Pemigatinib

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. Concomitant use of pemigatinib with St John’s wort is contra-indicated. If needed, other enzyme inducers (e.g. efavirenz) should be used under close surveillance.

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.

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.

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.

For patients with severe renal impairment, the dose of patients who are taking 13.5 mg pemigatinib once daily should be reduced to 9 mg once daily and the dose of patients who are taking 9 mg pemigatinib once daily should be reduced to 4.5 mg once daily.

For patients with severe hepatic impairment, the dose of patients who are taking 13.5 mg pemigatinib once daily should be reduced to 9 mg once daily and the dose of patients who are taking 9 mg pemigatinib once daily should be reduced to 4.5 mg once daily.

Pemigatinib geometric mean ratios (90% CI) for C_max 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.

There are no available data from the use of pemigatinib in pregnant women. Studies in animals have shown reproductive toxicity. Based on animal data and pharmacology of pemigatinib, pemigatinib 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 pemigatinib and for 1 week following completion of therapy.

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.

Fertility

There are no data on the impact of pemigatinib on human fertility. Animal fertility studies have not been conducted with pemigatinib. 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.

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%).

Tabulated list of adverse reactions

Adverse reactions are presented in the table below. 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:

^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

Description of selected adverse reactions

Hyperphosphataemia

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.

Serous retinal detachment

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.