Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

JAKAFI (NDA-202192)

(RUXOLITINIB PHOSPHATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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01/31/2023 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Infection

Additions and/or revisions underlined:

…

Herpes Zoster and Herpes Simplex

Herpes zoster infection has been reported in patients receiving Jakafi [see Adverse Reactions (6.1)]. Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected.

Herpes simplex virus reactivation and/or dissemination has been reported in patients receiving Jakafi [see Adverse Reactions (6.2)]. Monitor patients for the development of herpes simplex infections. If a patient develops evidence of dissemination of herpes simplex, consider interrupting treatment with Jakafi; patients should be promptly treated and monitored according to clinical guidelines.

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added subsection:

The following adverse reactions have been identified during post-approval use of Jakafi. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Infections and Infestations: Herpes simplex virus reactivation and/or dissemination

12/19/2022 (SUPPL-27)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined

Myelofibrosis

The safety and effectiveness of Jakafi for treatment of myelofibrosis in pediatric patients have not been established.

Polycythemia Vera

The safety and effectiveness of Jakafi for treatment of polycythemia vera in pediatric patients have not been established.

…

Other Myeloproliferative Neoplasms, Leukemias, and Solid Tumors

The safety and effectiveness of ruxolitinib were assessed but not established in a single-arm trial (NCT01164163) in patients with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms. The patients included 18 children (age 2 to < 12 years) and 14 adolescents (age 12 to < 17 years). Overall, 19% of patients received more than one cycle. No new safety signals were observed in pediatric patients in this trial.

The safety and effectiveness of ruxolitinib in combination with chemotherapy for treatment of high-risk, de novo CRLF2 rearranged or JAK pathway–mutant Ph-like acute lymphoblastic leukemia (ALL) were assessed but not established in a single-arm trial (NCT02723994). The patients included 2 infants (age < 2 years), 42 children (age 2 to < 12 years) and 62 adolescents (age 12 to < 17 years). No new safety signals were observed in pediatric patients in this trial.

…

09/27/2021 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Thrombocytopenia, Anemia and Neutropenia

Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia [see Adverse Reactions (6.1)].

5.2 Risk of Infection

Serious bacterial, mycobacterial, fungal and viral infections have occurred [see Adverse Reactions (6.1)]. Delay starting therapy with Jakafi …

5.3 Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi

… When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.7)], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly.

5.4 Non-Melanoma Skin Cancer (NMSC)

5.5 Lipid Elevations

Treatment with Jakafi has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides [see Adverse Reactions (6.1)]. The effect of these lipid parameter elevations …

The following three subsections are newly added:

5.6 Major Adverse Cardiovascular Events (MACE)

Another JAK-inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.

5.7 Thrombosis

Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. In patients with MF and PV treated with Jakafi in clinical trials, the rates of thromboembolic events were similar in Jakafi and control treated patients.

Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

5.8 Secondary Malignancies

Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding NMSC (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi, particularly in patients with a known secondary malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

6 Adverse Reactions

Newly added to the bulleted line listing:

Lipid Elevations [see Warnings and Precautions (5.5)]
Major Adverse Cardiovascular Events (MACE) [see Warnings and Precautions (5.6)]
Thrombosis [see Warnings and Precautions (5.7)]
Secondary Malignancies [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Myelofibrosis

The safety of Jakafi was assessed in 617 patients in six clinical studies …

In a double-blind, randomized, placebo-controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse reactions were thrombocytopenia and anemia [see Table 13]. Thrombocytopenia, anemia and neutropenia are dose-related effects. The three most frequent nonhematologic adverse reactions were bruising, dizziness and headache [see Table 12].

Table 12: Myelofibrosis: Nonhematologic Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment

Description of Selected Adverse 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 …

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 × 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in < 1% of patients receiving Jakafi and < 1% of patients receiving control regimens. Patients with a platelet count of 100 × 109/L to 200 × 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 × 109/L (17% versus 7%).

Neutropenia

In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia.

Table 13 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Table 13: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo Controlled Study a

Polycythemia Vera

… Table 14 presents the most frequent nonhematologic adverse reactions occurring up to Week 32.

Table 14: Polycythemia Vera: Nonhematologic Adverse Reactions Occurring in greater than or equal to 5% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment

Clinically relevant laboratory abnormalities are shown in Table 15.

Table 15: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment a

Acute Graft-Versus-Host Disease

… The most common adverse reaction leading to treatment discontinuation was infection (10%). Table 16 shows the adverse reactions other than laboratory abnormalities.

Table 16: Acute Graft-Versus-Host Disease: Nonhematologic Adverse Reactions Occurring in greater than or equal to 15% of Patients in the Open-Label, Single-Cohort Study

Selected laboratory abnormalities during treatment with Jakafi are shown in Table 17.

Table 17: Acute Graft-Versus-Host Disease: Selected Laboratory Abnormalities Worsening from Baseline in the Open-Label, Single Cohort Study

Chronic Graft-Versus-Host Disease

In a Phase 3, randomized, open-label, multi-center study, 165 patients were treated with Jakafi and 158 patients were treated with best available therapy for cGVHD failing treatment with steroids with or without other immunosuppressive drugs [see Clinical Studies (14.4)]; sixty-five patients crossed over from best available therapy to treatment with Jakafi, for a total of 230 patients treated with Jakafi. The median duration of exposure to Jakafi for the study was 49.7 weeks (range, 0.7 to 144.9 weeks) in the Jakafi arm. One hundred and nine (47%) patients were on Jakafi for at least 1 year.

There were five fatal adverse reactions to Jakafi, including 1 from toxic epidermal necrolysis and 4 from neutropenia, anemia and/or thrombocytopenia. An adverse reaction resulting in treatment discontinuation occurred in 18% of patients treated with Jakafi. An adverse reaction resulting in dose modification occurred in 27%, and an adverse reaction resulting in treatment interruption occurred in 23%. The most common hematologic adverse reactions (incidence > 35%) are anemia and thrombocytopenia. The most common nonhematologic adverse reactions (incidence greater than or equal to 20%) are infections (pathogen not specified) and viral infection.

Table 18 presents the most frequent nonlaboratory adverse reactions occurring up to Cycle 7 Day 1 of randomized treatment.

Table 18: Chronic Graft-Versus-Host Disease: All-Grade (greater than or equal to 10%) and Grades 3-5 (greater than or equal to 3%) Nonlaboratory Adverse Reactions Occurring in Patients in the Open- Label, Active-controlled Study up to Cycle 7 Day 1 of Randomized Treatment Newly added table; please refer to label for complete information.

Clinically relevant laboratory abnormalities are shown in Table 19.

Table 19: Chronic Graft-Versus-Host Disease: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Cycle 7 Day 1 of Randomized Treatment a Newly added table; please refer to label for complete information.

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Effect of Other Drugs on Jakafi

Fluconazole

Concomitant use of Jakafi with fluconazole increases ruxolitinib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of exposure-related adverse reactions. Avoid concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily. Reduce the Jakafi dosage when used concomitantly with fluconazole doses of less than or equal to 200 mg [see Dosage and Administration (2.5)].

Strong CYP3A4 Inhibitors

Concomitant use of Jakafi with strong CYP3A4 inhibitors increases ruxolitinib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of exposure-related adverse reactions. Reduce the Jakafi dosage when used concomitantly with strong CYP3A4 inhibitors except in patients with aGVHD or cGVHD [see Dosage and Administration (2.5)].

Strong CYP3A4 Inducers

Concomitant use of Jakafi with strong CYP3A4 inducers may decrease ruxolitinib exposure [see Clinical Pharmacology (12.3)], which may reduce efficacy of Jakafi. …

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

… The safety and effectiveness of Jakafi for treatment of steroid-refractory aGVHD has been established for treatment of children 12 years and older. Use of Jakafi in pediatric patients with steroid-refractory aGVHD is supported by evidence from adequate and well-controlled trials of Jakafi in adults [see Clinical Studies (14.3)] and additional pharmacokinetic and safety data in pediatric patients. The safety and effectiveness of Jakafi for treatment of steroid-refractory aGVHD has not been established in pediatric patients younger than 12 years old.

The safety and effectiveness of Jakafi for treatment of cGVHD after failure of one or two lines of systemic therapy has been established for treatment of children 12 years and older. Use of Jakafi in pediatric patients with cGVHD after failure of one or two lines of systemic therapy is supported by evidence from adequate and well-controlled trials of Jakafi in adults and adolescents [see Clinical Studies (14.3, 14.4)] and additional pharmacokinetic and safety data in pediatric patients. The safety and effectiveness of Jakafi for treatment of cGVHD has not been established in pediatric patients younger than 12 years old.

Jakafi was evaluated in a single-arm, dose-escalation study (NCT01164163) …

8.5 Geriatric Use

Additions and/or revisions underlined:

… Clinical studies of Jakafi in patients with aGVHD did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.

Of the total number of patients with cGVHD treated with Jakafi in clinical trials, 11% were 65 years and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients.

8.6 Renal Impairment

Additions and/or revisions underlined:

Total exposure of ruxolitinib and its active metabolites increased with moderate (CLcr 30 to 59 mL/min) and severe (CLcr 15 to 29 mL/min) renal impairment, and ESRD (CLcr less than 15 mL/min) on dialysis [see Clinical Pharmacology (12.3)]. Modify Jakafi dosage as recommended [see Dosage and Administration (2.6)].

8.7 Hepatic Impairment

Additions and/or revisions underlined:

… Reduce Jakafi dosage as recommended in patients with MF or PV with hepatic impairment [see Dosage and Administration (2.6)]. Reduce Jakafi dosage as recommended for patients with Stage 4 liver aGVHD.

Monitor blood counts more frequently for toxicity and modify the Jakafi dosage for adverse reactions if they occur for patients with Score 3 liver cGVHD [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Thrombocytopenia, Anemia and Neutropenia

… Advise patients to observe for and report bleeding [see Warnings and Precautions (5.1)].

Infections

… Inform patients regarding the early signs and symptoms of herpes zoster and of progressive multifocal leukoencephalopathy, and advise patients to seek advice of a clinician if such symptoms are observed [see Warnings and Precautions (5.2)].

Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi

… Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician [see Warnings and Precautions (5.3)].

Non-Melanoma Skin Cancer

Inform patients that Jakafi may increase their risk of certain non-melanoma skin cancers. Advise patients to inform their healthcare provider if they have ever had any type of skin cancer or if they observe any new or changing skin lesions [see Warnings and Precautions (5.4)].

Lipid Elevations

Inform patients that Jakafi may increase blood cholesterol, and of the need to monitor blood cholesterol levels [see Warnings and Precautions (5.5)].

Newly added information:

Major Adverse Cardiovascular Events (MACE)

Advise patients that events of major adverse cardiovascular events (MACE) including myocardial infarction, stroke, and cardiovascular death, have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which Jakafi is not indicated. Advise patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions (5.6)].

Thrombosis

Advise patients that events of DVT and PE have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which Jakafi is not indicated. Advise patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE [see Warnings and Precautions (5.7)].

Secondary Malignancies

Advise patients, especially current or past smokers and patients with a known secondary malignancy (other than a successfully treated NMSC), that lymphoma and other malignancies (excluding NMSC) have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which Jakafi is not indicated [see Warnings and Precautions (5.8)].

Additions and/or revisions underlined:

Drug-Drug Interactions

Advise patients to inform their healthcare providers of all medications they are taking, including over-the-counter medications, herbal products and dietary supplements [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Dialysis

Inform patients on dialysis that their dose should not be taken before dialysis but only following dialysis [see Dosage and Administration (2.6)].

Lactation

Inform women not to breastfeed during treatment with Jakafi and for two weeks after the final dose [see Use in Specific Populations (8.2)].

09/22/2021 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Non-Melanoma Skin Cancer (NMSC)

(Subsection title revised)

5.6 Major Adverse Cardiovascular Events (MACE)

(Newly added subsection)

5.7 Thrombosis

(Newly added subsection)

Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

5.8 Secondary Malignancies

(Newly added subsection)

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Lipid Elevations [see Warnings and Precautions (5.5)]
Major Adverse Cardiovascular Events (MACE) [see Warnings and Precautions (5.6)]
Thrombosis [see Warnings and Precautions (5.7)]
Secondary Malignancies [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

(Extensive revisions; please refer to label)

7 Drug Interactions

7.1 Effect of Other Drugs on Jakafi

(Subsection title added; Additions and/or revisions underlined)

Fluconazole

Concomitant use of Jakafi with fluconazole increases ruxolitinib exposure [see Clinical Pharmacology (11.3)], which may increase the risk of exposure-related adverse reactions. Avoid concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily. Reduce the Jakafi dosage when used concomitantly with fluconazole doses of less than or equal to 200 mg [see Dosage and Administration (2.5)].

Strong CYP3A4 Inhibitors

Concomitant use of Jakafi with strong CYP3A4 inhibitors increases ruxolitinib exposure [see Clinical Pharmacology (11.3)], which may increase the risk of exposure-related adverse reactions. Reduce the Jakafi dosage when used concomitantly with strong CYP3A4 inhibitors except in patients with aGVHD or cGVHD [see Dosage and Administration (2.5)].

Strong CYP3A4 Inducers

Concomitant use of Jakafi with strong CYP3A4 inducers may decrease ruxolitinib exposure [see Clinical Pharmacology (11.3)], which may reduce efficacy of Jakafi. Monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Clinical Pharmacology (11.3)].

8 Use in Specific Populations

8.3 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of Jakafi for treatment of myelofibrosis or polycythemia vera in pediatric patients have not been established.

The safety and effectiveness of Jakafi for treatment of steroid-refractory aGVHDhas been established for treatment of children 12 years and older. Use of Jakafi in pediatric patients with steroid-refractory aGVHD is supported by evidence from adequate and well-controlled trials of Jakafi in adults [see Clinical Studies (13.3)] and additional pharmacokinetic and safety data in pediatric patients. The safety and effectiveness of Jakafi for treatment of steroid-refractory aGVHD has not been established in pediatric patients younger than 12 years old.

The safety and effectiveness of Jakafi for treatment of cGVHD after failure of one or two lines of systemic therapy has been established for treatment of children 12 years and older. Use of Jakafi in pediatric patients with cGVHD after failure of one or two lines of systemic therapy is supported by evidence from adequate and well-controlled trials of Jakafi in adults and adolescents [see Clinical Studies (13.3, 13.4)] and additional pharmacokinetic and safety data in pediatric patients. The safety and effectiveness of Jakafi for treatment of cGVHD has not been established in pediatric patients younger than 12 years old.

…

8.4 Geriatric Use

(Additions and/or revisions underlined)

Of the total number of patients with MF in clinical studies with Jakafi, 52% were 65 years and older, while 15% were 75 years and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients.

Clinical studies of Jakafi in patients with aGVHD did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.

8.5 Renal Impairment

(Additions and/or revisions underlined)

Total exposure of ruxolitinib and its active metabolites increased with moderate (CLcr 30 to 59 mL/min) and severe (CLcr 15 to 29 mL/min) renal impairment, and ESRD (CLcr less than 15 mL/min) on dialysis [see Clinical Pharmacology (11.3)]. Modify Jakafi dosage as recommended [see Dosage and Administration (2.6)].

8.6 Hepatic Impairment

(Additions and/or revisions underlined)

Exposure of ruxolitinib increased with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment [see Clinical Pharmacology (11.3)].

Reduce Jakafi dosage as recommended in patients with MF or PV with hepatic impairment [see Dosage and Administration (2.6)]. Reduce Jakafi dosage as recommended for patients with Stage 4 liver aGVHD.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

…

Major Adverse Cardiovascular Events (MACE)

Thrombosis

Secondary Malignancies

…

PATIENT INFORMATION

(Extensive revisions; please refer to label)

01/14/2020 (SUPPL-19)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience in Myelofibrosis

(addition underlined)

…

Table 11 presents the most common nonhematologic adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.

(please refer to label to view Table 11)

…

6.2 Clinical Trial Experience in Polycythemia Vera

(revisions underlined)

…

Table 13: Polycythe mia Vera: Nonhematologic Adverse Reactions Occurring in equal to or greater than 5%of Patie nts on Jakafi in the Ope n-Labe l, Active -controlle d Study up to

Week 32 of Randomize d Treatment

(please refer to label to view Table 13)

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(addition underlined)

…

The most common side effects of Jakafi in adults with certain types of MF and PV include:

low platelet counts (thrombocytopenia)
dizziness
low red blood cell counts (anemia)
headache
bruising
diarrhea

…

05/24/2019 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2Risk of Infection

(addition underlined)

…Use active surveillance and prophylactic antibiotics according to clinical guidelines.

…

6 Adverse Reactions

6.3 Clinical Trial Experience in Acute Graft-Versus-Host Disease

(new subsection added)

In a single-arm, open-label study, 71 adults (ages 18-73 years) were treated with Jakafi for acute GVHD failing treatment with steroids with or without other immunosuppressive drugs. The median duration of treatment with Jakafi was 46 days (range, 4-382 days).

There were no fatal adverse reactions to Jakafi. An adverse reaction resulting in treatment discontinuation occurred in 31% of patients. The most common adverse reaction leading to treatment discontinuation was infection (10%). Table 15 shows the adverse reactions other than laboratory abnormalities.

(please refer to label to view Table 15)

Selected laboratory abnormalities during treatment with Jakafi are shown in Table 16.

(please refer to label to view Table 16)

7 Drug Interactions

(additions underlined)

…

Strong CYP3A4 inhibitors

Concomitant administration of Jakafi with strong CYP3A4 inhibitors increases ruxolitinib exposure. Increased exposure may increase the risk of exposure-related adverse reactions. Consider dose reduction when administering Jakafi with strong CYP3A4 inhibitors . In patients with acute GVHD, reduce Jakafi dose as recommended only when coadministered with ketoconazole, and monitor blood counts more frequently for toxicity and adjust the dose if necessary when coadministered with itraconazole.

…

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

The safety and effectiveness of Jakafi for treatment of myelofibrosis or polycythemia vera in pediatric patients have not been established.

The safety and effectiveness of Jakafi for treatment of steroid-refractory acute graft-versus-host disease (GVHD) have been established for treatment of children 12 years and older. Use of Jakafi in pediatric patients with steroid-refractory acute GVHD us supported by evidence from an adequate and well-controlled trial of Jakafi in adults and additional pharmacokinetic and safety data in pediatric patients.

…

Overall, 38 (81%) patients were treated with no more than a single cycle of Jakafi, while 3, 1, 2, and 3 patients received 2, 3, 4, and 5 or more cycles, respectively. A protocol-defined maximal tolerated dose was not observed, but since few patients were treated for multiple cycles, tolerability with continued use was not assessed adequately to establish a recommended Phase 2dose higher than the recommended dose for adults. The safety profile in children was similar to that seen in adults.

…

8.5 Geriatric Use

(additions underlined)

…

Clinical studies of Jakafi in patients with acute GVHD did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal Impairment

(subsection revised, additions underlined)

Total exposure of ruxolitinib and its active metabolites increased with moderate (CLcr 30 mL/min to 59 mL/min) and severe (CLcr 15 mL/min to 29 mL/min) impairment, and ESRD on dialysis .Reduce Jakafi dose as recommended.

8.7 Hepatic Impairment

(subsection revised, additions underlined)

Exposure of ruxolitinib increased with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment .Reduce Jakafi dose as recommended in patients with MF or PV and any hepatic impairment.

Monitor blood counts more frequently for toxicity and consider 5 mg once daily for patients with Stage 3 or 4 liver GVHD.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(additions underlined)

…

The most common side effects of Jakafi in adults with certain types of MF and PV include:

low platelet counts (thrombocytopenia)
dizziness
low red blood cell counts (anemia)
headache
bruising

The most common side effects of Jakafi in people with acute graft versus host disease (GVHD) include:

low red blood cell counts (anemia)
infections
low platelet counts (thrombocytopenia)
fluid retention
low white blood cell counts (neutropenia)

These are not all the possible side effects of Jakafi.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Incyte Corporation at 1-855-463-3463.

…

10/26/2018 (SUPPL-16)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information:

Juvenile Animal Toxicity Data

Administration of ruxolitinib to juvenile rats resulted in effects on growth and bone measures. When administered starting at postnatal day 7 (the equivalent of a human newborn) at doses of 1.5 to 75 mg/kg/day, evidence of fractures occurred at doses ? 30 mg/kg/day, and effects on body weight and other bone measures [e.g., bone mineral content, peripheral quantitative computed tomography, and x-ray analysis] occurred at doses ? 5 mg/kg/day. When administered starting at postnatal day 21 (the equivalent of a human 2-3 years of age) at doses of 5 to 60 mg/kg/day, effects on body weight and bone occurred at doses ? 15 mg/kg/day, which were considered adverse at 60 mg/kg/day. Males were more severely affected than females in all age groups, and effects were generally more severe when administration was initiated earlier in the postnatal period. These findings were observed at exposures that are at least 27% the clinical exposure at the maximum recommended dose of 25 mg twice daily.

12/06/2017 (SUPPL-15)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information:

… have not been established. Jakafi was evaluated in a single-arm, dose-escalation study (NCT01164163) in 27 pediatric patients with relapsed or refractory solid tumors (Cohort A) and 20 with leukemias or myeloproliferative neoplasms (Cohort B). The patients had a median age of 14 years (range, 2 to 21 years) and included 18 children (age 2 to less than 12 years), and 14 adolescents (age 12 to less than 17 years). The dose levels tested were 15, 21, 29, 39, or 50 mg/m2 twice daily in 28-day cycles with up to 6 patients per dose group.

Overall, 38 (81%) patients were treated with no more than a single cycle of Jakafi, while 3, 1, 2, and 3 patients received 2, 3, 4, and 5 or more cycles, respectively. A protocol-defined maximal tolerated dose was not observed, but since few patients were treated for multiple cycles, tolerability with continued use was not assessed adequately to establish a recommended Phase 2 dose. The safety profile in children was similar to that seen in adults.

10/10/2017 (SUPPL-14)

Approved Drug Label (PDF)

7 Drug Interactions

(section revised; additions and revisions underlined)

Fluconazole

Concomitant administration of Jakafi with fluconazole doses greater than 200 mg daily may increase ruxolitinib exposure due to inhibition of both the CYP3A4 and CYP2C9 metabolic pathways. Increased exposure may increase the risk of exposure-related adverse reactions. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily.

Strong CYP3A4 inhibitors

Strong CYP3A4 inducers

Concomitant administration of Jakafi with strong CYP3A4 inducers may decrease ruxolitinib exposure. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, additions underlined)

Risk Summary

When pregnant rats and rabbits were administered ruxolitinib during the period of organogenesis adverse developmental outcomes occurred at doses associated with maternal toxicity (see Data). There are no studies with the use of Jakafi in pregnant women to inform drug-associated risks.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk in the U.S. general population of major birth defects is 2% to 4% and miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

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 were no treatment-related malformations. Adverse developmental outcomes, such as 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.

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).

8.2 Lactation

(PLLR conversion, additions underlined)

Risk Summary

No data are available regarding the presence of ruxolitinib in human milk, the effects on the breast fed infant, or the effects on milk production. Ruxolitinib and/or its metabolites were present in the milk of lactating rats (see Data). Because many drugs are present in human milk and because of the potential for thrombocytopenia and anemia shown for Jakafi in human studies, discontinue breastfeeding during treatment with Jakafi and for two weeks after the final dose.

Data

Animal Data

Lactating rats were administered a single dose of [14C]-labeled ruxolitinib (30 mg/kg) on postnatal Day 10, after which plasma and milk samples were collected for up to 24 hours. The AUC for total radioactivity in milk was approximately 13-fold the maternal plasma AUC. Additional analysis showed the presence of ruxolitinib and several of its metabolites in milk, all at levels higher than those in maternal plasma.

8.6 Renal Impairment

(subsection revised, additions underlined)

Reduce the Jakafi dosage when administering Jakafi to patients with MF and moderate (CLcr 30 mL/min to 59 mL/min as estimated using Cockcroft-Gault) or severe renal impairment (CLcr 15 mL/min to 29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L.

Reduce the Jakafi dosage for patients with PV and moderate (CLcr 30 to 59 mL/min) or severe renal impairment (CLcr 15 to 29 mL/min).

Reduce the Jakafi dosage for all patients with ESRD on dialysis.

8.7 Hepatic Impairment

(subsection revised, additions underlined)

Reduce the Jakafi dosage when administering Jakafi to patients with MF and any degree of hepatic impairment (Child-Pugh Class A, B and C) and with a platelet count between 50 X 109/L and 150 X 109/L.

Reduce the Jakafi dosage for patients with PV and hepatic impairment (Child-Pugh Class A, B and C).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Lactation

Inform women not to breastfeed during treatment with Jakafi and for two weeks after the final dose.

…

03/10/2016 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

Risk of Infection

Hepatitis B: Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking Jakafi. The effect of Jakafi on viral replication in patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines.

Lipid Elevations

Treatment with Jakafi has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined in patients treated with Jakafi. Assess lipid parameters approximately 8-12 weeks following initiation of Jakafi therapy. Monitor and treat according to clinical guidelines for the management of hyperlipidemia.