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Pemigatinib

Brand name: Pemazyre
Drug class: Antineoplastic Agents
Chemical name: 11-(2,6-difluoro-3,5-dimethoxyphenyl)-13-ethyl-4-(morpholin-4-ylmethyl)-5,7,11,13-tetrazatricyclo[7.4.0.02,6]trideca-1,3,6,8-tetraen-12-one
Molecular formula: C24H27F2N5O4
CAS number: 1513857-77-6

Medically reviewed by Drugs.com on Apr 15, 2022. Written by ASHP.

Introduction

Antineoplastic agent; potent and selective small-molecule inhibitor of fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, and FGFR3).

Uses for Pemigatinib

Cholangiocarcinoma

Treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 genomic aberration (e.g., fusion, rearrangement).

Accelerated approval based on objective response rate of 36% in a cohort of patients with unresectable locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 genomic aberration. Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Designated an orphan drug by FDA for treatment of cholangiocarcinoma.

Pemigatinib Dosage and Administration

General

Pretreatment Screening

  • Confirm presence of FGFR2 fusion or rearrangement prior to initiation of therapy.

  • Perform ophthalmologic examination, including optical coherence tomography, prior to initiation of therapy.

  • Verify pregnancy status in females of reproductive potential.

Patient Monitoring

  • Monitor serum phosphate concentrations during therapy.

  • Perform ophthalmologic examinations, including optical coherence tomography, every 2 months during the first 6 months of therapy, and then every 3 months thereafter; if visual disturbances occur, perform ophthalmologic examinations urgently and follow-up every 3 weeks until resolution of symptoms or discontinuation of the drug.

Administration

Oral Administration

Administer orally once daily without regard to food at approximately the same time of day.

Swallow tablets whole; do not split, crush, chew, or dissolve.

Dosage

Adults

Cholangiocarcinoma
Oral

13.5 mg once daily on days 1–14 of each 21-day cycle. Continue therapy until disease progression or unacceptable toxicity occurs.

If concomitant use with potent or moderate CYP3A inhibitors cannot be avoided, adjust dosage of pemigatinib.

Dosage Modification for Toxicity
Oral

Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of drug may be necessary. When dosage modification is required, reduce dosage of pemigatinib as described in Table 1.

Table 1. Dosage Reduction for Pemigatinib Toxicity.1

Dosage Reduction Level

Dosage Reduction after Recovery from Toxicity (Initial Dose = 13.5 mg once daily on days 1–14 of each 21-day cycle)

First

Resume at 9 mg once daily on days 1–14 of each 21-day cycle

Second

Resume at 4.5 mg once daily on days 1–14 of each 21-day cycle

Third

Permanently discontinue drug

Ocular Effects
Oral

For retinal pigment epithelial detachment, temporary interruption, dosage reduction, and/or permanent discontinuance may be necessary (see Table 2).

Table 2. Dosage Modification of Pemigatinib for Retinal Pigment Epithelial Detachment.1

Severity

Dosage Modification

Asymptomatic and stable on serial eye exams

Continue pemigatinib therapy

Symptomatic or worsening on serial eye exams

Withhold therapy

If symptoms resolve or signs of retinal pigment epithelial detachment improve on subsequent eye exams; reduce dosage (see Table 1)

If the toxicity does not resolve or improve on examination, consider permanent discontinuance of drug based on clinical status

Hyperphosphatemia
Oral

If hyperphosphatemia occurs, temporary interruption, dosage reduction, and/or permanent discontinuance may be necessary (see Table 3).

Table 3. Dosage Modification of Pemigatinib for Hyperphosphatemia.1

Serum Phosphate Concentration (mg/dL)

Dosage Modification

7–10

Initiate phosphate lowering therapy and monitor serum phosphate concentrations weekly

First occurrence: Withhold therapy if serum phosphate concentrations do not improve to <7 mg/dL within 2 weeks of initiating phosphate lowering therapy; resume therapy at same dosage when serum phosphate concentrations improve to <7 mg/dL

Subsequent occurrences: Withhold therapy if serum phosphate concentrations do not improve to <7 mg/dL within 2 weeks of initiating phosphate lowering therapy; resume therapy at reduced dosage when serum phosphate concentrations improve to <7 mg/dL (see Table 1)

>10

Initiate phosphate lowering therapy and monitor serum phosphate concentrations weekly

Withhold therapy if serum phosphate concentrations do not improve to ≤10 mg/dL within 1 week of initiating phosphate lowering therapy; resume therapy at next lower dosage level when serum phosphate concentrations improve to <7 mg/dL (see Table 1)

If serum phosphate concentrations >10 mg/dL recur following 2 levels of dosage reduction, permanently discontinue drug

Other Adverse Effects
Oral

For other grade 3 adverse reactions, temporarily interrupt therapy for 2 weeks; upon improvement to grade 1 or baseline, resume therapy at a dosage reduced by 1 dose level. (See Table 1.)

For grade 3 adverse reactions that do not improve within 2 weeks of withholding therapy, permanently discontinue drug.

For grade 4 adverse reactions, permanently discontinue drug.

Special Populations

Hepatic Impairment

Severe hepatic impairment (total bilirubin concentration >3 times the ULN with any AST concentration): Reduce pemigatinib dosage to 9 mg orally once daily on days 1–14 of each 21-day cycle.

Mild (total bilirubin concentration 1–1.5 times the ULN or AST concentration exceeding the ULN) or moderate (total bilirubin concentration 1.5–3 times the ULN with any AST concentration) hepatic impairment: No dosage adjustment necessary.

Renal Impairment

Severe renal impairment (GFR 15–29 mL/minute per 1.73 m2 estimated by the Modification of Diet in Renal Disease [MDRD] equation): Reduce pemigatinib dosage to 9 mg orally once daily on days 1–14 of each 21-day cycle.

Mild or moderate renal impairment (GFR 30–89 mL/minute): No dosage adjustment necessary.

Geriatric Patients

No specific dosage recommendations.

Cautions for Pemigatinib

Contraindications

  • None.

Warnings/Precautions

Ocular Effects

Retinal pigment epithelial detachment resulting in blurred vision, visual floaters, or photopsia reported. Median time to initial onset is 62 days. Incidence of asymptomatic retinal pigment epithelial detachment unknown. Ophthalmologic examination, including optical coherence tomography, not performed routinely in clinical trials.

Dry eye symptoms also reported. Administer ocular demulcents as needed.

Perform ophthalmologic examinations, including optical coherence tomography, prior to initiation of therapy, every 2 months during the first 6 months of therapy, and then every 3 months thereafter; if visual disturbances occur, perform ophthalmologic examinations urgently and follow-up every 3 weeks until resolution of symptoms or discontinuation of the drug. If ocular toxicities occur, interrupt therapy, reduce dosage, or permanently discontinue drug.

Hyperphosphatemia and Soft Tissue Mineralization

Can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and nonuremic calciphylaxis. Elevated serum phosphate concentration occurs secondary to FGFR inhibition. Median time to onset is 8 days (range: 1–169 days) following initiation of therapy.

Monitor serum phosphate concentrations during therapy. If serum phosphate concentration >5.5 mg/dL occurs, initiate low-phosphate diet. If serum phosphate concentration >7 mg/dL occurs, initiate phosphate lowering therapy; may need to temporarily interrupt therapy, reduce dosage, and/or permanently discontinue drug.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryofetal toxicity and teratogenicity demonstrated in animals.

Confirm pregnancy status prior to initiating therapy. Avoid pregnancy during therapy. Women of reproductive potential should use effective methods of contraception while receiving pemigatinib and for 1 week after the final dose. Advise men who are partners of such women to use effective methods of contraception while receiving the drug and for 1 week after the final dose. If used during pregnancy, apprise patient of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether pemigatinib is distributed into milk, affects milk production, or affects nursing infants.

Women should not breast-feed during therapy and for 1 week following the final dose.

Females and Males of Reproductive Potential

Advise females of reproductive potential to use effective contraception during treatment with pemigatinib and for 1 week following the last dose of the drug.

Advise males with female partners of reproductive potential to use effective contraception during treatment with pemigatinib and for 1 week following the last dose of the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients.

In animal studies, changes in growing teeth (complete loss of ameloblasts with associated secondary changes; malaligned, whitened, broken, and trimmed/thinned incisors) and bones (physeal and cartilage dysplasia) observed.

Geriatric Use

In the principal efficacy study, 32% of patients were ≥65 years of age and 8% were ≥75 years of age; no clinically important differences in safety or efficacy relative to younger adults.

Hepatic Impairment

Mild (total bilirubin concentration >1–1.5 times the ULN or AST concentration exceeding the ULN) to moderate (total bilirubin concentration >1.5–3 times the ULN with any AST concentration) hepatic impairment does not substantially affect pharmacokinetics of pemigatinib.

Pemigatinib exposure is increased in patients with severe hepatic impairment (total bilirubin concentration >3 times the ULN with any AST concentration); dosage adjustment is recommended.

Renal Impairment

Mild to moderate renal impairment (GFR 30–89 mL/minute per 1.73 m2) does not substantially affect pharmacokinetics of pemigatinib.

Systemic exposure of pemigatinib not substantially altered in patients with end-stage renal disease (GFR <15 mL/minute per 1.73 m2) requiring dialysis.

Severe renal impairment (GFR 15–29 mL/minute per 1.73 m2 estimated by the Modification of Diet in Renal Disease [MDRD] equation) increases exposure of pemigatinib; dosage adjustment is recommended.

Pemigatinib increases Scr by decreasing tubular secretion of creatinine; does not affect GFR.

Common Adverse Effects

Adverse reactions reported in ≥20% of patients: Hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, dry skin.

Interactions for Pemigatinib

Principally metabolized by CYP3A4.

In vitro, pemigatinib is not an inhibitor of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 or an inducer of CYP isoenzymes 1A2, 2B6, or 3A4.

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Inhibitor of P-gp, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1.

Drugs Affecting Hepatic Microsomal Enzymes

Potent or moderate inhibitors of CYP3A: Possible increased systemic exposure of pemigatinib and increased risk of pemigatinib toxicity. Moderate CYP3A inhibitors may increase systemic exposure of pemigatinib by approximately 50–80%. Avoid concomitant use. If concomitant use cannot be avoided, reduce dosage of pemigatinib by 4.5 mg (e.g., from 13.5 mg to 9 mg once daily, from 9 mg to 4.5 mg once daily). When potent or moderate CYP3A inhibitor is discontinued, resume pemigatinib (after 3 elimination half-lives of the CYP3A inhibitor) at dosage used prior to initiation of the CYP3A inhibitor.

Potent or moderate inducers of CYP3A: Possible decreased pemigatinib plasma concentrations and reduced pemigatinib efficacy. Avoid concomitant use.

Drugs Affecting or Affected by Transport Systems

P-gp or BCRP inhibitors: Pharmacokinetic interactions unlikely.

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles (e.g., itraconazole)

Itraconazole: Increased AUC or peak plasma concentration of pemigatinib by 88 or 17%, respectively

Avoid concomitant use

If concomitant use cannot be avoided, reduce dosage of pemigatinib by 4.5 mg (e.g., from 13.5 mg to 9 mg once daily, from 9 mg to 4.5 mg once daily)

When potent or moderate CYP3A inhibitor is discontinued, resume pemigatinib (after 3 elimination half-lives of the CYP3A inhibitor) at dosage used prior to initiation of the CYP3A inhibitor

Histamine H2-receptor antagonists (e.g., ranitidine)

Ranitidine: No clinically meaningful effect on systemic exposure to pemigatinib

Metformin

No clinically important changes in blood glucose concentration

Proton-pump inhibitors (e.g., esomeprazole)

Esomeprazole: No clinically important effect on systemic exposure of pemigatinib

Rifampin

Decreased AUC or peak plasma concentration of pemigatinib by 85 or 62%, respectively

Avoid concomitant use

Pemigatinib Pharmacokinetics

Absorption

Bioavailability

Steady-state concentration is dose proportional over dosage range of 1–20 mg.

Median time to peak plasma concentration is 1.13 hours.

Steady-state concentrations achieved after 4 days of once-daily dosing; median accumulation ratio is 1.63.

Food

Administration with a high-fat, high-calorie meal (approximately 1000 calories with approximately 50% of calories from fat) did not affect pemigatinib pharmacokinetics.

Special Populations

Mild (total bilirubin concentration >1–1.5 times the ULN or AST concentration exceeding the ULN) to moderate (total bilirubin concentration >1.5–3 times the ULN with any AST concentration) hepatic impairment: No effect on pharmacokinetics of pemigatinib.

Severe hepatic impairment (total bilirubin concentration >3 times the ULN with any AST concentration): Pemigatinib exposure increased by 136%.

Mild to moderate renal impairment (GFR 30–89 mL/minute per 1.73 m2): No effect on pharmacokinetics of pemigatinib.

Severe renal impairment (GFR 15–29 mL/minute per 1.73 m2): Pemigatinib exposure increased by 59%.

End-stage renal disease requiring intermittent hemodialysis: Pharmacokinetics not substantially affected.

Distribution

Extent

Not known whether pemigatinib is distributed into human milk.

Plasma Protein Binding

90.6%; independent of concentration.

Elimination

Metabolism

Metabolized principally by CYP3A4.

Elimination Route

Eliminated primarily in feces (82.4%; 1.4% as unchanged drug) and to a lesser extent in urine (12.6%; 1% as unchanged drug).

Half-life

15.4 hours.

Special Populations

Clearance not affected by age (range: 21–79 years), sex, race, or body weight (range: 40–156 kg).

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

  • A potent and selective inhibitor of FGFR1, FGFR2, and FGFR3.

  • FGFR signaling pathway involved in proliferation and processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis); aberrant expression of FGFR signaling implicated in pathogenesis of various solid tumors. Inhibition of constitutive FGFR signaling reduces cell viability in cell lines with aberrant FGFR expression.

  • Serum phosphate concentration is a marker of FGFR inhibition; serum phosphate concentrations increase in concentration-dependent manner across dosage range of 1–20 mg once daily.

  • Demonstrates antitumor activity in mice bearing human tumor xenografts harboring FGFR1, FGFR2, or FGFR3 genomic aberrations, including cholangiocarcinoma that expressed the FGFR-2-Transformer-2 beta homolog (TRA2b) fusion protein.

  • Also inhibits FGFR4 with a half-maximal inhibitory concentration approximately 100 times higher than the half-maximal inhibitory concentration for FGFR1, FGFR2, or FGFR3.

Advice to Patients

  • Advise the patient to read the FDA-approved patient labeling (Patient Information).

  • Advise patients that pemigatinib may cause ocular toxicity including retinal pigment epithelial detachment and to immediately inform their healthcare provider if they experience any visual changes. Also advise patients that they should use artificial tears or substitutes, hydrating or lubricating eye gels in order to prevent or treat dry eyes.

  • Inform patients that they may experience increased phosphate concentrations and soft tissue mineralization and of the need to monitor serum phosphate concentrations. They should immediately inform their healthcare provider of any symptoms related to acute change in phosphate concentrations such as muscle cramps, numbness, or tingling around the mouth.

  • Advise patients that pemigatinib may cause nail disorders.

  • Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of pregnancy.

  • Advise females of reproductive potential to use effective contraception during treatment with pemigatinib and for 1 week after the final dose.

  • Advise males with female partners who are of reproductive potential or pregnant to use effective contraception during treatment and for 1 week after receiving the final dose of pemigatinib.

  • Advise patients not to breast-feed during treatment with pemigatinib and for 1 week after the final dose.

  • Instruct patients that if they miss a dose by ≥4 hours or if they vomit after taking a dose, to resume dosing with the next scheduled dose. Extra tablets should not be taken to make up for the missed dose.

  • Instruct patients do not crush, chew, split or dissolve tablets.

  • Advise patients to avoid grapefruit products during treatment with pemigatinib.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pemigatinib is available only from a designated specialty pharmacy. Contact the manufacturer for additional information.

Pemigatinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

4.5 mg

Pemazyre

Incyte

9 mg

Pemazyre

Incyte

13.5 mg

Pemazyre

Incyte

AHFS DI Essentials™. © Copyright 2022, Selected Revisions April 15, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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