceptor
`
` Antagonist
`
` Antiarrhythmic
`
` Anti-gout
`
`
`
`
`Table 8. Drugs That are Contraindicated with KALETRA
` Drugs Within Class
` Clinical Comments
`
`
`That are
`Contraindicated with
`
` KALETRA
`
` Alfuzosin
`
`
`
` Potentially increased alfuzosin concentrations can
`
` result in hypotension.
`
`
` Dronedarone
`
` Colchicinea
`
`
`
` Antimycobacterial Rifampin
`
`
`
` Potential for cardiac arrhythmias.
`
`
` Potential for serious and/or life-threatening reactions
` in patients with renal and/or hepatic impairment.
`
`
`
` May lead to loss of virologic response and possible
`
` resistance to KALETRA or to the class of protease
`
`inhibitors or other co-administered antiretroviral
`
` agents.
` 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
`peripheral vasospasm and ischemia of the
`
` extremities and other tissues.
` Potential for cardiac arrhythmias.
`
` Potential for the increased risk of alanine
`
` transaminase (ALT) elevations.
` St. John's Wort
`
`
`
`
` May lead to loss of virologic response and possible
`
`
` (hypericum perforatum) resistance to KALETRA or to the class of protease
`
`
` inhibitors.
`
` Lovastatin, simvastatin Potential for myopathy including rhabdomyolysis.
`
`
`
`
` Lurasidone
`
` Pimozide
`
`
`
`
`
`
` Ergot Derivatives Dihydroergotamine,
`
` ergotamine,
` methylergonovine
`
` GI Motility Agent Cisapride
`
`
` Elbasvir/grazoprevir
`Hepatitis C direct
`
` acting antiviral
` Herbal Products
`
`
`
`
`
`
` Antipsychotics
`
`
`HMG-CoA
`Reductase
`
` Inhibitors
` PDE5 Inhibitor
`
`
`
`
`
`
`
`
`
`
`
`
` Sildenafilb (Revatio®)
`
`
` when used for the
`
` treatment of pulmonary
`
` arterial hypertension
`
`
` Sedative/Hypnotics Triazolam;
` orally administered
`
` midazolamc
` a see Drug Interactions (7), Table 13 for colchicine doses in patients with normal hepatic and
`
`
`
`
`renal function.
` b see Drug Interactions (7), Table 13 for co-administration of sildenafil in patients with erectile
`
`
`
` dysfunction.
` c see Drug Interactions (7), Table 13 for parenterally administered midazolam.
`
`
`
` Potential for sildenafil-associated adverse events,
`
`including visual abnormalities, hypotension,
`
` prolonged erection, and syncope.
`
`
`
`
`
` Prolonged or increased sedation or respiratory
`
` depression.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4017646
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2030, Page 8
`
`

`

`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
` 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions
` Initiation of KALETRA, a CYP3A inhibitor, in patients receiving medications metabolized by
`
`
`
`
` CYP3A or initiation of medications metabolized by CYP3A in patients already receiving
` KALETRA, may increase plasma concentrations of medications metabolized by CYP3A.
`
` Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations
`
` of KALETRA, 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 KALETRA.
`
` • Loss of therapeutic effect of KALETRA and possible development of resistance.
`
`
`
`
`
`
`
`
`
`See Table 13 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 KALETRA therapy; review concomitant
`
`
`
`medications during KALETRA therapy, and monitor for the adverse reactions associated with
`
`
`
`the concomitant medications [see Contraindications (4) and Drug Interactions (7)].
`
`
`
`
`5.2 Toxicity in Preterm Neonates
`
`
`KALETRA oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol
`
`
`(15.3% w/v). When administered concomitantly with propylene glycol, ethanol competitively
`
`
`inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm
`
`
`neonates may be at increased risk of propylene glycol-associated adverse events due to
`
`
`diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential
`
`adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV
`
`
`block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and
`
`
`respiratory complications leading to death have been reported, predominantly in preterm
`
`
`neonates receiving KALETRA oral solution.
`
`KALETRA oral solution should not be used in preterm neonates in the immediate postnatal
`
`period because of possible toxicities. A safe and effective dose of KALETRA oral solution in
`this patient population has not been established. However, if the benefit of using KALETRA oral
`
`
`solution to treat HIV infection in infants immediately after birth outweighs the potential risks,
`
`
`
`infants should be monitored closely for increases in serum osmolality and serum creatinine, and
`for toxicity related to KALETRA oral solution including: hyperosmolality, with or without lactic
`
`
`acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures,
`hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of alcohol and
`propylene glycol from all medicines that are to be given to infants should be taken into account
`
`
`in order to avoid toxicity from these excipients [see Dosage and Administration (2.3) and
`
`
`
`Overdosage (10)].
`
`
`5.3 Pancreatitis
`
`Pancreatitis has been observed in patients receiving KALETRA therapy, including those who
`developed marked triglyceride elevations. In some cases, fatalities have been observed. Although
`a causal relationship to KALETRA has not been established, marked triglyceride elevations are a
`
`
`
`Reference ID: 4017646
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2030, Page 9
`
`

`

`
`
` risk factor for development of pancreatitis [see Warnings and Precautions (5.9)]. Patients with
`
` advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and
`
`
` patients with a history of pancreatitis may be at increased risk for recurrence during KALETRA
`
`
` therapy.
` 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 occur. Patients who exhibit these signs or symptoms should be evaluated and
`KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate.
`
`
`
`
`
`
`
`5.4 Hepatotoxicity
`
`Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment
`
`may be at increased risk for developing or worsening of transaminase elevations or hepatic
`
`
`
`decompensation with use of KALETRA.
`
`There have been postmarketing reports of hepatic dysfunction, including some fatalities. These
`
`
`have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant
`
`medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with
`
`
`KALETRA therapy has not been established.
`
`
`Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1
`
`mono-infected and uninfected patients as early as 7 days after the initiation of KALETRA in
`
`
`
`
`
`
`conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious;
`
`however, a definitive causal relationship with KALETRA therapy has not been established.
`
`
`Appropriate laboratory testing should be conducted prior to initiating therapy with KALETRA
`
`and patients should be monitored closely during treatment. Increased AST/ALT monitoring
`
`should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially
`
`during the first several months of KALETRA treatment [see Use in Specific Populations (8.6)].
`
`
`
`5.5 QT Interval Prolongation
`
`Postmarketing cases of QT interval prolongation and torsade de pointes have been reported
`although causality of KALETRA could not be established. Avoid use in patients with congenital
`
`
`long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval
`
`[see Clinical Pharmacology (12.3)].
`
`
`
`5.6 PR Interval Prolongation
`
`
`Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree
`
`atrioventricular block have been reported. KALETRA should be used with caution in patients
`
`with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic
`
`
`heart disease or cardiomyopathies, as these patients may be at increased risk for developing
`
`
`cardiac conduction abnormalities.
`
`The impact on the PR interval of co-administration of KALETRA 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 KALETRA with these drugs
`
`
`
`should be undertaken with caution, particularly with those drugs metabolized by CYP3A.
`
`
`Clinical monitoring is recommended [see Clinical Pharmacology (12.3)].
`
`
`
`
`Reference ID: 4017646
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2030, Page 10
`
`

`

` 5.7 Diabetes Mellitus/Hyperglycemia
`
`
` New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia
`
` have been reported during post-marketing 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 KALETRA.
`
`
`5.8 Immune Reconstitution Syndr