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The safety of PEMAZYRE was evaluated in
FIGHT-2031

The safety of PEMAZYRE was evaluated in 34 patients who were treated for MLN with FGFR1 rearrangement. Patients were treated with PEMAZYRE 13.5 mg once daily on a continuous schedule (the approved recommended dosing schedule) or for 14 days on followed by 7 days off therapy (an unapproved dosing 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).1

  • 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.
  • 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) dosage interruptions and reductions occurred in 80% of patients.

Adverse reactions (≥15%) in patients receiving PEMAZYRE in FIGHT-2031

PEMAZYRE N=34
Adverse Reactions
N=34
All Gradesa,%
N=34
Grade 3 or 4, %
Metabolism and nutrition disorders
 
Hyperphosphatemiab
74
2.9
Decreased appetite
24
6
Skin and subcutaneous tissue disorders
 
Nail toxicityc
62
21
Alopecia
59
0
Rashd
35
6
Dry skine
24
0
Palmar-plantar
erythrodysaesthesiaf
18
9
Gastrointestinal disorders
 
Stomatitisg
53
15
Diarrhea
50
2.9
Abdominal painh
35
2.9
Constipation
32
2.9
Dry mouth
32
0
Dyspepsia
24
0
Nausea
21
0
Eye disorders
 
Dry eyei
50
6
Retinal pigment epithelial
detachmentj
26
0
Vision blurred
21
2.9
Trichiasis
18
2.9
General disorders
 
Fatiguek
44
9
Edema peripheral
21
0
Pyrexia
18
2.9
Blood and lymphatic disorders
 
Anemia
35
18
Respiratory, thoracic, and mediastinal disorders
 
Epistaxis
29
0
Musculoskeletal and connective tissue disorders
 
Pain in extremity
26
12
Back painl
24
9
Nervous system disorders
 
Dizziness
21
0

aGraded per NCI CTCAE 4.03.

bIncludes 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.

cIncludes 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.

dIncludes dermatitis, dermatitis acneiform, lichen planus, rash, rash macular, and skin exfoliation.

eIncludes dry skin and xerosis.

fIncludes palmar-erythemia, palmer-plantar erythrodysaesthesia, and plantar erythema.

gIncludes aphthous ulcer, cheilitis, lip ulceration, mouth ulceration, pharyngeal inflammation, stomatitis, and tongue ulceration.

hIncludes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal rigidity.

iIncludes dry eye, keratitis, lacrimation increased, meibomian gland dysfunction, and punctate keratitis.

jIncludes detachment of retinal pigment epithelium, maculopathy, retinal detachment, retinal disorder, retinal thickening, serous retinal detachment, and subretinal fluid.

kIncludes asthenia and fatigue.

lIncludes back pain and spinal pain.

Select laboratory abnormalities (≥20%) worsening from baseline in patients receiving PEMAZYRE in FIGHT-2031

PEMAZYRE N=34a
Laboratory Abnormality
N=34
All Gradesb,%
N=34
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 phosphatec
97
2.9
Increased alkaline phosphatase
62
9
Increased alanine aminotransferase
50
12
Increased aspartate aminotransferase
47
9
Increased creatinined
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

aThe 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.

bGraded per NCI CTCAE 4.03.

cGraded per NCI CTCAE 5.0.

dBased on comparison to upper limit of normal.

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.

RPED was observed in patients treated with PEMAZYRE

Advise patients to inform you of any vision changes while taking PEMAZYRE1

PEMAZYRE can cause retinal pigment epithelial detachment (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.1

  • 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%1
    • The median time to first onset of RPED was 56 days
    • RPED led to dose interruption of PEMAZYRE in 3.1% of patients
    • 1.3% of patients required dose reduction for RPED
    • 0.2% of patients discontinued treatment due to RPED
    • RPED resolved or improved to Grade 1 levels in 76% of patients who required dosage modification 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.

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.1

When to perform a comprehensive ophthalmological examination, including OCT1

Image showing when to perform an ophthalmological examination Image showing when to perform an ophthalmological examination

Dosage modifications for RPED1

  • 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 was observed in patients treated with PEMAZYRE1

  • 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
  • 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

Recommendations for management of hyperphosphatemia1

Monitor for hyperphosphatemia.

  • 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

Dose modifications for hyperphosphatemia1

Severity
PEMAZYRE Dosage Modification

Serum phosphate
>7 mg/dL -
≤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

Potential for embryo-fetal toxicity

Embryo-fetal toxicity1

  • 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 malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve at the clinical dose of 13.5 mg

Advise patients of potential risks1

Pregnant women

Advise pregnant women of the potential risk to the fetus.

Female patients

Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.

Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of pregnancy.

Advise patients not to breastfeed during treatment with PEMAZYRE and for 1 week after the last dose.

Male patients

Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.

References:

1. PEMAZYRE Prescribing Information. Incyte Corporation. 2. DOF.

INDICATIONS AND USAGE

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

IMPORTANT SAFETY INFORMATION

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 in the prescribing information for PEMAZYRE.

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.

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. 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 as recommended in the prescribing information.

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.

Adverse Reactions: Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement

Serious adverse reactions occurred in 53% of patients receiving PEMAZYRE at all dosages (n=34). 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%).

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.

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.

The most common (≥ 20%) adverse reactions were hyperphosphatemia (74%), nail toxicity (62%), alopecia (59%), stomatitis (53%), diarrhea (50%), dry eye (50%), fatigue (44%), rash (35%), abdominal pain (35%), anemia (35%), constipation (32%), dry mouth (32%), epistaxis (29%), retinal pigment epithelial detachment (26%), extremity pain (26%), decreased appetite (24%), dry skin (24%), dyspepsia (24%), back pain (24%), nausea (21%), blurred vision (21%), peripheral edema (21%), and dizziness (21%).

Drug Interactions

Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce the dose of PEMAZYRE if concomitant use with a strong or moderate CYP3A inhibitor cannot be avoided. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE.

Special Populations

Advise lactating women not to breastfeed during treatment with PEMAZYRE and for 1 week after the last dose.

Reduce the recommended dose of PEMAZYRE for patients with severe renal impairment as described in the prescribing information.

Reduce the recommended dose of PEMAZYRE for patients with severe hepatic impairment as described in the prescribing information.

INDICATIONS AND USAGE

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