Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Hyperphosphataemia
Hyperphosphataemia is a pharmacodynamic effect expected with pemigatinib administration (see section 5.1). Prolonged hyperphosphataemia can cause precipitation of calcium-phosphate crystals that can lead to hypocalcaemia, soft tissue mineralization, anemia, secondary hyperparathyroidism, muscle cramps, seizure activity, QT interval prolongation, and arrhythmias (see section 4.2). Soft tissue mineralization, including cutaneous calcification, calcinosis and non-uraemic calciphylaxis have been observed with pemigatinib treatment.

Recommendations for management of hyperphosphataemia include dietary phosphate restriction, administration of phosphate-lowering therapy, and dose modification when required (see section 4.2).
Phosphate-lowering therapy was used by 19 % of patients during treatment with pemigatinib (see section 4.8).

Hypophosphataemia
Discontinuing phosphate-lowering therapy and diet should be considered during pemigatinib treatment breaks or if serum phosphate level falls below normal range. Severe hypophosphataemia may present with confusion, seizures, focal neurologic findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis, and haemolytic anemia (see section 4.2). 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 mineralization.

Serous retinal detachment
Pemigatinib can cause serous retinal detachment reactions, which may present with symptoms such as blurred vision, visual floaters, or photopsia (see section 4.8). This can moderately influence the ability to drive and use machines (see section 4.7).

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 (see section 4.2).

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 pemigatinib 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
Pemigatinib can cause dry eye (see section 4.8). Patients should use ocular demulcents, in order to prevent or treat dry eye, as needed.

Embryo-foetal toxicity
Based on the mechanism of action and findings in an animal reproduction study (see section 5.3), pemigatinib 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 to use effective contraception during treatment with pemigatinib and for 1 week after the last dose.
Male patients with female partners of childbearing potential should be advised to use effective contraception during treatment with pemigatinib and for at least 1 week after the last dose (see section 4.6).

Blood creatinine increase
Pemigatinib 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 (see section 4.8). Alternative markers of renal function should be considered if persistent elevations in serum creatinine are observed.

Combination with proton pump inhibitors
Concomitant use of pemigatinib with proton pump inhibitors should be avoided (see section 4.5).

Combination with strong CYP3A4 inhibitors
Concomitant use of pemigatinib with strong CYP3A4 inhibitors requires dose adjustment (see sections 4.2 and 4.5). Patients should be advised to avoid eating grapefruit or drinking grapefruit juice while taking pemigatinib.

Combination with strong or moderate CYP3A4 inducers
Concomitant use of pemigatinib with strong or moderate CYP3A4 inducers is not recommended (see section 4.5).



CNS metastasis
Since untreated or progressing brain/CNS metastasis were not allowed in the study, efficacy in this population has not been evaluated and no dose recommendations can be made, however the blood-brain barrier penetration of pemigatinib is expected to be low (see section 5.3).

Contraception
Based on findings in an animal study and its mechanism of action, Pemazyre can cause foetal harm when administered to a pregnant woman. Women of childbearing age being treated with Pemazyre should be advised not to become pregnant and men being treated with Pemazyre should be advised not to father a child during treatment. An effective method of contraception should be used in women of childbearing potential and in men with women partners of childbearing potential during treatment with Pemazyre and for 1 week following completion of therapy (see section 4.6).

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

Effects on Driving

4.7   Effects on ability to drive and use machines

Pemigatinib has moderate influence on the ability to drive and use machines. Adverse reactions such as fatigue and visual disturbances have been associated with pemigatinib. Therefore, caution should be recommended when driving or operating machines (see section 4.4).