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Select FGFR-Inhibition–Related Adverse Reactions1

PEMAZYRE targets and inhibits FGFR1, 2, and 3

Graphic outline of a man surrounded by icons representing areas of the body affected by adverse reactions Graphic outline of a man surrounded by icons representing areas of the body affected by adverse reactions Graphic outline of a man surrounded by icons representing areas of the body affected by adverse reactions

For more information on adverse reactions with PEMAZYRE, please visit the Safety page.

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Icon representing Retinal pigment epithelial detachment Retinal pigment epithelial detachment (RPED)

Monitoring

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

Perform ophthalmological examinations, including OCT

OCT is a non-invasive imaging test that uses light waves to map and measure the thickness of distinctive layers of the retina.6

  • Prior to initiation

    of therapy
  • arrow
  • Every 2 months

    for the first 6 months of treatment
  • arrow
  • Every 3 months

    thereafter during treatment

OCT, as part of routine monitoring during treatment with PEMAZYRE, may be covered by patient insurance (medical or vision policies), but coverage should be confirmed.

OCT, optical coherence tomography.

Management

  • For onset of visual symptoms, refer patient 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
Recommended dose modification of PEMAZYRE for RPED
Graphic showing the recommended dose modification of PEMAZYRE for RPED Graphic showing the recommended dose modification of PEMAZYRE for RPED
 
Graphic with text – FGFR INHIBITION RELATED EFFECT

Management of RPED in clinical trials

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
  • Dose modifications:
    • - RPED resolved or improved to Grade 1 levels in 87.5% of patients who required dosage modification for RPED
    • - 0.4% of patients required dose reduction for RPED
    • - RPED led to dose interruption of PEMAZYRE in 1.7% of patients
    • - 0.4% of patients permanently discontinued treatment due to RPED

Clinical trials of PEMAZYRE did not conduct routine monitoring, including OCT, to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.

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Scientific Background

FGFR and the retinal epithelium
Optical coherence tomography (OCT) image of normal retina
Optical coherence tomography (OCT) image of normal retina.7 Reprinted with permission.
FGF/FGFR  pathway plays an essential role in the retinal epithelium:
  • Fibroblast growth factor (FGF)  is a neurotrophic factor found in the retinal pigment epithelium (RPE)7
  • FGF  promotes growth in immature RPE cells and helps prevent apoptosis of mature cells7
  • FGFR-mitogen-activated protein kinase (MAPK) signaling helps protect the RPE from injury7
RPED May Be a Related Effect of FGFR Inhibition2
Optical coherence tomography (OCT) image of exudative retinal detachment
Optical coherence tomography (OCT) image of exudative retinal detachment. Adapted from Simunovic MP, et al. BMC Ophthalmol. 2020;20(1):349.8

RPED is characterized by the accumulation of fluid under the retina9
  • RPED does not represent an actual, physical tear or separation of the retina7
  • Treatment of RPED is conservative; it often resolves within days without requiring treatment7
PEMAZYRE is an FGFR-inhibitor, and therefore can cause RPED; this may cause symptoms such as blurred vision, visual floaters, or photopsia.1

Kidney icon Hyperphosphatemia and soft tissue mineralization

Monitoring

Monitor for Hyperphosphatemia1: In the FIGHT-202 study, serum phosphate was measured on Day 1 of every cycle following a 1-week dosing holiday, starting with the second cycle of treatment with PEMAZYRE.10

Management

PEMAZYRE Recommended Dosage Modification: Hyperphosphatemia1
Serum phosphate > 5.5 mg/dL
arrow Initiate a low-phosphate diet
Serum phosphate > 7 to ≤10 mg/dL
arrow Initiate phosphate lowering therapy
Monitor serum phosphate weekly
arrow Withhold PEMAZYRE
if levels are not <7 mg/dL within 2 weeks of starting phosphate-lowering therapy
arrow
Resume PEMAZYRE at the same dose when phosphate levels are <7 mg/dL for first occurrence
arrow
For subsequent recurrences, resume at a lower dose

Serum phosphate > 10 mg/dL
arrow Initiate phosphate lowering therapy
Monitor serum phosphate weekly
arrow Withhold PEMAZYRE
if levels are not ≤10 mg/dL within 1 week after starting phosphate-lowering therapy
arrow
Resume PEMAZYRE at the next lower dose level when phosphate levels are
<7 mg/dL
arrow
If there is recurrence of serum phosphate >10 mg/dL following 2 dose reductions,
Permanently discontinue PEMAZYRE
 
Graphic with text – FGFR INHIBITION RELATED EFFECT

Management of hyperphosphatemia in clinical trials

Among patients taking PEMAZYRE in the FIGHT-202 study (n=146):
  • All cases of hyperphosphatemia were Grade 1 or 21
  • Phosphate binders were used by 27 of 146 patients (18%) and diuretics by 1 of 146 patients (1%)4
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
  • No patients discontinued treatment due to hyperphosphatemia10
  • 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
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Scientific Background

Increase in Phosphate Levels is an Effect Related to FGFR Inhibition3,4

FGF23, an FGFR ligand, is involved in phosphate homeostasis by reducing uptake of phosphate by the kidney.11

FGFR inhibition may lead to blockade of FGF23 signaling and in turn cause hyperphosphatemia.3

  • Hyperphosphatemia is often asymptomatic12
  • Hyperphosphatemia can be associated with soft tissue and organ calcifications12

Dermatologic/Mucosal adverse reactions

  • Graphic of a finger with nail – representing nail toxicity Nail toxicity
  • Graphic of profile of head – representing stomatitis Stomatitis
  • Graphic of hair follicle – representing alopecia Alopecia

Management

Nail Toxicity: Potential Management Approaches5
In the FIGHT-202 study, examples of nail toxicity included:
Onychomadesis Paronychia Onycholysis Nail hypertrophy Nail dystrophy Nail discoloration

Consider counseling and education on the potential for nail changes before initiation of treatment5

Preventative strategies may include avoidance of:5
  • Prolonged contact with water
  • Repeated trauma
  • Friction
  • Pressure on the nails and nail beds
Patients may be advised to:5
  • Limit the use of nail polish removers or hardeners
  • Avoid biting nails or cutting nails too short
  • Use topical emollients
  • Wear loose-fitting socks and footwear

Preventative correction of nail curvature may be considered.5
 
Graphic with text – FGFR INHIBITION RELATED EFFECT

Management of nail toxicity in clinical trials

Among patients taking PEMAZYRE in the FIGHT-202 study (n=146):
  • 43% experienced nail toxicity1
    • - 2.1% experienced Grades 3 or 4 nail toxicity1
  • Dose modifications:
    • - 3% required dose reduction for nail toxicity4
    • - 4% required dose interruption for nail toxicity4
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Stomatitis: Potential Management Approaches

Consider counseling and education on the potential for stomatitis before initiation of treatment

Preventative strategies may include5:
  • Dental work to address tooth and gum disease before start of treatment
  • Education regarding the importance of thorough and frequent cleaning of the oral cavity
Patients may be advised to5:
  • Avoid salty, spicy, or citrus-based foods
  • Avoid hot beverages
Potential management approaches may include13:
  • Use of coating agents, such as bismuth salicylate, sucralfate, or other antacids
  • Water-soluble mouth/lip lubricants
  • “Magic mouthwash” (may include antifungals, antibacterials, steroids, and/or local anesthetics)
  • Topical analgesics or oral analgesics
  • Topical anesthetics
 
Graphic with text – FGFR INHIBITION RELATED EFFECT

Management of stomatitis in clinical trials:

Among patients taking PEMAZYRE in the FIGHT-202 study (n=146):1
  • 35% experienced stomatitis1
    • - 5% experienced Grades 3 or 4 stomatitis1
  • Dose modifications:
    • - 5 patients required dose reductions for stomatitis4
    • - 11 patients required dose interruptions for stomatitis4
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Alopecia: Potential Management Approaches

Preventative measures normally considered for patients undergoing traditional chemotherapy (eg, scalp compression, scalp cooling, medications) may not be applicable5

Management approaches to consider may include5:
  • Prophylactic or reactive topical medications for the scalp to encourage hair regrowth
  • Topical high potency corticosteroid
  • Camouflaging methods which create the appearance of naturally fuller hair
Attention should be focused on early identification and management.5
 
Graphic with text – FGFR INHIBITION RELATED EFFECT

Management of alopecia in clinical trials:

Among patients taking PEMAZYRE in the FIGHT-202 study (n=146):1
  • 49% experienced alopecia
    • - No patients experienced Grades 3 or 4 alopecia
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Scientific Background

FGFR inhibition and dermatologic events

Nail toxicity, stomatitis, and alopecia have been observed with FGFR inhibition.5

The pathophysiological mechanisms of these events are not fully understood.5

  • Several possible mechanisms have been proposed, including5:
    • - Inhibition of FGFR in keratinocytes, inducing dysregulation of hair-follicle homeostasis and epidermal proliferation
    • - Inhibiting hormonal FGF signaling by FGF-19, -21, and -23
 

For additional information about adverse reactions and dose modifications, please see the Full Prescribing Information for PEMAZYRE.

References:

1. PEMAZYRE Prescribing Information. Wilmington, DE: Incyte Corporation. 2. Mahipal A, Tella SH, Kommalapati A, Yu J, Kim R. Prevention and treatment of FGFR inhibitor-associated toxicities. Crit Rev Oncol Hematol. 2020;155:103091. Epub ahead of print. 3. Valle JW, Larmarca A, Goyal L, Barriuso J, Zhu AX. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 2017;7(9):943-962. 4. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21(5):671-684. 5. Lacouture ME, Sibaud V, Anadkat MJ, et al. Dermatologic adverse events associated with selective fibroblast growth factor receptor inhibitors: overview, prevention, and management guidelines. Oncologist. 2021;26(2):e316-e326. 6. American Academy of Ophthalmology. What is optical coherence tomography? https://www.aao.org/eye-health/treatments/what-is-optical-coherence-tomography. Accessed April 16, 2021. 7. van der Noll R, Leijen S, Neuteboom GHG, Beijnen JH, Schellens JHM. Effect of inhibition on the FGFR-MAPK signaling pathway on the development of ocular toxicities. Cancer Treat Rev. 2013;39(6):664-672. 8. Simunovic MP, Shao EH, Osaadon P. Ab-externo drainage with continuous anterior chamber infusion for non-resolving exudative retinal detachment: a case report. BMC Ophthalmol. 2020;20(1):349. 9. Amer R, Nalci H, Yalҫindağ N, et al. Exudative retinal detachment. Surv Ophthalmol. 2017;62(6),723-769. 10. Data on file. Incyte Corporation. Wilmington, DE. 11. Yanochko GM, Vitsky J, Heyen JR, et al. Pan-FGFR inhibition leads to blockade of FGF23 signaling, soft tissue mineralization, and cardiovascular dysfunction. Toxicol Sci. 2013;135(2);451-464. 12. Leung J, Crook M. Disorders of phosphate metabolism. J Clin Pathol. 2019;72:741-747. 13. O’Brien CP. Management of stomatitis. Can Fam Physician. 2009;55(9):891-892.

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 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 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, 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.

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]). 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 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.

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 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).