6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere in the labeling:

Ocular Toxicity [see Warnings and Precautions (5.1)]
Hyperphosphatemia and Soft Tissue Mineralization [see Warnings and Precautions (5.2)]

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 pooled safety population described in the WARNINGS AND PRECAUTIONS section reflects exposure to PEMAZYRE at a starting dose of 13.5 mg orally once daily (intermittent or continuous administration) in 635 patients with advanced malignancies. Among the 635 patients, 31% were exposed for 6 months or longer and 11% were exposed greater than one year, including patients with previously treated, advanced, or metastatic cholangiocarcinoma in FIGHT-202 and patients with MLNs with FGFR1 rearrangement in FIGHT-203.

Cholangiocarcinoma

FIGHT-202

The safety of PEMAZYRE was evaluated in FIGHT-202, which included 146 patients with previously treated, locally advanced or metastatic cholangiocarcinoma [see Clinical Studies (14.1)]. Patients were treated orally with PEMAZYRE 13.5 mg once daily for 14 days on followed by 7 days off therapy until disease progression or unacceptable toxicity. The median duration of treatment was 181 days (range: 7 to 730 days).

The median age of PEMAZYRE-treated patients was 59 years (range 26-78), 58% were females, and 71% were White.

Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE. Serious adverse reactions in ≥ 2% of patients who received PEMAZYRE included abdominal pain, pyrexia, cholangitis, pleural effusion, acute kidney injury, cholangitis infective, failure to thrive, hypercalcemia, hyponatremia, small intestinal obstruction, and urinary tract infection. Fatal adverse reactions occurred in 4.1% of patients, including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received PEMAZYRE. Adverse reactions requiring permanent discontinuation in ≥ 1% of patients included intestinal obstruction and acute kidney injury.

Dosage interruptions due to an adverse reaction occurred in 43% of patients who received PEMAZYRE. Adverse reactions requiring dosage interruption in ≥ 1% of patients included stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, fatigue, abdominal pain, AST increased, asthenia, pyrexia, ALT increased, cholangitis, small intestinal obstruction, alkaline phosphatase increased, diarrhea, hyperbilirubinemia, electrocardiogram QT prolonged, decreased appetite, dehydration, hypercalcemia, hyperphosphatemia, hypophosphatemia, back pain, pain in extremity, syncope, acute kidney injury, onychomadesis, and hypotension.

Dose reductions due to an adverse reaction occurred in 14% of patients who received PEMAZYRE. Adverse reactions requiring dosage reductions in ≥ 1% of patients who received PEMAZYRE included stomatitis, arthralgia, palmar-plantar erythrodysesthesia syndrome, asthenia, and onychomadesis.

Table 3 summarizes the adverse reactions in FIGHT-202. Table 4 summarizes laboratory abnormalities in FIGHT-202.

Table 3: Adverse Reactions (≥ 15%) in Patients Receiving PEMAZYRE in FIGHT-202
* Graded per NCI CTCAE 4.03. † Includes hyperphosphatemia and blood phosphorous increased; graded based on clinical severity and medical interventions taken according to the "investigations-other, specify" category in NCI CTCAE v4.03. ‡ Includes hypophosphatemia and blood phosphorous decreased. § Includes nail toxicity, nail disorder, nail discoloration, nail dystrophy, nail hypertrophy, nail ridging, nail infection, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia. ¶ Includes dry eye, keratitis, lacrimation increased, pinguecula, and punctate keratitis.
Adverse Reaction	PEMAZYRE N=146
Adverse Reaction	All Grades* (%)	Grades 3 or 4 (%)
Metabolism and nutrition disorders
Hyperphosphatemia†	60	0
Decreased appetite	33	1.4
Hypophosphatemia‡	23	12
Dehydration	15	3.4
Skin and subcutaneous tissue disorders
Alopecia	49	0
Nail toxicity§	43	2.1
Dry skin	20	0.7
Palmar-plantar erythrodysesthesia syndrome	15	4.1
Gastrointestinal disorders
Diarrhea	47	2.7
Nausea	40	2.1
Constipation	35	0.7
Stomatitis	35	5
Dry mouth	34	0
Vomiting	27	1.4
Abdominal pain	23	4.8
General disorders
Fatigue	42	4.8
Edema peripheral	18	0.7
Nervous system disorders
Dysgeusia	40	0
Headache	16	0
Eye disorders
Dry eye¶	35	0.7
Musculoskeletal and connective tissue disorders
Arthralgia	25	6
Back pain	20	2.7
Pain in extremity	19	2.1
Infections and infestations
Urinary tract infection	16	2.7
Investigations
Weight loss	16	2.1

Clinically relevant adverse reactions occurring in ≤ 10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 0.5% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N=635]). Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic calciphylaxis associated with hyperphosphatemia were observed with PEMAZYRE treatment.

Table 4: Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients Receiving PEMAZYRE in FIGHT-202
* The denominator used to calculate the rate varied from 142-146 based on the number of patients with a baseline value and at least one post-treatment value. † Graded per NCI CTCAE 4.03. ‡ Based on CTCAE 5.0 grading. § Graded based on comparison to upper limit of normal.
	PEMAZYRE* N=146
Laboratory Abnormality	All Grades† (%)	Grades 3 or 4 (%)
Hematology
Decreased hemoglobin	43	6
Decreased lymphocytes	36	8
Decreased platelets	28	3.4
Increased leukocytes	27	0.7
Decreased leukocytes	18	1.4
Chemistry
Increased phosphate‡	94	0
Decreased phosphate	68	38
Increased alanine aminotransferase	43	4.1
Increased aspartate aminotransferase	43	6
Increased calcium	43	4.1
Increased alkaline phosphatase	41	11
Increased creatinine§	41	1.4
Decreased sodium	39	12
Increased glucose	36	0.7
Decreased albumin	34	0
Increased urate	30	10
Increased bilirubin	26	6
Decreased potassium	26	5
Decreased calcium	17	2.7
Increased potassium	12	2.1
Decreased glucose	11	1.4

Increased Creatinine

Within the first 21-day cycle of PEMAZYRE dosing, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the 7 days off therapy. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].

Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement

FIGHT-203

The safety of PEMAZYRE was evaluated in FIGHT-203, which included 34 patients who were treated for MLN with FGFR1 rearrangement [see Clinical Studies (14.2)]. Patients were treated with PEMAZYRE 13.5 mg once daily on a continuous schedule (the approved recommended starting dosage) or for 14 days on followed by 7 days off therapy (an unapproved dosage regimen in MLN with FGFR1 rearrangement) until disease progression, unacceptable toxicity, or they were able to receive allogeneic stem cell transplant. The median duration of treatment was 205 days (range: 30-1347 days).

Serious adverse reactions occurred in 53% of patients receiving PEMAZYRE at all dosages. Serious adverse reactions in > 5% of patients included acute kidney injury. Fatal adverse reactions occurred in 9% of patients who received PEMAZYRE, including acute kidney injury, multiple organ dysfunction syndrome, and malignant neoplasm progression, occurring in one patient each.

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received PEMAZYRE at all dosages. Adverse reactions requiring permanent discontinuation included cardiac failure, multiple organ dysfunction syndrome, blood alkaline phosphatase increase, and calciphylaxis.

In patients who started treatment on the recommended dosage (n = 20), adverse reactions requiring dosage interruption of PEMAZYRE occurred in 80% of patients. Adverse reactions which required dosage interruption in > 2 patients treated at the recommended dosage included nail toxicities (20%) and hyperphosphatemia (15%).

Dose reductions of PEMAZYRE due to an adverse reaction occurred in 80% of patients who started treatment on the recommended dosage. Adverse reactions requiring dose reductions occurring in > 2 patients were nail toxicities (20%), hyperphosphatemia (20%), and alopecia (15%).

The most common (≥ 20%) adverse reactions were hyperphosphatemia, nail toxicity, alopecia, stomatitis, diarrhea, dry eye, fatigue, rash, abdominal pain, anemia, constipation, dry mouth, epistaxis, serous retinal detachment, extremity pain, decreased appetite, dry skin, dyspepsia, back pain, nausea, blurred vision, peripheral edema, and dizziness.

The most common (≥ 20%) laboratory abnormalities were increased phosphate, decreased lymphocytes, decreased leukocytes, increased alkaline phosphatase, decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased neutrophils, increased creatinine, decreased phosphate, decreased sodium, increased glucose, decreased platelets, decreased calcium, increased calcium, decreased potassium, and increased bilirubin.

Table 5 summarizes the adverse reactions in FIGHT-203.

Table 5: Adverse Reactions (≥ 15%) in Patients Receiving PEMAZYRE in FIGHT-203
Adverse Reaction	PEMAZYRE N=34
Adverse Reaction	All Grades* (%)	Grade 3 or 4 (%)
* Graded per NCI CTCAE 4.03. † Includes hyperphosphatemia and blood phosphorous increased; graded based on clinical severity and medical interventions taken according to the "investigations-other, specify" category in NCI CTCAE v4.03. ‡ Includes ingrowing nail, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail growth abnormal, nail infection, nail pigmentation, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia. § Includes dermatitis, dermatitis acneiform, lichen planus, rash, rash macular, and skin exfoliation. ¶ Includes dry skin and xerosis. # Includes palmar erythema, palmar-plantar erythrodysaesthesia, and plantar erythema. Þ Includes aphthous ulcer, cheilitis, lip ulceration, mouth ulceration, pharyngeal inflammation, stomatitis, and tongue ulceration. ß Includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal rigidity. à Includes dry eye, keratitis, lacrimation increased, meibomian gland dysfunction, and punctate keratitis è Includes detachment of retinal pigment epithelium, maculopathy, retinal detachment, retinal disorder, retinal thickening, serous retinal detachment, and subretinal fluid. ð Includes asthenia and fatigue. ø Includes back pain and spinal pain.
Metabolism and nutrition disorders
Hyperphosphatemia†	74	2.9
Decreased appetite	24	6
Skin and subcutaneous tissue disorders
Nail toxicity‡	62	21
Alopecia	59	0
Rash§	35	6
Dry skin¶	24	0
Palmar-plantar erythrodysaesthesia#	18	9
Gastrointestinal disorders
StomatitisÞ	53	15
Diarrhea	50	2.9
Abdominal painß	35	2.9
Constipation	32	2.9
Dry mouth	32	0
Dyspepsia	24	0
Nausea	21	0
Eye disorders
Dry eyeà	50	6
Retinal pigment epithelial detachmentè	26	0
Vision blurred	21	2.9
Trichiasis	18	2.9
General disorders
Fatigueð	44	9
Edema peripheral	21	0
Pyrexia	18	2.9
Blood and lymphatic system disorders
Anemia	35	18
Respiratory, thoracic, and mediastinal disorders
Epistaxis	29	0
Musculoskeletal and connective tissue disorders
Pain in extremity	26	12
Back painø	24	9
Nervous system disorders
Dizziness	21	0

Table 6 summarizes laboratory abnormalities in FIGHT-203.

Table 6: Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in Patients Receiving PEMAZYRE in FIGHT-203
* The denominator used to calculate the rate varied from 31 to 34 based on the number of patients with a baseline value and at least one post-treatment value. † Graded per NCI CTCAE 4.03. ‡ Graded per NCI CTCAE 5.0. § Based on comparison to upper limit of normal.
Laboratory Abnormality	PEMAZYRE N=34*
Laboratory Abnormality	All Grades† (%)	Grade 3 or 4 (%)
Hematology
Decreased lymphocytes	65	16
Decreased leukocytes	65	15
Decreased hemoglobin	53	9
Decreased neutrophils	45	12
Decreased platelets	29	15
Chemistry
Increased phosphate‡	97	2.9
Increased alkaline phosphatase	62	9
Increased alanine aminotransferase	50	12
Increased aspartate aminotransferase	47	9
Increased creatinine§	44	0
Decreased phosphate	41	26
Decreased sodium	41	9
Increased glucose	33	3
Decreased calcium	26	2.9
Increased calcium	26	2.9
Decreased potassium	24	2.9
Increased bilirubin	21	0

Other clinically significant laboratory abnormalities: Prothrombin time/international normalized ratio was elevated in 16% (Grade 1 or 2 elevation) of patients. Uric acid was elevated in 18% of patients, including 2.9% with a Grade 3 or 4 elevation.