HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use JAKAFI
`safely and effectively. See full prescribing information for JAKAFI.
`
`JAKAFI™ (ruxolitinib) tablets, for oral use
`Initial U.S. Approval: 2011
`
`__________________ INDICATIONS AND USAGE
`_________________
`Jakafi is a kinase inhibitor indicated for treatment of patients with
`intermediate or high-risk myelofibrosis, including primary myelofibrosis,
`
`
`post-polycythemia vera myelofibrosis and post-essential thrombocythemia
`
`myelofibrosis. (1)
` _______________
`______________
`DOSAGE AND ADMINISTRATION
`
`
`The starting dose of Jakafi is 20 mg given orally twice daily for patients
`
`•
`with a platelet count greater than 200 X 109/L, and 15 mg twice daily for
`
`patients with a platelet count between 100 X 109/L and 200 X 109/L.
`(2.1)
`Perform a complete blood count before initiating therapy with Jakafi.
`Monitor complete blood counts every 2 to 4 weeks until doses are
`
`stabilized, and then as clinically indicated. Modify dose for
`thrombocytopenia. (2.1) (2.2)
`Increase dose based on response and as recommended to a maximum of
`
`
`25 mg twice daily. Discontinue after 6 months if no spleen reduction or
`symptom improvement (2.3)
`
`______________ DOSAGE FORMS AND STRENGTHS
`
`Tablets: 5 mg, 10 mg, 15 mg, 20 mg and 25 mg. (3)
` ____________________
`CONTRAINDICATIONS
`
`None. (4)
`_______________
` ______________
`WARNINGS AND PRECAUTIONS
`
`
`Thrombocytopenia, anemia and neutropenia can occur. Manage by dose
`•
`reduction, or interruption or transfusion. (5.1)
`
`_____________
`
`___________________
`
`•
`
`
`
`•
`
`
`
`
`
`•
`
`
`
`•
`
`
`
`•
`
`
`
`
`
`
`
`
`
`Assess patients for signs and symptoms of infection and initiate
`appropriate treatment promptly. Serious infections should have resolved
`before starting therapy with Jakafi. (5.2)
`
`____________________ADVERSE REACTIONS____________________
`The most common hematologic adverse reactions (incidence > 20%) are
`
`thrombocytopenia and anemia. The most common non-hematologic adverse
`reactions (incidence >10%) are bruising, dizziness and headache. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Incyte
`Corporation at 1-855-463-3463 or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch.
`
`____________________DRUG INTERACTIONS____________________
`
`Strong CYP3A4 Inhibitors: Reduce Jakafi starting dose to 10 mg twice
`•
`daily for patients with a platelet count greater than or equal to
`100 X 109/L and concurrent use of strong CYP3A4 inhibitors. Avoid in
`patients with platelet counts less than 100 X 109/L. (2.4) (7.1)
`
` _______________
`USE IN SPECIFIC POPULATIONS _______________
`
`
`Renal Impairment: Reduce Jakafi starting dose to 10 mg twice daily for
`•
`patients with moderate (CrCl 30-59 mL/min) or severe renal impairment
`(CrCl 15-29 mL/min) and a platelet count between 100 X 109/L and
`150 X 109/L. Avoid in patients with end stage renal disease (CrCl less
`than 15 mL/min) not requiring dialysis and in patients with moderate or
`severe renal impairment and a platelet count less than 100 X 109/L. (2.5)
`(8.6)
`Hepatic Impairment: Reduce Jakafi starting dose to 10 mg twice daily
`for patients with any degree of hepatic impairment and a platelet count
`between 100 X 109/L and 150 X 109/L. Avoid in patients with hepatic
`impairment with platelet counts less than 100 X 109/L. (2.5) (8.7)
`Nursing Mothers: Discontinue nursing or discontinue the drug taking
`into account the importance of the drug to the mother. (8.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`
`
`Revised: 11/2011
`
`
`
`
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Thrombocytopenia, Anemia and Neutropenia
`17.2 Infections
`17.3 Drug-drug Interactions
`17.4 Dialysis
`17.5 Compliance
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`2
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Starting Dose
`2.2 Dose Modification Guidelines for Thrombocytopenia
`2.3 Dose Modification Based on Response
`2.4 Dose Adjustment with Concomitant Strong CYP3A4 Inhibitors
`
`2.5 Organ Impairment
`2.6 Method of Administration
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Thrombocytopenia, Anemia and Neutropenia
`5.2 Infections
` ADVERSE REACTIONS
`6.1 Clinical Trials Experience
` DRUG INTERACTIONS
`
`7.1 Drugs That Inhibit or Induce Cytochrome P450 Enzymes
`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
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`12.4 Thorough QT Study
`
` NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`6
`
`7
`
`8
`
`13
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`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`INDICATIONS AND USAGE
`1.
`Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis,
`including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential
`thrombocythemia myelofibrosis.
`
`DOSAGE AND ADMINISTRATION
`
`
`2.
`Recommended Starting Dose
`2.1
`The recommended starting dose of Jakafi is based on platelet count (Table 1). A complete blood
`count (CBC) and platelet count must be performed before initiating therapy, every 2 to 4 weeks
`until doses are stabilized, and then as clinically indicated [see Warnings and Precautions (5.1)].
`Doses may be titrated based on safety and efficacy.
`
`Proposed Jakafi Starting Doses
`Table 1:
`Platelet Count
`Starting Dose
`Greater than 200 X 109/L
`
` 20 mg orally twice daily
`100 X 109/L to 200 X 109/L
`
` 15 mg orally twice daily
`
`
`Dose Modification Guidelines for Thrombocytopenia
`2.2
`Treatment Interruption
`Interrupt treatment for platelet counts less than 50 X 109/L. After recovery of platelet counts
`above this level, dosing may be restarted or increased following recovery of platelet counts to
`
` acceptable levels. Table 2 illustrates the maximum allowable dose that may be used in restarting
`Jakafi after a previous interruption.
`
`Table 2:
`
`Maximum Restarting Doses for Jakafi After Safety Interruption*
`Maximum Dose When
`Restarting Jakafi Treatment *
`
` 20 mg twice daily
`
` 15 mg twice daily
`10 mg twice daily for at least 2 weeks; if stable,
`
`may increase to 15 mg twice daily
`5 mg twice daily for at least 2 weeks; if stable,
`
` may increase to 10 mg twice daily
`
` Current Platelet Count
`
`Greater than or equal to 125 X 109/L
`
` 100 to less than 125 X 109/L
`75 to less than 100 X 109/L
`
`
`50 to less than 75 X 109/L
`
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`Less than 50 X 109/L
` Continue hold
`
`
`*Maximum doses are displayed. When restarting, begin with a dose at least 5 mg twice
`daily below the dose at interruption.
`
`Dose Reductions
`Dose reductions should be considered if the platelet counts decrease as outlined in Table 3 with
`the goal of avoiding dose interruptions for thrombocytopenia.
`
`
`Table 3:
`
`
`Platelet Count
`
`Dosing Recommendations for Thrombocytopenia
`Dose at Time of Platelet Decline
`5 mg
`20 mg
`15 mg
`10 mg
`twice daily
`twice daily
`twice daily
`twice daily
`
`
`
`
`New Dose
`New Dose
`New Dose
`New Dose
`
`
`
`
`
` 15 mg
`twice daily No Change No Change No Change
`
`
`10 mg
`10 mg
`twice daily No Change No Change
`twice daily
`
`
`
`5 mg
`5 mg
`5 mg
`twice daily No Change
`twice daily
`twice daily
`Hold
`Hold
`Hold
`Hold
`
`25 mg
`twice daily
`
`New Dose
`
` 20 mg
`
`twice daily
`
`10 mg
`twice daily
`
`5 mg
`twice daily
`Hold
`
`100 to less than 125 X 109/L
`
`75 to less than 100 X 109/L
`
`50 to less than 75 X 109/L
`Less than 50 X 109/L
`
`
`Dose Modification Based on Response
`2.3
`If efficacy is considered insufficient and platelet and neutrophil counts are adequate, doses may
`be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. Doses should
`
`not be increased during the first 4 weeks of therapy and not more frequently than every 2 weeks.
`Discontinue treatment after 6 months if there is no spleen size reduction or symptom
`improvement since initiation of therapy with Jakafi.
`Based on limited clinical data, long-term maintenance at a 5 mg twice daily dose has not shown
`responses and continued use at this dose should be limited to patients in whom the benefits
`outweigh the potential risks.
`Consider dose increases in patients who meet all of the following conditions:
`
`a. Failure to achieve a reduction from pretreatment baseline in either palpable spleen
`length of 50% or a 35% reduction in spleen volume as measured by CT or MRI;
`b. Platelet count greater than 125 X 109/L at 4 weeks and platelet count never below
`
`100 X 109/L;
`c. ANC levels greater than 0.75 X 109/L.
`
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`Dose Adjustment with Concomitant Strong CYP3A4 Inhibitors
`2.4
`On the basis of pharmacokinetic studies in healthy volunteers, when administering Jakafi with
`strong CYP3A4 inhibitors (such as but not limited to boceprevir, clarithromycin, conivaptan,
`grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil,
`nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin,
`voriconazole), the recommended starting dose is 10 mg twice daily for patients with a platelet
`count greater than or equal to 100 X 109/L. Additional dose modifications should be made with
`careful monitoring of safety and efficacy.
`Concurrent administration of Jakafi with strong CYP3A4 inhibitors should be avoided in patients
`with platelet counts less than 100 X 109/L [see Drug Interactions (7.1)].
`
`2.5
`
`Organ Impairment
`
`Renal Impairment
`On the basis of pharmacokinetic studies in volunteers with renal impairment, the recommended
`starting dose is 10 mg twice daily for patients with a platelet count between 100 X 109/L and
`150 X 109/L and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29
`mL/min). Additional dose modifications should be made with careful monitoring of safety and
`efficacy.
`The recommended starting dose for patients with end stage renal disease on dialysis is 15 mg for
`patients with a platelet count between 100 X 109/L and 200 X 109/L or 20 mg for patients with a
`platelet count of greater than 200 X 109/L. Subsequent doses should be administered on dialysis
`days following each dialysis session. Additional dose modifications should be made with careful
`monitoring of safety and efficacy.
`Jakafi should be avoided in patients with end stage renal disease (CrCl less than 15 mL/min) not
`requiring dialysis and in patients with moderate or severe renal impairment with platelet counts
`less than 100 X 109/L [see Use in Specific Populations (8.6)].
`Hepatic Impairment
`On the basis of pharmacokinetic studies in volunteers with hepatic impairment, the
`recommended starting dose is 10 mg twice daily for patients with a platelet count between
`100 X 109/L and 150 X 109/L. Additional dose modifications should be made with careful
`monitoring of safety and efficacy.
`Jakafi should be avoided in patients with hepatic impairment with platelet counts less than
`100 X 109/L [see Use in Specific Populations (8.7)].
`
`Method of Administration
`2.6
`Jakafi is dosed orally and can be administered with or without food.
`If a dose is missed, the patient should not take an additional dose, but should take the next usual
`prescribed dose.
`When discontinuing Jakafi therapy for reasons other than thrombocytopenia, gradual tapering of
`the dose of Jakafi may be considered, for example by 5 mg twice daily each week.
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`For patients unable to ingest tablets, Jakafi can be administered through a nasogastric tube (8
`French or greater) as follows:
`• Suspend one tablet in approximately 40 mL of water with stirring for approximately
`
` 10 minutes.
`• Within 6 hours after the tablet has dispersed, the suspension can be administered through a
`nasogastric tube using an appropriate syringe.
`The tube should be rinsed with approximately 75 mL of water. The effect of tube feeding
`preparations on Jakafi exposure during administration through a nasogastric tube has not been
`evaluated.
`
`DOSAGE FORMS AND STRENGTHS
`3.
`5 mg tablets - round and white with “INCY” on one side and “5” on the other.
`10 mg tablets - round and white with “INCY” on one side and “10” on the other.
`15 mg tablets - oval and white with “INCY” on one side and “15” on the other.
`20 mg tablets - capsule-shaped and white with “INCY” on one side and “20” on the other.
`25 mg tablets - oval and white with “INCY” on one side and “25” on the other.
`
`
`
`CONTRAINDICATIONS
`
`
`4.
` None.
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5.
`Thrombocytopenia, Anemia and Neutropenia
`5.1
`
`Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia,
`anemia and neutropenia. A complete blood count must be performed before initiating therapy
`with Jakafi [see Dosage and Administration (2.1)].
`Patients with platelet counts of less than 200 X 109/L at the start of therapy are more likely to
`develop thrombocytopenia during treatment.
`Thrombocytopenia was generally reversible and was usually managed by reducing the dose or
`temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered
`[see Dosage and Administration (2.2), and Adverse Reactions (6.1)].
`Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for
`patients developing anemia may also be considered.
`Neutropenia (ANC less than 0.5 X 109/L) was generally reversible and was managed by
`temporarily withholding Jakafi [see Adverse Reactions (6.1)].
`
`Complete blood counts should be monitored as clinically indicated and dosing adjusted as
`required [see Dosage and Administration (2.2), and Adverse Reactions (6.1)].
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`Infections
`5.2
`
`Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal
`and viral infections. Active serious infections should have resolved before starting therapy with
`Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of
`infection and initiate appropriate treatment promptly.
`
`Herpes Zoster
`Physicians should inform patients about early signs and symptoms of herpes zoster and advise
`patients to seek treatment as early as possible [see Adverse Reactions (6.1)].
`
`ADVERSE REACTIONS
`
`
`6.
`
`Clinical Trials Experience
`6.1
`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 safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of
`follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies.
`In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months
`(range 0.5 to 17 months), with 88.7% of patients treated for more than 6 months and 24.6%
`treated for more than 12 months. One hundred and eleven (111) patients started treatment at
`15 mg twice daily and 190 patients started at 20 mg twice daily.
`In a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with
`Jakafi. The most frequent adverse drug reactions were thrombocytopenia and anemia [see
`
`Table 5]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most
`frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 4].
`
`Discontinuation for adverse events, regardless of causality, was observed in 11.0% of patients
`treated with Jakafi and 10.6% of patients treated with placebo.
`
`Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return
`to pretreatment levels over a period of approximately 1 week. There have been isolated cases of
`patients discontinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical
`course continued to worsen; however, it has not been established whether discontinuation of
`therapy contributed to the clinical course in these patients. When discontinuing therapy for
`reasons other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered
`[see Dosage and Administration (2.6)].
`Table 4 presents the most common adverse reactions occurring in patients who received Jakafi in
`the double-blind, placebo-controlled study during randomized treatment.
`
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`
`
`Grade 3
`(%)
`0
`0
`0
`0.7
`0.7
`0
`0
`
`Grade 4
`(%)
`0
`0
`0
`0.7
`0
`0
`0
`
`Table 4:
`
`
`
`Adverse Reactions Occurring in Patients on Jakafi in the Double-blind,
`
`Placebo-controlled Study During Randomized Treatment
`
`Jakafi
`(N=155)
`
`Placebo
`(N=151)
`
`All
`All
`Gradesa
`Grades
`Grade 4
`Grade 3
`
`(%)
`Adverse Reactions
`(%)
`(%)
`(%)
`Bruisingb
`14.6
`0
`0.6
`23.2
`
` Dizzinessc
`
`7.3
`0
`0.6
`18.1
`5.3
`0
`0
`14.8
`Headache
` Urinary Tract Infectionsd
`5.3
`0
`0
`9.0
`
` Weight Gaine
`1.3
`0
`0.6
`7.1
`0.7
`0
`0
`5.2
`Flatulence
` Herpes Zosterf
`
`0.7
`0
`0
`1.9
`
` a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
`
`
`
`b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site
`
`hematoma, increased tendency to bruise, petechiae, purpura
`c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis
`d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria,
`
`
`bacteria urine, bacteria urine identified, nitrite urine present
`e includes weight increased, abnormal weight gain
`
`
`f includes herpes zoster and post-herpetic neuralgia
`
`
`
`
`
` Description of Selected Adverse Drug Reactions
`Anemia
`In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher
`anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of
`anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of
`approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually
`recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This
`pattern was observed in patients regardless of whether they had received transfusions during
`therapy.
`In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of
`patients receiving placebo received red blood cell transfusions during randomized treatment.
`Among transfused patients, the median number of units transfused per month was 1.2 in patients
`treated with Jakafi and 1.7 in placebo treated patients.
`Thrombocytopenia
`In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia,
`the median time to onset was approximately 8 weeks. Thrombocytopenia was generally
`reversible with dose reduction or dose interruption. The median time to recovery of platelet
`counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of
`patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of
`
` treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9%
`
`
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`of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X
`109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared
`
` to patients with a platelet count greater than 200 X 109/L (16.5% versus 7.2%).
`Neutropenia
`In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of
`neutropenia.
`Table 5 provides the frequency and severity of clinical hematology abnormalities reported for
`patients receiving treatment with Jakafi or placebo in the placebo-controlled study.
`
`Table 5:
`
`Worst Hematology Laboratory Abnormalities in the Placebo-controlled
`
` Studya
`
`
`
`Jakafi
`(N=155)
`
`Grade 4
`(%)
`3.9
`11.0
`1.9
`
`All
`Grades
`(%)
`30.5
`86.8
`4.0
`
`Placebo
`(N=151)
`
`Grade 3
`(%)
`1.3
`15.9
`0.7
`
`Grade 4
`(%)
`0
`3.3
`1.3
`
`All
`Gradesb
`Grade 3
`Laboratory Parameter
`(%)
`(%)
`9.0
`69.7
`Thrombocytopenia
`34.2
`96.1
`Anemia
`5.2
`18.7
`Neutropenia
`a Presented values are worst Grade values regardless of baseline
` b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
`
`Additional Data from the Placebo-controlled Study
`25.2% of patients treated with Jakafi and 7.3% of patients treated with placebo developed newly
`
` occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of
`greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no
`Grade 4 ALT elevations.
`17.4% of patients treated with Jakafi and 6.0% of patients treated with placebo developed newly
`
`occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of
`Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.
`16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly
`occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol
`elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations.
`
`
`
`DRUG INTERACTIONS
`
`
`7.
`7.1
`Drugs That Inhibit or Induce Cytochrome P450 Enzymes
`Ruxolitinib is predominantly metabolized by CYP3A4.
`Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%,
`
` respectively, with Jakafi administration (10 mg single dose) following ketoconazole 200 mg
`
`
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`twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life
`was also prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the
`pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib
`
` AUC following concurrent administration with ketoconazole.
`When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is recommended
`[see Dosage and Administration (2.4)]. Patients should be closely monitored and the dose titrated
`based on safety and efficacy.
` Mild or moderate CYP3A4 inhibitors: There was an 8% and 27% increase in the Cmax and
`
`
`AUC of ruxolitinib, respectively, with Jakafi administration (10 mg single dose) following
`erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to
`receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3
`inhibition was consistent with the corresponding exposure information.
`No dose adjustment is recommended when Jakafi is coadministered with mild or moderate
`CYP3A4 inhibitors (eg, erythromycin).
`
` CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively,
`with Jakafi administration (50 mg single dose) following rifampin 600 mg once daily for
`10 days, compared to receiving Jakafi alone in healthy subjects. In addition, the relative exposure
`to ruxolitinib’s active metabolites increased approximately 100%. This increase may partially
`explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3
`inhibition.
`No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer.
`Patients should be closely monitored and the dose titrated based on safety and efficacy.
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.
`Pregnancy
`8.1
`
`Pregnancy Category C
` There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal
`
`toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced
`fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus.
` Ruxolitinib was administered orally to pregnant rats or rabbits during the period of
`
`organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits.
`There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal
`weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose
`results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum
`recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8%
`and increased late resorptions were noted at the highest and maternally toxic dose of
`60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum
`recommended dose.
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`In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib
`from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related
`adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and
`development parameters at the highest dose evaluated (34% the clinical exposure at the
`maximum recommended dose of 25 mg twice daily).
`
`Nursing Mothers
`8.3
`
`It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites
`
`were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal
`plasma. Because many drugs are excreted in human milk and because of the potential for serious
`adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue
`nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
`
`Pediatric Use
`8.4
`
`The safety and effectiveness of Jakafi in pediatric patients have not been established.
`
`Geriatric Use
`8.5
`
`Of the total number of myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years
`of age and older. No overall differences in safety or effectiveness of Jakafi were observed
`between these patients and younger patients.
`
`
`Renal Impairment
`8.6
`The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in
`healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min
`(N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min
`(N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were
`also enrolled.
`The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal
`impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib
`
`metabolites increased with increasing severity of renal impairment. This was most marked in the
`subjects with end stage renal disease requiring hemodialysis. The change in the
`pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in
`
`metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some
`active metabolites by dialysis cannot be ruled out.
`When administering Jakafi to patients with moderate (CrCl 30-59 mL/min) or severe renal
`impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L
`and patients with end stage renal disease on dialysis a dose reduction is recommended [see
`Dosage and Administration (2.5)].
`
`Hepatic Impairment
`8.7
`
`The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in
`healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B
`(N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was
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`increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe
`hepatic impairment compared to patients with normal hepatic function. The terminal elimination
`half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1­
`5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition,
`was consistent with the corresponding increase in ruxolitinib exposure except in the severe
`(Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more
`prolonged in some subjects than expected based on plasma concentrations of ruxolitinib.
`When administering Jakafi to patients with any degree of hepatic impairment and with a platelet
`count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and
`Administration (2.5)].
`
`
`OVERDOSAGE
`10.
`There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been
`given with acceptable acute tolerability. Higher than recommended repeat doses are associated
`with increased myelosuppression including leukopenia, anemia and thrombocytopenia.
`Appropriate supportive treatment should be given.
`Hemodialysis is not expected to enhance the elimination of ruxolitinib.
`
`CN
`
`(R)
`
`H3PO4
`
`H
`NN
`
`N
`
`
`DESCRIPTION
`11.
`Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H-pyrrolo[2,3­
`d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and a molecular
`weight of 404.36. Ruxolitinib phosphate has the following structural formula:
`
`
`
`
`
`
`
`Ruxolitinib phosphate is a white to off-white to light pink powder and is soluble in aqueous
`buffers across a pH range of 1 to 8.
`
`
`Jakafi (ruxolitinib) Tablets are for oral administration. Each tablet contains ruxolitinib phosphate
`equivalent to 5 mg, 10 mg, 15 mg, 20 mg and 25 mg of ruxolitinib free base together with
`microcrystalline cellulose, lactose monohydrate, magnesium stearate, colloidal silicon dioxide,
`sodium starch glycolate, povidone and hydroxypropyl cellulose.
`
`N
`
`N
`H
`
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`CLINICAL PHARMACOLOGY
`
`
`12.
`12.1 Mechanism of Action
`Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which
`mediate the signaling of a number of cytokines and growth factors that are important for
`hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal
`transducers and activators of transcription) to cytokine receptors, activation and subsequent
`localization of STATs to the nucleus leading to modulation of gene expression.
`Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) known to be associated with
`dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617F-positive MPN, oral
`administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F
`mutant cells in the spleen and decreased circulating inflammatory cytokines (eg, TNF-α, IL-6).
`
`12.2
`Pharmacodynamics
`
`
`Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy
`subjects and MF patients. Jakafi administration resulted in maximal inhibition of STAT3
`phosphorylation 2 hours after dosing which returned to near baseline by 10 hours in both healthy
`subjects and myelofibrosis patients.
`
`12.3
`
`
`
`Pharmacokinetics
`
`Absorption
`In clinical studies, ruxolitinib is rapidly absorbed after oral Jakafi administration with maximal
`plasma concentration (Cmax) achieved within 1 to 2 hours post-dose. Based on a mass balance
`study in humans, oral absorption of ruxolitinib was estimated to be at least 95%. Mean
`ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single dose range of
`5 to 200 mg. There were no clinically relevant changes in the pharmacokinetics of ruxolitinib
`upon administration of Jakafi with a high-fat meal, with the mean Cmax moderately decreased
`(24%) and the mean AUC nearly unchanged (4% increase).
`
`Distribution
`The apparent volume of distribution of ruxolitinib at steady-state is 53 to 65 L in myelofibrosis
`patients. Binding to plasma proteins in vitro is approximately 97%, mostly to albumin.
`
`Metabolism
`In vitr