JANSSEN
`
`PHARMACEUTICALS
`
`
`NIZORAL
`
`
`(KETOCONAZOLE)
`
`TABLETS
`
`
`
`WARNING:
`NIZORAL® Tablets should be used only when other effective antifungal therapy is not
`available or tolerated and the potential benefits are considered to outweigh the potential
`risks.
`
`Hepatotoxicity
`Serious hepatotoxicity, including cases with a fatal outcome or requiring liver
`transplantation has occurred with the use of oral ketoconazole. Some patients had no
`obvious risk factors for liver disease. Patients receiving this drug should be informed by
`the physician of the risk and should be closely monitored. See WARNINGS section.
`
`QT Prolongation and Drug Interactions Leading to QT Prolongation
`
`
`Co-administration of the following drugs with ketoconazole is contraindicated: dofetilide,
`quinidine, pimozide, cisapride. Ketoconazole can cause elevated plasma concentrations
`of these drugs and may prolong QT intervals, sometimes resulting in life-threatening
`
` ventricular dysrhythmias such as torsades de pointes. See CONTRAINDICATIONS,
`WARNINGS, and PRECAUTIONS: Drug Interactions sections.
`
`
`
`
`
`DESCRIPTION
`
`NIZORAL is a synthetic broad-spectrum antifungal agent available in scored white
`tablets, each containing 200 mg ketoconazole base for oral administration. Inactive
`ingredients are colloidal silicon dioxide, corn starch, lactose, magnesium stearate,
`
`microcrystalline cellulose, and povidone. Ketoconazole is cis-1- acetyl-4-[4-[[2-(2,4­
`dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl]
`piperazine and has the following structural formula:
`
`
`
`Reference ID: 3347210
`
`
`
`1
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 1
`
`

`

`Ketoconazole is a white to slightly beige, odorless powder, soluble in acids, with a
`molecular weight of 531.44.
`
`CLINICAL PHARMACOLOGY
`Pharmacokinetics
`Mean peak plasma levels of approximately 3.5 µg/mL are reached within 1 to 2 hours,
`
` following oral administration of a single 200 mg dose taken with a meal. Subsequent
`plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and
`
`
` 8 hours thereafter. Following absorption from the gastrointestinal tract, NIZORAL is
`converted into several inactive metabolites. The major identified metabolic pathways are
`oxidation and degradation of the imidazole and piperazine rings, oxidative O­
`dealkylation and aromatic hydroxylation. About 13% of the dose is excreted in the urine,
`of which 2 to 4% is unchanged drug. The major route of excretion is through the bile into
`the intestinal tract. In vitro, the plasma protein binding is about 99% mainly to the
`albumin fraction. Only a negligible proportion of ketoconazole reaches the cerebrospinal
`fluid. Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and
`absorption.
`
`Electrocardiogram
`Pre-clinical electrophysiological studies have shown that ketoconazole inhibits the
`
` rapidly activating component of the cardiac delayed rectifier potassium current,
`prolongs the action potential duration, and may prolong the QTc interval. Data from some
`clinical PK/PD studies and drug interaction studies suggest that oral dosing with
`
` ketoconazole at 200 mg twice daily for 3-7 days can result in an increase of the QTc
`interval: a mean maximum increase of about 6 to 12 msec was seen at ketoconazole peak
`plasma concentrations about 1-4 hours after ketoconazole administration.
`
`MICROBIOLOGY
`Mechanism of Action
`Ketoconazole blocks the synthesis of ergosterol, a key component of the fungal cell
`membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol
`14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal
`cell membrane. This results in an accumulation of methylated sterol precursors and a
`depletion of ergosterol within the cell membrane thus weakening the structure and
`function of the fungal cell membrane.
`
`Activity In Vitro & In Vivo
`NIZORAL Tablets are active against clinical infections with Blastomyces dermatitidis,
`Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis.
`
`
`
`Reference ID: 3347210
`
`2
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 2
`
`

`

`INDICATIONS AND USAGE
`NIZORAL® Tablets should be used only when other effective antifungal therapy is not
`available or tolerated and the potential benefits are considered to outweigh the potential
`risks.
`
`NIZORAL (ketoconazole) Tablets are indicated for the treatment of the following
`
` systemic fungal infections in patients who have failed or who are intolerant to other
`therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and
`
` paracoccidioidomycosis. NIZORAL Tablets should not be used for fungal meningitis
`because it penetrates poorly into the cerebrospinal fluid.
`
`CONTRAINDICATIONS
`Drug Interactions
`Coadministration of a number of CYP3A4 substrates is contraindicated with NIZORAL
`
`
` Tablets. Coadministration with ketoconazole can cause elevated plasma concentrations of
`these drugs and may increase or prolong both therapeutic and adverse effects. For
`example, increased plasma concentrations of some of these drugs can lead to QT
`prolongation and ventricular tachyarrhythmias including occurrences of torsades de
`pointes, a potentially fatal arrhythmia. See WARNINGS section, and PRECAUTIONS:
`Drug Interactions section for specific examples.
`
`Liver Disease
`The use of NIZORAL® Tablets is contraindicated in patients with acute or chronic liver
`disease.
`
`
`Hypersensitivity
`NIZORAL is contraindicated in patients who have shown hypersensitivity to the drug.
`
`WARNINGS
`NIZORAL® Tablets should be used only when other effective antifungal therapy is not
`available or tolerated and the potential benefits are considered to outweigh the potential
`risks.
`
`Hepatotoxicity
`
`Serious hepatotoxicity, including cases with a fatal outcome or requiring liver
`transplantation, has occurred with the use of oral ketoconazole. Some patients had no
`obvious risk factors for liver disease. Serious hepatotoxicity was reported both by
`patients receiving high doses for short treatment durations and by patients receiving low
`
`doses for long durations.
`
`
`
`Reference ID: 3347210
`
`3
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 3
`
`

`

`The hepatic injury has usually, but not always, been reversible upon discontinuation of
`NIZORAL® Tablets treatment. Cases of hepatitis have been reported in children.
`
`At baseline, obtain laboratory tests (such as SGGT, alkaline phosphatase, ALT, AST,
`total bilirubin (TBL), Prothrombin Time (PT), International Normalization Ratio (INR),
`and testing for viral hepatitides). Patients should be advised against alcohol consumption
`while on treatment. If possible, use of other potentially hepatotoxic drugs should be
`avoided in patients receiving NIZORAL® Tablets.
`
`Prompt recognition of liver injury is essential. During the course of treatment, serum
`ALT should be monitored weekly for the duration of treatment. If ALT values increase to
`a level above the upper limit of normal or 30 percent above baseline, or if the patient
`develops symptoms, ketoconazole treatment should be interrupted and a full set of liver
`tests should be obtained. Liver tests should be repeated to ensure normalization of values.
`Hepatotoxicity has been reported with restarting oral ketoconazole (rechallenge). If it is
`decided to restart oral ketoconazole, monitor the patient frequently to detect any recurring
`liver injury from the drug.
`
`QT Prolongation and Drug Interactions Leading to QT Prolongation
`Ketoconazole can prolong the QT interval. Co-administration of the following drugs with
`ketoconazole
`is contraindicated: dofetilide, quinidine, pimozide, and cisapride.
`
`Ketoconazole can cause elevated plasma concentrations of these drugs which may
`prolong the QT interval, sometimes resulting in life-threatening ventricular dysrhythmias
`such as torsades de pointes.
`
`Adrenal Insufficiency
`NIZORAL® Tablets decrease adrenal corticosteroid secretion at doses of 400 mg and
`higher. This effect is not shared with other azoles. The recommended dose of 200 mg -
`400 mg daily should not be exceeded.
`
`
`Adrenal function should be monitored in patients with adrenal insufficiency or with
`borderline adrenal function and in patients under prolonged periods of stress (major
`surgery, intensive care, etc.).
`
`Adverse Reactions Associated with Unapproved Uses
`Ketoconazole has been used in high doses for the treatment of advanced prostate cancer
`and for Cushing’s syndrome when other treatment options have failed. The safety and
`
`
`effectiveness of ketoconazole have not been established in these settings and the use of
`ketoconazole for these indications is not approved by FDA.
`
`In a clinical trial involving 350 patients with metastatic prostatic cancer, eleven deaths
`were reported within two weeks of starting treatment with high doses of ketoconazole
`
`
`
`Reference ID: 3347210
`
`4
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 4
`
`

`

`tablets (1200 mg/day). It is not possible to ascertain from the information available
`whether death was related to ketoconazole therapy or adrenal insufficiency in these
`patients with serious underlying disease.
`
` Hypersensitivity
`
`Anaphylaxis has been reported after the first dose. Several cases of hypersensitivity
`reactions including urticaria have also been reported.
`
`Enhanced Sedation
`Co-administration of NIZORAL® Tablets with oral midazolam, oral triazolam or
`alprazolam has resulted in elevated plasma concentrations of these drugs. This may
`potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or
`chronic administration of these agents. Concomitant administration of NIZORAL®
`
`
`Tablets with oral triazolam, oral midazolam, or alprazolam is contraindicated. (See
`CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions sections.)
`
`Myopathy
`Co-administration of CYP3A4 metabolized HMG-CoA reductase inhibitors such as
`
`is contraindicated with NIZORAL® Tablets.
`simvastatin, and
`lovastatin
`(See
`CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions sections.)
`
`PRECAUTIONS
`General
`NIZORAL Tablets have been demonstrated to lower serum testosterone. Once therapy
`
`with NIZORAL Tablets has been discontinued, serum testosterone levels return to
`
`baseline values. Testosterone levels are impaired with doses of 800 mg per day and
`abolished by 1600 mg per day. Clinical manifestations of decreased testosterone
`concentrations may include gynecomastia, impotence and oligospermia.
`
`Information for Patients
`Patients should be instructed to report any signs and symptoms which may suggest liver
`dysfunction so that appropriate biochemical testing can be done. Such signs and
`symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, abdominal
`pain, jaundice, dark urine or pale stools (see WARNINGS section).
`
`Drug Interactions
`Drugs that affect the absorption, distribution, metabolism, and excretion of ketoconazole
` may alter the plasma concentrations of ketoconazole. For example, gastric acid
`
`
`suppressants (e.g., antacids, histamine H2-blockers, proton pump inhibitors) have been
`shown to reduce plasma concentrations of ketoconazole.
`
`
`
`Reference ID: 3347210
`
`5
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 5
`
`

`

`Ketoconazole is a substrate and potent inhibitor of CYP3A4. Therefore, the following
`drug interactions may occur when NIZORAL® is co-administered with other drugs that
`interact with CYP3A4. (See Table 1 and Table 2 for an overview of these drug
`interactions; details are provided in the text that follows these tables.)
`
`1. NIZORAL® may decrease the elimination of drugs metabolized by CYP3A4,
`
`thereby increasing their plasma concentrations. Increased exposure to these
`drugs may cause an increase or prolongation of their therapeutic and/or
`adverse effects. Concomitant use with NIZORAL® Tablets is contraindicated
`
`
`for drugs known to present a risk of serious side effects with increased
`exposure (see BOXED WARNING, CONTRAINDICATIONS section, and
`PRECAUTIONS: Drug Interactions, Table 1). For others, monitoring of
`
`plasma concentrations is advised when possible. Clinical signs and symptoms
`associated with these drugs should be monitored, with dosage adjusted as
`needed.
`
`
`2. Inducers of CYP3A4 may decrease the plasma concentrations of ketoconazole
`(see Table 2). NIZORAL® may not be effective in patients concomitantly
`
`taking one of these drugs. Therefore, administration of these drugs with
`NIZORAL® is not recommended.
`
`
`3. Other inhibitors of CYP3A4 may increase the plasma concentrations of
`take NIZORAL®
`
`ketoconazole
`(see Table 2). Patients who must
`concomitantly with one of these drugs should be monitored closely for signs
`or symptoms of increased or prolonged pharmacologic effects of NIZORAL® .
`
`
`
`Table 1. Selected Drugs That Have Been Shown To or Are Predicted To Have
`Their Plasma Concentrations Altered By NIZORAL®*
`
`Systemic exposure to these drugs is increased significantly by the addition of
`ketoconazole:
`Concomitant use with ketoconazole is contraindicated.
`
`
`Alprazolam, midazolam, triazolam
`
`
`HMG-CoA reductase inhibitors
`(lovastatin, simvastatin)
`
`Cisapride
`
`Dofetilide
`
`Nisoldipine
`
`
`Pimozide
`
`
`
`Reference ID: 3347210
`
`
`6
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 6
`
`

`

`Eplerenone
`
`alkaloids
`Ergot
`dihydroergotamine)
`
`
`
`Quinidine
`
`(ergotamine,
`
`
`
`Systemic exposure to these drugs is increased by ketoconazole:
`Careful monitoring, with possible adjustment in dosage, is recommended.
`
`
`Alfentanil, fentanyl, sulfentanil
`
`Indinavir, saquinavir
`
`Amlodipine, felodipine, nicardipine,
`nifedipine
`
`Methylprednisolone
`
`Bosentan
`
`Buspirone
`
`Busulfan
`
`Carbamazepine
`
`Cilostazol
`
`Cyclosporine
`
`Digoxin
`
`Docetaxel, paclitaxel
`
`Oral anti-coagulants
`
`* This list is not all-inclusive.
`
`Rifabutin
`
`Sildenafil
`
`Sirolimus (co-administration not
`recommended)
`
`Tacrolimus
`
`Telithromycin
`
`Tolterodine
`
`Trimetrexate
`
`Verapamil
`
`Vinca alkaloids (vincristine, -
`vinblastine, vinorelbine)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3347210
`
`
`7
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 7
`
`

`

`Table 2. Selected Drugs That Have Been Shown To or Are Predicted
`To Alter The Plasma Concentration Of NIZORAL®
`
`
`Systemic exposure to ketoconazole is reduced significantly by these drugs:
`Concomitant use with ketoconazole is not recommended.
`
`
`Carbamazepine
`
`Phenytoin
`
`Gastric Acid Suppressants (antacids,
`antimuscarinics, histamine H2-blockers,
`proton pump inhibitors, sucralfate)
`
`Rifampin, rifabutin, isoniazid
`
`Nevirapine
`
`
`
`
`
`Systemic exposure to ketoconazole is increased significantly by this drug:
`Dose reduction of ketoconazole should be considered
`
`Ritonavir
`
`
`
`* This list is not all-inclusive.
`
`1.
`
`Effects of ketoconazole on other drugs
`
`1.1
`
`Systemic exposure to the following drugs is significantly increased by co-
`administration of ketoconazole. Concomitant use of these drugs with
`
`NIZORAL® Tablets is contraindicated:
`
`
`Alprazolam, midazolam, triazolam
`Co-administration of NIZORAL® Tablets with alprazolam, midazolam, or
`
`triazolam has resulted in elevated plasma concentrations of these drugs. This may
`potentiate and prolong hypnotic and sedative effects, especially with repeated or
`these agents. Concomitant administration of
`chronic administration of
`
`NIZORAL® Tablets with alprazolam, oral midazolam, and oral triazolam is
`contraindicated. (See CONTRAINDICATIONS and WARNINGS sections.)
`Special precaution and patient monitoring are required with concomitant
`parenteral midazolam, because the sedative effect may be prolonged.
`
`Cisapride
`Oral ketoconazole potently inhibits the metabolism of cisapride resulting in a
`
`mean eight-fold increase in AUC of cisapride, which can lead to prolongation of
`QT interval. Therefore concomitant administration of NIZORAL® Tablets with
`
`
`
`Reference ID: 3347210
`
`
`8
`
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 8
`
`

`

`BOXED
`(See
`contraindicated.
`is
`cisapride
`CONTRAINDICATIONS, and WARNINGS sections.)
`
`WARNING,
`
`Dofetilide
`The class III antiarrhythmic dofetilide is known to prolong the QT interval. The
`potential increase in dofetilide plasma concentrations when administered
`concomitantly with ketoconazole could result in serious cardiovascular events
`including QTc prolongation and rare occurrences of torsades de pointes.
`Therefore, concomitant administration of NIZORAL® Tablets with dofetilide is
`
`contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and
`WARNINGS sections.)
`
`Eplerenone
`Ketoconazole increases the eplerenone AUC by roughly 5-fold, thereby
`increasing the risk for hyperkalemia and hypotension. Co-administration of
`NIZORAL® and eplerenone is contraindicated. (See CONTRAINDICATIONS
`section.)
`
`Ergot Alkaloids
`Elevated concentrations of ergot alkaloids can cause ergotism, i.e., a risk for
`vasospasm potentially leading to cerebral ischemia and/or ischemia of the
`extremities. Concomitant
`administration of
`ergot
`alkaloids
`such
`as
`dihydroergotamine and ergotamine with NIZORAL® Tablets is contraindicated.
`(See CONTRAINDICATIONS section.)
`
`HMG-CoA Enzyme Inhibitors (lovastatin, simvastatin)
`Co-administration of ketoconazole with CYP3A4-metabolized HMG-CoA
`reductase inhibitors such as simvastatin, and lovastatin, may increase the risk of
`skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration
`of NIZORAL® Tablets with
`
`these HMG-CoA
`reductase
`inhibitors
` is
`contraindicated. (See CONTRAINDICATIONS and WARNINGS sections.)
`
` Nisoldipine
`
`Pre-treatment with and concomitant administration of ketoconazole resulted in a
`
` 24-fold and 11-fold increase in mean AUC and Cmax of nisoldipine, respectively,
`treatment with nisoldipine 5 mg alone. Concomitant
`compared with
`administration of ketoconazole with nisoldipine
`is contraindicated. (See
`CONTRAINDICATIONS section.)
`
`
`
`Reference ID: 3347210
`
`9
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 9
`
`

`

`Pimozide
`Pimozide is known to prolong the QT interval and is partially metabolized by
`CYP3A4. Co-administration of NIZORAL® and pimozide could result in serious
`
` cardiovascular events including QTc prolongation and rare occurrences of
`
` torsades de pointes, and is therefore contraindicated. (See BOXED WARNING,
`CONTRAINDICATIONS, and WARNINGS sections.)
`
`Quinidine
`The class IA antiarhythmic quinidine is known to prolong the QT interval. The
`potential
`increase
`in quinidine plasma concentrations when administered
`concomitantly with ketoconazole could result in serious cardiovascular events
`including QTc prolongation and rare occurrences of torsades de pointes.
`Therefore, concomitant administration of NIZORAL® Tablets with quinidine is
`
`contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and
`WARNINGS sections.)
`
`1.2. Co-administration of ketoconazole with the following agents was shown or is
`expected to result in increased exposure to these drugs. Therefore, careful
`monitoring of plasma concentrations or adverse events of these drugs is
`recommended. Adjustment of dosage of these drugs may be needed.
`
`Alfentanil, sufentanil, fentanyl
`In vitro data suggest that alfentanil, sufentanil and fentanyl are metabolized by
`CYP3A4. Concomitant administration of NIZORAL® Tablets and alfentanil,
`sufentanil, or fentanyl may increase plasma concentrations of the latter drugs.
`
`Amlodipine, felodipine, nicardipine, nifedipine
`CYP3A4 metabolized calcium channel blockers such as amlodipine, felodipine,
`nicardipine, and nifedipine should be used cautiously with NIZORAL® Tablets as
`
`ketoconazole may cause several-fold increases in plasma concentrations of these
`calcium channel blockers.
`
`Bosentan
`Concomitant administration of ketoconazole increased the Cmax and AUC of
`bosentan 2.1- and 2.3 – fold, respectively. No dosage adjustment of bosentan is
`needed but close monitoring for increased bosentan-associated adverse effects is
`recommended.
`
`Buspirone
`
`Concomitant administration of buspirone with ketoconazole may result in
`
`significant increases in plasma concentrations of buspirone. When administered
`
`
`
`Reference ID: 3347210
`
`10
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 10
`
`

`

`with NIZORAL® Tablets, a low initial dose of buspirone with subsequent dosage
`adjustment based on clinical assessment is recommended.
`
`Busulfan
`NIZORAL® Tablets may decrease the clearance and thus increase the systemic
`exposure to busulfan.
`
`Carbamazepine
` In vivo studies have demonstrated an increase in plasma carbamazepine
`
`concentrations
`in subjects concomitantly
`receiving ketoconazole. Close
`monitoring of plasma carbamazepine concentrations is recommended whenever
`ketoconazole is given to patients stabilized on carbamazepine therapy.
`
`Cilostazol
`Ketoconazole had been shown to increase both cilostazol AUC and Cmax by about
`
` two-fold when administered concurrently. Co-administration of ketoconazole with
`
` cilostazol resulted in increased incidences of adverse effects, such as headache.
`
` When NIZORAL® Tablets is administered concomitantly with cilostazol, the
`prescriber should consider up to a 50% reduction in cilostazol dosage.
`
`Cyclosporine
`
`
`Ketoconazole tablets may alter the metabolism of cyclosporine, thereby resulting
` in elevated cyclosporine plasma concentrations. Dosage adjustment may be
`
`
` required if cyclosporine or tacrolimus is given concomitantly with NIZORAL®
`Tablets.
`
`Digoxin
`Rare cases of elevated plasma concentrations of digoxin have been reported. It is
`not clear whether this was due to the combination of therapy. It is, therefore,
`advisable to monitor digoxin concentrations in patients receiving ketoconazole.
`
`Docetaxel
`In the presence of ketoconazole, the clearance of docetaxel in cancer patients was
`shown to decrease by 50%. When docetaxel and NIZORAL® are administered
`
`together, dosage reduction in docetaxel may be necessary in order to minimize the
`
`incidence of toxicities associated with docetaxel.
`
`
`Indinavir, saquinavir
`Concomitant administration of NIZORAL® and protease inhibitors metabolized
`
`increase plasma
`by CYP3A4, such as
`indinavir and saquinavir, may
`
`concentrations of these protease inhibitors. Dosage reduction of indinavir is
`recommended when administering ketoconazole concomitantly. No dosage
`
`
`11
`
`
`
`Reference ID: 3347210
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 11
`
`

`

`adjustments are recommended when saquinavir and ketoconazole are co­
`administered for a short period of time.
`
`Methylprednisolone
` NIZORAL® Tablets may alter the metabolism of methylprednisolone, resulting in
`
`elevated plasma concentrations of methylprednisolone. Dose adjustments may be
`required if methylprednisolone is given concomitantly with NIZORAL® Tablets.
`
`Oral anti-coagulants
`Oral imidazole compounds such as ketoconazole may enhance the anticoagulant
`effect of coumarin-like drugs, thus the anticoagulant effect should be carefully
`titrated and monitored.
`
`Oral hypoglycemic agents
` Because severe hypoglycemia has been reported in patients concomitantly
`
`receiving oral miconazole (an imidazole) and oral hypoglycemic agents, such a
`potential interaction involving the latter agents when used concomitantly with
`ketoconazole tablets (an imidazole) cannot be ruled out.
`
`Rifabutin
`Ketoconazole was shown to inhibit the CYP-mediated metabolism of rifabutin in
`
` vitro. Co-administration with NIZORAL® Tablets may result in elevated plasma
`concentrations of rifabutin.
`
`Sildenafil
`Ketoconazole had been shown to increase sildenafil plasma concentrations. When
`used concomitantly with NIZORAL® Tablets, a 50% reduction in sildenafil
`starting dose should be considered.
`
`Sirolimus
`Multiple-dose ketoconazole had been shown to increase sirolimus Cmax and AUC
`by 4.3-fold and 10.9-fold, respectively. The concomitant use of NIZORAL®
`
`Tablets and sirolimus is not recommended.
`
`Tacrolimus
`
`Ketoconazole had been shown to decrease the oral clearance of tacrolimus
`thereby leading to a 2-fold increase in tacrolimus oral bioavailability. Adjustment
`
`in tacrolimus dosage may be required if tacrolimus is given concomitantly with
`NIZORAL® Tablets.
`
`
`
`Reference ID: 3347210
`
`12
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 12
`
`

`

`Telithromycin
`Ketoconazole increased the AUC of telithromycin by 1.5 to 2-fold. Use caution
`when administering telithromycin concurrently with NIZORAL® Tablets since
`this may result in an increased risk for telithromycin associated adverse events.
`
`Tolterodine
`In the presence of ketoconazole, the apparent oral clearance of tolterodine
`decreased resulting in at least a two-fold increase in tolterodine. For patients
`
` receiving ketoconazole, a 50% reduction in the initial tolterodine dosage is
`recommended.
`
`Trimetrexate
`In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In
`
` vitro animal models have demonstrated that ketoconazole potently inhibits the
`
` metabolism of trimetrexate. Patients treated concomitantly with trimetrexate and
`
` NIZORAL® Tablets should be carefully monitored for trimetrexate-associated
`toxicities.
`
`Verapamil
`Findings of in vitro metabolic studies indicate that verapamil is metabolized by
`enzymes including CYP3A4. Ketoconazole may increase verapamil serum
`concentrations. Caution should be taken when co-administering verapamil with
`NIZORAL® Tablets.
`
`Vinca Alkaloids (vincristine, vinblastine, vinorelbine)
`
` NIZORAL® may inhibit the metabolism of vinca alkaloids metabolized by
`CYP3A4. Close monitoring for toxicities associated with vincristine, vinblastine,
`or vinorelbine is recommended when co-administered with NIZORAL® Tablets.
`
`2.
`
`Effects of other drugs on ketoconazole
`
`2.1
`
`Drugs affecting the absorption of ketoconazole
`
`Gastric Acid Suppressors/Neutralizers
`Studies have shown that absorption of ketoconazole is impaired when gastric acid
`production is decreased. Reduced plasma concentrations of ketoconazole were
`
`reported when NIZORAL® Tablets were administered with antacids,
`antimuscarinics, histamine H2-blockers, proton pump inhibitors (omeprazole,
`lansoprazole) and sucralfate. (See PRECAUTIONS, Drug Interactions (General)
`section.)
`
`
`
`Reference ID: 3347210
`
`13
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 13
`
`

`

`
` 2.2 Drugs that were shown or are expected to significantly reduce the systemic
`exposure to ketoconazole
`
`Co-administration of ketoconazole with potent CYP3A4 enzyme inducers is not
`recommended.
`
`Carbamazepine
`Concomitant administration of ketoconazole tablets with carbamazepine may alter
`
`the metabolism of one or both of the drugs. Close monitoring for both plasma
`is
`concentrations of carbamazepine and
`reduced ketoconazole efficacy
`recommended.
`
`Nevirapine
`Ketoconazole AUC and Cmax decreased by a median of 63% and 40%,
`
`respectively, in HIV-infected patients who were given nevirapine 200 mg once
`daily for two weeks along with ketoconazole 400 mg daily. Concomitant
`administration of NIZORAL® Tablets and nevirapine is not recommended.
`
`Phenytoin
`Concomitant administration of ketoconazole with phenytoin may alter the
`
`metabolism of one or both of the drugs. Close monitoring for both plasma
`concentrations of phenytoin and reduced efficacy of NIZORAL® Tablets is
`recommended.
`
`Rifampin, rifabutin, isoniazid
`Concomitant administration of rifampin and rifabutin with ketoconazole tablets
`reduces the blood concentrations of the latter. INH (Isoniazid) was also reported
`to affect ketoconazole concentrations adversely. These antitubercular drugs
`should not be given concomitantly with NIZORAL® Tablets.
`
`2.3
`
`Drugs that significantly increase the systemic exposure to ketoconazole
`
`Ritonavir
`Concomitant administration of ritonavir with ketoconazole tablets increases was
`shown to increase the oral bioavailability of ketoconazole. Therefore, when
`ritonavir is to be given concomitantly, higher doses (>200 mg/day) of
`NIZORAL® Tablets should not be used.
`
`
`
`
`
`
`
`
`
`Reference ID: 3347210
`
`14
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 14
`
`

`

`3.
`
`Other drug interactions
`
`Alcohol
`Rare cases of a disulfiram-like reaction to alcohol have been reported. These
`experiences have been characterized by flushing, rash, peripheral edema, nausea,
`and headache. Symptoms resolved within a few hours.
`
`Loratadine
`After the co-administration of 200 mg oral ketoconazole twice daily and one 20
`
` mg dose of loratadine to 11 subjects, the AUC and Cmax of loratadine averaged
`302% (±142 S.D.) and 251% (± 68 S.D.), respectively, of those obtained after co­
`treatment with placebo. The AUC and Cmax of descarboethoxyloratadine, an
`active metabolite, averaged 155% (± 27 S.D.) and 141% (± 35 S.D.), respectively.
`However, no related changes were noted in the QTc on ECG taken at 2, 6, and 24
`hours after the coadministration. Also, there were no clinically significant
`differences in adverse events when loratadine was administered with or without
`ketoconazole.
`
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Ketoconazole did not show any signs of mutagenic potential when evaluated using the
`dominant lethal mutation test or the Ames Salmonella microsomal activator assay.
`Ketoconazole was not carcinogenic in an 18-month, oral study in Swiss albino mice or a
`24-month oral carcinogenicity study in Wistar rats at dose levels of 5, 20 and 80
`mg/kg/day. The high dose in these studies was approximately 1x (mouse) or 2x (rat) the
`clinical dose in humans based on a mg/m2 comparison.
`
`Pregnancy
`Teratogenic effects: Pregnancy Category C: Ketoconazole has been shown to be
`teratogenic (syndactylia and oligodactylia) in the rat when given in the diet at
`80 mg/kg/day (2 times the maximum recommended human dose, based on body surface
`area comparisons). However, these effects may be related to maternal toxicity, evidence
`
`of which also was seen at this and higher dose levels.
`
`
`There are no adequate and well controlled studies in pregnant women. NIZORAL
`
` Tablets should be used during pregnancy only if the potential benefit justifies the
`potential risk to the fetus.
`
`Nonteratogenic Effects
`Ketoconazole has also been found to be embryotoxic in the rat when given in the diet at
`doses higher than 80 mg/kg during the first trimester of gestation.
`
`
`
`Reference ID: 3347210
`
`15
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2019, Page 15
`
`

`

`In addition, dystocia (difficult labor) was noted in rats administered oral ketoconazole
`
` during the third trimester of gestation. This occurred when ketoconazole was
`administered at doses higher than 10 mg/kg (about one fourth the maximum human dose,
`based on body surface area comparison).
`
`Nursing Mothers
`Ketoconazole has been shown to be excreted in the milk. Mothers who are under
`treatment with NIZORAL® Tablets should not breast feed.
`
`Pediatric Use
`
`NIZORAL Tablets have not been systematically studied in children of any age, and
`
`essentially no information is available on children under 2 years. NIZORAL Tablets
`
`should not be used in pediatric patients unless the potential benefit outweighs the risks.
`
`ADVERSE REACTIONS
`Because clinical trials are conducted under widely varying conditions, adverse reaction
`rates observed in the clinical trials of a drug cannot be directly compared to rates in the
`clinical trials of another drug and may not reflect the rates observed in practice.
`
`The following adverse reactions were reported in clinical trials:
`
`
`Immune System Disorders: anaphylactoid reaction
`
`
`
`Endocrine Disorders: gynecomastia
`
`
`Metabolism and Nutrition Disorders: alcohol intolerance, anorexia, hyperlipidemia,
`
`increased appetite
`
`
`
`
` Psychiatric Di