ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Risk of Infections and Hepatitis B Reactivation [see Warnings and Precautions (5.1 )]
Thrombocytopenia and Neutropenia [see Warnings and Precautions (5.2 )]
Hepatotoxicity [see Warnings and Precautions (5.3 )]
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.4 )]
Major Adverse Cardiovascular Events [see Warnings and Precautions (5.5 )]
Thrombosis [see Warnings and Precautions (5.6 )]
Malignancies [see Warnings and Precautions (5.7 )]
Symptom Exacerbation Following Interruption or Discontinuation of Treatment [see Warnings and Precautions (5.8 )]

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of OJJAARA was evaluated in 215 patients in 2 clinical trials (MOMENTUM and SIMPLIFY‑1 anemic subgroup [hemoglobin (Hb) <10 g/dL]) [see Clinical Studies (14 )] .

MOMENTUM

Patients in the MOMENTUM trial had been previously treated with a JAK inhibitor and were randomly assigned 2:1 to receive double‑blind OJJAARA 200 mg orally once daily (n = 130) or danazol 300 mg orally twice daily (n = 65) for 24 weeks, after which they were eligible to receive open‑label OJJAARA in an extended treatment phase. Among patients who received OJJAARA, 72% were exposed for 24 weeks or longer and 52% were exposed for 48 weeks or longer [see Clinical Studies (14 )] .

Serious adverse reactions occurred in 35% of patients who received OJJAARA during the randomized treatment period of the MOMENTUM trial; the most common serious adverse reactions (≥2%) included bacterial infection (8%), viral infection (5%), hemorrhage (4%), acute kidney injury (3%), pneumonia (3%), pyrexia (3%), thrombosis (3%), syncope (2%), thrombocytopenia (2%), and renal and urinary tract infection (2%). Fatal adverse reactions occurred in 12% of patients who received OJJAARA; the most common (≥2%) fatal adverse reaction was viral infection (5%).

Permanent discontinuation of OJJAARA due to an adverse reaction occurred in 18% of patients during the randomized treatment period of the MOMENTUM trial. Adverse reactions that resulted in permanent discontinuation (≥2%) included viral infection (2%) and thrombocytopenia (2%). Dosage reduction or treatment interruption due to an adverse reaction occurred in 34% of patients. Adverse reactions requiring dosage reduction and/or treatment interruption (≥2%) included thrombocytopenia (13%), bacterial infection (2%), diarrhea (2%), and neutropenia (2%).

Among the 130 patients treated with OJJAARA during the randomized treatment period of MOMENTUM, the most common adverse reactions (≥20%) were thrombocytopenia, diarrhea, hemorrhage, and fatigue (Table 2 ).

Table 2: Adverse Reactions Occurring in ≥5% of Patients Receiving OJJAARA during Randomized Treatment in MOMENTUM
^aStudy was not designed to evaluate meaningful comparisons of the incidence of adverse reactions across treatment groups.
^bAdverse reactions graded using CTCAE v.5.
^cGrouped term includes other related terms.
^dExcludes opportunistic infections.
Adverse Reaction	OJJAARA n = 130		Danazol ^a n = 65
All Grades ^b %	Grade ≥3 %	All Grades %	Grade ≥3 %
Thrombocytopenia ^c	28	22	17	12
Diarrhea ^c	22	0	9	2
Hemorrhage ^c	22	2	18	8
Fatigue ^c	21	2	20	5
Nausea ^c	16	2	9	3
Bacterial infection ^c,d	15	8	18	8
Abdominal pain ^c	13	1	18	3
Viral infection ^c,d	12	5	3	0
Pruritus ^c	11	2	11	0
Elevated liver enzymes ^c	10	2	9	3
Pyrexia ^c	10	2	8	0
Cough ^c	8	0	5	0
Paresthesia ^c	8	1	2	0
Dizziness ^c	8	2	2	0
Vomiting ^c	8	1	0	0
Rash ^c	6	0	11	0
Renal and urinary tract infection ^c,d	6	2	11	5
Arrhythmia ^c	5	1	6	2
Neutropenia	5	5	3	3

SIMPLIFY‑1

Patients in the SIMPLIFY‑1 trial were JAK inhibitor naïve and randomly assigned 1:1 to receive double‑blind OJJAARA 200 mg orally once daily (n = 215) or ruxolitinib 5 to 20 mg orally twice daily (n = 217). Upon completion of the double‑blind treatment phase, all patients were eligible to receive OJJAARA during the open‑label phase. The safety of OJJAARA was evaluated in the population of patients with MF who were anemic at study entry. SIMPLIFY‑1 enrolled 180 anemic patients who received OJJAARA (n = 85) or ruxolitinib (n = 95). Among these anemic patients who received OJJAARA, 78% were exposed for 24 weeks or longer and 61% were exposed for 48 weeks or longer [see Clinical Studies (14 )] .

Serious adverse reactions occurred in 28% of the anemic patients who received OJJAARA during the randomized treatment period of the SIMPLIFY‑1 trial; the most common serious adverse reactions (≥2%) included bacterial infection (7%), pneumonia (6%), heart failure (4%) arrhythmia (2%), and respiratory failure (2%). A fatal adverse reaction (bacterial infection) occurred in 1 patient who received OJJAARA.

Permanent discontinuation of OJJAARA due to an adverse reaction occurred in 19% of the anemic patients during the randomized treatment period of the SIMPLIFY‑1 trial. Adverse reactions that resulted in permanent discontinuation of OJJAARA (≥2%) included bacterial infection (2%), dizziness (2%), fatigue (2%), hypotension (2%), and thrombocytopenia (2%). Dosage reductions or treatment interruptions of OJJAARA due to an adverse reaction occurred in 21% of patients. Adverse reactions requiring dosage reduction and/or treatment interruption (≥2%) were thrombocytopenia (8%), pneumonia (4%), bacterial infection (2%), abdominal pain (2%), elevated liver enzymes (2%), and hypotension (2%).

Among the 85 anemic patients treated with OJJAARA during the randomized treatment period of SIMPLIFY‑1, the most common adverse reactions (≥20%) were dizziness, fatigue, bacterial infection, hemorrhage, thrombocytopenia, diarrhea, and nausea (Table 3 ).

Table 3: Adverse Reactions Occurring in ≥5% of Anemic Patients Receiving OJJAARA during Randomized Treatment in SIMPLIFY-1
^aStudy was not designed to evaluate meaningful comparisons of the incidence of adverse reactions across treatment groups.
^bAdverse reactions graded using CTCAE v.4.03.
^cGrouped term includes other related terms.
^dExcludes opportunistic infections.
Adverse Reactions	OJJAARA n = 85 Baseline Hb <10 g/dL		Ruxolitinib ^a n = 95 Baseline Hb <10 g/dL
Adverse Reactions	All Grades ^b %	Grade ≥3 %	All Grades %	Grade ≥3 %
Dizziness ^c	24	1	15	2
Fatigue ^c	22	0	25	1
Bacterial infection ^c,d	21	8	12	2
Hemorrhage ^c	21	1	18	2
Thrombocytopenia ^c	21	11	34	6
Diarrhea ^c	20	1	20	1
Nausea ^c	20	0	3	1
Abdominal pain ^c	18	1	14	1
Cough ^c	14	0	11	0
Hypotension ^c	14	2	0	0
Pain in extremity	12	0	5	0
Pyrexia ^c	12	1	11	0
Rash ^c	12	0	3	0
Renal and urinary tract infection ^c,d	12	1	4	0
Elevated liver enzymes ^c	11	4	9	0
Headache ^c	11	0	16	0
Peripheral edema	11	0	8	0
Arrhythmia ^c	8	2	2	1
Paresthesia ^c	8	0	3	0
Pneumonia ^c	8	8	5	3
Vomiting ^c	8	0	5	0
Back pain	7	1	2	0
Viral infection ^c,d	6	0	13	2
Vitamin B1 deficiency	6	0	7	0

Other Adverse Reactions

Clinically relevant adverse reactions occurring in <5% of anemic patients in the MOMENTUM and SIMPLIFY‑1 studies include:

Eye Disorders: Blurred vision.

Infections and Infestations: Fungal infection (excludes opportunistic infections).

Musculoskeletal and Connective Tissue Disorders: Arthralgia.

Nervous System Disorders: Neuralgia, peripheral neuropathy, peripheral motor neuropathy, polyneuropathy, syncope.

Vascular Disorders: Flushing.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of OJJAARA. 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.

Immune System Disorders: Hypersensitivity.

Skin and Subcutaneous Tissue Disorders: Erythema multiforme, toxic epidermal necrolysis (TEN).

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