6 ADVERSE REACTIONS

The following clinically significant adverse reactions have been associated with SYNRIBO in clinical trials and are discussed in greater detail in other sections of the label.

Myelosuppression [see Warnings and Precautions (5.1)]
Bleeding [see Warnings and Precautions (5.2)]
Hyperglycemia [see Warnings and Precautions (5.3)]

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.

The safety data for SYNRIBO are from 3 clinical trials which enrolled a total of 163 adult patients with TKI resistant and/or intolerant chronic phase (N=108) and accelerated phase (N=55) CML. All patients were treated with initial induction therapy consisting of a dose of 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and a twice daily schedule for 7 consecutive days every 28 days (maintenance cycle).

Chronic Phase CML

The median duration of exposure for the 108 patients with chronic phase CML was 7.4 months (range 0 to 43 months). The median total cycles of exposure was 6 (range 1 to 41), and the median total dose delivered during the trials was 131 mg/m2 (range 1.2 to 678). Among the patients with chronic phase CML, 87% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 42% and 16% respectively. Of the 91 patients who received at least 2 cycles of treatment, 79 (87%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 2 (17 days) and cycle 3 (25 days) when more patients were receiving induction cycles.

Adverse reactions were reported for 99% of the patients with chronic phase CML. A total of 18% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to discontinuation were pancytopenia, thrombocytopenia, and increased alanine aminotransferase (each 2%). A total of 87% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction (Table 2).

Table 2: Adverse Reactions Occurringa in at Least 10% of Patients (Chronic Myeloid Leukemia – Chronic Phase)
	Number (%) of Patients (N=108)
Adverse reactions	All reactions	Grade 3 or 4 reactions
Patients with at least 1 commonly occurring adverse reaction	107 (99)	94 (87)
Blood and Lymphatic System Disorders
Thrombocytopenia	82 (76)	73 (68)
Anemia	66 (61)	39 (36)
Neutropenia	57 (53)	51 (47)
Lymphopenia	18 (17)	17 (16)
Bone Marrow Failure	11 (10)	11 (10)
Febrile Neutropenia	11 (10)	11 (10)
Gastrointestinal Disorders
Diarrhea	44 (41)	1 (1)
Nausea	38 (35)	1 (1)
Constipation	15 (14)	0
Abdominal Pain/Upper Abdominal Pain	25 (23)	0
Vomiting	13 (12)	0
General Disorders and Administration Site Conditions
Fatigue	31 (29)	5 (5)
Pyrexia	27 (25)	1 (1)
Asthenia	25 (23)	1 (1)
Edema Peripheral	17 (16)	0
Infusion and injection site related reactionsb	38 (35)	0
Infections and Infestationsc	52 (48)	12 (11)
Metabolism and Nutrition Disorders
Anorexia	11 (10)	1 (1)
Musculoskeletal and Connective Tissue Disorders
Arthralgia	20 (19)	1 (1)
Pain in Extremity	14 (13)	1 (1)
Back Pain	13 (12)	2 (2)
Myalgia	12 (11)	1 (1)
Nervous System Disorders
Headache	22 (20)	1 (1)
Psychiatric Disorders
Insomnia	13 (12)	1 (1)
Respiratory, Thoracic and Mediastinal Disorders
Cough	17 (16)	1 (1)
Epistaxis	18 (17)	1 (1)
Skin and Subcutaneous Tissue Disorders
Alopecia	16 (15)	0
Rash	12 (11)	0

a Occurred in the period between the first dose and 30 days after the last dose.

b Includes infusion related reaction, injection site erythema, injection site hematoma, injection site hemorrhage, injection site hypersensitivity, injection site induration, injection site inflammation, injection site irritation, injection site mass, injection site edema, injection site pruritus, injection site rash, and injection site reaction.

c Infection includes bacterial, viral, fungal, and non-specified.

Serious adverse reactions were reported for 51% of patients. Serious adverse reactions reported for at least 5% of patients were bone marrow failure and thrombocytopenia (each 10%), and febrile neutropenia (6%). Serious adverse reactions of infections were reported for 8% of patients.

Deaths occurred while on study in five (5%) patients with CP CML. Two patients died due to cerebral hemorrhage, one due to multi-organ failure, one due to progression of disease, and one from unknown causes.

Accelerated Phase CML

Median total cycles of exposure was 2 (range 1 to 29), and the median total dose delivered during the trials was 70 mg/m2. The median duration of exposure for the 55 patients with accelerated phase CML was 1.9 months (range 0 to 30 months). Of the patients with accelerated phase CML, 86% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 55% and 44% respectively. Of the 40 patients who received at least 2 cycles of treatment, 27 (68%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 3 (31 days) and cycle 8 (36 days).

Adverse reactions regardless of investigator attribution were reported for 100% patients with accelerated phase CML. A total of 33% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to withdrawal were leukocytosis (6%), and thrombocytopenia (4%). A total of 84% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction (Table 3).

Table 3: Adverse Reactions Occurringa in at Least 10% of Patients (Chronic Myeloid Leukemia – Accelerated Phase)
	Number (%) of Patients (N=55)
Adverse reactions	All reactions	Grade 3 or 4 reactions
Patients with at least 1 commonly occurring adverse reaction	55 (100)	47 (86)
Blood and Lymphatic System Disorders
Anemia	28 (51)	21 (38)
Febrile Neutropenia	11 (20)	9 (16)
Neutropenia	11 (20)	10 (18)
Thrombocytopenia	32 (58)	27 (49)
Gastrointestinal Disorders
Diarrhea	19 (35)	4 (7)
Nausea	16 (29)	2 (4)
Vomiting	9 (16)	1 (2)
Abdominal Pain/Upper Abdominal Pain	9 (16)	0
General Disorders and Administration Site Conditions
Fatigue	17 (31)	5 (9)
Pyrexia	16 (29)	1 (2)
Asthenia	13 (24)	1 (2)
Chills	7 (13)	0
Infusion and injection site related reactionsb	12 (22)	0
Infections and Infestationsc	31 (56)	11 (20)
Metabolism and Nutrition Disorders
Anorexia	7 (13)	1 (2)
Musculoskeletal and Connective Tissue Disorders
Pain in Extremity	6 (11)	1 (2)
Nervous System Disorders
Headache	7 (13)	0
Respiratory, Thoracic and Mediastinal Disorders
Cough	8 (15)	0
Dyspnea	6 (11)	1 (2)
Epistaxis	6 (11)	1 (2)

a Occurred in the period between the first dose and 30 days after the last dose.

b Includes infusion related reaction, injection site erythema, injection site hematoma, injection site hemorrhage, injection site hypersensitivity, injection site induration, injection site inflammation, injection site irritation, injection site mass, injection site edema, injection site pruritus, injection site rash, and injection site reaction.

c Infection includes bacterial, viral, fungal, and non-specified.

Serious adverse reactions were reported for 60% of patients. Serious adverse reactions reported for at least 5% of patients were febrile neutropenia (18%), thrombocytopenia (9%), anemia (7%), and diarrhea (6%). Serious adverse reactions of infections were reported for 11% of patients.

Death occurred while on study in 5 (9%) patients with AP CML. Two patients died due to cerebral hemorrhage and three due to progression of disease.

Laboratory Abnormalities in Chronic and Accelerated Phase CML

Grade 3/4 laboratory abnormalities reported in patients with chronic and accelerated phase CML are described in Table 4. Myelosuppression occurred in all patients treated with SYNRIBO [see Warnings and Precautions (5.1)]. Five patients with chronic phase CML and 4 patients with accelerated phase CML permanently discontinued SYNRIBO due to pancytopenia, thrombocytopenia, febrile neutropenia, or bone marrow necrosis. An event of hyperosmolar non-ketotic hyperglycemia was reported in one patient in the safety population and a similar case has been reported in the literature. Two patients with chronic phase CML permanently discontinued SYNRIBO due to elevated transaminases.

Table 4: Grade 3/4 Laboratory Abnormalities in Clinical Studies in Patients with Chronic Phase and Accelerated Phase CML
	Chronic Phase	Accelerated Phase
	%	%
Hematology Parameters
Hemoglobin Decreased	62	80
Leukocytes Decreased	72	61
Neutrophils Decreased	81	71
Platelets Decreased	85	88
Biochemistry Parameters
Alanine aminotransferase (ALT) Increased	6	2
Bilirubin Increased Creatinine Increased	9	6
Bilirubin Increased Creatinine Increased	9	16
Glucose Increased	10	15
Uric Acid Increased	56	57
Glucose Decreased	8	6

6.2 Additional Data from Safety Population

The following adverse reactions were reported in patients in the SYNRIBO clinical studies of patients with chronic phase and accelerated phase CML at a frequency of 1% to less than 10%. Within each category, adverse reactions are ranked on the basis of frequency.

Cardiac Disorders: tachycardia, palpitations, acute coronary syndrome, angina pectoris, arrhythmia, bradycardia, ventricular extrasystoles.

Ear and Labyrinth Disorders: ear pain, ear hemorrhage, tinnitus.

Eye Disorders: cataract, vision blurred, conjunctival hemorrhage, dry eye, lacrimation increased, conjunctivitis, diplopia, eye pain, eyelid edema.

Gastrointestinal Disorders: stomatitis, mouth ulceration, abdominal distension, dyspepsia, gastroesophageal reflux disease, gingival bleeding, aphthous stomatitis, dry mouth, hemorrhoids, gastritis, gastrointestinal hemorrhage, melena, mouth hemorrhage, oral pain, anal fissure, dysphagia, gingival pain, gingivitis.

General Disorders and Administration Site Conditions: mucosal inflammation, pain, chest pain, hyperthermia, influenza-like illness, catheter site pain, general edema, malaise.

Immune System Disorders: hypersensitivity.

Injury, Poisoning and Procedural Complications: contusion, transfusion reaction.

Metabolism and Nutrition Disorders: decreased appetite, diabetes mellitus, gout, dehydration.

Musculoskeletal and Connective Tissue Disorders: bone pain, myalgia, muscular weakness, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, musculoskeletal discomfort.

Nervous System Disorders: dizziness, cerebral hemorrhage, paresthesia, convulsion, hypoesthesia, lethargy, sciatica, burning sensation, dysgeusia, tremor.

Psychiatric Disorders: anxiety, depression, agitation, confusional state, mental status change.

Renal and Urinary Disorders: dysuria.

Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, nasal congestion, dysphonia, productive cough, rales, rhinorrhea, hemoptysis, sinus congestion.

Skin and Subcutaneous Tissue Disorders: erythema, pruritus, dry skin, petechiae, hyperhidrosis, night sweats, ecchymosis, purpura, skin lesion, skin ulcer, rash erythematous, rash papular, skin exfoliation, skin hyperpigmentation.

Vascular Disorders: hematoma, hypertension, hot flush, hypotension.