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The safety of PEMAZYRE (pemigatinib) was evaluated in FIGHT 2021

The safety of PEMAZYRE was evaluated in 146 adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma. Patients were treated orally with PEMAZYRE 13.5 mg once daily for 14 days on followed by 7 days off therapy in 21-day cycles until disease progression or unacceptable toxicity. The median duration of treatment was 181 days (range: 7 to 730 days).

  • The most common adverse reactions (incidence ≥20%) were 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.
  • 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.

Adverse reactions leading to permanent discontinuation
occurred in 9% of patients1

Adverse reactions ≥15% in patients receiving PEMAZYRE in FIGHT-2021

PEMAZYRE
N=146
Adverse Reaction
All Gradesa
(%)
Grades ≥3*
(%)
Metabolism and nutrition disorders
Hyperphosphatemiab
60
0
Decreased appetite
33
1.4
Hypophosphatemiac
23
12
Dehydration
15
3.4
Skin and subcutaneous tissue disorders
Alopecia
49
0
Nail toxicityd
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 eyee
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
 

*Only Grades 3 – 4 were identified.

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 hypophosphatemia and blood phosphorous decreased.

dIncludes nail toxicity, nail disorder, nail discoloration, nail dystrophy, nail hypertrophy, nail ridging, nail infection, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia.

eIncludes dry eye, keratitis, lacrimation increased, pinguecula, and punctate keratitis.

Clinically relevant adverse reactions occurring in ≤10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 1.3% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N=466]).

Select laboratory abnormalities (≥10%) worsening from baseline in patients receiving PEMAZYRE in FIGHT-2021

PEMAZYREa
N=146
Laboratory Abnormality
All Gradesb
(%)
Grades ≥3
(%)
Hematology
Decreased lymphocytes
36
8
Decreased platelets
28
3.4
Increased leukocytes
27
0.7
Decreased leukocytes
18
1.4
Chemistry
Increased phosphatec
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 creatinined
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
 

aThe 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.

bGraded per NCI CTCAE 4.03.

cBased on CTCAE 5.0 grading.

dGraded based on comparison to upper limit of normal.

Increased creatinine1

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.

Hyperphosphatemia was observed in patients treated with PEMAZYRE1

  • Among 466 patients who received PEMAZYRE across clinical trials, hyperphosphatemia was reported in 92% of patients based on laboratory values above the upper limit of normal1
  • The median time to onset of hyperphosphatemia was 8 days (range 1-169)1
  • Phosphate lowering therapy was used by 29% of patients during treatment with PEMAZYRE1
  • No patients discontinued treatment due to hyperphosphatemia2

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

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.

  • Among 466 patients who received PEMAZYRE across clinical trials, RPED occurred in 6% of patients, including Grade 3-4 RPED in 0.6%1
    • The median time to first onset of RPED was 62 days
    • RPED led to dose interruption of PEMAZYRE in 1.7% of patients
    • 0.4% of patients required dose reduction for RPED
    • 0.4% of patients discontinued treatment due to RPED
    • RPED resolved or improved to Grade 1 levels in 87.5% 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 466 patients who received PEMAZYRE across clinical trials, dry eye occurred in 27% of patients1
    • Grade 3-4 dry eye occurred in 0.6% of patients
    • Treat patients with ocular demulcents as needed

When to perform a comprehensive ophthalmological examination, including OCT1

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

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 (AUC) 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 final 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 final 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 final dose

References:

1. PEMAZYRE Prescribing Information. Incyte Corporation. 2. Data on file. Incyte Corporation. Wilmington, DE.

INDICATIONS AND USAGE

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.

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).

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 466 patients who received PEMAZYRE across clinical trials, RPED occurred in 6% of patients, including Grade 3-4 RPED in 0.6%. The median time to first onset of RPED was 62 days. RPED led to dose interruption of PEMAZYRE in 1.7% of patients, and dose reduction and permanent discontinuation in 0.4% and in 0.4% of patients, respectively. RPED resolved or improved to Grade 1 levels in 87.5% 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 466 patients who received PEMAZYRE across clinical trials, dry eye occurred in 27% of patients, including Grade 3-4 in 0.6% of patients. Treat patients with ocular demulcents as needed.

Hyperphosphatemia
Increases in phosphate levels are a pharmacodynamic effect of PEMAZYRE. Among 466 patients who received PEMAZYRE across clinical trials, hyperphosphatemia was reported in 92% 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 29% 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 final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the final dose.

Adverse Reactions
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, arthalgia, 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.

Clinically relevant adverse reactions occurring in ≤10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 1.3% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N=466]).

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 adverse reactions (incidence ≥20%) were hyperphosphatemia (60%), alopecia (49%), diarrhea (47%), nail toxicity (43%), fatigue (42%), dysgeusia (40%), nausea (40%), constipation (35%), stomatitis (35%), dry eye (35%), dry mouth (34%), decreased appetite (33%), vomiting (27%), arthralgia (25%), abdominal pain (23%), hypophosphatemia (23%), back pain (20%), and dry skin (20%).

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 final dose.

Please see Full Prescribing Information for PEMAZYRE.

INDICATIONS AND USAGE

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.

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).