6. ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)]
Risk of Infection [see Warnings and Precautions (5.2)]
Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3)]
Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]
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

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.

Myelofibrosis

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 MF 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 89% of patients treated for more than 6 months and 25% 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 patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 x 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 x 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy.

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].

Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo.

Table 12 presents the most common nonhematologic adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.

Table 12: Myelofibrosis: Nonhematologic Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment
* National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 † includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura ‡ includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis § includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present ¶ includes weight increased, abnormal weight gain # includes herpes zoster and post-herpetic neuralgia
	Jakafi (N=155)			Placebo (N=151)
Adverse Reactions	All Grades* (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Bruising†	23	< 1	0	15	0	0
Dizziness‡	18	< 1	0	7	0	0
Headache	15	0	0	5	0	0
Urinary Tract Infections§	9	0	0	5	< 1	< 1
Weight Gain¶	7	< 1	0	1	< 1	0
Flatulence	5	0	0	< 1	0	0
Herpes Zoster#	2	0	0	< 1	0	0

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. One patient (< 1%) 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 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 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 (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*
* Presented values are worst Grade values regardless of baseline † National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
	Jakafi (N=155)			Placebo (N=151)
Laboratory Parameter	All Grades† (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Thrombocytopenia	70	9	4	31	1	0
Anemia	96	34	11	87	16	3
Neutropenia	19	5	2	4	< 1	1

Additional Data from the Placebo-Controlled Study

25% of patients treated with Jakafi and 7% 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 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations.

17% of patients treated with Jakafi and 6% 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 < 1% for Jakafi with no Grade 3 or 4 AST elevations.

17% of patients treated with Jakafi and < 1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was < 1% for Jakafi with no Grade 3 or 4 cholesterol elevations.

Polycythemia Vera

In a randomized, open-label, active-controlled study, 110 patients with PV resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2)]. The most frequent adverse reaction was anemia. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi. Table 14 presents the most frequent nonhematologic adverse reactions occurring up to Week 32.

Table 14: Polycythemia Vera: Nonhematologic Adverse Reactions Occurring in ≥ 5% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment
* National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 † includes dizziness and vertigo ‡ includes dyspnea and dyspnea exertional § includes herpes zoster and post-herpetic neuralgia ¶ includes weight increased and abnormal weight gain # includes urinary tract infection and cystitis
	Jakafi (N=110)		Best Available Therapy (N=111)
Adverse Reactions	All Grades* (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Diarrhea	15	0	7	< 1
Dizziness†	15	0	13	0
Dyspnea‡	13	3	4	0
Muscle Spasms	12	< 1	5	0
Constipation	8	0	3	0
Herpes Zoster§	6	< 1	0	0
Nausea	6	0	4	0
Weight Gain¶	6	0	< 1	0
Urinary Tract Infections#	6	0	3	0
Hypertension	5	< 1	3	< 1

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*
* Presented values are worst Grade values regardless of baseline † National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
	Jakafi (N=110)			Best Available Therapy (N=111)
Laboratory Parameter	All Grades† (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Hematology
Anemia	72	< 1	< 1	58	0	0
Thrombocytopenia	27	5	< 1	24	3	< 1
Neutropenia	3	0	< 1	10	< 1	0
Chemistry
Hypercholesterolemia	35	0	0	8	0	0
Elevated ALT	25	< 1	0	16	0	0
Elevated AST	23	0	0	23	< 1	0
Hypertriglyceridemia	15	0	0	13	0	0

Acute Graft-Versus-Host Disease

In a single-arm, open-label study, 71 adults (ages 18-73 years) were treated with Jakafi for aGVHD failing treatment with steroids with or without other immunosuppressive drugs [see Clinical Studies (14.3)]. 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 16 shows the adverse reactions other than laboratory abnormalities.

Table 16: Acute Graft-Versus-Host Disease: Nonhematologic Adverse Reactions Occurring in ≥ 15% of Patients in the Open-Label, Single-Cohort Study
* Selected laboratory abnormalities are listed in Table 17 below † National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03
	Jakafi (N=71)
Adverse Reactions*	All Grades† (%)	Grade 3-4 (%)
Infections (pathogen not specified)	55	41
Edema	51	13
Hemorrhage	49	20
Fatigue	37	14
Bacterial infections	32	28
Dyspnea	32	7
Viral infections	31	14
Thrombosis	25	11
Diarrhea	24	7
Rash	23	3
Headache	21	4
Hypertension	20	13
Dizziness	16	0

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
* National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03
	Jakafi (N=71)
	Worst grade during treatment
Laboratory Parameter	All Grades* (%)	Grade 3-4 (%)
Hematology
Anemia	75	45
Thrombocytopenia	75	61
Neutropenia	58	40
Chemistry
Elevated ALT	48	8
Elevated AST	48	6
Hypertriglyceridemia	11	1

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 ≥ 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 (≥ 10%) and Grades 3-5 (≥ 3%) Nonlaboratory Adverse Reactions Occurring in Patients in the Open-Label, Active-controlled Study up to Cycle 7 Day 1 of Randomized Treatment
* Grouped terms that are composites of applicable adverse reaction terms. † National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03
Adverse Reaction*	Jakafi (N = 165)		Best Available Therapy (N = 158)
Adverse Reaction*	All Grades† (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)
Infections and infestations
Infections (pathogen not specified)	45	15	44	16
Viral infections	28	5	23	5
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	18	1	13	0
General disorders and administration site conditions
Pyrexia	16	2	9	1
Fatigue	13	1	10	2
Edema	10	1	12	1
Vascular disorders
Hypertension	16	5	13	7
Hemorrhage	12	2	15	2
Respiratory, thoracic and mediastinal disorders
Cough	13	0	8	0
Dyspnea	11	1	8	1
Gastrointestinal disorders
Nausea	12	0	13	2
Diarrhea	10	1	13	1

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*
* Presented values are worst Grade values regardless of baseline † National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03
Laboratory Test	Jakafi (N = 165)		Best Available Therapy (N = 158)
Laboratory Test	All Grades† (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)
Hematology
Anemia	82	13	75	8
Neutropenia	27	12	23	9
Thrombocytopenia	58	20	54	17
Chemistry
Hypercholesterolemia	88	10	85	8
Elevated AST	65	5	54	6
Elevated ALT	73	11	71	16
Gamma glutamyltransferase increased	81	42	75	38
Creatinine increased	47	1	40	2
Elevated lipase	38	12	30	9
Elevated amylase	35	8	25	4

6.2 Postmarketing Experience

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