PEMIGATINIB: 709 Adverse Event Reports & Safety Profile

Pemigatinib is a kinase inhibitor with the chemical name 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2 H -pyrrolo[3',2':5,6]pyrido[4,3- d ]pyrimidin-2-one. Pemigatinib has a molecular formula of C 24 H 27 F 2 N 5 O 4 and molecular mass of 487.5 g/mole. Pemigatinib has the following chemical structure: Pemigatinib is a white to off-white solid that is not hygroscopic. The solubility of pemigatinib is pH dependent with decreasing solubility observed with increasing pH. PEMAZYRE tablets are uncoated and for oral administration. Tablets are available containing 4.5 mg, 9 mg, or 13.5 mg of pemigatinib active ingredient. The inactive ingredients include magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

Chemical

Structure

AND USAGE PEMAZYRE is a kinase inhibitor indicated: for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test. ( 1 , 2.1 ) This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 , 2.1 ) For the treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement. ( 1 , 2.1 )

1.1 Cholangiocarcinoma PEMAZYRE is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span> . This indication is approved under accelerated approval based on overall response rate and duration of response <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span>. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

1.2 Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement PEMAZYRE is indicated for the treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.

AND ADMINISTRATION Cholangiocarcinoma: Confirm the presence of an FGFR2 fusion or rearrangement prior to initiation of treatment with PEMAZYRE. ( 2.1 ) Recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles. Continue treatment until disease progression or unacceptable toxicity occurs. ( 2.2 ) Myeloid/lymphoid neoplasms with FGFR1 rearrangement: Recommended dosage is 13.5 mg orally once daily. Continue treatment until disease progression or unacceptable toxicity. ( 2.2 ) All patients treated with PEMAZYRE: Swallow tablet whole, with or without food. ( 2.2 )

Severe Renal

Impairment: the recommended dosage of PEMAZYRE is 9 mg with the schedule (intermittent or continuous) designated for the indication. ( 2.5 , 8.6 , 12.3 )

Severe Hepatic

Impairment: the recommended dosage of PEMAZYRE is 9 mg with the schedule (intermittent or continuous) designated for the indication. ( 2.6 , 8.7 , 12.3 )

2.1 Patient Selection Select patients for the treatment of locally advanced or metastatic cholangiocarcinoma with PEMAZYRE based on the presence of an FGFR2 fusion or rearrangement as detected by an FDA-approved test <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span>. Information on FDA-approved test(s) for the detection of an FGFR2 fusion or rearrangement in cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics . Select patients for the treatment of relapsed or refractory myeloid/lymphoid neoplasms with FGFR1 rearrangement with PEMAZYRE based on the presence of an FGFR1 rearrangement <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span> . An FDA-approved test for detection of FGFR1 rearrangement in patients with relapsed or refractory myeloid/lymphoid neoplasm for selecting patients for treatment with PEMAZYRE is not available.

2.2 Recommended Dosage Take PEMAZYRE with or without food at approximately the same time every day <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Swallow tablets whole. Do not crush, chew, split, or dissolve tablets. If the patient misses a dose of PEMAZYRE by 4 or more hours or if vomiting occurs, resume dosing with the next scheduled dose.

Cholangiocarcinoma

The recommended dosage of PEMAZYRE is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy, in 21-day cycles. Continue treatment until disease progression or unacceptable toxicity occurs.

Myeloid/Lymphoid

Neoplasms with FGFR1 Rearrangement The recommended dosage of PEMAZYRE is 13.5 mg orally once daily on a continuous basis. Continue treatment until disease progression or unacceptable toxicity occurs.

2.3 Dosage Modification for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 1.

Table

1: Recommended Dose Reductions for PEMAZYRE for Adverse Reactions Dose Reduction Recommended Dosage Cholangiocarcinoma with FGFR2 Fusion or Rearrangement MLNs with FGFR1 Rearrangement First 9 mg once daily for first 14 days of each 21-day cycle 9 mg once daily Second 4.5 mg once daily for first 14 days of each 21-day cycle 4.5 mg once daily Third Discontinue 4.5 mg once daily for first 14 days of each 21-day cycle Permanently discontinue PEMAZYRE if unable to tolerate 4.5 mg once daily for 14 days of each 21-day cycle. The recommended dosage modifications for adverse reactions are provided in Table 2.

Table

2: Recommended Dosage Modifications for PEMAZYRE Adverse Reactions Adverse Reaction Severity Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Pemazyre

Dosage Modification Retinal Pigment Epithelial Detachment (RPED) [see Warnings and Precautions ( 5.1 )]

Rped

If asymptomatic and stable on serial examination, continue PEMAZYRE. If symptomatic or worsening on serial examination, withhold PEMAZYRE. If asymptomatic and improved on subsequent examination, resume PEMAZYRE at a lower dose If symptoms persist or examination does not improve, consider permanent discontinuation of PEMAZYRE, based on clinical status. Hyperphosphatemia [see Warnings and Precautions ( 5.2 )] Serum phosphate > 7 mg/dL to ≤ 10 mg/dL Initiate phosphate lowering therapy and monitor serum phosphate weekly. Withhold PEMAZYRE if levels are not < 7 mg/dL within 2 weeks of starting phosphate lowering therapy. Resume PEMAZYRE at the same dose when phosphate levels are < 7 mg/dL for first occurrence; resume at a lower dose level for subsequent recurrences. Serum phosphate >10 mg/dL Initiate phosphate lowering therapy and monitor serum phosphate weekly. Withhold PEMAZYRE if levels are not ≤ 10 mg/dL within 1 week after starting phosphate lowering therapy. Resume PEMAZYRE at the next lower dose level when phosphate levels are < 7 mg/dL. Permanently discontinue PEMAZYRE for recurrence of serum phosphate > 10 mg/dL following 2 dose reductions.

Other Adverse Reactions Grade

3 Withhold PEMAZYRE until resolves to Grade 1 or baseline. Resume PEMAZYRE at next lower dose if resolves within 2 weeks. Permanently discontinue PEMAZYRE if does not resolve within 2 weeks. Permanently discontinue PEMAZYRE for recurrent Grade 3 after 2 dose reductions.

Grade

4 Permanently discontinue PEMAZYRE.

2.4 Dosage Modification for Concomitant Use with Strong or Moderate CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. If concomitant use with a strong or moderate CYP3A inhibitor cannot be avoided: Reduce PEMAZYRE dosage from 13.5 mg to 9 mg. Reduce PEMAZYRE dosage from 9 mg to 4.5 mg. If concomitant use of a strong or moderate CYP3A inhibitor is discontinued, increase the PEMAZYRE dosage (after 3 plasma half-lives of the CYP3A inhibitor) to the dosage that was used before starting the strong or moderate inhibitor <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

2.5 Recommended Dosage for Severe Renal Impairment The recommended dosage of PEMAZYRE for patients with severe renal impairment (eGFR estimated by Modification of Diet in Renal Disease [MDRD] 15 mL/min/1.73 m 2 to 29 mL/min/1.73 m 2 ) is 9 mg with the schedule (intermittent or continuous) designated for the indication <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span> .

2.6 Recommended Dosage for Severe Hepatic Impairment The recommended dosage of PEMAZYRE for patients with severe hepatic impairment (total bilirubin &gt; 3 × ULN with any AST) is 9 mg with the schedule (intermittent or continuous) designated for the indication <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )]</span> .

None. None. ( 4 )

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 )] Cholangiocarcinoma: The most common adverse reactions (incidence ≥ 20%) are hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. ( 6.1 ) Myeloid/lymphoid neoplasms with FGFR1 rearrangement: The most common (≥ 20%) adverse reactions are 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Incyte Corporation at 1-855-463-3463 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span>. 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 Adverse Reaction PEMAZYRE N=146 All Grades Graded per NCI CTCAE 4.03. (%)

Grades

3 or 4 (%) Metabolism and nutrition disorders Hyperphosphatemia 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. 60 0 Decreased appetite 33

1.4 Hypophosphatemia Includes hypophosphatemia and blood phosphorous decreased. 23 12 Dehydration 15

3.4 Skin and subcutaneous tissue disorders Alopecia 49 0 Nail toxicity Includes nail toxicity, nail disorder, nail discoloration, nail dystrophy, nail hypertrophy, nail ridging, nail infection, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia. 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 Includes dry eye, keratitis, lacrimation increased, pinguecula, and punctate keratitis. 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 PEMAZYRE 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. N=146 Laboratory Abnormality All Grades Graded per NCI CTCAE 4.03. (%)

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 Based on CTCAE 5.0 grading. 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 Graded based on comparison to upper limit of normal. 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

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 All Grades Graded per NCI CTCAE 4.03. (%)

Grade

3 or 4 (%) Metabolism and nutrition disorders Hyperphosphatemia 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. 74

2.9 Decreased appetite 24 6 Skin and subcutaneous tissue disorders Nail toxicity 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. 62 21 Alopecia 59 0 Rash Includes dermatitis, dermatitis acneiform, lichen planus, rash, rash macular, and skin exfoliation. 35 6 Dry skin Includes dry skin and xerosis. 24 0 Palmar-plantar erythrodysaesthesia Includes palmar erythema, palmar-plantar erythrodysaesthesia, and plantar erythema. 18 9 Gastrointestinal disorders Stomatitis Includes aphthous ulcer, cheilitis, lip ulceration, mouth ulceration, pharyngeal inflammation, stomatitis, and tongue ulceration. 53 15 Diarrhea 50

2.9 Abdominal pain Includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal rigidity. 35

2.9 Constipation 32

2.9 Dry mouth 32 0 Dyspepsia 24 0 Nausea 21 0 Eye disorders Dry eye Includes dry eye, keratitis, lacrimation increased, meibomian gland dysfunction, and punctate keratitis 50 6 Retinal pigment epithelial detachment Includes detachment of retinal pigment epithelium, maculopathy, retinal detachment, retinal disorder, retinal thickening, serous retinal detachment, and subretinal fluid. 26 0 Vision blurred 21

2.9 Trichiasis 18

2.9 General disorders Fatigue Includes asthenia and fatigue. 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 pain Includes back pain and spinal pain. 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 Laboratory Abnormality PEMAZYRE N=34 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.

All Grades

Graded per NCI CTCAE 4.03. (%)

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 Graded per NCI CTCAE 5.0. 97

2.9 Increased alkaline phosphatase 62 9 Increased alanine aminotransferase 50 12 Increased aspartate aminotransferase 47 9 Increased creatinine Based on comparison to upper limit of normal. 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.

AND PRECAUTIONS Ocular Toxicity : PEMAZYRE can cause retinal pigment epithelial detachment. Perform ophthalmological examination including optical coherence tomography (OCT) prior to initiation of therapy, every 2 months for the first 6 months of treatment and every 3 months thereafter, and urgently at any time for visual symptoms. ( 2.3 , 5.1 ) Hyperphosphatemia and Soft Tissue Mineralization : PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Monitor for hyperphosphatemia and withhold, reduce the dose, or permanently discontinue based on duration and severity of hyperphosphatemia. ( 2.3 , 5.2 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to the fetus and use effective contraception. ( 5.3 , 8.1 , 8.3 )

5.1 Ocular Toxicity Retinal Pigment Epithelial Detachment (RPED) PEMAZYRE can cause RPED, which may cause symptoms such as blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE did not conduct routine monitoring including optical coherence tomography (OCT) to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.

Among

635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, RPED occurred in 11% of patients, including Grade 3-4 RPED in 1.3%. The median time to first onset of RPED was 56 days. RPED led to dose interruption of PEMAZYRE in 3.1% of patients, and dose reduction and permanent discontinuation in 1.3% and in 0.2% of patients, respectively. RPED resolved or improved to Grade 1 levels in 76% of patients who required dosage modification of PEMAZYRE for RPED. Perform a comprehensive ophthalmological examination including OCT prior to initiation of PEMAZYRE and every 2 months for the first 6 months and every 3 months thereafter during treatment. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of PEMAZYRE. Modify the dose or permanently discontinue PEMAZYRE as recommended [see Dosage and Administration ( 2.3 )] .

Dry Eye Among

635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, dry eye occurred in 31% of patients, including Grade 3-4 in 1.6% of patients. Treat patients with ocular demulcents as needed.

5.2 Hyperphosphatemia and Soft Tissue Mineralization PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Increases in phosphate levels are a pharmacodynamic effect of PEMAZYRE <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> .

Among

635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, hyperphosphatemia was reported in 93% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 8 days (range 1-169). Phosphate lowering therapy was required in 33% of patients receiving PEMAZYRE. Monitor for hyperphosphatemia and initiate a low phosphate diet when serum phosphate level is > 5.5 mg/dL. For serum phosphate levels > 7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia [see Dosage and Administration ( 2.3 )].

5.3 Embryo-Fetal Toxicity Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm when administered to a pregnant woman. Oral administration of pemigatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 13.5 mg. Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

INTERACTIONS Strong and Moderate CYP3A Inducers: Avoid concomitant use of PEMAZYRE. ( 7.1 ) Strong and Moderate CYP3A Inhibitors: Avoid concomitant use. If concomitant use cannot be avoided, reduce PEMAZYRE dosage. ( 2.4 , 7.1 )

7.1 Effect of Other Drugs on PEMAZYRE Strong and Moderate CYP3A Inducers Concomitant use of PEMAZYRE with a strong or moderate CYP3A inducer decreases pemigatinib plasma concentrations [ see Clinical Pharmacology ( 12.3 )], which may reduce the efficacy of PEMAZYRE. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE. Strong and Moderate CYP3A Inhibitors Concomitant use of a strong or moderate CYP3A inhibitor with PEMAZYRE increases pemigatinib plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>, which may increase the incidence and severity of adverse reactions. Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce PEMAZYRE dosage if concomitant use of strong and moderate CYP3A inhibitors cannot be avoided <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> .