KOSELUGO (Page 4 of 9)

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 data in the WARNINGS AND PRECAUTIONS reflects exposure to KOSELUGO in 74 pediatric patients who received a dosage ranging from 20 mg/m2 to 30 mg/m2 orally twice daily in SPRINT. Among these patients, the duration of KOSELUGO exposure, including dose interruptions, was 12 months or longer (91%), more than 2 years (74%), or more than 4 years (23%). The WARNINGS AND PRECAUTIONS also includes additional data from adult and pediatric patients who received KOSELUGO administered at various doses across a range of tumors in other clinical trials.

Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN)

The safety of KOSELUGO was evaluated in SPRINT Phase II Stratum 1 [see Clinical Studies (14)]. Eligible patients were 2-18 years of age with NF1 who had inoperable PN that was causing significant morbidity. Patients were excluded for abnormal LVEF, uncontrolled hypertension (blood pressure > the 95th percentile for age, height, and sex), any current or past history of RVO or RPED, intraocular pressure > 21 mmHg (or upper limit of normal adjusted by age), uncontrolled glaucoma, and inability to swallow whole capsules. Patients received KOSELUGO 25 mg/m2 orally twice daily (n=50). Among these patients, 88% were exposed for 12 months or longer and 66% were exposed for greater than 2 years.

Serious adverse reactions occurred in 24% of patients who received KOSELUGO. Serious adverse reactions that occurred in 2 or more patients were anemia, hypoxia and diarrhea.

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received KOSELUGO. Adverse reactions resulting in permanent discontinuation of KOSELUGO included increased blood creatinine, increased weight, diarrhea, paronychia, malignant peripheral nerve sheath tumor, acute kidney injury, and skin ulcer.

Dosage interruptions and dose reductions due to adverse reactions occurred in 80% and 24% of patients who received KOSELUGO, respectively. Adverse reactions requiring a dosage interruption or reduction in ≥ 5% of patients were vomiting, paronychia, diarrhea, nausea, abdominal pain, rash, skin infection, influenza-like illness, pyrexia and weight gain.

The most common adverse reactions (≥ 40%) were vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.

Table 6 presents the adverse reactions in SPRINT Phase II Stratum 1.

Table 6 Adverse Reactions (≥ 20%) in Patients Who Received KOSELUGO in SPRINT Phase II Stratum 1
*
Abdominal pain includes abdominal pain; abdominal pain upper
Stomatitis includes stomatitis; mouth ulceration
Rash (all) includes dermatitis acneiform; rash maculo-papular; erythema; rash pustular; rash; urticaria; exfoliative rash; rash pruritic; rash erythematous
§
Rash (acneiform) includes dermatitis acneiform
Paronychia includes paronychia; nail infection
#
Dermatitis includes dermatitis; dermatitis atopic; dermatitis diaper; eczema; seborrheic dermatitis; skin irritation
Þ
Hair changes include alopecia; hair color change
ß
Musculoskeletal pain includes pain in extremity; back pain; neck pain; musculoskeletal pain
à
Fatigue includes fatigue; malaise
è
Edema includes peripheral swelling; edema; localized edema
ð
Skin infection includes skin infection; abscess; cellulitis; impetigo; staphylococcal skin infection

Adverse Reaction

KOSELUGO

N=50

All Grades

(%)

Grade ≥ 3

(%) *

Gastrointestinal

Vomiting

82

6

Abdominal pain *

76

0

Diarrhea

70

16

Nausea

66

2

Stomatitis

50

0

Constipation

34

0

Skin and Subcutaneous Tissue

Rash (all)

80

6

Dry skin

60

0

Rash acneiform §

50

4

Paronychia

48

6

Pruritus

46

0

Dermatitis #

36

4

Hair changes Þ

32

0

Musculoskeletal and Connective Tissue

Musculoskeletal pain ß

58

0

General

Fatigue à

56

0

Pyrexia

56

8

Edema è

20

0

Nervous System

Headache

48

2

Respiratory, Thoracic and Mediastinal

Epistaxis

28

0

Renal and Urinary System

Hematuria

22

2

Proteinuria

22

0

Metabolism and Nutrition

Decreased appetite

22

0

Cardiac System

Decreased ejection fraction

22

0

Sinus tachycardia

20

0

Infections

Skin infection ð

20

2

* All events were Grade 3.

Clinically relevant adverse reactions that occurred < 20% of patients include:

Eye: visual impairment
Gastrointestinal Disorders: dry mouth
General Disorders: facial edema, including periorbital edema and face edema
Metabolism and Nutrition: increased weight
Renal and Urinary System: acute kidney injury
Respiratory, Thoracic & Mediastinal: dyspnea, including exertional dyspnea and dyspnea at rest
Vascular: hypertension

Table 7 presents the laboratory abnormalities in SPRINT Phase II Stratum 1.

Table 7 Select Laboratory Abnormalities (≥ 15%) Worsening from Baseline in Patients Who Received KOSELUGO in SPRINT Phase II Stratum 1
*
The denominator used to calculate the rate varied from 39 to 49 based on the number of patients with a baseline value and at least one post-treatment value.
Includes one Grade 4 increased CPK and one Grade 4 increased potassium.

Laboratory Abnormality

KOSELUGO

All Grades (%) *

Grade ≥ 3 (%)

Chemistry

Increased creatine phosphokinase (CPK)

79

7

Decreased albumin

51

0

Increased aspartate aminotransferase (AST)

41

2

Increased alanine aminotransferase (ALT)

35

4

Increased lipase

32

5

Increased potassium

27

4

Decreased potassium

18

2§

Increased alkaline phosphatase

18

0

Increased amylase

18

0

Increased sodium

18

0

Decreased sodium

16

0

Hematology

Decreased hemoglobin

41

4

Decreased neutrophils

33

4

Decreased lymphocytes

20

2

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