PRODUCT MONOGRAPH
INCLUDING PATIENT MEDICATION INFORMATIONPrPEMAZYRE™

Pemigatinib tablets
Tablets, 4.5 mg, 9 mg, and 13.5 mg, Oral
Protein Kinase Inhibitor (L01EX20)

PEMAZYRE™ is indicated for the treatment of adults with previously treated,unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast
growth factor receptor 2 (FGFR2) fusion or other rearrangement.
PEMAZYRE™ has been issued market authorization with conditions, pending the resultsof trials to verify its clinical benefit. Patients should be advised of the nature of
authorization. For further information for PEMAZYRE™, please refer to Health Canada’s
Notice of Compliance with conditions - drug products web site:
https://www.canada.ca/en/health-canada/services/drugs-health-products/drugproducts/notice-compliance/conditions.html

Incyte Corporation
1801 Augustine Cut-Off
Wilmington, DE 19803
USA
www.incyte.com

Date of Initial
Authorization:
September 8, 2021

Imported by:
Innomar Strategies
Oakville, ON
L6L 0C4
Submission Control No: 242569

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What is a Notice of Compliance with Conditions (NOC/c)?
An NOC/c is a form of market approval granted to a product on the basis of promisingevidence of clinical effectiveness following review of the submission by Health Canada.
Products authorized under Health Canada’s NOC/c policy are intended for the treatment,
prevention or diagnosis of a serious, life-threatening or severely debilitating illness. They havedemonstrated promising benefit, are of high quality and possess an acceptable safety profile
based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical
need in Canada or have demonstrated a significant improvement in the benefit/risk profile overexisting therapies. Health Canada has provided access to this product on the condition thatsponsors carry out additional clinical trials to verify the anticipated benefit within an agreed
upon time frame.

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TABLE OF CONTENTS
Sections or subsections that are not applicable at the time of authorization are not listed.
RECENT MAJOR LABEL CHANGESN/ATABLE OF CONTENTS.............................................................................................................. 3
PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 5
1

INDICATIONS .............................................................................................................. 5
1.1 Pediatrics ................................................................................................................... 5
1.2 Geriatrics ................................................................................................................... 5

2

CONTRAINDICATIONS ................................................................................................. 5

4

DOSAGE AND ADMINISTRATION................................................................................. 5
4.1 Dosing Considerations............................................................................................... 5
4.2 Recommended Dose and Dosage Adjustment ......................................................... 6
4.3 Missed Dose .............................................................................................................. 95

OVERDOSAGE ............................................................................................................. 96

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 9

7

WARNINGS AND PRECAUTIONS .................................................................................. 9
7.1 Special Populations ................................................................................................. 12
7.1.1 Pregnant Women .................................................................................................. 12
7.1.2 Breast-feeding ....................................................................................................... 12
7.1.3 Pediatrics (<18 years of age) ................................................................................. 12
7.1.4 Geriatrics (≥ 65 years of age)................................................................................. 128

ADVERSE REACTIONS ................................................................................................ 12
8.1 Adverse Reaction Overview .................................................................................... 12
8.2 Clinical Trial Adverse Reactions............................................................................... 13
8.3 Less Common Clinical Trial Adverse Reactions ....................................................... 16
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other
Quantitative Data.................................................................................................... 16

9

DRUG INTERACTIONS ............................................................................................... 18
9.2 Drug Interactions Overview .................................................................................... 18
9.4 Drug-Drug Interactions............................................................................................ 18
9.5 Drug-Food Interactions ........................................................................................... 21
9.6 Drug-Herb Interactions ........................................................................................... 21
9.7 Drug-Laboratory Test Interactions .......................................................................... 21

10

CLINICAL PHARMACOLOGY ....................................................................................... 21
10.1 Mechanism of Action .............................................................................................. 21
10.2 Pharmacodynamics ................................................................................................. 21
10.3 Pharmacokinetics .................................................................................................... 22

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11

STORAGE, STABILITY AND DISPOSAL ......................................................................... 23

PART II: SCIENTIFIC INFORMATION ...................................................................................... 24
13

PHARMACEUTICAL INFORMATION ........................................................................... 24

14

CLINICAL TRIALS ....................................................................................................... 25
14.1 Trial Design and Study Demographics ..................................................................... 25
14.2 Study Results ........................................................................................................... 27

16

NON-CLINICAL TOXICOLOGY ..................................................................................... 28

PATIENT MEDICATION INFORMATION ................................................................................. 30

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PART I: HEALTH PROFESSIONAL INFORMATION
1

INDICATIONSPEMAZYRE™ (pemigatinib) is indicated for the treatment of adults with previously treated,unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth
factor receptor 2 (FGFR2) fusion or other rearrangement.
Clinical effectiveness of PEMAZYRE™ is based on overall response rate (ORR) and duration of
response (DoR) from a single-arm Phase 2 trial in patients with specific FGFR2 rearrangements(see 14 CLINICAL TRIALS).
Treatment with PEMAZYRE™ should be initiated following confirmation of a FGFR2 fusion or
rearrangement using a validated test (see 14 CLINICAL TRIALS).
1.1

Pediatrics

Pediatrics (18 years of age): No data are available to Health Canada; therefore, Health Canada
has not authorized an indication for pediatric use (see 7 WARNINGS AND PRECAUTIONS,Special Populations).
1.2

Geriatrics

Geriatrics (≥ 65 years of age): Of the 146 patients treated with PEMAZYRE™ in study
FIGHT-202, 46 (31.5%) were ≥ 65 years. No overall differences in safety or effectiveness wereobserved between elderly and younger patients.
2

CONTRAINDICATIONSPEMZYRE™ is contraindicated in patients who are hypersensitive to this drug or to any
ingredient in the formulation, including any non-medicinal ingredient, or component of thecontainer. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND
PACKAGING.
4DOSAGE AND ADMINISTRATION

4.1

Dosing ConsiderationsPatients must be selected for the treatment of locally advanced or metastatic
cholangiocarcinoma with PEMAZYRE™ based on the confirmation of an FGFR2 fusion or
rearrangement by a validated test (see 7 WARNINGS AND PRECAUTIONS, General and
14 CLINICAL TRIALS).
Avoid concomitant use of strong or moderate CYP3A4 inhibitors with PEMAZYRE™.
Reduce the PEMAZYRE™ dose if co-administration with a strong or moderate CYP3A
inhibitor cannot be avoided (see 9 DRUG INTERACTIONS).
Avoid concomitant use of strong or moderate CYP3A4 inducers with PEMAZYRE™ (see9 DRUG INTERACTIONS).

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Dose reduction of PEMAZYRE™ is required in patients with severe renal or hepatic impairment(see 4 DOSAGE AND ADMINISTRATION, Special Populations).
Risk management for hyperphosphatemia

4.2

In all patients, initiate a low phosphate diet when phosphate level is > 5.5 mg/dL andconsider adding a phosphate lowering therapy when level is > 7 mg/dL. Adjust the doseof phosphate lowering therapy until phosphate level returns to < 7 mg/dL. Consider
discontinuing phosphate lowering therapy during PEMAZYRE™ treatment breaks or if
phosphate level falls below normal (see Table 1).
Recommended Dose and Dosage Adjustment

The recommended dosage of PEMAZYRE™ is 13.5 mg orally once daily for 14 consecutive days
followed by 7 days off therapy, in 21 day cycles. Continue treatment until disease progression
or unacceptable toxicity.
Health Canada has not authorized an indication for pediatric use (see 1 INDICATIONS,
Pediatrics).
Dose Modifications
The recommended dose reductions for adverse reactions are:First dose reduction: PEMAZYRE™ 9 mg taken orally once daily, 14 days on, 7 days off
therapy
Second dose reduction: PEMAZYRE™ 4.5 mg taken orally once daily, 14 days on, 7 days off
therapy.
Permanently discontinue if unable to tolerate PEMAZYRE™ 4.5 mg once daily
See Table 1.

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Table 1:

Dosage Modifications for Toxicities
Guidance for Interruption/Discontinuation of PEMAZYRE™

Adverse Reaction

PEMAZYRE™ Dose Modification

Hyperphosphatemia> 5.5 mg/dL - ≤ 7 mg/dL> 7 mg/dL - ≤ 10 mg/dL> 10 mg/dL

 Continue PEMAZYRE™ at current dose
 Initiate a low phosphate diet
 Continue PEMAZYRE™ at current dose, continue a low
phosphate diet, and initiate phosphate-binding
therapy.
 Monitor serum phosphate weekly, and adjust dose ofphosphate lowering therapy as needed until level
returns to < 7 mg/dL.
 Withhold PEMAZYRE™ if serum phosphate levels do not
return to < 7 mg/dL within 2 weeks of starting aphosphate lowering therapy. Restart PEMAZYRE™ atthe same dose when serum phosphate level returns to< 7 mg/dL.
 Upon recurrence of serum phosphate at > 7 mg/dL withphosphate-lowering therapy, reduce PEMAZYRE™
1 dose level.
 Continue PEMAZYRE™ at current dose, maintain a lowphosphate diet, and adjust phosphate-binding therapy.
 Continue to monitor serum phosphate weekly andadjust dose of phosphate lowering therapy as needed
until serum phosphate level returns to < 7 mg/dL.
 Withhold PEMAZYRE™ if serum phosphate levels
continue > 10 mg/dL for 1 week.
 Restart PEMAZYRE™ 1 dose level lower when serum
phosphate is < 7 mg/dL. If there is recurrence of serum
phosphate > 10 mg/dL following 2 dose reductions,permanently discontinue PEMAZYRE™.

Serous Retinal Detachment
Educational material to assist healthcare professionals with the diagnosis and managementof serous retinal detachment is available through the manufacturer.
Asymptomatic and stable onserial examination

PEMAZYRE™ Product Monograph Continue PEMAZYRE™ at current dose. Monitor as
described in Warnings and Precautions (Section 7)

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Guidance for Interruption/Discontinuation of PEMAZYRE™
Adverse Reaction
Symptomatic or worsening on
serial examination

PEMAZYRE™ Dose Modification
 Withhold PEMAZYRE™.
 If asymptomatic and improved on subsequentexamination, resume PEMAZYRE™ at next lower doselevel.
 If symptoms persist, consider permanent
discontinuation of PEMAZYRE™.

Other Adverse Reactions
Grade 1 or Grade 2

Continue PEMAZYRE™ treatment and treat the toxicity;
monitor as medically indicated.

Grade 3

 Interrupt PEMAZYRE™ up to 2 weeks (14 days) until the
toxicity has resolved to ≤ Grade 1.
 Restart PEMAZYRE™ at next lower dose if adverse
reaction resolves within 2 weeks; monitor as medicallyindicated.
 Permanently discontinue PEMAZYRE™ if adverse
reaction does not resolve within 2 weeks.
 Permanently discontinue PEMAZYRE™ for recurrent
Grade 3 adverse reaction after 2 dose reductions.

Grade 4

Permanently discontinue PEMAZYRE™

Special Populations
Renal impairment: For patients with severe renal impairment (GFR < 30 mL/min), the starting
dose of PEMAZYRE™ should be reduced to 9 mg. No dose adjustment is required for patientswith end stage renal disease who are receiving dialysis (see 10 CLINICAL PHARMACOLOGY,
Pharmacokinetics). No dose adjustment is recommended for patients with mild or moderate
renal impairment (glomerular filtration rate (GFR) ≥ 30 to < 90 mL/min estimated by
Modification of Diet in Renal Disease (MDRD) equation).
Hepatic impairment: For patients with severe hepatic impairment (total bilirubin > 3 × ULN
with any AST), the starting dose of PEMAZYRE™ should be reduced to 9 mg (see 10 CLINICALPHARMACOLOGY, Pharmacokinetics). No dose adjustment is recommended for patients withmild (total bilirubin > upper limit of normal (ULN) to 1.5 × ULN or AST > ULN) or moderate
hepatic impairment (total bilirubin > 1.5–3 × ULN with any AST).
Pediatric patients (< 18 years of age): Health Canada has not authorized an indication for
pediatric use.
Geriatric patients (≥ 65 years of age): No overall differences in efficacy or safety weredetected between these patients and in patients < 65 years of age. No specific dose

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adjustments are considered necessary for elderly patients (see 10 CLINICAL PHARMACOLOGY,
Pharmacokinetics).
4.3

Missed Dose

If the patient misses a dose of PEMAZYRE™ by 4 or more hours, the patient should not take themissed dose and should resume the usual dosing schedule the next day. If vomiting occurs any
time after taking PEMAZYRE™, the next dose should be taken at the next scheduled time.
5

OVERDOSAGE

There is no information on overdosage with PEMAZYRE™.
For management of a suspected drug overdose, contact your regional poison control centre.
6

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2:

Dosage Forms, Strengths, Composition and Packaging

Route of
Administration

Dosage Form /Strength/Composition

Non-medicinal Ingredients

Oral

Tablet 4.5 mg, 9 mg,
13.5 mg

Magnesium stearate, Microcrystalline
cellulose, Sodium starch glycolate

PEMAZYRE™ 4.5 mg tablets are round, white to off-white debossed on one side with “I” and“4.5” on the other side.
PEMAZYRE™ 9 mg tablets are oval, white to off-white debossed on one side with “I” and “9”on the other side.
PEMAZYRE™ 13.5 mg tablets are round, white to off-white debossed on one side with “I” and“13.5” on the other side.
PEMAZYRE™ 4.5 mg, 9 mg, and 13.5 mg tablets are available as a 14-day supply provided inblister packs (14 tablets).
7

WARNINGS AND PRECAUTIONSGeneralBefore taking PEMAZYRE™, patients must have confirmation of an FGFR2 fusion or otherrearrangement by a validated test. In the FIGHT-202 clinical trial, qualifying in-frame fusions
and other rearrangements were predicted to have a breakpoint within intron 17/exon 18 of
the FGFR2 gene, leaving the FGFR2 kinase domain intact (see 14 CLINICAL TRIALS).
Driving and Operating MachineryNo studies to establish the effects of pemigatinib on the ability to drive and use machines havebeen conducted. However, eye disorders such as central serous retinopathy have been notedwith FGFR inhibitors and with PEMAZYRE™ treatment. If patients experience symptoms

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affecting their vision, it is recommended that they do not drive or use machines until the effectsubsides.
Endocrine and Metabolism
Hyperphosphatemia
An increase in phosphate levels is a pharmacodynamic effect of PEMAZYRE™ (see 10 CLNICALPHARMACOLOGY, Pharmacokinetics). Hyperphosphatemia was reported in 59% of all patientstreated with PEMAZYRE™ in clinical trials, with a median time to onset of 14 days.
Phosphate-lowering therapy was used by 29% of patients during treatment with PEMAZYRE™.
Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic
calciphylaxis may be associated with hyperphosphatemia and has been observed with
PEMAZYRE™ treatment (see 8 ADVERSE REACTIONS).
Serum phosphate concentrations should be monitored, and a low phosphate diet should beinitiated when serum phosphate level is >5.5 mg/dL (see 7 WARNINGS AND PRECAUTIONS,
Monitoring and Laboratory Tests, and 4 DOSAGE AND ADMINISTRATION, Table 1).
Recommendations for additional management of hyperphosphatemia include administrationof phosphate-lowering therapy, and dose modification when required. Calcium-based antacids
and phosphate-based supplements should be avoided.
Hypophosphatemia
In the FIGHT-202 clinical trial, hypophosphatemia was reported in 22.6% of patients, with
≥Grade 3 reactions in 12.3% of patients. Dose interruption occurred in 1.4% of participants.
None of the events were serious, led to discontinuation or to dose reduction.
Severe hypophosphatemia may present with confusion, seizures, focal neurologic findings,
heart failure, respiratory failure, muscle weakness, rhabdomyolysis, and hemolytic anemia.
Discontinuing phosphate-lowering therapy and diet should be considered during pemigatinib
treatment breaks or if serum phosphate level falls below normal range.
For patients presenting with hyperphosphatemia or hypophosphatemia, additional closemonitoring and follow-up is recommended regarding dysregulation of bone mineralization.
Monitoring and Laboratory Tests
Serum Phosphate
Phosphate concentrations should be assessed 14 days after initiating PEMAZYRE™ and thenmonitored every 2 cycles (approximately 6 weeks) thereafter. For elevated phosphateconcentrations, follow dose modification guidelines in Table 1 (see 4 DOSAGE AND
ADMINISTRATION).
Ocular Testing
Perform ophthalmological examination including visual acuity test, slit-lamp examination,
fundoscopy, and OCT prior to initiation of therapy, and every 2 months for the first 6 monthsof treatment and every 3 months afterwards, and urgently at any time for visual symptoms.

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Increased Creatinine
Pemigatinib may increase serum creatinine due to a blockade of tubular secretion via renaltransporters OCT2 and MATE1. Within the first treatment cycle of PEMAZYRE™ dosing, serum
creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, andthen decreased during the 7 days off therapy. Alternative markers of renal function should beconsidered if persistent elevations in serum creatinine are observed.
Ophthalmologic
Serous Retinal Detachment
PEMAZYRE™ can cause serous retinal detachment events, which may present with symptoms
such as blurred vision, visual floaters, or photopsia.
Serous retinal detachment events occurred in 7.5% of all patients treated with PEMAZYRE™.
Events were generally Grade 1 or 2 (6.9%) in severity and nonserious; ≥ Grade 3 events
included detachment of retinal pigment epithelium in 1 patient (0.2%) and retinal detachment
in 2 patients (0.4%). Serous retinal detachment events led to discontinuation of PEMAZYRE™ in
2 patients (0.4%). Serous retinal detachment events leading to PEMAZYRE™ dose interruption
occurred in 1.7% of all patients and events leading to dose reduction occurred in 0.4% of
patients. In about 50% of the patients with an event, the events were self-limiting or resolved
following PEMAZYRE™ interruption, reduction, or discontinuation.
Perform ophthalmological examination including visual acuity test, slit-lamp examination,
fundoscopy, and OCT prior to initiation of therapy, and every 2 months for the first 6 monthsof treatment and every 3 months afterwards, and urgently at any time for visual symptoms.
Educational materials to assist healthcare professionals with the diagnosis and management ofserous retinal detachment are available through the manufacturer.
For serous retinal detachment events, follow the dose modification guidelines in Table 1(see 4 DOSAGE AND ADMINISTRATION).
Reproductive Health: Female and Male Potential
Fertility
No animal studies have been performed to evaluate whether or not PEMAZYRE™ affects
fertility in females or males.
Teratogenic Risk
Based on the mechanism of action and findings in an animal reproduction study, PEMAZYRE™
may cause fetal harm when administered to a pregnant woman. In an embryo-fetal toxicity
study, oral administration of pemigatinib to pregnant rats during the period of organogenesis
caused malformations and embryo-fetal death at maternal exposures that were less than thehuman exposure at the maximum recommended human dose based on area under the curve(AUC).
Advise pregnant women of the potential risk to the fetus. Advise female patients ofreproductive potential to use effective contraception during treatment with PEMAZYRE™ and

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for 1 month after the last dose. Advise male patients with female partners of reproductive
potential to use effective contraception during treatment with PEMAZYRE™ and for 1 monthafter the last dose.
7.1

Special Populations

7.1.1 Pregnant Women
PEMAZYRE™ may cause fetal harm and potential loss of pregnancy when administered topregnant women. There are no clinical data on the use of PEMAZYRE™ in pregnant women.
Verify pregnancy status of females of reproductive potential prior to initiating PEMAZYRE™.
PEMAZYRE™ should not be used during pregnancy. If PEMAZYRE™ is used during pregnancy, or
if the patient becomes pregnant while taking PEMAZYRE™, advise the patient of the potential
hazard to the fetus and counsel the patient about her clinical and therapeutic options. Advise
patients to contact their healthcare professional or if they become pregnant or pregnancy issuspected while being treated with PEMAZYRE™ and up to 1 month afterwards.
7.1.2 Breast-feeding
There are no data on the presence of pemigatinib or its metabolites in human milk or theireffects on either the breastfed child or on milk production. Because of the potential for serious
adverse reactions in breastfed children with PEMAZYRE™, advise women not to breastfeed
during treatment and for 1 month after the final dose.
7.1.3 Pediatrics (<18 years of age)
No data are available to Health Canada; therefore, Health Canada has not authorized anindication for pediatric use.
7.1.4 Geriatrics (≥ 65 years of age)
Of the 146 patients treated with PEMAZYRE™ in study FIGHT-202, 31.5% were 65 years andolder. No overall difference in safety was observed between elderly and younger patients.
8

ADVERSE REACTIONS

8.1

Adverse Reaction Overview

Based on the safety database of 146 patients with previously treated, advanced or metastatic
cholangiocarcinoma treated with pemigatinib monotherapy, the most common adverse
reactions (≥ 15%) were hyperphosphatemia, alopecia, diarrhea, fatigue, nail toxicity,dysgeusia, nausea, constipation, stomatitis, dry mouth, decreased appetite, vomiting, dry eye,arthralgia, abdominal pain, hypophosphatemia, dry skin , oedema peripheral, weightdecreased, headache, urinary tract infection, dehydration, hypercalcemia, and palmar-plantar
erythrodysaesthesia syndrome.
Grade ≥ 3 adverse events were reported in 64% of patients, most frequently (≥ 5%) hypophosphatemia
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(12.3%), arthralgia (6.2%), hyponatremia (5.5%), and stomatitis (5.5%).

Serious adverse events were reported in 45% of patients. The most common serious adverse
events (≥ 2%) were abdominal pain (4.8%), pyrexia (4.8%), cholangitis (3.4%), pleural effusion
3.4%), acute kidney injury (2.1%), cholangitis infective (2.1%), failure to thrive (2.1%),
hypercalcemia (2.1%), hyponatremia (2.1%), small intestinal obstruction (2.1%), and urinary
tract infection (2.1%).
Dose interruptions and dose reductions of pemigatinib due to adverse events occurred in 43%
and 14% of patients, respectively. Dose modifications (interruptions and/or reductions) due toadverse events were most commonly due to stomatitis (7.5%), palmar-plantar
erythrodysesthesia syndrome (5.5%), arthralgia (4.8%), and fatigue (4.1%). Permanent
discontinuation of pemigatinib due to adverse events occurred in 8.9% of patients, mostcommonly (≥1%) due to intestinal obstruction and acute kidney injury (2 patients each, 1.4%).
Fatal adverse reactions occurred in 4.1% of patients, including failure to thrive (2 patients,1.4%), and bile duct obstruction, cholangitis, sepsis, and pleural effusion (1 patient each,0.7%).
8.2

Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates
observed in the clinical trials may not reflect the rates observed in practice and should not becompared to the rates in the clinical trials of another drug. Adverse reaction information fromclinical trials is useful for identifying drug-related adverse events and for approximating rates.
The safety data described below reflect exposure to PEMAZYRE™ in Study FIGHT-202. This wasa Phase 2 study of 146 patients with previously treated, advanced, or metastatic
cholangiocarcinoma. Patients were treated with PEMAZYRE™ in 21 day cycles consisting of
13.5 mg oral dosing once daily for 14 days on / 7 days off therapy. The median duration oftreatment was 181 days (range: 7 to 730 days).
Treatment-emergent adverse events (TEAEs) reported in ≥ 15% of patients in FIGHT-202 arepresented in Table 3.

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Table 3:

Adverse Reactions (≥ 15%) in Patients Receiving PEMAZYRE™ in FIGHT-202
PEMAZYRE™
N=146
All Gradesa(%)

Grades ≥ 3*(%)

Hyperphosphatemiab

600Hypophosphatemiac

23

12Decreased appetite

33

1.4

Dehydration

15

2.1

Hypercalcemia

15

2.1

Alopecia

49

0Nail toxicityd

43

2.1

Dry skin20

0.7

Palmar-plantar erythrodysaesthesia syndrome

15

4.1

Diarrhea47

2.7

Nausea40

2.1

Constipation

35

0.7

Stomatitis

35

5.5

Dry mouth

34

0

Vomiting

27

1.4

Abdominal pain

23

4.8

Fatigue42

4.8

Edema peripheral

18

0.7

Dysgeusia

400Headache

160Adverse Reaction
Metabolism and nutrition disorders

Skin and subcutaneous tissue disorders

Gastrointestinal disorders

General disorders

Nervous system disorders

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PEMAZYRE™
N=146
All Gradesa(%)

Grades ≥ 3*
(%)

35

0.7

Arthralgia

25

6.2

Back pain

20

2.7

Pain in extremity

19

2.1

16

3.4

16

2.1

Adverse Reaction
Eye disorders
Dry eyeeMusculoskeletal and connective tissue disorders

Infections and Infestations
Urinary Tract Infection
Investigations
Weight decreased*Only Grades 3 – 4 were identified.
a Graded per NCI CTCAE 4.03.
b Includes hyperphosphatemia and blood phosphorous increased; graded based on clinicalseverity and medical interventions taken according to the "investigations-other, specify"
category in NCI CTCAE v4.03.
c Includes hypophosphatemia and blood phosphorous decreased.
dIncludes nail toxicity, nail disorder, nail discoloration, nail dystrophy, nail hypertrophy, nailridging, nail infection, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis,
and paronychia.
e Includes dry eye, keratitis, lacrimation increased, pinguecula, and punctate keratitis.
The following adverse reactions were reported with the administration of PEMAZYRE™ in
FIGHT-202 and other clinical trials:
Hyperphosphatemia
Prolonged hyperphosphatemia can cause precipitation of calcium-phosphate crystals that canlead to hypocalcemia, soft tissue mineralization, muscle cramps, seizure activity, QT interval
prolongation, and arrhythmias.
Hyperphosphatemia was reported in 59% of all patients treated with PEMAZYRE™ in clinical
trials, with 2 patients (0.5%) reporting a serious event. The median time to onset for any gradeof hyperphosphatemia was 14 days, with 60.3% of patients reporting first occurrences ofhyperphosphatemia during the first 6 months of pemigatinib exposure. Hyperphosphatemia
above 7 mg/dL and 10 mg/dL was experienced by 27% and 0% of patients, respectively.

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Adverse events of hyperphosphatemia led to dose interruption or dose reduction in 3.6% and0.9% of patients, respectively, in PEMAZYRE™ clinical trials.
Serous retinal detachment
PEMAZYRE™ can cause serous retinal detachment (SRD), which may cause symptoms such as
blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE™ did not conductroutine monitoring including optical coherence tomography (OCT) to detect asymptomatic
SRD; therefore, the incidence of asymptomatic SRD with PEMAZYRE™ is unknown.
Adverse reactions of SRD occurred in 7.5% of all patients treated with PEMAZYRE™ in clinical
trials. SRD events included serous retinal detachment, retinal detachment, detachment of
retinal pigmented epithelium, retinal thickening, subretinal fluid, chorioretinal folds,
chorioretinal scar, and maculopathy. Events were generally Grade 1 or 2 (6.9%) in severity andnon-serious; ≥ Grade 3 events included detachment of retinal pigment epithelium in 1 patient(0.2%) and retinal detachment in 2 patients (0.4%). Almost all first occurrences (93%) of SRD
occurred during the first 6 months of pemigatinib exposure.
Nail disorders
Nail toxicity events, most frequently reported as events of nail discoloration, onychomadesis,
and onycholysis, were common for patients treated with PEMAZYRE™ in clinical trials,
reported by 35.0% of patients. Nail toxicity events led to pemigatinib dose interruption in
4.7% of patients and dose reduction in 3.2% of patients. The median time to first nail toxicity
event was 3.7 months in patients treated with pemigatinib on an intermittent schedule (14days on therapy, followed by 7 days off treatment, in 21 day cycles), with approximately half ofall first events occurring during the first 6 months of pemigatinib exposure.
8.3

Less Common Clinical Trial Adverse Reactions

The following are clinically significant adverse reactions reported in less than 15% of patients
receiving PEMAZYRE™:
Blood and lymphatic disorders: anemia
Eye disorders: serous retinal detachment, retinal detachment, detachment of retinal
pigmented epithelium, retinal thickening, subretinal fluid, chorioretinal folds, chorioretinal
scar, and maculopathy
Gastrointestinal disorders: gastroesophageal reflux disease
General disorders: pyrexia
Musculoskeletal and connective tissue disorders: musculoskeletal stiffness, myalgia
Nervous system disorders: dizzinessRespiratory, thoracic and mediastinal disorders: epistaxis
Skin and subcutaneous tissue disorders: hair growth abnormal, trichiasis
8.4

Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative
Data

Abnormal laboratory findings are presented in Table 4.

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Table 4:

Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients
Receiving PEMAZYRE™ in FIGHT-202
PEMAZYRE™a
N=146
All Gradesb (%)

Grades ≥ 3 (%)

Decreased hemoglobin

43

5.5

Decreased lymphocytes

36

8.2

Decreased platelets

28

3.4

Increased leukocytes

27

0.7

Decreased leukocytes

18

1.4

Increased phosphatec

940Decreased phosphate

68

38

Increased alanine aminotransferase

43

4.1

Increased aspartate aminotransferase

43

6.2

Increased calcium

43

4.1

Increased alkaline phosphatase

41

11

Increased creatinined

41

1.4

Decreased sodium

39

12

Increased glucose

36

0.7

Decreased albumin

34

0

Increased urate

30

10Increased bilirubin

26

5.5

Decreased potassium

26

4.8

Decreased calcium

17

2.7

Increased potassium

12

2.1

Decreased glucose

11

1.4

Laboratory Abnormality
Hematology

ChemistryaThe denominator used to calculate the rate varied from 142-146 based on the number ofpatients with a baseline value and at least one post-treatment value.
b
Graded per NCI CTCAE 4.03.
cBased on CTCAE 5.0 grading.
dGraded based on comparison to upper limit of normal.

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9

DRUG INTERACTIONS

9.2

Drug Interactions Overview

Pemigatinib is primarily metabolized in humans by CYP3A4. Unchanged pemigatinib was the
major drug-related moiety in plasma, with only minor circulating metabolites.
CYP3A inhibitors
Co-administration of moderate or strong CYP3A inhibitors is predicted to increase thesteady-state exposure of pemigatinib. Co-administration of PEMAZYRE™ with moderate orstrong CYP3A inhibitors should be avoided. Reduce the PEMAZYRE™ dose if co-administration
with a strong or moderate CYP3A inhibitor cannot be avoided. For patients who are taking
PEMAZYRE™ 13.5 mg QD, reduce the PEMAZYRE™ dose to 9 mg QD and for patients who aretaking PEMAZYRE™ 9 mg QD, reduce PEMAZYRE™ dose to 4.5 mg QD.
CYP3A inducers
Co-administration of moderate or strong CYP3A inducers is predicted to decrease thesteady-state exposure of pemigatinib. Co-administration of PEMAZYRE™ with moderate orstrong CYP3A inducers should be avoided.
9.4

Drug-Drug Interactions

The drugs listed in Table 5 are based on clinical trial or theoretical based on
physiologically-based pharmacokinetic (PBPK) modeling.
Table 5:

Established or Potential Drug-Drug Interactions

Proper/Common
Name

Source ofEvidence

EffectClinical comment

Effect of CYP3A inhibitors on pemigatinib:
Strong CYP3A
inhibitor (eg.,itraconazole,
ketoconazole,
clarithromycin)

CT, T

PEMAZYRE™ Product Monograph

Increase in pemigatinib
exposureMean ratio (90% CI)
for Cmax was 117%
(107-129)

Mean ratio (90% CI)
for AUC was 188%
(175-203)

 May lead to increased
drug-related toxicity.
 Avoid
coadministration withstrong CYP3A
inhibitors.
 If coadministration
cannot be avoided,reduce the dose of
PEMAZYRE™.

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Proper/Common
Name

Source ofEvidence

EffectClinical comment

Moderate CYP3A
inhibitor (eg.,erythromycin,
diltiazem)

T

Pemigatinib exposure
increased by approximately
50% when co-administeredwith moderate CYP3A4
inhibitors.

 May lead to increased
drug-related toxicity.
 Avoid
coadministration withmoderate CYP3A
inhibitors If coadministration
cannot be avoided,reduce the dose of
PEMAZYRE™.

Weak CYP3A
inhibitor (eg.,fluvoxamine)TNo drug-drug interaction
was predicted

 No dose adjustment isrecommended.

Effect of CYP3A inducers on pemigatinib:
Strong CYP3A
inducer (eg.,rifampin)CT

Decrease in pemigatinib
exposure

Mean ratio (90% CI)
for Cmax was 38%(33.2, 43.5)
Mean ratio (90% CI)
for AUC was 14.9%(13.9, 16.1)

 May lead to decreased
activity Avoid
coadministration ofstrong CYP inducers.

Moderate CYP3A
inducer (eg.,efavirenz)

T

Pemigatinib exposure May lead to decreased
decreased by more than 50%
activity
when co-administered with
 Avoid
moderate CYP3A4 inducers.
coadministration ofmoderate CYP
inducers

Weak CYP3A inducer(eg.,
dexamethasone)TNo drug-drug interaction
was predicted.

 No dose adjustment isrecommended.

Acid-lowering medications

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Proper/Common
Name

Source ofEvidence

Proton pumpinhibitors (eg.,esomeprazole)CT

Effect

Clinical comment
Mean ratio (90% CI)
for Cmax was 65.3%(54.7, 78.0) when coadministered withesomeprazole

 No dose adjustment isrecommended.

Mean ratio (90% CI)
for AUC was 92.1%(88.6, 95.8) when coadministered withesomeprazole.
No clinically importantchange in pemigatinib
exposure
Histamine-2
antagonists (eg.,ranitidine)CT

Mean ratio (90% CI)
for Cmax was 97.9%(77.0, 124) when coadministered withranitidine relative topemigatinib alone.

 No dose adjustment isrecommended.

Mean ratio (90% CI)
for AUC was 103%(93.1, 114) when coadministered withranitidine relative topemigatinib alone.
No clinically importantchange in pemigatinib
exposure.
Legend: CT = Clinical Trial; T = Theoretical (simulation)
Effect of Pemigatinib on CYP Substrates
Pemigatinib at clinically relevant concentrations is not an inhibitor of CYP1A2, CYP2B6,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 or an inducer of CYP1A2, 2B6, and 3A4.
Transporters
Pemigatinib is a substrate of both P-gp and BCRP. P-gp or BCRP inhibitors are not expected toaffect pemigatinib exposure at clinically relevant concentrations.

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Pemigatinib is an inhibitor of P-gp, OCT2, and MATE1. PBPK modeling suggests pemigatinib
does not result in a clinically important change in exposure of P-gp or OCT2/MATE1 substrates.
Inhibition of OCT2/MATE1 may increase serum creatinine.
9.5

Drug-Food Interactions

PEMAZYRE™ can be administered with or without food (see 10 CLINICAL PHARMACOLOGY,
Pharmacokinetics). Grapefruit, grapefruit juice, and products containing grapefruit extract
may increase pemigatinib plasma concentrations and should be avoided.
9.6

Drug-Herb Interactions

Drug-herb interactions have not been studied (see 9 Drug Interactions, Drug-Drug
Interactions).
St. John’s Wort (Hypericum perforatum) is an inducer of CYP3A that may decrease pemigatinib
plasma concentrations and should be avoided.
9.7

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.
10

CLINICAL PHARMACOLOGY

10.1 Mechanism of Action
Pemigatinib is a small molecule kinase inhibitor of FGFR1, 2 and 3. Pemigatinib inhibits FGFR
phosphorylation and signaling and selectively decreases cell viability in cancer cell lines withactivating FGFR genetic alterations, including point mutations, amplifications, and fusions or
rearrangements. These genetic alterations in FGFR genes result in activation of FGFR signalingthat supports the proliferation and survival of malignant cells. In FGFR-activated cancer celllines, the concentration required for 50% inhibition (IC 50) was less than 2 nM. In preclinicalstudies, pemigatinib exhibited anti-tumor activity in mouse xenograft models of human tumors
with FGFR1, FGFR2, or FGFR3 activation including a patient-derived xenograft model ofcholangiocarcinoma that expressed an oncogenic FGFR2-Transformer-2 beta homolog (TRA2b)
fusion protein.
10.2 Pharmacodynamics
Cardiac Electrophysiology
A dedicated QT study has not been conducted. Based on evaluation of QTc interval in
116 patients in an open-label, dose escalation study, pemigatinib did not exhibit a large effect(i.e., > 20 ms) on the QTc interval.
Serum Phosphate
Pemigatinib increased serum phosphate level due to FGFR inhibition. In patients, the increase
in serum phosphate with pemigatinib was exposure-dependent, with increased risk ofhyperphosphatemia with higher pemigatinib exposure. In pemigatinib clinical trials,

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phosphate-lowering therapy and dose modifications were permitted to manage
hyperphosphatemia. To manage phosphate elevation, refer to Table 1 (see 4 DOSAGE AND
ADMINISTRATION).
10.3 Pharmacokinetics
Pemigatinib exhibits linear pharmacokinetics in the dose range of 1 to 20 mg. Following oral
administration of PEMAZYRE™ 13.5 mg once daily, steady-state was reached by 4 days with ageometric mean accumulation ratio of 1.6. Table 6 provides the pemigatinib steady-state
pharmacokinetic parameters for 13.5 mg once daily in cancer patients.
Table 6:

Geometric Mean (CV%) Pharmacokinetic Parameters of Pemigatinib at
Steady-State Following Administration of 13.5 mg QD PEMAZYRE™ in Patientswith Cancer
Cmax(nM)

Tmax (h)Steady236 nM
1.1(0.5-6) hState(56.4)
Tmax is presented as median (range)t½ (h)

AUC0(nM·h)

CL/F (L/h)

Vz/F (L)15.4 (51.6)

2620 (54.1)

10.6 (54.1)

235 (60.8)

Absorption: The median time to achieve peak pemigatinib plasma concentration (Tmax) was
1.13 (0.50-6.00) hours.
Effect of Food:
No clinically meaningful differences with pemigatinib pharmacokinetics were observed
following administration of a high-fat and high-calorie meal (approximately 1000 calories with150 calories from protein, 250 calories from carbohydrate, and 500-600 calories from fat inpatients with cancer.
Distribution: Pemigatinib is 90.6% bound to human plasma proteins, predominantly toalbumin. The estimated apparent volume of distribution was 235 L (60.8%) in patients withcancer following a 13.5 mg oral dose.
Metabolism: Pemigatinib is predominantly metabolized by CYP3A4 in vitro. Following oral
administration of a single 11 mg radiolabeled pemigatinib dose, unchanged pemigatinib was
the major drug-related moiety in plasma, and no metabolites > 10% of total circulating
radioactivity were observed.
Elimination: The geometric mean elimination half-life (t½) of pemigatinib was 15.4 (51.6% CV)
hours and the geometric mean apparent clearance (CL/F) was 10.6 L/h (54% CV) at 13.5 mg QD
in patients with advanced cancer.
Following a single oral dose of radiolabeled pemigatinib, 82.4% of the dose was recovered infeces (1.4% as unchanged) and 12.6% in urine (1% as unchanged).
Special Populations and Conditions

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Pediatrics (< 18 years of age): The pharmacokinetics of pemigatinib has not been studied inpediatric patients.
Geriatrics (≥ 65 years of age): In a population pharmacokinetic evaluation in cancer patients,
no relationship was apparent between pemigatinib oral clearance and patient age.
Effect of weight, gender and race: Population PK analysis showed that there are no clinically
relevant effects of body weight, gender or race on pemigatinib PK parameters.
Pregnancy and Breast-feeding: The pharmacokinetics of pemigatinib in patients who are
pregnant or breast-feeding has not been studied.
Hepatic Insufficiency: The population PK analysis shows that the clearance in participants withmild or moderate hepatic impairment is not statistically significantly different from theclearance in participants with normal hepatic function. A hepatic impairment study showedthat the geometric mean of Cmax and AUC0-∞ of pemigatinib in participants with moderate
hepatic impairment was 3.3% lower and 46% higher, respectively, than in healthy-matched
participants. The geometric mean Cmax and AUC0-∞ of pemigatinib in participants with severe
hepatic impairment was 5.8% lower and 74% higher, respectively, than in healthy-matched
participants. The data from this study indicate that there is evidence of a clinically significant
pemigatinib AUC increase for participants with severe hepatic impairment, and the dose of
PEMAZYRE™ should be reduced in these patients (see 4 DOSAGE AND ADMNISTRATION,
Special Populations). The exposure difference between participants with moderate hepatic
impairment and healthy–matched participants is not considered clinically meaningful.
Renal Insufficiency: Population PK analysis shows that the clearance in participants with mild
or moderate renal impairment is not statistically significantly different from the clearance inparticipants with normal renal function. A renal impairment study showed that the geometricmean of Cmax and AUC0-∞ of pemigatinib in participants with severe renal impairment was
35.4% lower and 59% higher, respectively, than healthy-matched participants. The geometricmean Cmax and AUC0-∞ of pemigatinib in participants with end-stage renal disease (ESRD)
before hemodialysis (HD) was 22.5% and 23.2% lower than healthy-matched participants,
respectively. The geometric mean Cmax and AUC0-∞ of pemigatinib in participants with ESRD
after HD was 10.0% and 8.7% lower than healthy-matched participants, respectively. The datafrom this study indicate that there is evidence of a clinically significant pemigatinib AUC
increase for participants with severe renal impairment and and the dose of PEMAZYRE™
should be reduced in these patients (see 4 DOSAGE AND ADMNISTRATION, Special
Populations). The exposure difference between participants with ESRD before or after HD and
healthy-matched participants is not clinically meaningful.
11

STORAGE, STABILITY AND DISPOSALStore PEMAZYRE™ tablets at room temperature (15 - 30°C).
PEMAZYRE™ must be kept out of the reach and sight of children.

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PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
Proper/Common name: pemigatinib
Chemical name: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one
Molecular formula and molecular mass: C24H27F2N5O4 487.5 g/mole
Structural formula:

Physicochemical properties: Pemigatinib is a white to off-white solid that is not hygroscopic.
Pemigatinib has low aqueous solubility (dose/solubility volume > 250 mL at 37°C) above pH 4.
The aqueous solubility of pemigatinib is pH dependent with decreasing solubility observedwith increasing pH in the physiologic range.

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14

CLINICAL TRIALS

14.1 Trial Design and Study Demographics
Table 7:

Study #

Summary of patient demographics for the clinical trial in previously treated,unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2
fusion or rearrangement
Study design

Dosage, route ofadministrationand duration

Studysubjects(n)

Mean age(range)Sex

INCB 54828-202 Multicenter,(FIGHT-202)
non(NCT02924376) randomized,
open-label,multi-cohort
trial

13.5 mg
PEMAZYRE™,
oral, once-daily(QD) for 14 days
followed by nodose for 7 days,in 3-week cycles.
PEMAZYRE™ was
administered
until diseaseprogression or
unacceptabletoxicity.

107

56 years(26-77 years)

42 male65 female

The efficacy population of Study FIGHT-202 (NCT02924376) consisted of 107 patients withlocally advanced or metastatic cholangiocarcinoma that had progressed on or after at least
1 prior therapy and who had an FGFR2 fusion or rearrangement. Qualifying in-frame fusions
and other rearrangements were predicted to have a breakpoint within intron 17/exon 18 of
the FGFR2 gene, leaving the FGFR2 kinase domain intact. Fibroblast growth factor receptor(FGFR) mutation status for screening and enrolment of patients was determined by a validated
clinical trial assay.
A summary of the demographics and baseline characteristics for the main efficacy cohort(Cohort A) is shown in Table 8.

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Table 8:

Summary of Patient Demographics for Clinical Trials in INCB 54828-202(FIGHT-202) in Cholangiocarcinoma
VariableAge (years)
Mean (STD)Median (range)
Age group, n (%)< 65 years≥ 65 years
Sex, n (%)
Male
FemaleRace, n (%)
White
Black or African American
Asian
OtheraMissing
ECOG status at baseline, n (%)
0
1
2
Renal impairment grade atbaselineb
NormalMild
Moderate
SevereHepatic impairment grade atbaselinec
NormalMild
Moderate
Cholangiocarcinoma location
Intrahepatic
Extrahepatic
Other
Missing
Metastatic diseasee
Locally advanced disease

PEMAZYRE™ Product Monograph

Cohort A
N = 107 (%)
55.3 (12.02)
56.0
26-77
82 (76.6)25 (23.4)
42 (39.3)
65 (60.7)
79 (73.8)
7 (6.5)
11 (10.3)
4 (3.7)6 (5.6)45 (42.1)
57 (53.3)
5 (4.7)42 (39.3)
47 (43.9)
18 (16.8)
048 (44.9)
52 (48.6)
7 (6.5)105 (98.1)
1 (0.9)01 (0.9)d88 (82.2)
16 (15.0)

Page 26 of 37

Note: Cohort determination is based on tumor FGF/FGFR status from
central genomics laboratory. Cohort A = FGFR2 rearrangements or fusions
a Includes Hispanic, Latino, or Spanish or not reported .
b Baseline renal impairment grade (normal, mild, moderate, or severe)
based on eGFR (calculated using the MDRD equation): normal renal
function = eGFR ≥ 90 mL/min/1.73 m2; mild renal impairment = eGFR ≥ 60
and < 90 mL/min/1.73 m2; moderate renal impairment = eGFR ≥ 30 to <60 mL/min/1.73 m2; severe renal impairment = eGFR < 30 mL/min/1.73 m2.
c Degree of hepatic impairment based on National Cancer Institute Hepatic
Working Group Criteria.
d At baseline, this participant had stage 4 cholangiocarcinoma (T3 N0 M1),
presumed intrahepatic, with current sites of disease in liver, omentum, andperitoneum.
3 Metastatic information is was not able to be confirmed for one
participant and missing for two participants.
The FGF/FGFR fusions or rearrangements analysed in Cohort A are provided in Table 9.
Table 9: FGF/FGFR Genetic Alterations Identified by Central Genomics Laboratory in≥ 2 Participants (Cohort A)
Cohort A
FGF/FGFR Alteration, n(N = 107)
FGFR2-BICC1
31a
FGFR2-N/A
5
FGFR2-KIAA1217
4
FGFR2-AHCYL1
3
FGFR2-ARHGAP24
2
FGFR2-AFF42
FGFR2-CCDC62
FGFR2-MACF12
FGFR2-NOL4
2
FGFR2-NRAP2
FGFR2-PAWR2
FGFR2-SLMAP
2
a FGFR2 rearrangement confirmed but gene partner not identified/available.
14.2 Study Results
The major efficacy outcome measures were objective response rate (ORR) and duration of
response (DoR), as determined by independent review committee (IRC) according to RECIST
v1.1.

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The median duration of therapy was 6.0 months, and the median duration of efficacy
follow-up was 15.4 months.
Efficacy results are summarized in Table 10.
The median time to response was 2.7 months (range 0.7 – 6.9 months).
Table 10:

Efficacy Results
Cohort A (FGFR2 Fusion or Rearrangement)
Efficacy Evaluable Population(N = 107)
35.5% (26.5, 45.4)
2.8%
32.7%
9.1 (6.0, 14.5)

ORR (95% CI)
Complete response
Partial response
Median duration of response (months) (95%CI)aa
The 95% CI was calculated using the Brookmeyer and Crowley method.
ORR- CR+PR
CI= Confidence Interval
Note: Data are from IRC per RECIST v1.1, and complete and partial responses are confirmed.
16 NON-CLINICAL TOXICOLOGY

General Toxicology
Rats
In a 3-month repeat-dose toxicity study, once daily oral pemigatinib was administered to rats
at doses up to 1.05 mg/kg/day (resulting in systemic exposure of approximately 2 times the
AUC in patients who received the recommended dose of 13.5 mg). Deaths were observed at
the highest dose level (1.05 mg/kg/day). Toxicity was observed at all dose levels and included
weight loss, bilateral corneal crystals, soft tissue and vascular mineralization,
hyperphosphatemia and physeal and teeth dysplasia. Soft tissue mineralization included theheart, lung, stomach, duodenum, kidney, skeletal muscle, spinal cord and eyes. Teeth
dysplasia was clinically manifested by missing or broken incisors. Phosphate aberrations andcorneal crystallization showed evidence of recovery after 6 weeks, whereas tissue
mineralization, physeal and teeth dysplasia, and weight loss did not.
Cynomolgus Monkeys
In a 3-month repeat-dose toxicity study, once daily oral pemigatinib was administered tomonkeys at doses up to 1 mg/kg/day (resulting in systemic exposure of approximately 60% of
the AUC in patients who received the recommended dose of 13.5 mg). Toxicity was observedat all dose levels and included hyperphosphatemia and physeal dysplasia. Recovery wasevident, but not complete 6 weeks after cessation of dosing. Soft tissue mineralization inmonkeys was observed at 3 mg/kg/day in the 10 day range finding study; this dose was nottolerated and resulted in exposure approximately 2.7 times higher than the AUC in patientsadministered who received the recommended dose of 13.5 mg.

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Carcinogenicity
Carcinogenicity studies with pemigatinib have not been conducted.
Genotoxicity
Pemigatinib was not mutagenic in a bacterial mutagenicity assay, and was not clastogenic in an
in vitro chromosome aberration assay or in an in vivo micronucleus assay in rats.
Reproductive and Developmental Toxicology
Impairment of Fertility
No dedicated animal studies with pemigatinib have been conducted to evaluate the effects ofpemigatinib on fertility in females or males.
Developmental Toxicity
Pemigatinib was evaluated in rats in a dose range-finding embryo-fetal developmental andtoxicokinetic study, in which pregnant rats received once daily oral doses of 0.1, 0.3, and
1.0 mg/kg/day of pemigatinib during the period of organogenesis from gestational day 6 to 17.
Treatment with pemigatinib at dose levels ≥ 0.3 mg/kg caused 100% embryo-fetal mortality
due to post-implantation loss. Pemigatinib reduced maternal body weight at dose levels≥ 0.3 mg/kg and gravid uterine weight at dose levels ≥ 0.1 mg/kg. At the 0.1 mg/kg dose level,
pemigatinib reduced fetal body weight and caused vertebral anomalies, major blood vessel
variations and reduced ossification of ribs and presacral vertebrae. Systemic exposure (AUC) inrats at doses of 0.1 mg/kg and 0.3 mg/kg is approximately 20% and 60% of the AUC in patients
who received the recommended dose of 13.5 mg pemigatinib, respectively.

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READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINEPATIENT MEDICATION INFORMATIONPrPEMAZYRE™

pemigatinib tablets
Read this carefully before you start taking PEMAZYRE™ and each time you get a refill. This
leaflet is a summary and will not tell you everything about this drug. Talk to your healthcare
professional about your medical condition and treatment and ask if there is any new
information about PEMAZYRE™
What is PEMAZYRE™ used for?
For the following indication, PEMAZYRE™ has been approved with conditions (NOC/c). Thismeans it has passed Health Canada’s review and can be bought and sold in Canada, but the
manufacturer has agreed to complete more studies to make sure the drug works the way it
should. For more information, talk to your healthcare professional.
PEMAZYRE™ is used to treat adults with a type of cancer called cholangiocarcinoma (bileduct caner) when it: has a type of abnormality in a specific gene called Fibroblast Growth Factor
Receptor 2 (FGFR2); and has been treated previously cannot be removed with surgery
 is at an advanced stage or has spread to other parts of the body (called metastatic).
A test will be done to find out if the cancer has an FGFR2 gene abnormality. This is to makesure that PEMAZYRE™ is right for you.

What is a Notice of Compliance with Conditions (NOC/c)?
A Notice of Compliance with Conditions (NOC/c) is a type of approval to sell a drug in
Canada.
Health Canada only gives an NOC/c to a drug that treats, prevents, or helps identify a serious
or life-threatening illness. The drug must show promising proof that it works well, is of highquality, and is reasonably safe. Also, the drug must either respond to a serious medical needin Canada, or be much safer than existing treatments.
Drug makers must agree in writing to clearly state on the label that the drug was given an
NOC/c, to complete more testing to make sure the drug works the way it should, to actively
monitor the drug’s performance after it has been sold, and to report their findings to Health
Canada.

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How does PEMAZYRE™ work?
Fibroblast growth factor receptors (FGFRs) are proteins found on cells. These help cells growand divide. Some people with bile duct cancer have FGFRs that are more active than normal.
PEMAZYRE™ works by blocking the activity of FGFRs. This should slow down the growth andspread of bile duct cancer cells.
What are the ingredients in PEMAZYRE™?
Medicinal ingredients: pemigatinib
Non-medicinal ingredients: magnesium stearate, microcrystalline cellulose, sodium starchglycolate
PEMAZYRE™ comes in the following dosage forms:
Tablets, 4.5 mg, 9 mg, and 13.5 mg
Do not use PEMAZYRE™ if: you are allergic to pemigatinib or to any of the other ingredients in PEMAZYRE™
including any part of the container.
To help avoid side effects and ensure proper use, talk to your healthcare professional before
you take PEMAZYRE™. Talk about any health conditions or problems you may have,including if you: have problems swallowing tablets
 have severe liver problems
 have severe kidney problems
Other warnings you should know about:
Treatment with PEMAZYRE™ can cause serious side effects, including: Hyperphosphatemia (high phosphate levels in your blood) or hypophosphatemia (lowlevels of phosphate in your blood): Your healthcare professional will do blood tests tocheck levels of phosphate in your blood. These tests will be done 14 days after you
start PEMAZYRE™. They will be repeated about every 6 weeks. If your levels are toohigh or too low, you may need to: change the amount of phosphate you eat in your diet; change your dose of PEMAZYRE™, or start or stop taking other medications that affect the amount of phosphate inyour blood.
Because of the risk for hyperphosphatemia, avoid using antacids that contain calcium
and supplements that are phosphate-based.
 High levels of creatinine in your blood, which may be a sign that you are having kidney
problems.
 Eye and vision problems, including: dry eye. If this happens you may need to use artificial tears or somethingsimilar.
 inflamed eyes (including inflammation of the cornea, which is the front part ofthe eye) increased tears

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

serous retinal detachment. This is when fluid builds up in the eye and causes
the retina to detach. Your healthcare professional will check your eyes andvision before you start taking PEMAZYRE™, every 2 months for the first
6 months of your treatment and then every 3 months thereafter. If you
develop any changes in your vision during your treatment with PEMAZYRE™
such as: blurred vision, flashes of light, or seeing black spots, tell yourhealthcare professional. You may need to see an eye specialist (anophthalmologist) right away.

See the Serious Side Effects and What To Do About Them table, below, for more informationon these and other serious side effects.
Female patients – Pregnancy and breastfeeding: If you are pregnant, or are still able to get pregnant and / or breastfeed, there are
specific risks you must discuss with your healthcare professional.
 You should not be pregnant while you are taking PEMAZYRE™. It may harm yourunborn baby or make you lose the pregnancy.
 For females who are able to get pregnant: Your healthcare professional will do a pregnancy test before you start
treatment with PEMAZYRE™.
 Use effective birth control during your treatment with PEMAZYRE™ and for
1 month after your last dose. Talk to your healthcare professional about
available birth control methods.
 If, during your treatment, you become pregnant or think you are pregnant,tell your healthcare professional right away.
 It is not known if PEMAZYRE™ passes into breastmilk. Do not breastfeed while you aretaking PEMAZYRE™ and for 1 month after your last dose. Talk to your healthcare
professional about the best way to feed your baby during this time.
Male patients – Pregnancy: Use effective birth control each time you have sex with a woman who can get
pregnant. This is necessary during your treatment with PEMAZYRE™ and for 1 monthafter your last dose.
 If, during your treatment, your partner thinks she is pregnant, tell your healthcare
professional right away.
Driving and using machines: Before you do tasks which may require special attention, wait
until you know how you respond to PEMAZYRE™. If you experience vision problems, do not
drive or use tools or machines until the side effect goes away.
Tell your healthcare professional about all the medicines you take, including any drugs,
vitamins, minerals, natural supplements or alternative medicines.
The following may interact with PEMAZYRE™: Medicines to treat fungal infections called itraconazole and oral ketoconazole.
 Medicines to treat infections called clarithromycin and erythromycin.
 A medicine to treat HIV infection called efavirenz.

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A medicine to treat high blood pressure or chest pain called diltiazem.
A medicine to treat tuberculosis or other bacterial infections called rifampin.
An herbal remedy mainly used to treat depression called St. John’s Wort.

Do not eat or drink grapefruit products or products that contain grapefruit extract during yourtreatment with PEMAZYRE™. These can affect the way the medicine works.
How to take PEMAZYRE™: Take exactly as your healthcare professional tells you. Check with your doctor or
pharmacist if you are not sure.
 Take one tablet with or without food, once per day, at about the same time each day.
 Take your PEMAZYRE™ every day for 14 days (2-weeks) in a row. This is followed by
7 days (1-week) with no treatment (treatment-free week). Two weeks of treatment and
one week with no treatment make up a 21-day cycle.
 Swallow tablets whole. Do not crush, chew, split or dissolve tablet
Usual dose: 13.5 mg per day for 14 days followed by 7 days with no treatment.
You may receive a lower dose if you are taking certain medications or have severe kidney orliver problems.
Your healthcare professional may change your dose of PEMAZYRE™, or may temporarily orcompletely stop your treatment. This may happen if you develop certain side effects or yourdisease gets worse.
Overdose:
If you think you, or a person you are caring for, have taken too much PEMAZYRE™, contact a
healthcare professional, hospital emergency department or regional poison control centre
immediately, even if there are no symptoms.
Missed Dose:
If it is 4 or more hours later than when you should have taken your PEMAZYRE™ dose, or if you
vomit after taking your dose:

do NOT make up the dose. Skip it and continue with your next dose at the usual
time. Do not take an extra dose the next day to make up for the missed dose.

If it is less than 4 hours later than when you should have taken your dose, take it as soon as
you remember. Continue with your next dose at the usual time.
What are possible side effects from using PEMAZYRE™?
These are not all the possible side effects you may feel when taking PEMAZYRE™. If you
experience any side effects not listed here, contact your healthcare professional.
hair loss
abnormal hair growth
feeling tired
dizziness

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headachenose bleeds
feverdecreased appetite

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taste changes
heartburn or indigestion
dry mouth
mouth sores
nauseavomiting
constipation

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diarrhea
abdominal painback pain
pain in the arms or legs
muscle pain and stiffness
swelling of the arms and legs
weight decreased

PEMAZYRETM can cause abnormal blood test results. Your healthcare professional will do blood
tests during your treatment and will interpret the results.
Serious side effects and what to do about them
Talk to your healthcare professional
Symptom / effect
Only if severe
In all cases
VERY COMMON
Hyperphosphatemia (highblood phosphate levels): muscle
cramps and tingling
Hypophosphatemia (low blood
phosphate levels): muscle
weakness and pain, confusion,
seizures, tea-coloured urine,
heart or breathing problems
Nail or skin problems: nails
separating from the bed; nailpain, breaking of the nails,
infected skin around the nails;
color or texture changes, dry
skinPalmar-Plantar
erythrodysaesthesia (hand-footsyndrome): swelling, peeling or
tenderness, mainly on thehands and feet
Arthralgia: joint pain
Urinary tract infection(infection of the urinary
system): pain or burning
sensation while urinating,frequent urination, blood in the
urine

PEMAZYRE™ Product Monograph

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and get immediate
medical help

✓

✓

✓

✓
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Serious side effects and what to do about them
Talk to your healthcare professional
Symptom / effect
Only if severe
In all cases
Dehydration: feeling thirsty,
infrequent urination, feeling
dizzy or tired, dark yellow urine,
dry mouth and lips
Hypercalcemia (high blood
calcium levels): increase in urine
production, increase in thirst,
nausea, weakness, confusion
Anemia (decreased number of
red blood cells): fatigue,
weakness, loss of energy, fastheart rate, pale complexion,
shortness of breath
Hyponatremia (low blood
sodium levels): nausea,
vomiting, fatigue, headache,confusion, seizure
COMMON
Vision problems including
serous retinal detachment(when fluid builds up under the
retina): blurred vision, blackspots, flashes of light,
inflammation of the cornea, dryeyeTrichiasis: eyelashes growinward to the eye
Kidney problems: passing low
amounts of urine, nausea,swelling in legs and ankles,
confusion, difficulty breathing
Cholangitis (infection of thebiliary tract): abdominal pain,
fever, chills, jaundice (yellowingof the skin or whites of theeyes), nausea, vomiting
Pleural effusion (a buildup of
fluid between the tissues thatline the lungs

PEMAZYRE™ Product Monograph

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and get immediate
medical help

✓

✓

✓

✓

✓

✓
✓

✓

✓

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Serious side effects and what to do about them
Talk to your healthcare professional
Symptom / effect
Only if severe
In all cases
Failure to thrive (a decline inadults, often associated withphysical frailty, functional
disability, and /orneuropsychiatric impairment):
weight loss, weakness,decreased physical activity,difficulty in performing selfcare, change in mental status
Sepsis (a serious condition
caused by infection and the
body’s response to infection
potentially leading to organ
dysfunction): low bloodpressure, fast heart rate, fever,decrease in urination, difficulty
breathing, altered mental
status.
Intestinal obstruction (aninterruption to the flow of theintestines): abdominal pain ordistention, nausea, vomiting
Bile duct obstruction (blockageof the bile duct that transports
bile from the liver to thegallbladder and small intestine):
abdominal pain, dark urine,
fever, itching, jaundice(yellowing of the skin or whitesof the eyes,) nausea, vomiting,pale colored stools

Stop taking drug
and get immediate
medical help

✓

✓

✓

✓

If you have a troublesome symptom or side effect that is not listed here or becomes badenough to interfere with your daily activities, talk to your healthcare professional.

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Reporting Side Effects
You can report any suspected side effects associated with the use of health products to
Health Canada by:

Visiting the Web page on Adverse Reaction Reporting(https://www.canada.ca/en/health-canada/services/drugs-healthproducts/medeffect-canada/adverse-reaction-reporting.html) for information on how
to report online, by mail or by fax; orCalling toll-free at 1-866-234-2345.



NOTE: Contact your health professional if you need information about how to manage yourside effects. The Canada Vigilance Program does not provide medical advice.
Storage:
Store PEMAZYRE™ between 15°C to 30°C.
Keep out of sight and reach of children.
If you want more information about PEMAZYRE™:

Talk to your healthcare professional
Find the full product monograph that is prepared for healthcare professionals andincludes this Patient Medication Information by visiting the Health Canada website; themanufacturer’s website (www.incytebiosciences.ca), or by calling 1-833-309-2759.

This leaflet was prepared by Incyte Corporation.
Wilmington, Delaware 19803 USA
Last Revised September 8, 2021

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