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Safety

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The safety of PEMAZYRE® (pemigatinib) was investigated in the FIGHT–202 clinical study (N=147)

The safety of PEMAZYRE® (pemigatinib) was investigated in the FIGHT–202 clinical study (N=147)

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Table 1. Most common adverse reactions

Table 2. Adverse reactions observed in FIGHT–202 study — frequency reported by incidence of treatment-emergent events

FIGHT–202 was a multicentre, open-label, single-arm study to evaluate the efficacy and safety of PEMAZYRE in previously treated patients with locally advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA).

Patients received PEMAZYRE in 21-day cycles, consisting of 13.5 mg once-daily oral dosing for 14 days, followed by 7 days off therapy. PEMAZYRE was administered until disease progression or unacceptable toxicity.

The most common adverse reactions were hyperphosphataemia, alopecia, diarrhoea, nail toxicity, fatigue, nausea, stomatitis, constipation, dysgeusia, dry mouth, arthralgia, dry eye, hypophosphataemia, dry skin and palmar-plantar erythrodysaesthesia syndrome (Table 1).

The most common serious adverse reactions were hyponatraemia (2.0%) and blood creatinine increase (1.4%). No serious adverse reaction led to PEMAZYRE dose reduction. One serious adverse reaction of hyponatraemia (0.7%) led to dose interruption. One serious adverse reaction of blood creatinine increase (0.7%) led to dose discontinuation. Eye disorders serious adverse reactions were retinal detachment (0.7%), non-arteritic optic ischaemic neuropathy (0.7%) and retinal artery occlusion (0.7%).

Adverse reactions observed in the FIGHT–202 study are presented in Table 2. Frequency categories are very common (≥1/10) and common (≥1/100 to <1/10). Within each frequency grouping, the adverse reactions are presented in order of decreasing frequency.

Hyperphosphataemia
Hypophosphataemia
Serous retinal detachment
Blood creatinine increase

Hyperphosphataemia was observed in patients treated with PEMAZYRE

Hyperphosphataemia was observed in patients treated with PEMAZYRE

Hyperphosphataemia is a pharmacodynamic effect expected with PEMAZYRE administration. Prolonged hyperphosphataemia can cause precipitation of calcium-phosphate crystals that can lead to hypocalcaemia, soft tissue mineralisation, secondary hyperparathyroidism, muscle cramps, seizure activity, QT interval prolongation and arrhythmias. Soft tissue mineralisation, including cutaneous calcification, calcinosis and non-uraemic calciphylaxis have been observed with PEMAZYRE treatment.

Hyperphosphataemia was reported in 60.5% of all patients treated with PEMAZYRE. Hyperphosphataemia above 7 mg/dL and 10 mg/dL was experienced by 27.2% and 0.7% of patients, respectively. Hyperphosphataemia usually develops within the first 15 days. None of the reactions were ≥ Grade 3 in severity, serious or led to discontinuation of PEMAZYRE. Dose interruption occurred in 1.4% of patients and reduction in 0.7% of patients.

Recommendations for management of hyperphosphataemia

Recommendations include dietary phosphate restriction, administration of phosphate-lowering therapy and dose modification when required (Table 3). Phosphate-lowering therapy was used by 19% of patients during treatment with PEMAZYRE.

In all patients, a low-phosphate diet should be initiated when serum phosphate level is >5.5 mg/dL, and adding a phosphate-lowering therapy should be considered when level is >7 mg/dL. The dose of phosphate-lowering therapy should be adjusted until serum phosphate level returns to <7 mg/dL.

Table 3. Dose modifications for hyperphosphataemia

Discontinuing phosphate-lowering therapy and diet should be considered during PEMAZYRE treatment breaks or if serum phosphate level falls below normal range. Severe hypophosphataemia may present with confusion, seizures, focal neurological findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis and haemolytic anaemia.

For patients presenting with hyperphosphataemia or hypophosphataemia, additional close monitoring and follow-up is recommended regarding dysregulation of bone mineralisation.

Results from the FIGHT–202 clinical study suggest that dietary phosphate restriction and/or administration of phosphate-lowering therapy along with the 1-week dose holiday were effective strategies for managing this on-target effect of PEMAZYRE.

Hypophosphataemia

Hypophosphataemia

Discontinuing phosphate-lowering therapy and diet should be considered during PEMAZYRE treatment breaks or if serum phosphate level falls below normal range. Severe hypophosphataemia may present with confusion, seizures, focal neurological findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis and haemolytic anaemia. In the FIGHT–202 study, hypophosphataemia reactions were ≥ Grade 3 in 14.3% of participants. None of the events were serious, led to discontinuation or to dose reduction. Dose interruption occurred in 1.4% of participants.

For patients presenting with hyperphosphataemia or hypophosphataemia, additional close monitoring and follow-up is recommended regarding dysregulation of bone mineralisation.

Serous retinal detachment was observed in patients treated with PEMAZYRE

Serous retinal detachment was observed in patients treated with PEMAZYRE

PEMAZYRE can cause serous retinal detachment reactions, which may present with symptoms such as blurred vision, visual floaters or photopsia. This can moderately influence the ability to drive and use machines.

Serous retinal detachment occurred in 4.8% of all patients treated with PEMAZYRE. Reactions were generally Grade 1 or 2 (4.1%) in severity; ≥ Grade 3 and serious reactions included retinal detachment in 1 patient (0.7%). Two adverse reactions of retinal detachment (0.7%) and detachment of retinal pigment epithelium (0.7%) led to dose interruption. None of the reactions led to dose reduction or discontinuation.

Recommendations for management of serous retinal detachment

Ophthalmological examination, including optical coherence tomography (OCT), should be performed prior to initiation of therapy and every 2 months for the first 6 months of treatment, every 3 months afterwards, and urgently at any time for visual symptoms. For serous retinal detachment reactions, the dose modification guidelines should be followed (Table 4).

During the conduct of the clinical study, there was no routine monitoring including OCT to detect asymptomatic serous retinal detachment; therefore, the incidence of asymptomatic serous retinal detachment with PEMAZYRE is unknown.

Careful consideration should be taken with patients that have clinically significant medical eye disorders, such as retinal disorders, including, but not limited to, central serous retinopathy, macular/retinal degeneration, diabetic retinopathy and previous retinal detachment.

Dry eye

PEMAZYRE can cause dry eye. Patients should use ocular demulcents, in order to prevent or treat dry eye, as needed.

Table 4. Dose modifications for serous retinal detachment

Blood creatinine increase

Blood creatinine increase

PEMAZYRE may increase serum creatinine by decreasing renal tubular secretion of creatinine; this may occur due to inhibition of renal transporters OCT2 and MATE1 and may not affect glomerular function. Within the first cycle, 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. Alternative markers of renal function should be considered if persistent elevations in serum creatinine are observed.

Embryo-foetal toxicity

Based on the mechanism of action and findings in an animal reproduction study, PEMAZYRE can cause foetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus. Women of childbearing potential should be advised not to become pregnant and men should be advised not to father a child during treatment. An effective method of contraception should be used during treatment with PEMAZYRE and for 1 week following completion of therapy.

A pregnancy test should be performed before treatment initiation to exclude pregnancy.

Central nervous system (CNS) metastasis

Since untreated or progressing brain/CNS metastasis were not allowed in FIGHT-202, efficacy in this population has not been evaluated and no dose recommendations can be made; however, the blood-brain barrier penetration of PEMAZYRE is expected to be low.

Reference:
Swiss Professional Information PEMAZYRE® (pemigatinib) on www.swissmedicinfo.ch.

Table 5. Dose adjustments for other adverse reactions

Table 1. Most common adverse reactions

Adverse reaction Incidence, %
Hyperphosphataemia 60.5
Alopecia 49.7
Diarrhoea 47.6
Nail toxicity 44.9
Fatigue 43.5
Nausea 41.5
Stomatitis 38.1
Constipation 36.7
Dysgeusia 36.1
Dry mouth 34.0
Arthralgia 29.9
Dry eye 27.9
Hypophosphataemia 23.8
Dry skin 21.8
Palmar-plantar erythrodysaesthesia syndrome 16.3

Reference:
Swiss Professional Information PEMAZYRE® (pemigatinib) on www.swissmedicinfo.ch.

Table 2. Adverse reactions observed in FIGHT–202 study – frequency reported by incidence of treatment-emergent events. Frequency categories are very common (≥1/10) and common (≥1/100 to <1/10). Within each frequency grouping, the adverse reactions are presented in order of decreasing frequency

System organ class Frequency Adverse reactions
Metabolism and nutrition disorders Very common Hyperphosphataemia (60.5%),a hypophosphataemia (23.8%),b hyponatraemia (10.9%)
Nervous system disorders Very common Dysgeusia (36.1%)
Eye disorders Very common Dry eye (27.9%)
Common Trichiasis, punctate keratitis, serous retinal detachment,c blurred vision
Gastrointestinal disorders Very common Diarrhea (47.6%), nausea (41.5%), stomatitis (38.1%),
constipation (36.7%), dry mouth (34.0%)
Skin and subcutaneous
tissue disorders		 Very common Alopecia (49.7%), nail toxicity (44.9%),d dry skin (21.8%), palmar-plantar erythrodysaesthesia syndrome (16.3%)
Common Abnormal hair growth
Musculoskeletal and connective tissue disorders Very common Arthralgia (29.9%)
General disorders and administration site conditions Very common Fatigue (43.5%)
Kidney and urinary tract disorders Very common Blood creatinine increased (11.6%)

aIncludes hyperphosphataemia and blood phosphorous increased.
bIncludes hypophosphataemia and blood phosphorous decreased.
cIncludes serous retinal detachment, retinal detachment, detachment of retinal pigmented epithelium, retinal thickening, subretinal fluid, chorioretinal folds, chorioretinal scar and maculopathy.
d Includes nail toxicity, nail disorder, nail discolouration, nail dystrophy, nail hypertrophy, nail ridging, nail infection, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis and paronychia.
Reference:
Swiss Professional Information PEMAZYRE® (pemigatinib) on www.swissmedicinfo.ch.

Table 3. Dose modifications for hyperphosphataemia

Serum phosphate Dose modification
>5.5–≤7 mg/dL
  • PEMAZYRE should be continued at current dose.
>7–≤10 mg/dL
  • PEMAZYRE should be continued at current dose, phosphate-lowering therapy should be initiated, serum phosphate should be monitored weekly, dose of phosphate-lowering therapy should be adjusted as needed until level returns to <7 mg/dL.
  • PEMAZYRE should be withheld if levels do not return to <7 mg/dL within 2 weeks of starting a phosphate-lowering therapy. PEMAZYRE and phosphate-lowering therapy should be restarted at the same dose when level returns to <7 mg/dL.
  • Upon recurrence of serum phosphate at >7 mg/dL with phosphate-lowering therapy, PEMAZYRE should be reduced 1 dose level.
>10 mg/dL
  • PEMAZYRE should be continued at current dose, phosphate-lowering therapy should be initiated, serum phosphate should be monitored weekly and dose of phosphate-lowering therapy should be adjusted as needed until level returns to <7 mg/dL.
  • PEMAZYRE should be withheld if levels continue >10 mg/dL for 1 week. PEMAZYRE and phosphate-lowering therapy should be restarted 1 dose level lower when serum phosphate is <7 mg/dL.
  • If there is recurrence of serum phosphate >10 mg/dL following 2 dose reductions, PEMAZYRE should be permanently discontinued.

Reference:
Swiss Professional Information PEMAZYRE® (pemigatinib) on www.swissmedicinfo.ch.

Table 4. Dose modifications for serous retinal detachment

Adverse reaction Dose modification
Asymptomatic
  • PEMAZYRE should be continued at current dose. Monitoring should be performed as described.
Moderate decrease in visual acuity (best corrected visual acuity 20/40 or better or ≤3 lines of decreased vision from baseline); limiting instrumental activities of daily living
  • PEMAZYRE should be withheld until resolution. If improved on subsequent examination, PEMAZYRE should be resumed at the next lower dose level.
  • If it recurs, symptoms persist or examination does not improve, permanent discontinuation of PEMAZYRE should be considered based on clinical status.
Marked decrease in visual acuity (best corrected visual acuity worse than 20/40 or >3 lines decreased vision from baseline up to 20/200); limiting activities of daily living
  • PEMAZYRE should be withheld until resolution. If improved on subsequent examination, PEMAZYRE may be resumed at 2 dose levels lower.
  • If it recurs, symptoms persist or examination does not improve, permanent discontinuation of PEMAZYRE should be considered.
Visual acuity worse than 20/200 in affected eye; limiting activities of daily living
  • PEMAZYRE should be withheld until resolution. If improved on subsequent examination, PEMAZYRE may be resumed at 2 dose levels lower.
  • If it recurs, symptoms persist or examination does not improve, permanent discontinuation of PEMAZYRE should be considered.

Reference:
Swiss Professional Information PEMAZYRE® (pemigatinib) on www.swissmedicinfo.ch.

Table 5. Dose adjustments for other adverse reactions

Adverse reaction PEMAZYRE dose adjustment
Grade 3 adverse reaction
  • PEMAZYRE should be withheld until reduction to Grade 1 or resolution of the adverse reaction.
  • If there is an improvement, PEMAZYRE should be resumed at the lower dose if the adverse reaction resolves within 2 weeks.
  • Permanent discontinuation of PEMAZYRE should be considered if the adverse reaction does not resolve within 2 weeks.
  • In case of Grade 3 recurrence after 2 dose reductions, permanent discontinuation of PEMAZYRE should be considered.
Grade 4 adverse reaction
  • Permanent discontinuation of PEMAZYRE should be considered.

Reference:
Swiss Professional Information PEMAZYRE® (pemigatinib) on www.swissmedicinfo.ch.

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CH/PEMA/P/23/0005
Date of preparation: April 2023
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