`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`
`
`
`
`
`
`
` NOXAFIL safely and effectively. See full prescribing information
`
` for NOXAFIL.
`
`
`
`NOXAFIL® (posaconazole) injection, for intravenous use
`
`
`
`
` NOXAFIL ® (posaconazole) delayed-release tablets, for oral use
`
` NOXAFIL ® (posaconazole) oral suspension
`
` Initial U.S. Approval: 2006
`
`
`
`
`
`
` ---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`
` Dosage and Administration (2)
`
` 11/2015
` Warnings and Precautions, Vincristine Toxicity (5.6)
`
`
` 09/2016
`
`
`
`
`
`
`
`
`
`
`
` ----------------------------INDICATIONS AND USAGE ----------------------------
` Noxafil is an azole antifungal agent indicated for:
`
`
`
`
` injection, delayed-release tablets, and oral suspension
`
`
` • prophylaxis of invasive Aspergillus and Candida infections in
`
`
`
` patients who are at high risk of developing these infections due to
`
`
` being severely immunocompromised, such as HSCT recipients with
`
` GVHD or those with hematologic malignancies with prolonged
`
`
`
`
`
` neutropenia from chemotherapy. (1.1)
`
`
` Oral suspension
` • treatment of oropharyngeal candidiasis (OPC), including OPC
`
`
`
` refractory (rOPC) to itraconazole and/or fluconazole. (1.2)
`
`
`
`
`
` ----------------------- DOSAGE AND ADMINISTRATION -----------------------
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Noxafil delayed-release
`
` tablets and oral suspension are not
`
` interchangeable due to the differences in the dosing of each
`
` formulation. Therefore, follow the specific dosage recommendations for
`
` each of the formulations. (2.3, 2.4)
`
`
`
`
` Dose and Duration of Therapy
`
` Indication
`
` Injection*:
`
` Prophylaxis of
`
`
`
`Loading dose: 300 mg Noxafil injection
`
` invasive
`
`
`intravenously twice a day on the first day.
`
`
`Aspergillus and
`
`
`Maintenance dose: 300 mg Noxafil injection
`Candida
` intravenously once a day thereafter. Duration of
`
`
`infections
`therapy is based on recovery from neutropenia
`
`
` or immunosuppression. (2.1)
`Delayed-Release Tablets†:
`
`Loading dose: 300 mg (three 100 mg
`
`
`
`
`delayed-release tablets) twice a day on the first
`
`day.
`
`Maintenance dose: 300 mg (three 100 mg
`
`
`delayed-release tablets) once a day, starting on
`
`
`the second day. Duration of therapy is based
`
`
`
`on recovery from neutropenia or
`
`immunosuppression. (2.2)
`
`Oral Suspension‡: 200 mg (5 mL) three times
`
`
`
`
`
`
`a day. Duration of therapy is based on recovery
` from neutropenia or immunosuppression. (2.3)
`
`Oral Suspension‡:
`
`Loading dose: 100 mg (2.5 mL) twice a day on
`
`
`
` the first day.
` Maintenance dose: 100 mg (2.5 mL) once a
`
` day for 13 days. (2.3)
`Oral Suspension‡: 400 mg (10 mL) twice a
`
`
`
` day. Duration of therapy is based on the
`
`
`severity of the patient’s underlying disease and
`clinical response. (2.3)
`
`
`
`
` Oropharyngeal
`
` Candidiasis
`
`(OPC)
`
`
`
`
` OPC Refractory
`
` (rOPC) to
`Itraconazole
`and/or
`
`Fluconazole
`
`
` *Noxafil injection must be administered through an in-line filter.
` Administer by intravenous infusion over approximately 90 minutes via
`
`
`
`
` a central venous line. Never give Noxafil injection as an intravenous
`
`
`
` bolus injection. (2)
`
`†Noxafil delayed-release tablets should be taken with food. (2)
`
`
`‡Noxafil oral suspension should be taken with a full meal. (2)
`
`
`
`
`
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`
`
`
`
`• Noxafil injection: 300 mg per 16.7 mL (18 mg per mL) (3)
`
`
`
`
`
`Reference ID: 3983525
`
`
`
`
`
`1
`
`
`
`
`
`• Noxafil delayed-release tablet 100 mg (3)
`
`
`
`
`• Noxafil oral suspension 40 mg per mL (3)
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS ------------------------------­
`
`• Do not administer to persons with known hypersensitivity to
`
`posaconazole or other azole antifungal agents. (4.1)
`
`
`
`
`
`• Do not coadminister Noxafil with the following drugs; Noxafil
`
`
`increases concentrations of:
`o
`
`
`
`Sirolimus: can result in sirolimus toxicity (4.2, 7.1)
`o CYP3A4 substrates (pimozide, quinidine): can result in QTc
`
`
`
`
`
`interval prolongation and cases of TdP (4.3, 7.2)
`o HMG-CoA Reductase
`
`Inhibitors Primarily Metabolized
`
`
`
`Through CYP3A4: can lead to rhabdomyolysis (4.4, 7.3)
`o
`
`
`
`
`Ergot alkaloids: can result in ergotism (4.5, 7.4)
`
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------­
`
`
`
`
`
`• Calcineurin Inhibitor Toxicity: Noxafil increases concentrations of
`cyclosporine or tacrolimus; reduce dose of cyclosporine and
`
`
`tacrolimus and monitor concentrations frequently. (5.1)
`
`
`
`
`• Arrhythmias and QTc Prolongation: Noxafil has been shown to
`
`prolong the QTc interval and cause cases of TdP. Administer with
`
`
`caution to patients with potentially proarrhythmic conditions. Do not
`
`
`to prolong QTc
`interval and
`administer with drugs known
`metabolized through CYP3A4. Correct K+, Mg++, and Ca++ before
`
`
`
`
`
`
`
`starting Noxafil. (5.2)
`
`
`
`
`
`• Hepatic Toxicity: Elevations in LFTs may occur. Discontinuation
`
`
`
`should be considered in patients who develop abnormal LFTs or
`
`
`monitor LFTs during treatment. (5.3)
`
`
`
`
`• Noxafil injection should be avoided in patients with moderate or
`
`severe renal impairment (creatinine clearance <50 mL/min), unless
`
`
`an assessment of the benefit/risk to the patient justifies the use of
`
`Noxafil injection. (5.4, 8.6)
`
`
`
`
`
`• Midazolam: Noxafil can prolong hypnotic/sedative effects. Monitor
`
`
`
`
`patients and benzodiazepine receptor antagonists should be
`
`
`available. (5.5, 7.5)
`
`
`
`
`
`• Vincristine Toxicity: Concomitant administration of azole antifungals,
`
`
`
`including Noxafil, with vincristine has been associated with
`
`neurotoxicity and other serious adverse reactions; reserve azole
`
`
`antifungals, including Noxafil, for patients receiving a vinca alkaloid,
`
`
`including vincristine, who have no alternative antifungal treatment
`
`options. (5.6, 7.10)
`
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------­
`
`
`
`
`
`
`• Common treatment-emergent adverse reactions in studies with
`
`
`
`posaconazole are diarrhea, nausea, fever, vomiting, headache,
`
`coughing, and hypokalemia. (6.2)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`
`
`
`
`
`
`
`
`
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­
`
`
`
`
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`
`-------------------------------DRUG INTERACTIONS ------------------------------­
`
`
` Interaction Drug
`
`
` Rifabutin, phenytoin, efavirenz,
`
` cimetidine, esomeprazole*
`
`
` Other drugs metabolized by
`
` CYP3A4
`
`
`
`
`
` Digoxin
`
` Interaction
`
`
` Avoid coadministration unless
`
` the benefit outweighs the risks
`
`
`
` (7.6, 7.7, 7.8, 7.9)
`
` Consider dosage adjustment
`
` and monitor for adverse effects
`
`
`
` and toxicity (7.1, 7.10, 7.11)
`Monitor digoxin plasma
`
` concentrations (7.12)
` Fosamprenavir,
`
` Monitor for breakthrough fungal
`
` metoclopramide*
`
`
` infections (7.6, 7.13)
`
`
` *The drug interactions with esomeprazole and metoclopramide do
` not apply to posaconazole tablets.
`
`
`
`
`
`
`
`
` ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­
` • Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`
`
`
`
`taking
`
` • Nursing Mothers: Discontinue drug or nursing,
`in
`
`
` consideration the importance of drug to the mother. (8.3)
` • Severe renal impairment: Monitor closely for breakthrough fungal
`
`
`
`
`
`
` infections. (8.6)
`
`
`
`
`
`
` to
`
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2038, Page 1
`
`

`

`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`
`
`
`approved patient labeling.
`
`
`
`
`Revised: 09/2016
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`
`
`INDICATIONS AND USAGE
`
`
`
`
`1.1 Prophylaxis of Invasive Aspergillus and Candida Infections
`
`
`
`
`1.2 Treatment of Oropharyngeal Candidiasis Including
`
`
`Oropharyngeal Candidiasis Refractory to Itraconazole and/or
`
`
`Fluconazole
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`
`Important Administration Instructions for Noxafil Injection,
`
`2.1
`
`
`
`
`
`Noxafil Delayed-Release Tablets and Noxafil Oral
`
`
`Suspension
`
`
`
`
`2.2 Dosage, Preparation, Intravenous Line Compatibility and
`
`
`Administration of Noxafil Injection
`
`
`2.3 Dosage and Administration Instructions for Noxafil Delayed-
`
`
`Release Tablets
`
`
`
`
`2.4 Dosage and Administration Instructions for Noxafil Oral
`
`
`Suspension
`
`
`
`2.5 Non-Interchangeability between Noxafil Delayed-Release
`
`
`
`
`Tablets and Noxafil Oral Suspension
`
`
`
`
`
`2.6 Dosage Adjustments in Patients with Renal Impairment
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`
`4.1 Hypersensitivity
`
`
`
`4.2 Use with Sirolimus
`
`
`
`4.3 QT Prolongation with Concomitant Use with CYP3A4
`
`
`Substrates
`
`
`
`4.4 HMG-CoA Reductase Inhibitors Primarily Metabolized
`
`
`Through CYP3A4
`
`
`
`4.5 Use with Ergot Alkaloids
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Calcineurin-Inhibitor Drug Interactions
`
`
`
`5.2 Arrhythmias and QT Prolongation
`
`
`
`5.3 Hepatic Toxicity
`
`
`
`5.4 Renal Impairment
`
`
`
`5.5 Use with Midazolam
`
`
`
`
`5.6 Vincristine Toxicity
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Serious and Otherwise Important Adverse Reactions
`
`
`
`
`6.2 Clinical Trials Experience
`
`
`
`6.3 Postmarketing Experience
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`Immunosuppressants Metabolized by CYP3A4
`
`7.1
`
`
`
`7.2 CYP3A4 Substrates
`
`
`
`
`
`7.3 HMG-CoA Reductase Inhibitors (Statins) Primarily
`
`
`Metabolized Through CYP3A4
`
`
`
`7.4 Ergot Alkaloids
`
`
`
`
`7.5 Benzodiazepines Metabolized by CYP3A4
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`7.6 Anti-HIV Drugs
`
`
`
`7.7 Rifabutin
`
`
`
`7.8 Phenytoin
`
`
`
`7.9 Gastric Acid Suppressors/Neutralizers
`
`
`
`7.10 Vinca Alkaloids
`
`
`
`7.11 Calcium Channel Blockers Metabolized by CYP3A4
`
`
`
`7.12 Digoxin
`
`
`
`
`7.13 Gastrointestinal Motility Agents
`
`
`
`7.14 Glipizide
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.3 Nursing Mothers
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`
`8.6 Renal Impairment
`
`
`
`
`8.7 Hepatic Impairment
`
`
`
`8.8 Gender
`
`
`
`8.9 Race
`
`
`
`8.10 Weight
`
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`
`12.4 Microbiology
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`
`14 CLINICAL STUDIES
`
`
`
`
`14.1 Prophylaxis of Aspergillus and Candida Infections with
`
`
`Posaconazole Oral Suspension
`
`
`14.2 Treatment of Oropharyngeal Candidiasis with Posaconazole
`
`
`Oral Suspension
`
`
`
`
`
`14.3 Posaconazole Oral Suspension Treatment of Oropharyngeal
`
`
`Candidiasis Refractory to Treatment with Fluconazole or
`
`
`Itraconazole
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`17.1 Administration
`
`
`
`17.2 Drug Interactions
`
`
`
`17.3 Serious and Potentially Serious Adverse Reactions
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`
`
`are not listed.
`
`INDICATIONS AND USAGE
`1
`
`
`
`Prophylaxis of Invasive Aspergillus and Candida Infections
`
`1.1
`
`
`
`
`
`Noxafil® injection, delayed-release tablets, and oral suspension are indicated for prophylaxis of
`
`
`
`
`
`
`
`
`invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections
`
`
`
`
`
`
`
`
`due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT)
`
`
`
`
`recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged
`
`
`
`
`
`
`
`neutropenia from chemotherapy.
`
`Noxafil injection is indicated in patients 18 years of age and older.
`
`
`Noxafil delayed-release tablets and oral suspension are indicated in patients 13 years of age and
`
`
`older.
`
`
`Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory
`
`1.2
`
`
`
`
`
`to Itraconazole and/or Fluconazole
`
`
`
`
`
`
`
`
`Reference ID: 3983525
`
`
`
`
`
`
`
` 2
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2038, Page 2
`
`

`

`
`
`
` Noxafil oral suspension is indicated for the treatment of oropharyngeal candidiasis, including
` oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.
`
`
`
` 2
`
`
`2.1
`
` DOSAGE AND ADMINISTRATION
`
`
`
`Important Administration Instructions for Noxafil Injection, Noxafil Delayed-Release Tablets
`
`and Noxafil Oral Suspension
`
`
`
`•
`
`
`
`
`Noxafil delayed-release tablets and oral suspension are not to be used interchangeably due to the
`
`
`
`
`differences in the dosing of each formulation [see Dosage and Administration (2.3, 2.4, 2.5)].
`
`
`
`
`Noxafil injection
`
`
`
`
`
`
`• Administer via a central venous line, including a central venous catheter or peripherally inserted
`
`
`central catheter (PICC), by slow intravenous infusion over approximately 90 minutes [see Dosage
`
`and Administration (2.2)].
`
`
`
`
`
`
`
`
`
`
`
`
`If a central venous catheter is not available, Noxafil injection may be administered through a
`
`
`
`
`peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in
`
`
`
`
`advance of central venous line placement or to bridge the period during which a central venous line is
`
`
`replaced or is in use for other intravenous treatment.
`
`
`
`• When multiple dosing is required, the infusion should be done via a central venous line.
`
`
`
`
`
`
`
`
`
`• Never administer Noxafil injection as an intravenous bolus injection.
`
`Noxafil delayed-release tablets
`
`
`
`
`
`
`• Swallow tablets whole. Do not divide, crush, or chew.
`
`
`
`
`• Administer with food [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
`
`
`Noxafil oral suspension
`
`
`
`
`
`
`
`• Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage
`
`
`
`(e.g., ginger ale) in patients who cannot eat a full meal [see Dosage and Administration (2.4)]
`
`
`
`• Co-administration of drugs that can decrease the plasma concentrations of posaconazole should
`
`generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients
`
`
`
`
`
`
`should be monitored closely for breakthrough fungal infections [see Drug Interactions (7.6, 7.7, 7.8,
`
`
`
`
`7.9, 7.13)]
`
`
`
`Noxafil delayed-release tablets and Noxafil oral suspension
`
`
`
`
`
`
`
`
`
`
`• Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal
`
`
`infections when receiving Noxafil delayed-release tablets or oral suspension.
`
`
`
`
`
`
`
`
`Dosage, Preparation, Intravenous Line Compatibility and Administration of Noxafil
`2.2
`
`Injection
`
`
`Dosage:
`
`
`
`
` Indication
`
` Prophylaxis of invasive Aspergillus
`
`
` and Candida infections
`
`
`
`
`
`
`
`Table 1: Dosage for Noxafil Injection
` Dose and Duration of Therapy
`
`
`
` Loading dose:
` 300 mg Noxafil injection intravenously twice a day on the
`
`
` first day.
` Maintenance dose:
`
`300 mg Noxafil injection intravenously once a day, starting
`
`
`
`
`
`
`on the second day. Duration of therapy is based on recovery
`
`
`
`
`from neutropenia or immunosuppression.
`
`
`
`
`
`
`
`
` Preparation:
`
`
`
`
`
`Reference ID: 3983525
`
`3
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2038, Page 3
`
`

`

`
`
`
`
`
`
`
` • Equilibrate the refrigerated vial of Noxafil (posaconazole) injection to room temperature.
`
`
`
`
`
`
`
`• To prepare the required dose, aseptically transfer one vial (16.7 mL) of Noxafil injection (containing
`
`
`
`
`
`
`300 mg of posaconazole in solution) to an intravenous bag (or bottle) of a compatible admixture
`diluent (as described in Table 2), to achieve a final concentration of posaconazole that is between 1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`mg/mL and 2 mg/mL. Use of other diluents is not recommended because they may result in
`
`particulate formation.
`
`
`
`
`
`
`
`
`• Noxafil injection is a single dose sterile solution without preservatives. Once admixed, the product
`
`
`should be used immediately. If not used immediately, the solution can be stored up to 24 hours
`
`
`
`
`
`
`
`refrigerated 2-8°C (36-46°F). Noxafil injection is for single use only and any unused solution should
`
`be discarded.
`
`
`
`• Parenteral drug products should be inspected visually for particulate matter prior to administration,
`
`
`
`
`
`
`
`
`
`whenever solution and container permit. Once admixed, the solution of Noxafil ranges from colorless
`
`
`
`
`
`to yellow. Variations of color within this range do not affect the quality of the product.
`
`
`
`Intravenous Line Compatibility:
`
`
`
`
`
`A study was conducted to evaluate physical compatibility of Noxafil injection with injectable drug products
`
`
`
`
`
`
`and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined
`
`
`through visual observations, measurement of particulate matter and turbidity. Compatible diluents and
`
`drug products are listed in Tables 2 and 3 below. Any diluents or drug products not listed in the tables
`
`
`
`
`
`
`
`
`
`
`
`below should not be co-administered through the same intravenous line (or cannula).
`
`
`
`
`
`• Noxafil injection can be infused at the same time through the same intravenous line (or cannula) with
`
`
`the following compatible diluents:
`
`
`
`Table 2: Compatible Diluents
`
` 0.45% sodium chloride
`
` 0.9% sodium chloride
`
` 5% dextrose in water
`
`
` 5% dextrose and 0.45% sodium chloride
`
` 5% dextrose and 0.9% sodium chloride
` 5% dextrose and 20 mEq potassium chloride
`
`
`
`
`
`
` • Noxafil injection can be infused at the same time through the same intravenous line (or cannula) with
`
`
`
`
`
`
`
`
`
`
`
`
`the following drug products prepared in 5% dextrose in water or sodium chloride 0.9%. Co­
`
`
`
`administration of drug products prepared in other diluents may result in particulate formation.
`
`
`
`
`
`
`
`Table 3: Compatible Drugs
`
` Amikacin sulfate
`
` Caspofungin
`
` Ciprofloxacin
`
` Daptomycin
` Dobutamine hydrochloride
`
` Famotidine
`
` Filgrastim
`
` Gentamicin sulfate
` Hydromorphone hydrochloride
`
`
` Levofloxacin
`
` Lorazepam
`
` Meropenem
`
` Micafungin
` Morphine sulfate
`
`
` Norepinephrine bitartrate
`
` Potassium chloride
`
`
`
`Reference ID: 3983525
`
`4
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2038, Page 4
`
`

`

`
`
`
`
` Vancomycin hydrochloride
`
`
`
`through a 0.22 micron polyethersulfone (PES) or
`
`
`•
`
`
`Incompatible Diluents:
`
`
`Noxafil injection must not be diluted with the following diluents:
`
`
`
`Lactated Ringer’s solution
`
`5% dextrose with Lactated Ringer’s solution
`
`
`
`4.2% sodium bicarbonate
`
`
`
`Administration:
`
`
`
`
`injection must be administered
`• Noxafil
`
`polyvinylidene difluoride (PVDF) filter.
`
`
`
`
`• Administer via a central venous line, including a central venous catheter or PICC by slow infusion
`
`
`
`
`
`over approximately 90 minutes. Noxafil injection is not for bolus administration.
`
`
`
`
`
`
`
`
`
`
`
`
`If a central venous catheter is not available, Noxafil injection may be administered through a
`
`
`
`
`
`
`
`
`
`
`
`peripheral venous catheter only as a single dose in advance of central venous line placement or to
`
`
`
`
`bridge the period during which a central venous line is replaced or is in use for other treatment.
`
`
`
`• When multiple dosing is required, the infusion should be done via a central venous line. When
`
`administered through a peripheral venous catheter, the infusion should be administered over
`
`
`
`approximately 30 minutes. Note: In clinical trials, multiple peripheral infusions given through the same
`
`
`vein resulted in infusion site reactions [see Adverse Reactions (6.2)].
`
`
`
`
`
`
`
`Dosage and Administration Instructions for Noxafil Delayed-Release Tablets
`2.3
`
`
`Dosage:
`
`
`
`
`Table 4: Dosage for Noxafil Delayed-Release Tablets
` Dose and Duration of Therapy
`
` Indication
`
`
`
`
`
` Prophylaxis of invasive Aspergillus and
` Candida infections
`
`
`
`
` Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a
`
`
`day on the first day.
`
`
`
`
`
`
`Maintenance dose: 300 mg (three 100 mg delayed-release tablets)
`
`
`
`once a day, starting on the second day. Duration of therapy is based
`
`
`
`
`on recovery from neutropenia or immunosuppression.
`
`
`Administration Instructions for Noxafil Delayed-Release Tablets:
`
`
`
`
`
`
`
`
`• Swallow tablets whole. Do not divide, crush, or chew.
`
`
`
`
`
`
`
`
`• Administer Noxafil delayed-release tablets with food to enhance the oral absorption of posaconazole
`
`
`and optimize plasma concentrations [see Clinical Pharmacology (12.3)].
`
`
`
`• Noxafil delayed-release tablets should be used only for the prophylaxis indication.
`
`
`• Noxafil delayed-release tablets generally provide higher plasma drug exposures than Noxafil oral
`
`
`
`
`
`
`
`
`suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for
`
`
`the prophylaxis indication.
`
`
`
`
`
`
`Dosage and Administration Instructions for Noxafil Oral Suspension
`
`
`
`2.4
`
`
`Dosage:
`
`
`
`
`
`Table 5: Dosage for Noxafil Oral Suspension
`
`5
`
`
`
`
`Reference ID: 3983525
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2038, Page 5
`
`

`

`
`
`
`
` Indication
`
`
`
` Dose and Duration of Therapy
`
`
`
`
` Prophylaxis of invasive Aspergillus
`
` and Candida infections
`
`
`
`
`
`
` 200 mg (5 mL) three times a day. The duration of therapy is based on
` recovery from neutropenia or immunosuppression.
`
`
`
`
`
`
` Oropharyngeal Candidiasis
`
`
`
` Loading dose: 100 mg (2.5 mL) twice a day on the first day.
`
`
`
`
`
` Maintenance dose: 100 mg (2.5 mL) once a day for 13 days.
`
`
`
`
`
`
` Oropharyngeal Candidiasis Refractory
`
` to Itraconazole and/or Fluconazole
`
` 400 mg (10 mL) twice a day. Duration of therapy should be based on
`
`
`
`
`
`
` the severity of the patient’s underlying disease and clinical response.
`
`
`Administration Instructions for Noxafil Oral Suspension:
`
`
`
`
`
`
`
`
`
`
`
`• Shake Noxafil oral suspension well before use. Administer with measured dosing spoon (see Figure
`
`1) provided.
`
`
`
`
`
`
`
`Figure 1: A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.
`
`
`
`
`
`
`
`• Rinse the spoon with water after each administration and before storage.
`
`
`
`
`
`• Administer each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes)
`
`
`
`
`following a full meal to enhance the oral absorption of Noxafil and optimize plasma concentrations
`
`
`[see Clinical Pharmacology (12.3)].
`
`
`
`
`• For patients who cannot eat a full meal, Noxafil delayed-release tablets should be used instead of
`
`Noxafil oral suspension. Noxafil delayed-release tablets should be used only for the prophylaxis
`
`
`indication. Noxafil delayed-release tablets provide higher plasma drug exposures than Noxafil oral
`
`suspension under fasted conditions [See Dosage and Administration (2.5)].
`
`
`
`
`
`
`In patients who cannot eat a full meal and for whom Noxafil delayed-release tablets or Noxafil
`
`
`injection are not options, administer each dose of Noxafil oral suspension with a liquid nutritional
`
`
`supplement or an acidic carbonated beverage (e.g., ginger ale).
`
`
`
`
`
`
`
`• For patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic
`
`
`
`
`carbonated beverage and who do not have the option of taking Noxafil delayed-release tablets or
`
`
`
`
`
`
`Noxafil injection, an alternative antifungal therapy should be considered or patients should be
`
`monitored closely for breakthrough fungal infections.
`
`
`
`•
`
`
`
`
`
`
`Non-Interchangeability between Noxafil Delayed-Release Tablets and Noxafil Oral
`2.5
`Suspension
`
`
`Noxafil delayed-release tablets and oral suspension are not to be used interchangeably due to the
`
`
`
`
`
`
`
`
`
`
`
`
`differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for
`
`
`each of the formulations [see Dosage and Administration (2.3, 2.4)].
`
`
`
`
`
`Dosage Adjustments in Patients with Renal Impairment
`2.6
`
`
`
`The pharmacokinetics of Noxafil oral suspension and delayed-release tablets are not significantly
`
`
`
`
`
`
`
`
`
`
`affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild
`
`
`to severe renal impairment.
`
`
`
`
`
`
`
`• Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50
`
`
`mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection.
`
`
`
`
`In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50
`
`
`
`
`
`
`
`
`mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, Betadex Sulfobutyl
`
`
`Ether Sodium (SBECD), is expected to occur. Serum creatinine levels should be closely monitored in
`
`
`•
`
`
`
`Reference ID: 3983525
`
`6
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2038, Page 6
`
`

`

`
`
`
`
` these patients, and, if increases occur, consideration should be given to changing to oral Noxafil
`
` therapy.
`
`
`
`
`
` 3
`
`
`
` DOSAGE FORMS AND STRENGTHS
` Noxafil injection is available in Type I glass vials closed with bromobutyl rubber stopper and aluminum
`
`
` seal containing 300 mg per 16.7 mL of solution (18 mg of posaconazole per mL).
`
`
` Noxafil 100 mg delayed-release tablets are available as yellow, coated, oblong tablets, debossed with
`
`
` "100" on one side.
` Noxafil oral suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant
`
`
`
`
` closures containing 105 mL of suspension (40 mg of posaconazole per mL).
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4
` CONTRAINDICATIONS
`
`
`
` 4.1
` Hypersensitivity
` Noxafil is contraindicated in persons with known hypersensitivity to posaconazole or other azole
`
` antifungal agents.
` Use with Sirolimus
`
`
` 4.2
`
`
`
` Noxafil is contraindicated with sirolimus. Concomitant administration of Noxafil with sirolimus increases
` the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug
`
`
`
`
`
`
`
`
` Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`
`
` QT Prolongation with Concomitant Use with CYP3A4 Substrates
`
` 4.3
`
`
` Noxafil is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant
`
`
` administration of Noxafil with the CYP3A4 substrates, pimozide and quinidine may result in increased
`
`
`
` plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see
`
`
`
`
`
` Warnings and Precautions (5.2) and Drug Interactions (7.2)].
`
`
`
` HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4
`
` 4.4
` Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through
`
`
`
`
`
`
` CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma
`
`
`
`
`
` concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions (7.3) and Clinical
`
`
`
`
`
`
`
`
`
`
`
`
` Pharmacology (12.3)].
`
`
` Use with Ergot Alkaloids
`
` 4.5
`
`
`
` Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and
`
` dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].
`
`
`
`
`
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
` 5.1
`
` Calcineurin-Inhibitor Drug Interactions
`
`
` Concomitant administration of Noxafil with cyclosporine or tacrolimus increases the whole blood
`
`
`
` trough concentrations of
` these calcineurin-inhibitors
`
`
`[see Drug
`
` Interactions (7.1) and Clinical
`
`
`
` Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in
`
`
`
`
`
`
`
`
` clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent
`
`
` monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during
`
`
`
`
`
`
`
` and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted
`
` accordingly.
`
`
` Arrhythmias and QT Prolongation
`
` 5.2
`
`
`
`
` Some azoles, including posaconazole, have been associated with prolongation of the QT interval on
`
`
`the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking
`
` posaconazole.
`
`
`
` Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in
` the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were
`
`
`
`
`
`
`
` recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age)
`
`
`
` administered posaconazole oral suspension 400 mg BID with a high-fat meal. In this pooled analysis, the
`
` mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the
`
`
`
`
`
`
`
`
` recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small
`
`
`
`
`
` number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval
`
`
`
`
`
`
`
`
`
`7
`
`
`
`
`Reference ID: 3983525
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2038, Page 7
`
`

`

`
`
`
`
`
` change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a
` QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.
`
`
`
`
`
`
`
`
`
`
`
` Posaconazole should be administered with caution to patients with potentially proarrhythmic
`
`
` conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized
`
`
`
`
`
`
`
`
`
`
`
`
`
` through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)]. Rigorous attempts to correct
`
`
`
`
`
`
`
` potassium, magnesium, and calcium should be made before starting posaconazole.
`
`
`
` 5.3
` Hepatic Toxicity
`
`
` Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate
`
` aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported
`
` in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of
`
` therapy, and in some instances these tests normalized without drug interruption. Cases of more severe
`
`
`
`
`
`
`
` hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients
`
`
`
`
`
`
`
`with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with
`
`
`
`
`
`
`
` in subjects receiving
` posaconazole. These severe hepatic reactions were seen primarily
` the
` posaconazole oral suspension 800 mg daily (400 mg BID or 200 mg QID) in clinical trials.
`
`
` Liver function tests should be evaluated at the start of and during the course of posaconazole therapy.
`
` Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for
`
`
`
`
`
`
`
` the development of more severe hepatic injury. Patient management should include laboratory evaluation
`
`
`
` of hepatic function (particularly liver function tests and bilirubin). Discontinuation of posaconazole must be
`
`
` considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to
`
`
`
`
` posaconazole.
`
`
`
` Renal Impairment
` 5.4
`
`
`
`
` Due to the variability in exposure with Noxafil delayed-release tablets and oral suspension, patients
`
` with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage
`
`
`
` and Administration (2.6) and Use in Specific Populations (8.6)].
`
`
`
`
`
` Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50
`
`
` mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In
`
` patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Noxafil injection,
`
`
` accumulation of the intravenous vehicle, SBECD, is expecte