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Safety

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The safety of PEMAZYRE® (pemigatinib) was investigated in the FIGHT–202 clinical study (N=147)1,2

The safety of PEMAZYRE® (pemigatinib) was investigated in the FIGHT–202 clinical study (N=147)1,2

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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).1

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.1

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

Serious adverse reactions were reported in 46.3% (n=68) of patients. The most common serious adverse reactions were hyponatraemia (2.0% [n=3]) and blood creatinine increase (1.4% [n=2]). 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.1,2

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, undesirable effects are presented in order of decreasing seriousness.1

Download the PEMAZYRE adverse event management and dosing guide

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, anaemia, secondary hyperparathyroidism, muscle cramps, seizure activity, QT interval prolongation and arrhythmias. Soft tissue mineralisation, including cutaneous calcification and calcinosis, have been observed with PEMAZYRE treatment.1

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% and 0% 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% (n=2) of patients and reduction in 0.7% (n=1) of patients.1,2

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 28.5% of patients during treatment with PEMAZYRE.1

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. Prolonged hyperphosphataemia can cause precipitation of calcium-phosphate crystals that can lead to hypocalcaemia, soft tissue mineralisation, muscle cramps, seizure activity, QT interval prolongation and arrhythmias. Soft tissue mineralisation, including cutaneous calcification and calcinosis, have been observed with PEMAZYRE treatment.1

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.1

For patients presenting with hyperphosphataemia or hypophosphataemia, additional close monitoring and follow-up is recommended regarding dysregulation of bone mineralisation.1

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.1

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 12.3% of participants. None of the events were serious, led to discontinuation or to dose reduction. Dose interruption occurred in 1.4% (n=2) of participants.1,2

For patients presenting with hyperphosphataemia or hypophosphataemia, additional close monitoring and follow-up is recommended regarding dysregulation of bone mineralisation.1

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.1

Serous retinal detachment occurred in 4.8% of all patients treated with PEMAZYRE. Reactions were generally Grade 1 or 2 (3.4%) in severity; ≥ Grade 3 and serious reactions included retinal detachment in 1 patient (0.7%). Two adverse reactions of retinal detachment (0.7% [n=1]) and detachment of retinal pigment epithelium (0.7% [n=1]) led to dose interruption. None of the reactions led to dose reduction or discontinuation.1,2

Recommendations for management of serous retinal detachment

Ophthalmological examination, including optical coherence tomography 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).1

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.1

Dry eye

PEMAZYRE can cause dry eye. Patients should use ocular demulcents, in order to prevent or treat dry eye, as needed.1

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.1

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.1

  • Women of childbearing potential should be advised to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.1
  • Male patients with female partners of childbearing potential should be advised to use effective contraception during treatment with PEMAZYRE and for at least 1 week after the last dose.1

A pregnancy test should be performed before treatment initiation to exclude pregnancy.1

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.1

References:
1. PEMAZYRE® (pemigatinib). Summary of Product Characteristics. 2021.
2. Incyte Data on File.

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