Pemazyre · 4.8 Undesirable effects · 1

HOS-099388 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most common adverse reactions were 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 %), and palmar-plantar erythrodysaesthesia syndrome (16.3 %). The most common serious adverse reactions were hyponatremia (2.0 %) and blood creatinine increase (1.4 %). No serious adverse reaction led to pemigatinib dose reduction. One serious adverse reaction of hyponatremia (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 ischemic neuropathy (0.7 %) and retinal artery occlusion (0.7 %). 8 Tabulated list of adverse reactions Adverse reactions are presented in table 4. Frequency categories are very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 4: Adverse reactions reported in clinical studies System organ class Frequency Adverse reactions Metabolism and nutrition Hyponatraemia, Hyperphosphataemiaa, Very common disorders Hypophosphataemiab Nervous system disorders Very common Dysgeusia Very common Dry eye Eye disorders Serous retinal detachmentc, Punctate Common keratitis, Vision blurred, Trichiasis Nausea, Stomatitis, Diarrhoea, Gastrointestinal disorders Very common Constipation, Dry mouth Palmar-plantar erythrodysaesthesia Very common syndrome, Nail toxicityd, Alopecia, Dry Skin and subcutaneous tissue skin diso

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HOS-099384 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant use with St John’s wort (see section 4.5).

HOS-099383 · has-indication-information · PDF-Seite 2

Pemazyre monotherapy is indicated for the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy.

HOS-099386 · has-interaction-information · PDF-Seite 7

Effects of other medicinal products on pemigatinib Strong CYP3A4 inhibitors A strong CYP3A4 inhibitor (itraconazole 200 mg once daily) increased pemigatinib AUC geometric mean by 88 % (90 % CI of 75 %, 103 %), which may increase the incidence and severity of adverse reactions with pemigatinib. Patients who are taking 13.5 mg pemigatinib once daily should have their dose reduced to 9 mg once daily and patients who are taking 9 mg pemigatinib once daily should have their dose reduced to 4.5 mg once daily (see section 4.2). CYP3A4 inducers A strong CYP3A4 inducer (rifampin 600 mg once daily) decreased pemigatinib AUC geometric mean by 85 % (90 % CI of 84 %, 86 %), which may decrease the efficacy of pemigatinib. Concurrent use of strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbital, rifampicin) should be avoided during treatment with pemigatinib (see section 4.4). Concomitant use of pemigatinib with St John’s wort is contra-indicated (see section 4.3). If needed, other enzyme inducers (e.g. efavirenz) should be used under close surveillance. Proton pump inhibitors Pemigatinib geometric mean ratios (90 % CI) for Cmax and AUC were 65.3 % (54.7, 78.0) and 92.1 % (88.6, 95.8), respectively, when co-administered in healthy subjects with esomeprazole (a proton pump inhibitor) relative to pemigatinib alone. Co-administration of a proton pump inhibitor (esomeprazole) did not result in a clinically important change in pemigatinib exposure. However, in more than one third of patients given PPIs, a significant reduction of the exposure of pemigatinib was observed. PPIs should be avoided in patients receiving pemigatinib (see section 4.4). H2-receptors antagonists Co-administration of ranitidine did not result in a clinically important change in pemigatinib exposure. Effects of pemigatinib on other medicinal products Effect of pemigatinib on CYP2B6 substrates In vitro studies indicate that pemigatinib induces CYP2B6. Co-administration of pemigatinib with CYP2B6 substrates (e.g. cyclophosphamide, ifosfamide, methadone, efavirenz) may decrease their exposure. Close clinical surveillance is recommended when pemigatinib is administered with these medicinal products or any CYP2B6 substrate having a narrow therapeutic index. Effect of pemigatinib on P-gp substrates In vitro, pemigatinib is an inhibitor of P-gp. Co-administration of pemigatinib with P-gp substrates (e.g. digoxin, dabigatran, colchicine) may increase their exposure and thus their toxicity.

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HOS-099387 · has-pregnancy-information · PDF-Seite 8

Contraception in men and women/women of childbearing potential Based on findings in an animal study and its mechanism of action, pemigatinib can cause foetal harm when administered to a pregnant woman. Women of childbearing potential being treated with pemigatinib should be advised not to become pregnant and men being treated with pemigatinib 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 pemigatinib and for 1 week following completion of therapy. Since the effect of pemigatinib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy. Pregnancy There are no available data from the use of pemigatinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Based on animal data and pharmacology of pemigatinib, Pemazyre should not be used during pregnancy unless the clinical condition of the women requires treatment with pemigatinib. A pregnancy test should be performed before treatment initiation to exclude pregnancy. Breast-feeding It is unknown whether pemigatinib or its metabolites are excreted in human milk. A risk to the breast- fed child cannot be excluded. Breast-feeding should be discontinued during treatment with Pemazyre and for 1 week following completion of therapy. Fertility There are no data on the impact of pemigatinib on human fertility. Animal fertility studies have not been conducted with pemigatinib (see section 5.3). Based on the pharmacology of pemigatinib, impairment of male and female fertility cannot be excluded.

HOS-099385 · has-warning-information · PDF-Seite 5

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. 5 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 se

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