HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use BIAXIN
` safely and effectively. See full prescribing information for BIAXIN.
`
`
`
`BIAXIN® Filmtab® (clarithromycin) tablets, for oral use
`
`
`
`
`
`BIAXIN® XL Filmtab® (clarithromycin extended-release tablets), for oral
`
`
`
`
`use
`BIAXIN® Granules (clarithromycin) for oral suspension
`
`
`
`Initial U.S. Approval: 1991
`
`
`
`
`
`
`
`
`
`RECENT MAJOR CHANGES
`
`
`
`
`
`
`
`
`
` Warnings and Precautions, Serious Adverse Reactions with
` Concomitant Use with Other Drugs (5.4)
`
`
`
`
`
`
`
`
`
`
`
` 10/2015
`
`
`
`
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
` BIAXIN is a macrolide antimicrobial indicated for mild to moderate
` infections caused by designated, susceptible bacteria in the following:
`
`
`
`
`
` • Acute Bacterial Exacerbation of Chronic Bronchitis in Adults (1.1)
`
`
`
` • Acute Maxillary Sinusitis (1.2)
`
`
`
` • Community-Acquired Pneumonia (1.3)
`
` • Pharyngitis/Tonsillitis (1.4)
`
`
`
`
` • Uncomplicated Skin and Skin Structure Infections (1.5)
`
`
`
` • Acute Otitis Media in Pediatric Patients (1.6)
`
`
`
`
`
` • Treatment and Prophylaxis of Disseminated Mycobacterial Infections (1.7)
`
`
` • Helicobacter pylori Infection and Duodenal Ulcer Disease in Adults (1.8)
`
`
`
`
`
`
` Limitations of Use
`
`
`
`
`BIAXIN XL Filmtab is indicated only for acute bacterial exacerbation of
`
`
`chronic bronchitis, acute maxillary sinusitis, and community-acquired
`
`
`pneumonia in adults. (1.9)
`
`
`
`To reduce the development of drug-resistant bacteria and maintain the
`
`
`
`effectiveness of BIAXIN and other antibacterial drugs, BIAXIN should be
`
`
`used only to treat or prevent infections that are proven or strongly suspected to
`
`
`be caused by bacteria. (1.9)
`
`
`
`
`
`
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`• Adults: BIAXIN 250 mg or 500 mg every 12 hours for 7–14 days; BIAXIN
`
`
`
`XL 1 gram every 24 hours for 7–14 days (2.2)
`• H. pylori eradication (in combination with lansoprazole/amoxicillin,
`
`
`
`
`
`omeprazole/amoxicillin, or omeprazole): BIAXIN 500 mg every 8 or 12
`
`
`hours for 10–14 days. See full prescribing information (FPI) for additional
`
`
`information. (2.3)
`
`
`
`• Pediatric Patients: BIAXIN 15 mg/kg/day divided every 12 hours for 10
`
`
`
`days (2.4)
`
`
`
`• Mycobacterial Infections: BIAXIN 500 mg every 12 hours; BIAXIN 7.5
`
`
`
`
`
`
`mg/kg up to 500 mg every 12 hours in pediatric patients (2.5)
`
`• Reduce dose in moderate renal impairment with concomitant atazanavir or
`
`
`
`
`ritonavir-containing regimens and in severe renal impairment (2.6)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1 INDICATIONS AND USAGE
`
`
`
`
`
`1.1 Acute Bacterial Exacerbation of Chronic Bronchitis
`
`
`1.2 Acute Maxillary Sinusitis
`
`1.3 Community-Acquired Pneumonia
`
`1.4 Pharyngitis/Tonsillitis
`
`1.5 Uncomplicated Skin and Skin Structure Infections
`
`
`1.6 Acute Otitis Media
`
`
`
`1.7 Treatment and Prophylaxis of Disseminated Mycobacterial Infections
`
`
`
`
`1.8 Helicobacter pylori Infection and Duodenal Ulcer Disease
`
`1.9 Limitations of Use
`
`1.10 Usage
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Important Administration Instructions
`
`2.2 Adult Dosage
`
`
`
`2.3 Combination Dosing Regimens for H. pylori Infection
`
`2.4 Pediatric Dosage
`
`
`2.5 Dosage Regimens for Mycobacterial Infections
`
`
`2.6 Dosage Adjustment in Patients with Renal Impairment
`
`
`2.7 Dosage Adjustment Due to Drug Interactions
`
`Reference ID: 3937416
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
`
`• Tablets: 250 mg and 500 mg (3)
`
`
`
`• Extended-release Tablets: 500 mg (3)
`
`
`
`
`
`
`• Granules for Oral Suspension: 125 mg/5 mL and 250 mg/5 mL (3)
`
`
`
`
`
`
`CONTRAINDICATIONS
`
`
`
`
`• Hypersensitivity to clarithromycin or any macrolide drug (4.1)
`
`
`
`• Cisapride, pimozide, lovastatin/simvastatin, ergotamine/dihydroergotamine
`
`
`
`
`(4.2, 4.5, 4.6)
`
`
`
`• History of cholestatic jaundice/hepatic dysfunction with use of
`
`
`
`clarithromycin (4.3)
`
`
`
`• Colchicine in renal or hepatic impairment (4.4)
`
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`• Severe acute hypersensitivity reactions: Discontinue BIAXIN if occurs
`
`
`(5.1)
`
`
`• QT prolongation: Avoid BIAXIN in patients with known QT prolongation
`
`
`
`
`or receiving drugs known to prolong the QT interval, ventricular arrhythmia
`
`
`
`(torsade de pointes), hypokalemia/hypomagnesemia, significant
`
`
`
`
`bradycardia, or taking Class IA or III antiarrhythmics (5.2)
`
`
`• Hepatotoxicity: Discontinue if signs and symptoms of hepatitis occur (5.3)
`
`
`
`
`
`• Serious adverse reactions can occur due to drug interactions of BIAXIN
`
`
`with colchicine, some HMG CoA reductase inhibitors, some calcium
`
`
`channel blockers, and other drugs (5.4)
`• Clostridium difficile associated diarrhea (CDAD): Evaluate if diarrhea
`
`
`
`
`
`
`occurs (5.5)
`
`
`
`
`• Embryofetal toxicity: BIAXIN should not be used in pregnant women
`
`except in clinical circumstances where no alternative therapy is appropriate
`
`(5.6)
`
`
`• Exacerbation of myasthenia gravis (5.7)
`
`
`
`
`
`
`ADVERSE REACTIONS
`
`
`
`
`
`
`Most frequent adverse reactions for both adult and pediatric populations in
`
`
`
`clinical trials: abdominal pain, diarrhea, nausea, vomiting, dysgeusia (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 BIAXIN can alter the concentrations of other drugs. The
`
`
`
`potential for drug-drug interactions must be considered prior to and during
`
`
`
`
`therapy. (4, 5.2, 5.4, 7)
`
`
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`Geriatric: Increased risk of torsades de pointes (8.5)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`Revised: 5/2016
`
`
`
`
`
`2.8 Reconstitution of BIAXIN Granules
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`
`4.1 Hypersensitivity
`4.2 Cardiac Arrhythmias
`
`
`4.3 Cholestatic Jaundice/Hepatic Dysfunction
`
`
`4.4 Colchicine
`
`4.5 HMG-CoA Reductase Inhibitors
`
`4.6 Ergot Alkaloids
`
`4.7 Contraindications for Co-administered Drugs
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Acute Hypersensitivity Reactions
`
`
`5.2 QT Prolongation
`
`5.3 Hepatotoxicity
`
`5.4 Serious Adverse Reactions Due to Concomitant Use with Other Drugs
`
`
`5.5 Clostridium difficile Associated Diarrhea
`
`
`5.6 Embryofetal Toxicity
`
`5.7 Exacerbation of Myasthenia Gravis
`
`5.8 Development of Drug Resistant Bacteria
`
`
`
`6 ADVERSE REACTIONS
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 1
`
`

`

`
` 6.1 Clinical Trials Experience
`
` 6.2 Postmarketing Experience
`
` 7 DRUG INTERACTIONS
` 8 USE IN SPECIFIC POPULATIONS
`
` 8.1 Pregnancy
` 8.3 Nursing Mothers
`
` 8.4 Pediatric Use
`
` 8.5 Geriatric Use
` 8.6 Renal and 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
` 13.2 Animal Toxicology and/or Pharmacology
`
`
` 14 CLINICAL STUDIES
` 14.1 Mycobacterial Infections
`
`
`
` 14.2 Otitis Media
` 14.3 H. pylori Eradication to Decrease the Risk of Duodenal Ulcer
`
`
` Recurrence
`
`
` 15 REFERENCES
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 17 PATIENT COUNSELING INFORMATION
`
` *Sections or subsections omitted from the full prescribing information are not
`
` listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3937416
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
` 1.1 Acute Bacterial Exacerbation of Chronic Bronchitis
` BIAXIN (Filmtab, Granules) and BIAXIN XL Filmtab are indicated in adults for the treatment
`
`
`of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae,
`Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae [see
`
`
`Indications and Usage (1.9)].
`
`
`
`1.2 Acute Maxillary Sinusitis
`
`BIAXIN (Filmtab, Granules) and BIAXIN XL Filmtab (in adults) are indicated for the treatment
`
`
`of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae,
`Moraxella catarrhalis, or Streptococcus pneumoniae [see Indications and Usage (1.9)].
`
`
`
`
`1.3 Community-Acquired Pneumonia
`
`BIAXIN (Filmtab, Granules) and BIAXIN XL Filmtab are indicated [see Indications and Usage
`
`
`
`
`
`(1.9)] for the treatment of mild to moderate infections caused by susceptible isolates due to:
`
`
`
`• Haemophilus influenzae (in adults)
`
`
`
`
`• Haemophilus parainfluenzae (BIAXIN XL Filmtab in adults)
`
`
`
`
`
`• Moraxella catarrhalis (BIAXIN XL Filmtab in adults)
`
`
`
`
`• Mycoplasma pneumoniae, Streptococcus pneumoniae, Chlamydophila pneumoniae (BIAXIN
`
`
`
`XL Filmtab [in adults]; BIAXIN Filmtab and BIAXIN Granules [in adults and pediatric
`
`
`
`
`patients])
`
`
`
`
`1.4 Pharyngitis/Tonsillitis
`
`BIAXIN Filmtab and BIAXIN Granules are indicated for the treatment of mild to moderate
`
`
`
`infections caused by susceptible isolates due to Streptococcus pyogenes as an alternative in
`
`
`individuals who cannot use first line therapy.
`
`
`1.5 Uncomplicated Skin and Skin Structure Infections
`
`BIAXIN Filmtab and BIAXIN Granules are indicated for the treatment of mild to moderate
`
`
`
`infections caused by susceptible isolates due to Staphylococcus aureus, or Streptococcus
`
`
`
`pyogenes.
`
`
`Reference ID: 3937416
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 3
`
`

`

`
`1.6 Acute Otitis Media
`
`
`BIAXIN Filmtab and BIAXIN Granules are indicated in pediatric patients for the treatment of
`
`mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae,
`
`
`Moraxella catarrhalis, or Streptococcus pneumoniae [see Clinical Studies (14.2)].
`
`
`
`
`
`
`1.7 Treatment and Prophylaxis of Disseminated Mycobacterial Infections
`
`
`
`BIAXIN Filmtab and BIAXIN Granules are indicated for the treatment of mild to moderate
`
`
`infections caused by susceptible isolates due to Mycobacterium avium or Mycobacterium
`
`
`intracellulare in patients with advanced HIV infection [see Clinical Studies (14.1)].
`
`
`
`1.8 Helicobacter pylori Infection and Duodenal Ulcer Disease
`
`
`
`
`BIAXIN Filmtab is given in combination with other drugs in adults as described below to
`eradicate H. pylori. The eradication of H. pylori has been demonstrated to reduce the risk of
`
`
`
`
`
`duodenal ulcer recurrence [see Clinical Studies (14.3)].
`
`
`
`
`
`• BIAXIN Filmtab in combination with amoxicillin and PREVACID (lansoprazole) or
`
`
`
`
`PRILOSEC (omeprazole) Delayed-Release Capsules, as triple therapy, are indicated for the
`treatment of patients with H. pylori infection and duodenal ulcer disease (active or five-year
`
`
`
`
`history of duodenal ulcer) to eradicate H. pylori.
`
`
`
`
`
`• BIAXIN Filmtab in combination with PRILOSEC (omeprazole) capsules are indicated for
`
`the treatment of patients with an active duodenal ulcer associated with H. pylori infection.
`
`
`
`
`
`
`
`
`Regimens which contain BIAXIN Filmtab as the single antibacterial agent are more likely to
`
`
`be associated with the development of clarithromycin resistance among patients who fail
`
`therapy. Clarithromycin-containing regimens should not be used in patients with known or
`
`suspected clarithromycin resistant isolates because the efficacy of treatment is reduced in this
`
`setting.
`
`
`
`1.9 Limitations of Use
`
`BIAXIN XL Filmtab is indicated only for acute maxillary sinusitis, acute bacterial exacerbation
`
`
`
`
`
`of chronic bronchitis, and community-acquired pneumonia in adults. The efficacy and safety of
`
`
`BIAXIN XL Filmtab in treating other infections for which BIAXIN Filmtab and BIAXIN
`
`
`Granules are approved have not been established.
`
`There is resistance to macrolides in certain bacterial infections caused by Streptococcus
`
`
`pneumoniae and Staphylococcus aureus. Susceptibility testing should be performed when
`
`clinically indicated.
`
`
`1.10 Usage
`
`To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN
`
`
`and other antibacterial drugs, BIAXIN should be used only to treat or prevent infections that are
`
`
`proven or strongly suspected to be caused by susceptible bacteria. When culture and
`
`susceptibility information are available, they should be considered in selecting or modifying
`
`antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns
`
`may contribute to the empiric selection of therapy.
`
`
`
`Reference ID: 3937416
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 4
`
`

`

`
`
` 2 DOSAGE AND ADMINISTRATION
`
` 2.1 Important Administration Instructions
`
`
`
`
`
` BIAXIN Filmtab and BIAXIN Granules may be given with or without food.
` BIAXIN XL Filmtab should be taken with food. Swallow BIAXIN XL Filmtab whole; do not
`
`
` chew, break or crush BIAXIN XL Filmtab.
`
`
`
`
`
`
` 2.2 Adult Dosage
`
` The recommended dosages of BIAXIN Filmtab and BIAXIN XL Filmtab for the treatment of
`
`
` mild to moderate infections in adults are listed in Table 1.
`
`
`
`
`
`
`
`
`
`
`
` Infection
`
`
`
`Table 1. Adult Dosage Guidelines
`
`
` BIAXIN Filmtab
`
` Dosage
` Duration
`(every 12
`
` (days)
`
` hours)
`250 to 500
`
` mga
`
` 500 mg
`
`
` 250 mgc
`
` 250 mg
`
`
`
` 250 mg
`
`
`
` BIAXIN XL Filmtab
`
`
` Dosage
`
` Duration
`(every 24
`
` (days)
`
` hours)
`
` 1 gram
`
` 1 gram
`
` 1 gramc
` -
`
`
` -
`
` 7
`
`
` 14
`
` 7
`
` -
`
` -
`
`
`
`
`
`
`
`7b-14
`
` 14
`
` 7d-14
`
` 10
`
` 7-14
`
`Acute bacterial exacerbation of chronic
`
` bronchitis
` Acute maxillary sinusitis
`
` Community-acquired pneumonia
`
` Pharyngitis/Tonsillitis
` Uncomplicated skin and skin structure
`
` infections
` Treatment and prophylaxis of
`
`
` disseminated Mycobacterium avium
`
` disease [see Dosage and Administration
`
`
` (2.5)]
`
` H.pylori eradication to reduce the risk of
` duodenal ulcer recurrence with
`
` amoxicillin and omeprazole or
`
` lansoprazole [see Dosage and
`
` Administration (2.3)]
`
` H.pylori eradication to reduce the risk of
`
` duodenal ulcer recurrence with
`
` omeprazole [see Dosage and
`
`
` Administration (2.3)]
` a For M. catarrhalis and S. pneumoniae use 250 mg. For H. influenzae and H. parainfluenzae,
`
`
`
`use 500 mg.
`
` b For H parainfluenzae, the duration of therapy is 7 days.
`
`
`
`
`c For H. parainfluenzae and M. catarrhalis use BIAXIN XL tablets only.
`
`
`
`
`
`d For H. influenzae, the duration of therapy is 7 days.
`
`
`
`
`e BIAXIN therapy should continue if clinical response is observed. BIAXIN can be discontinued
`
` when the patient is considered at low risk of disseminated infection.
`
`
`
`
`
` 500 mge
`
`
`
`
`
` -
`
`
`
` 500 mg
`
`
`
` 10-14
`
`
` 500 mg every
`
` 8 hours
`
`
`
` 14
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` -
`
`
`
` -
`
`
`
` -
`
`
`
` -
`
`
`
` -
`
`
`
` -
`
`
`
`
`
`Reference ID: 3937416
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 5
`
`

`

`
`
`
`
`
`
` 2.3 Combination Dosing Regimens for H. pylori Infection
`
`
`
` • Triple therapy: BIAXIN Filmtab/lansoprazole/amoxicillin
`
`
`
`
` The recommended adult dosage is 500 mg BIAXIN Filmtab, 30 mg lansoprazole, and 1 gram
` amoxicillin, all given every 12 hours for 10 or 14 days [see Indications and Usage (1.8) and
`
`
`
`
` Clinical Studies (14.3)].
`
` • Triple therapy: BIAXIN Filmtab/omeprazole/amoxicillin
`
`
`
`
`
` The recommended adult dosage is 500 mg BIAXIN Filmtab, 20 mg omeprazole, and 1 gram
` amoxicillin; all given every 12 hours for 10 days. In patients with an ulcer present at the time
`
`
` of initiation of therapy, an additional 18 days of omeprazole 20 mg once daily is
` recommended for ulcer healing and symptom relief [see Indications and Usage (1.8) and
`
`
`
`
` Clinical Studies (14.3)].
`
` • Dual therapy: BIAXIN Filmtab/omeprazole
`
`
`
`
`
` The recommended adult dosage is 500 mg BIAXIN Filmtab given every 8 hours and 40 mg
` omeprazole given once every morning for 14 days. An additional 14 days of omeprazole 20
`
` mg once daily is recommended for ulcer healing and symptom relief [see Indications and
`
`
`
`
` Usage (1.8) and Clinical Studies (14.3)].
`
`
`
`
`
`
`
`
`
`
`
`2.4 Pediatric Dosage
`
`The recommended daily dosage is 15 mg/kg/day divided every 12 hours for 10 days (up to the
`
`
`
`
`
`adult dose). Refer to dosage regimens for mycobacterial infections in pediatric patients for
`
`
`additional dosage information [see Dosage and Administration (2.5)].
`
`
`2.5 Dosage Regimens for Mycobacterial Infections
`
`For the treatment of disseminated infection due to Mycobacterium avium complex (MAC),
`
`
`BIAXIN Filmtab and BIAXIN Granules are recommended as the primary agents. BIAXIN
`
`
`
`Filmtab and BIAXIN Granules should be used in combination with other antimycobacterial
`
`drugs (e.g. ethambutol) that have shown in vitro activity against MAC or clinical benefit in MAC
`
`
`
`
`treatment [see Clinical Studies (14.1)].
`
`
`Adult Patients
`
`
`For treatment and prophylaxis of mycobacterial infections in adults, the recommended dose of
`
`
`BIAXIN is 500 mg every 12 hours.
`
`Pediatric Patients
`For treatment and prophylaxis of mycobacterial infections in pediatric patients, the
`
`recommended dose is 7.5 mg/kg every 12 hours up to 500 mg every 12 hours. [See Use in
`
`Specific Populations (8.4) and Clinical Studies (14.1)].
`
`
`
`
`BIAXIN therapy should continue if clinical response is observed. BIAXIN can be discontinued
`when the patient is considered at low risk of disseminated infection.
`
`
`
`2.6 Dosage Adjustment in Patients with Renal Impairment
`
`
`
`See Table 2 for dosage adjustment in patients with moderate or severe renal impairment with or
`
`
`without concomitant atazanavir or ritonavir-containing regimens [see Drug Interactions (7)].
`
`
`
`
`Reference ID: 3937416
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 6
`
`

`

`
`
`
`
`
`
` Table 2. BIAXIN Dosage Adjustments in Patients with Renal Impairment
`
`
` Recommended BIAXIN
`
` Dosage Reduction
`
` Reduce the dosage of
`
` BIAXIN by 50%
`
` Reduce the dosage of
`
` BIAXIN by 50%
`
` Reduce the dosage of
`
` BIAXIN by 75%
`
`
`
`
` Patients with severe renal impairment (CLcr of <30 mL/min)
` Patients with moderate renal impairment (CLcr of 30 to 60
`
`
`
` mL/min) taking concomitant atazanavir or ritonavir-containing
`
`
` regimens
`
` Patients with severe renal impairment (CLcr of <30 mL/min) taking
` concomitant atazanavir or ritonavir-containing regimens
`
`
`
`
`
`
`
`
`
`
`
` 2.7 Dosage Adjustment Due to Drug Interactions
`
` Decrease the dose of BIAXIN by 50 % when co-administered with atazanavir [see Drug
`
`
`
` Interactions (7)]. Dosage adjustments for other drugs when co-administered with BIAXIN may
`
` be recommended due to drug interactions [see Drug Interactions (7)].
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.8 Reconstitution of BIAXIN Granules
`
`
`
` The supplied BIAXIN Granules must be reconstituted with water prior to administration of
`BIAXIN for oral suspension. Table 3 below indicates the volume of water to be added when
` reconstituting. To reconstitute:
`
` a. Add half the volume of water to the bottle containing the BIAXIN granules and shake
`
`
`
`vigorously.
`
`
` b. Add the remainder of water to the bottle and shake.
`
`
`
`
`
`
`
`Shake well before each use. After mixing, store at 15° to 30°C (59° to 86°F) and use within
`
`
`14 days. Do not refrigerate.
`
`
`
`
`
`
`
`
`
`
`
`Table 3. Volume of Water to be Added When Reconstituting BIAXIN Granules
`Clarithromycin Concentration After
`Amount of Water to
`
` Total Volume After
` be Added
`
`
`
` Reconstitution
` Reconstitution
`
`
`
` 50 mL
` 125 mg/5 mL
` 27 mL
`
` 100 mL
`
` 125 mg/5 mL
`
` 55 mL
`
` 50 mL
`
` 250 mg/5 mL
`
` 27 mL
`
` 100 mL
`
` 250 mg/5 mL
`
` 55 mL
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
` BIAXIN is available as:
`
`
` • BIAXIN Filmtab (yellow oval film-coated tablet):
`
`
`
` ◦ 250 mg: imprinted in blue with the “a” logo and KT
`
` ◦ 500 mg: debossed with the “a” logo on one side and KL on the opposite side
`
` • BIAXIN XL Filmtab (yellow oval film-coated extended-release tablet):
`
`
`
`
`
`
`Reference ID: 3937416
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 7
`
`

`

`
` ◦ 500 mg: debossed with the “a” logo and KJ
`
` • BIAXIN Granules (white to off-white granules before reconstitution; white to off-white
`
`
`
` opaque suspension after reconstitution):
`
`
`
` ◦ 125 mg/5 mL concentration available in 50 mL and 100 mL bottles
`
`
`
` ◦ 250 mg/5 mL concentration available in 50 mL and 100 mL bottles
`
`
`
`
`
`
`
`4 CONTRAINDICATIONS
`
`
`4.1 Hypersensitivity
`
`BIAXIN is contraindicated in patients with a known hypersensitivity to clarithromycin,
`erythromycin, or any of the macrolide antibacterial drugs [see Warnings and Precautions (5.1)].
`
`
`
`
`
`4.2 Cardiac Arrhythmias
`
`Concomitant administration of BIAXIN with cisapride and pimozide is contraindicated [see
`
`
`Drug Interactions (7)].
`
`
`There have been postmarketing reports of drug interactions when clarithromycin is co­
`administered with cisapride or pimozide, resulting in cardiac arrhythmias (QT prolongation,
`
`ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to
`
`
`inhibition of metabolism of these drugs by BIAXIN. Fatalities have been reported.
`
`
`
`
`4.3 Cholestatic Jaundice/Hepatic Dysfunction
`
`BIAXIN is contraindicated in patients with a history of cholestatic jaundice or hepatic
`
`dysfunction associated with prior use of clarithromycin.
`
`
`4.4 Colchicine
`
`Concomitant administration of BIAXIN and colchicine is contraindicated in patients with renal
`
`
`or hepatic impairment.
`
`
`4.5 HMG-CoA Reductase Inhibitors
`
`Do not use BIAXIN concomitantly with HMG-CoA reductase inhibitors (statins) that are
`
`
`
`extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of
`
`
`myopathy, including rhabdomyolysis [see Warnings and Precautions (5.4) and Drug
`
`
`
`
`Interactions (7)].
`
`
`
`4.6 Ergot Alkaloids
`
`Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is
`
`contraindicated [see Drug Interactions (7)].
`
`
`
`
`
`4.7 Contraindications for Co-administered Drugs
`
`For information about contraindications of other drugs indicated in combination with BIAXIN,
`refer to their full prescribing information (contraindications section).
`
`
`Reference ID: 3937416
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 8
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`

`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
` 5.1 Acute Hypersensitivity Reactions
` In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson
`
`
` Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms
`
` (DRESS), and Henoch-Schonlein purpura, discontinue BIAXIN therapy immediately and
`
` institute appropriate treatment.
`
` 5.2 QT Prolongation
`
` BIAXIN has been associated with prolongation of the QT interval and infrequent cases of
`
`
` arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing
`
`
` surveillance in patients receiving BIAXIN. Fatalities have been reported.
`
` Avoid BIAXIN in the following patients:
`
` • patients with known prolongation of the QT interval, ventricular cardiac arrhythmia,
`
`
`
` including torsades de pointes
`
`
`
`
` • patients receiving drugs known to prolong the QT interval [see also Contraindications (4.2)]
`
`
`
` • patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or
`
`
`
` hypomagnesemia, clinically significant bradycardia and in patients receiving Class IA
`
`
` (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Elderly patients may be more susceptible to drug-associated effects on the QT interval [see Use
`
`
`
`in Specific Populations (8.5)].
`
`
`
`5.3 Hepatotoxicity
`
`Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic
`
`hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic
`
`
`dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal
`
`
`
`outcome has been reported and generally has been associated with serious underlying diseases
`and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark
`
`
`
`urine, pruritus, or tender abdomen. Discontinue BIAXIN immediately if signs and symptoms of
`
`hepatitis occur.
`
`
`5.4 Serious Adverse Reactions Due to Concomitant Use with Other Drugs
`
`
`
`Drugs metabolized by CYP3A4: Serious adverse reactions have been reported in patients taking
`BIAXIN concomitantly with CYP3A4 substrates. These include colchicine toxicity with
`
`
`colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia with
`
`
`disopyramide; hypotension and acute kidney injury with calcium channel blockers metabolized
`
`by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney
`
`injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years
`
`of age or older. Use BIAXIN with caution when administered concurrently with medications that
`
`
`induce the cytochrome CYP3A4 enzyme. The use of BIAXIN with simvastatin, lovastatin,
`
`
`ergotamine, or dihydroergotamine is contraindicated [see Contraindications (4.5, 4.6) and Drug
`
`
`
`
`Interactions (7)].
`
`
`
`Reference ID: 3937416
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 9
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`

`

` Colchicine: Life-threatening and fatal drug interactions have been reported in patients treated
`
`with BIAXIN and colchicine. Clarithromycin is a strong CYP3A4 inhibitor and this interaction
`
`may occur while using both drugs at their recommended doses. If co-administration of BIAXIN
`
`
`
`and colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of
`
`colchicine. Monitor patients for clinical symptoms of colchicine toxicity. Concomitant
`administration of BIAXIN and colchicine is contraindicated in patients with renal or hepatic
`
`impairment [see Contraindications (4.4) and Drug Interactions (7)].
`
`
`
`
`HMG-CoA Reductase Inhibitors (statins): Concomitant use of BIAXIN with lovastatin or
`
`
`
`simvastatin is contraindicated [see Contraindications (4.5)] as these statins are extensively
`
`
`
`
`metabolized by CYP3A4, and concomitant treatment with BIAXIN increases their plasma
`concentration, which increases the risk of myopathy, including rhabdomyolysis. Cases of
`
`rhabdomyolysis have been reported in patients taking BIAXIN concomitantly with these statins.
`
`
`If treatment with BIAXIN cannot be avoided, therapy with lovastatin or simvastatin must be
`
`
`
`suspended during the course of treatment.
`
`Exercise caution when prescribing BIAXIN with atorvastatin or pravastatin. In situations where
`
`the concomitant use of BIAXIN with atorvastatin or pravastatin cannot be avoided, atorvastatin
`
`
`
`
`dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily. Use of
`
`a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. It is
`
`recommended to prescribe the lowest registered dose if concomitant use cannot be avoided.
`
`Oral Hypoglycemic Agents/Insulin: The concomitant use of BIAXIN and oral hypoglycemic
`
`
`agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs
`
`
`such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by
`
`clarithromycin may be involved and could cause hypoglycemia when used concomitantly.
`Careful monitoring of glucose is recommended [see Drug Interactions (7)].
`
`
`
`Quetiapine: Use quetiapine and clarithromycin concomitantly with caution. Co-administration
`
`
`
`could result in increased quetiapine exposure and quetiapine related toxicities such as
`
`
`somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant
`
`syndrome, and QT prolongation. Refer to quetiapine prescribing information for
`
`
`recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as
`
`
`clarithromycin [see Drug Interactions (7)].
`
`
`
`
`Oral Anticoagulants: There is a risk of serious hemorrhage and significant elevations in INR and
`prothrombin time when BIAXIN is co-administered with warfarin. Monitor INR and
`
`prothrombin times frequently while patients are receiving BIAXIN and oral anticoagulants
`
`
`
`concurrently [see Drug Interactions (7)].
`
`
`
`Benzodiazepines: Increased sedation and prolongation of sedation have been reported with
`
`concomitant administration of BIAXIN and triazolobenzodiazepines, such as triazolam and
`
`
`midazolam [see Drug Interactions (7)].
`
`
`
`5.5 Clostridium difficile Associated Diarrhea
`
`
`Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all
`
`
`
`
`antibacterial agents, including BIAXIN, and may range in severity from mild diarrhea to fatal
`
`
`
`
`
`colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to
`
`
`overgrowth of C. difficile.
`
`
`
`Reference ID: 3937416
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 10
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`

`

`
` C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
`
` producing strains of C. difficile cause increased morbidity and mortality, as these infections can
`
`
`
`
`
` be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in
` all patients who present with diarrhea following antibacterial use. Careful medical history is
`
`
`
` necessary since CDAD has been reported to occur over two months after the administration of
`
`
` antibacterial agents.
` If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile
`
`may need to be discontinued. Appropriate fluid and electrolyte management, protein
`supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be
`
`
`instituted as clinically indicated.
`
`
`
`
`5.6 Embryofetal Toxicity
`
`Clarithromycin should not be used in pregnant women except in clinical circumstances where no
`alternative therapy is appropriate. If BIAXIN is used during pregnancy, or if pregnancy occurs
`
`while the patient is taking this drug, the patient should be apprised of the potential hazard to the
`
`fetus. Clarithromycin has demonstrated adverse effects on pregnancy outcome and/or embryo-
`
`fetal development in monkeys, rats, mice, and rabbits at doses that produced plasma levels 2
`times to 17 times the serum levels achieved in humans treated at the maximum recommended
`
`
`
`human doses [see Use in Specific Populations (8.1)].
`
`
`
`
`5.7 Exacerbation of Myasthenia Gravis
`
`Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic
`
`
`syndrome has been reported in patients receiving BIAXIN therapy.
`
`
`
`5.8 Development of Drug Resistant Bacteria
`
`Prescribing BIAXIN in the absence of a proven or strongly suspected bacterial infection or a
`
`
`prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
`
`development of drug-resistant bacteria.
`
`
`
`
`
`
`
`
`6 ADVERSE REACTIONS
`
`The following serious adverse reactions are described below and elsewhere in the labeling:
`
`• Acute Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
`
`
`
`
`• QT Prolongation [see Warnings and Precautions (5.2)]
`
`
`
`
`
`• Hepatotoxicity [see Warnings and Precautions (5.3)]
`
`
`
`
`
`• Serious Adverse Reactions Due to Concomitant Use with Other Drugs [see Warnings and
`
`
`
`Precautions (5.4)]
`
`
`• Clostridium difficile Associated Diarrhea [see Warnings and Precautions (5.5)]
`
`
`
`
`
`• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.7)]
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3937416
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2017, Page 11
`
`

`

` 6.1 Clinical Trials Experience
`
`
` Because clinical studies are conducted under widely varying conditions, adverse reaction rates
` observed in the clinical