PEMAZYRE 13.5mg tablets medication leaflet

Pemazyre 4.5 mg tablets

Pemazyre 9 mg tablets

Pemazyre 13.5 mg tablets

Pemazyre 4.5 mg tablets

Each tablet contains 4.5 mg of pemigatinib.

Pemazyre 9 mg tablets

Each tablet contains 9 mg of pemigatinib.

Pemazyre 13.5 mg tablets

Each tablet contains 13.5 mg of pemigatinib.

For the full list of excipients, see section 6.1.

Tablet.

Pemazyre 4.5 mg tablets

Round (5.8 mm), white to off-white tablet debossed on one side with 'I' and '4.5' on the reverse.

Pemazyre 9 mg tablets

Oval (10 × 5 mm), white to off-white tablet debossed on one side with 'I' and '9' on the reverse.

Pemazyre 13.5 mg tablets

Round (8.5 mm), white to off-white tablet debossed on one side with 'I' and '13.5' on the reverse.

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

Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients withbiliary tract cancer.

FGFR 2 fusion positivity status must be known prior to initiation of Pemazyre therapy. Assessment for

FGFR 2 fusion positivity in tumor specimen should be performed with an appropriate diagnostic test.

The recommended dose is 13.5 mg pemigatinib taken once daily for 14 days followed by 7 days offtherapy.

If a dose of pemigatinib is missed by 4 or more hours or vomiting occurs after taking a dose, anadditional dose should not be administered and dosing should be resumed with the next scheduleddose.

Treatment should be continued as long as the patient does not show evidence of disease progression orunacceptable toxicity.

In all patients, a low-phosphate diet should be initiated when serum phosphate level is > 5.5 mg/dLand adding a phosphate-lowering therapy should be considered when level is > 7 mg/dL. The dose ofphosphate-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 tohypocalcaemia, soft tissue mineralization, muscle cramps, seizure activity, QT interval prolongation,and arrhythmias (see section 4.4).

Discontinuing phosphate-lowering therapy and diet should be considered during Pemazyre treatmentbreaks or if serum phosphate level falls below normal range. Severe hypophosphataemia may presentwith confusion, seizures, focal neurologic findings, heart failure, respiratory failure, muscle weakness,rhabdomyolysis, and haemolytic anemia (see section 4.4).

Dose adjustment due to drug interaction

Concomitant use of pemigatinib with strong CYP3A4 inhibitors

Concurrent use of strong CYP3A4 inhibitors, including grapefruit juice, should be avoided duringtreatment with pemigatinib. If co-administration with a strong CYP3A4 inhibitor is necessary, thedose of patients who are taking 13.5 mg pemigatinib once daily should be reduced to 9 mg once dailyand the dose of patients who are taking 9 mg pemigatinib once daily should be reduced to 4.5 mg oncedaily (see sections 4.4 and 4.5).

Management of toxicities

Dose modifications or interruption of dosing should be considered for the management of toxicities.

Pemigatinib dose reductions levels are summarised in table 1.

Table 1: Recommended pemigatinib dose reduction levels

Dose Dose reduction levels

First Second13.5 mg taken orally once daily 9 mg taken orally once daily 4.5 mg taken orally once dailyfor 14 days followed by 7 days for 14 days on, followed by for 14 days on, followed byoff therapy 7 days off therapy 7 days off therapy

Treatment should be permanently discontinued if patient is unable to tolerate 4.5 mg pemigatinib oncedaily.

Dose modifications for hyperphosphataemia are provided in table 2.

Table 2: Dose modifications for hyperphosphataemia

Adverse reaction pemigatinib dose modification> 5.5 mg/dL - ≤ 7 mg/dL * pemigatinib should be continued at current dose.

> 7 mg/dL - ≤ 10 mg/dL * pemigatinib should be continued at current dose, phosphate-lowering therapy should be initiated, serum phosphate shouldbe monitored weekly, dose of phosphate lowering therapyshould be adjusted as needed until level returns to < 7 mg/dL.

* pemigatinib should be withheld if levels do not return to<7 mg/dL within 2 weeks of starting a phosphate loweringtherapy. pemigatinib and phosphate-lowering therapy should berestarted at the same dose when level returns to < 7 mg/dL.

* Upon recurrence of serum phosphate at > 7 mg/dL withphosphate-lowering therapy, pemigatinib should be reduced 1dose level.

> 10 mg/dL * pemigatinib should be continued at current dose, phosphate-lowering therapy should be initiated, serum phosphate shouldbe monitored weekly and dose of phosphate lowering therapyshould be adjusted as needed until level returns to < 7 mg/dL.

* pemigatinib should be withheld if levels continue > 10 mg/dLfor 1 week. pemigatinib and phosphate-lowering therapy shouldbe restarted 1 dose level lower when serum phosphate is<7 mg/dL.

* If there is recurrence of serum phosphate > 10 mg/dL following2 dose reductions, pemigatinib should be permanentlydiscontinued.

Dose modifications for serous retinal detachment are provided in table 3.

Table 3: Dose modifications for serous retinal detachment

Adverse reaction pemigatinib dose modification

Asymptomatic * pemigatinib should be continued at current dose. Monitoringshould be performed as described in section 4.4.

Moderate decrease in visual * pemigatinib should be withheld until resolution. If improvedacuity (best corrected visual on subsequent examination, pemigatinib should be resumed atacuity 20/40 or better or ≤ the next lower dose level.3 lines of decreased vision * If it recurs, symptoms persist or examination does not improve,from baseline); limiting permanent discontinuation of pemigatinib should be consideredinstrumental activities of based on clinical status.daily living

Marked decrease in visual * pemigatinib should be withheld until resolution. If improvedacuity (best corrected visual on subsequent examination, pemigatinib may be resumed at 2acuity worse than 20/40 or > dose levels lower.3 lines decreased vision from * If it recurs, symptoms persist or examination does not improve,baseline up to 20/200); permanent discontinuation of pemigatinib should belimiting activities of daily considered, based on clinical status.living

Visual acuity worse than * pemigatinib should be withheld until resolution. If improved20/200 in affected eye; on subsequent examination, pemigatinib may be resumed at 2limiting activities of daily dose levels lower.living * If it recurs, symptoms persist or examination does not improve,permanent discontinuation of pemigatinib should beconsidered, based on clinical status.

The dose of pemigatinib is the same in elderly patients as younger adult patients (see section 5.1).

Dose adjustment is not required for patients with mild, moderate renal impairment or End Stage Renal

Disease (ESRD) on haemodialysis. For patients with severe renal impairment, the dose of patients whoare taking 13.5 mg pemigatinib once daily should be reduced to 9 mg once daily and the dose ofpatients who are taking 9 mg pemigatinib once daily should be reduced to 4.5 mg once daily (seesection 5.2).

Dose adjustment is not required for patients with mild or moderate hepatic impairment. For patientswith severe hepatic impairment, the dose of patients who are taking 13.5 mg pemigatinib once dailyshould be reduced to 9 mg once daily and the dose of patients who are taking 9 mg pemigatinib oncedaily should be reduced to 4.5 mg once daily (see section 5.2).

The safety and efficacy of Pemazyre in patients less than 18 years of age have not been established.

No data are available.

Pemazyre is for oral use. The tablets should be taken at approximately the same time every day.

Patients should not crush, chew, split or dissolve the tablets. Pemigatinib may be taken with or withoutfood.

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

Hyperphosphataemia is a pharmacodynamic effect expected with pemigatinib administration (seesection 5.1). Prolonged hyperphosphataemia can cause precipitation of calcium-phosphate crystals thatcan lead to hypocalcaemia, soft tissue mineralization, anemia, secondary hyperparathyroidism, musclecramps, seizure activity, QT interval prolongation, and arrhythmias (see section 4.2). Soft tissuemineralization, including cutaneous calcification, calcinosis and non-uraemic calciphylaxis have beenobserved 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 (seesection 4.8).

Hypophosphataemia

Discontinuing phosphate-lowering therapy and diet should be considered during pemigatinib treatmentbreaks or if serum phosphate level falls below normal range. Severe hypophosphataemia may presentwith confusion, seizures, focal neurologic findings, heart failure, respiratory failure, muscle weakness,rhabdomyolysis, and haemolytic anemia (see section 4.2). Hypophosphataemia reactions were ≥ Grade3 in 14.3 % of participants. None of the events were serious, led to discontinuation or to dosereduction. Dose interruption occurred in 1.4 % of participants.

For patients presenting with hyperphosphataemia or hypophosphataemia, additional close monitoringand 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 asblurred vision, visual floaters, or photopsia (see section 4.8). This can moderately influence the abilityto drive and use machines (see section 4.7).

Ophthalmological examination, including optical coherence tomography (OCT) should be performedprior to initiation of therapy and every 2 months for the first 6 months of treatment, every 3 monthsafterwards, and urgently at any time for visual symptoms. For serous retinal detachment reactions, thedose modification guidelines should be followed (see section 4.2).

During the conduct of the clinical study, there was no routine monitoring, including OCT, to detectasymptomatic serous retinal detachment; therefore, the incidence of asymptomatic serous retinaldetachment with pemigatinib is unknown.

Careful consideration should be taken with patients that have clinically significant medical eyedisorders, 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 toprevent 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 shouldbe advised of the potential risk to the foetus. Women of childbearing potential should be advised touse 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 effectivecontraception during treatment with pemigatinib and for at least 1 week after the last dose (see section4.6).

Blood creatinine increase

Pemigatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine; thismay occur due to inhibition of renal transporters OCT2 and MATE1 and may not affect glomerularfunction. Within the first cycle, serum creatinine increased (mean increase of 0.2 mg/dL) and reachedsteady state by Day 8, and then decreased during the 7 days off therapy (see section 4.8). Alternativemarkers of renal function should be considered if persistent elevations in serum creatinine areobserved.

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 sections4.2 and 4.5). Patients should be advised to avoid eating grapefruit or drinking grapefruit juice whiletaking pemigatinib.

Combination with strong or moderate CYP3A4 inducers

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

CNS metastasis

Since untreated or progressing brain/CNS metastasis were not allowed in the study, efficacy in thispopulation has not been evaluated and no dose recommendations can be made, however theblood-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 harmwhen administered to a pregnant woman. Women of childbearing age being treated with Pemazyreshould be advised not to become pregnant and men being treated with Pemazyre should be advised notto father a child during treatment. An effective method of contraception should be used in women ofchildbearing 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 of other medicinal products on pemigatinib

Strong CYP3A4 inhibitors

A strong CYP3A4 inhibitor (itraconazole 200 mg once daily) increased pemigatinib AUC geometricmean by 88 % (90 % CI of 75 %, 103 %), which may increase the incidence and severity of adversereactions with pemigatinib. Patients who are taking 13.5 mg pemigatinib once daily should have theirdose reduced to 9 mg once daily and patients who are taking 9 mg pemigatinib once daily should havetheir 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 meanby 85 % (90 % CI of 84 %, 86 %), which may decrease the efficacy of pemigatinib. Concurrent use ofstrong CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbital, rifampicin) should beavoided 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 protonpump 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 ofpemigatinib 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 theirexposure. Close clinical surveillance is recommended when pemigatinib is administered with thesemedicinal 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. Pemigatinibadministration should be separated by at least 6 hours before or after administration of P-gp substrateswith a narrow therapeutic index.

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 harmwhen administered to a pregnant woman. Women of childbearing potential being treated withpemigatinib should be advised not to become pregnant and men being treated with pemigatinib shouldbe advised not to father a child during treatment. An effective method of contraception should be usedin women of childbearing potential and in men with women partners of childbearing potential duringtreatment with pemigatinib and for 1 week following completion of therapy. Since the effect ofpemigatinib on the metabolism and efficacy of contraceptives has not been investigated, barriermethods 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 haveshown 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 requirestreatment with pemigatinib. A pregnancy test should be performed before treatment initiation toexclude pregnancy.

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 Pemazyreand for 1 week following completion of therapy.

There are no data on the impact of pemigatinib on human fertility. Animal fertility studies have notbeen 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 suchas fatigue and visual disturbances have been associated with pemigatinib. Therefore, caution should berecommended 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 reactionof hyponatremia (0.7 %) led to dose interruption. One serious adverse reaction of blood creatinineincrease (0.7 %) led to dose discontinuation.

Eye disorders serious adverse reactions were retinal detachment (0.7 %), non-arteritic optic ischemicneuropathy (0.7 %) and retinal artery occlusion (0.7 %).

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 adisorders Very common Hyponatraemia, Hyperphosphataemia ,

Hypophosphataemiab

Nervous system disorders Very common Dysgeusia

Very common Dry eye

Eye disorders c

Common Serous retinal detachment , Punctatekeratitis, Vision blurred, Trichiasis

Gastrointestinal disorders Very common Nausea, Stomatitis, Diarrhoea,

Constipation, Dry mouth

Palmar-plantar erythrodysaesthesiad

Skin and subcutaneous tissue Very common syndrome, Nail toxicity , Alopecia, Drydisorders skin

Common Hair growth abnormal

Uncommon Cutaneous calcification

Musculoskeletal and connectivetissue disorders Very common Arthralgia

General disorders andadministration site conditions Very common Fatigue

Investigations Very common Blood creatinine increaseda Includes Hyperphosphataemia and Blood phosphorous increased. See below “Hyperphosphataemia”.b Includes Hypophosphataemia and Blood phosphorous decreasedc 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

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 suggestthat dietary phosphate restriction and/or administration of phosphate-lowering therapy along with the1-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

Serous retinal detachment occurred in 4.8 % of all patients treated with pemigatinib. Reactions weregenerally Grade 1 or 2 (4.1 %) in severity; ≥ Grade 3 and serious reactions included retinal detachmentin 1 patient (0.7 %). Two adverse reactions of retinal detachment (0.7 %) and detachment of retinalpigment epithelium (0.7 %) led to dose interruption. None of the reactions led to dose reduction ordiscontinuation.

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. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no information on overdose of pemigatinib.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EN02

Pemigatinib is a kinase inhibitor of FGFR1, 2 and 3 which inhibits FGFR phosphorylation andsignalling and decreases cell viability in cells expressing FGFR genetic alterations, including pointmutations, amplifications, and fusions or rearrangements. FGFR2 fusions/rearrangements are strongoncogenic drivers and are the most common FGFR alteration occurring, almost exclusively, in 10-16 % of intrahepatic cholangiocarcinoma (CCA).

Serum phosphate

Pemigatinib increased serum phosphate level as a consequence of FGFR inhibition. In pemigatinibclinical studies, phosphate-lowering therapy and dose modifications were permitted to managehyperphosphataemia (see sections 4.2, pct. 4.4 and 4.8).

Clinical studies

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 unresectablecholangiocarcinoma. The efficacy population consists of 108 patients (107 patients with intrahepaticdisease) that had progressed after at least 1 prior therapy and who had FGFR2 fusion orrearrangement, as determined by the test performed at a central laboratory.

Patients received Pemazyre in 21-days 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 unacceptabletoxicity. The major efficacy outcome measures were objective response rate (ORR) and duration ofresponse (DoR), as determined by independent review committee (IRC) according to RECIST v1.1.

The median age was 55.5 years (range: 26 to 77 years), 23.1 % were ≥65 years, 61.1 % were female,and 73.1 % were Caucasian. Most (95.4 %) patients had a baseline Eastern Cooperative Oncology

Group (ECOG) performance status of 0 (42.6 %) or 1 (52.8 %). All patients had at least 1 prior line ofsystemic therapy, 27.8 % had 2 prior lines of therapy, and 12.0 % had 3 or more prior lines of therapy.

Ninety-six percent of patients had received prior platinum-based therapy including 78 % with priorgemcitabine/cisplatin.

Efficacy results are summarised in table 5.

The median time to response was 2.69 months (range 0.7 - 16.6 months).

Table 5: Efficacy results

Cohort A (FGFR2 fusion or rearrangement)

Efficacy Evaluable Population(N = 108)

ORR (95 % CI) 37.0 % (27.94, 46.86)

Complete response (N) 2.8 % (3)

Partial response (N) 34.3 % (37)

Median duration of response (months) (95 % 9.13 (6.01, 14.49)

CI)a

Kaplan-Meier estimates of duration ofresponse (95 % CI)3 months 100.0 (100.0, 100.0)6 months 67.8 (50.4, 80.3)9 months 50.5 (33.3, 65.4)12 months 41.2 (24.8, 56.8)

ORR- CR+PR

CI= Confidence Interval

Note: Data are from IRC per RECIST v1.1, and complete and partial responses are confirmed.a The 95 % CI was calculated using the Brookmeyer and Crowley's method

In the clinical study of pemigatinib, 23.1 % of patients were 65 years and older, and 4.6 % of patientswere 75 years and older. No difference in efficacy response was detected between these patients and inpatients < 65 years of age.

The European Medicines Agency has waived the obligation to submit the results of studies with

Pemazyre in all subsets of the paediatric population in the treatment of cholangiocarcinoma. Seesection 4.2 for information in pediatric use.

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited. The European Medicines Agencywill review new information on this medicinal product at least every year and this SmPC will beupdated as necessary.

Pemigatinib exhibits linear pharmacokinetics in the dose range of 1 to 20 mg. Following oraladministration of Pemazyre 13.5 mg once daily, steady-state was reached by 4 days with a geometricmean accumulation ratio of 1.6. The geometric mean steady-state AUC0-24h was 2620 nM·h (54 % CV)and Cmax was 236 nM (56 % CV) for 13.5 mg once daily.

Median time to achieve peak plasma concentration (tmax) was 1 to 2 hours.

No clinically meaningful differences with pemigatinib pharmacokinetics were observed followingadministration of a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately50 % of total caloric content of the meal from fat) in patients with cancer.

Pemigatinib is 90.6 % bound to human plasma proteins, predominantly to albumin. The estimatedapparent volume of distribution was 235 L (60.8 %) in patients with cancer.

Pemigatinib is predominantly metabolised by CYP3A4 in vitro. Following oral administration of asingle 13.5 mg radiolabeled pemigatinib dose, unchanged pemigatinib was the major drug-relatedmoiety in plasma, and no metabolites > 10 % of total circulating radioactivity were observed.

Following oral administration of pemigatinib 13.5 mg once daily in patients with cancer, the geometricmean elimination half-life (t½) was 15.4 (51.6 % CV) hours and the geometric mean apparentclearance (CL/F) was 10.6 L/h (54 % CV).

Excretion

Following a single oral dose of radiolabeled pemigatinib, 82.4 % of the dose was recovered in faeces(1.4 % as unchanged) and 12.6 % in urine (1 % as unchanged).

The effect of renal impairment on the pharmacokinetics of pemigatinib was evaluated in a renalimpairment study in subjects with normal renal function (GFR ≥ 90 mL/min), severe renal function(GFR < 30 mL/min and not on hemodialysis) and End Stage Renal Disease (ESRD) (GFR < 30mL/min and on hemodialysis). In subjects with the severe renal impairment, the geometric mean ratios(90 % CI) compared to normal controls were 64.6 % (44.1 %, 94.4 %) for Cmax and 159 % (95.4 %,264 %) for AUC0-∞. In the subjects with ESRD before hemodialysis, the geometric mean ratios (90 %

CI) was 77.5 % (51.2 %, 118 %) for Cmax and 76.8 % (54.0 %, 109 %) for AUC0-∞. Besides, inparticipants with ESRD after hemodialysis, the geometric mean ratios (90 % CI) were 90.0 % (59.3 %,137 %) for Cmax and 91.3 % (64.1 %, 130 %) for AUC0-∞. Based on these results, pemigatinib doseshould be reduced for patients with severe renal impairment (see section 4.2).

The effect of hepatic impairment on the pharmacokinetics of pemigatinib was evaluated in a hepaticimpairment study in subjects with normal hepatic function, moderate (Child-Pugh class B) and severe(Child-Pugh class C) hepatic impairment. In subjects with moderate hepatic impairment, the geometricmean ratios (90 % CI) compared to normal controls, were 96.7 % (59.4 %, 157 %) for Cmax and 146 %(100 %, 212 %) for AUC0-∞. In subjects with severe hepatic impairment, the GMR (90 % CI) was94.2 % (68.9 %, 129 %) for Cmax and 174 % (116 %, 261 %) for AUC0-∞. Based on these results, nodose adjustment is recommended for patients with mild and moderate hepatic impairment. However,pemigatinib dose should be reduced for patients with severe hepatic impairment (see section 4.2).

Pemigatinib at clinically relevant concentrations is not an inhibitor of CYP1A2, CYP2B6, CYP2C8,

CYP2C9, CYP2C19, CYP2D6 and CYP3A4 or an inducer of CYP1A2 and CYP3A4.

Pemigatinib is a substrate of both P-gp and BCRP. P-gp or BCRP inhibitors are not expected to affectpemigatinib exposure at clinically relevant concentrations.

In vitro, pemigatinib is an inhibitor of OATP1B3, OCT2, and MATE1. Inhibition of OCT2 mayincrease serum creatinine.

The most prominent findings following repeat-dose administration of pemigatinib in both rats andmonkeys were attributed to the intended pharmacology of pemigatinib (FGFR1, FGFR2, and FGFR3inhibition), including hyperphosphataemia, physeal dysplasia, and soft tissue mineralization; some ofthese findings were observed at exposures (AUC) lower than therapeutic. Mineralization was observedin numerous tissues including kidneys, stomach, arteries, ovaries (monkey only), and eyes (cornea, ratonly). Soft tissue mineralization was not reversible, while physeal and cartilage findings werereversible. In addition, changes of the bone marrow (rats) and kidney lesions were observed.

Pemigatinib was not mutagenic in a bacterial mutagenicity assay, nor clastogenic in an in vitrochromosome aberration assay, and did not result in induction of bone marrow micronuclei in an invivo micronucleus assay in rats.

Carcinogenicity studies with pemigatinib have not been conducted.

No specific animal studies with pemigatinib have been conducted to evaluate the effects of pemigatinibon fertility. In repeated dose toxicity studies, oral administration of pemigatinib did not result in anydose-related adverse effects on male and female reproductive organs.

Developmental toxicity

In rats, administration of pemigatinib at ≥ 0.3 mg/kg/day during the period of organogenesis resultedin 100 % postimplantation loss. At 0.1 mg/kg/day, an increase in foetal skeletal malformations andmajor blood vessels variations, reduced ossification, and decrease foetal body weight were observed.

Exposure at that dose is approximately 20 % of the clinical exposure at the maximum recommendedhuman dose of 13.5 mg based on AUC.

Safety pharmacology

In vitro, pemigatinib showed an IC50 for hERG inhibition > 8 μM (the highest feasible concentrationbased on solubility), that is > 360-fold higher than the clinical steady-state unbound Cmax at the dose of13.5 mg. In vivo, there were no adverse findings in safety pharmacology assessments of pemigatinib,including in vivo respiratory and central nervous system function studies in rats and cardiovascularstudy in monkeys.

Microcrystalline cellulose (E-460)

Sodium starch glycolate (Type A)

Magnesium stearate (E-572)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

PVC/Al blister containing 14 tablets. Carton box containing 14 or 28 tablets.

Not all pack sizes may be marketed.

No special requirements for disposal.

Incyte Biosciences Distribution B.V.

Paasheuvelweg 251105 BP Amsterdam

Netherlands

Pemazyre 4.5 mg tablets

EU/1/21/1535/001

EU/1/21/1535/002

Pemazyre 9 mg tablets

EU/1/21/1535/003

EU/1/21/1535/004

Pemazyre 13.5 mg tablets

EU/1/21/1535/005

EU/1/21/1535/006

Date of first authorisation: 26 March 2021

Date of latest renewal: 23 February 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.