Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Incyte Biosciences Distribution B.V., Paasheuvelweg 25, 1105 BP Amsterdam, Netherlands
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).
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).
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.
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.
Pemigatinib can cause dry eye (see section 4.8). Patients should use ocular demulcents, in order to prevent or treat dry eye, as needed.
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).
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.
Concomitant use of pemigatinib with proton pump inhibitors should be avoided (see section 4.5).
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.
Concomitant use of pemigatinib with strong or moderate CYP3A4 inducers is not recommended (see section 4.5).
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).
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).
A pregnancy test should be performed before treatment initiation to exclude pregnancy.
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).
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.
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).
Co-administration of ranitidine did not result in a clinically important change in pemigatinib exposure.
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 P-gp substrate having a narrow therapeutic index.
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. Pemigatinib administration should be separated by at least 6 hours before or after administration of P-gp substrates with a narrow therapeutic index.
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.
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.
It is unknown whether pemigatinib or its metabolites are excreted in human milk. A risk to the breastfed child cannot be excluded. Breast-feeding should be discontinued during treatment with Pemazyre and for 1 week following completion of therapy.
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.
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).
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%).
Adverse reactions are presented in table 4. 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.
Table 4. Adverse reactions observed in FIGHT-202 study – frequency reported by incidence of treatment emergent events:
| System organ class | Frequency | Adverse reactions |
|---|---|---|
| Metabolism and nutrition disorders | Very common | Hyponatraemia, Hyperphosphataemiaa, Hypophosphataemiab |
| Nervous system disorders | Very common | Dysgeusia |
| Eye disorders | Very common | Dry eye |
| Common | Serous retinal detachmentc, Punctate keratitis, Vision blurred, Trichiasis | |
| Gastrointestinal disorders | Very common | Nausea, Stomatitis, Diarrhoea, Constipation, Dry mouth |
| Skin and subcutaneous tissue disorders | Very common | Palmar-plantar erythrodysaesthesia syndrome, Nail toxicityd, Alopecia, Dry skin |
| Common | Hair growth abnormal | |
| Musculoskeletal and connective tissue disorders | Very common | Arthralgia |
| General disorders and administration site conditions | Very common | Fatigue |
| Investigations | Very common | Blood creatinine increased |
a Includes Hyperphosphataemia and Blood phosphorous increased. See below “Hyperphosphataemia”.
b Includes Hypophosphataemia and Blood phosphorous decreased
c Includes Serous retinal detachment, Retinal detachment, Detachment of retinal pigmented epithelium, Retinal thickening, Subretinal fluid, Chorioretinal folds, Chorioretinal scar, and Maculopathy. See below “Serous retinal detachment”.
d Includes Nail toxicity, Nail disorder, Nail discolouration, Nail dystrophy, Nail hypertrophy, Nail ridging, Nail infection, Onychalgia, Onychoclasis, Onycholysis, Onychomadesis, Onychomycosis and Paronychia
Hyperphosphataemia was reported in 60.5% of all patients treated with pemigatinib. 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 pemigatinib. Dose interruption occurred in 1.4% patients and reduction in 0.7% of patients. These results 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 pemigatinib.
Recommendations for management of hyperphosphataemia are provided in sections 4.2 and 4.4.
Serous retinal detachment occurred in 4.8% of all patients treated with pemigatinib. 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 are provided in sections 4.2 and 4.4.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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