pemigatinib

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications:

Pronunciation:
pem-i-ga-ti-nib

Trade Name(s)

Pemazyre

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

fibroblast growth factor receptor inhibitor

Indications

Previously treated, unresectable locally advanced, or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.
Relapsed or refractory myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) rearrangement.

Action

FGFR kinase inhibitor that binds to and inhibits FGFR1, FGFR2, and FGFR3 enzyme activity, which results in decreased FGFR-related signaling and decreased cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions.

Therapeutic Effect(s):

Decreased spread of locally advanced or metastatic cholangiocarcinoma and relapsed/refractory myeloid/lymphoid neoplasms.

Pharmacokinetics

Absorption: Rapidly absorbed; extent of absorption unknown.

Distribution: Extensively distributed to tissues.

Protein Binding: 90.6%.

Metabolism and Excretion: Primarily metabolized in the liver via CYP3A4 isoenzyme. Primarily excreted in feces (82%; 1.4% unchanged), with 12.6% excreted in urine (1% unchanged).

Half-life: 15.4 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	1.1 hr	24 hr

Contraindication/Precautions

Contraindicated in:

OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Severe renal impairment (dose ↓ required);
Severe hepatic impairment (dose ↓ required);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: peripheral edema

Derm: alopecia, dry skin, nail discoloration, nail hypertrophy, nail infection, palmar-plantar erythrodysesthesia syndrome

EENT: dry eyes, retinal pigment epithelial detachment, blurred vision, visual floaters

Endo: hyperglycemia, hypoglycemia

F and E: dehydration, hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia

GI: ↑ liver enzymes, abdominal pain, constipation, diarrhea, dry mouth, hyperbilirubinemia, hypoalbuminemia, nausea, stomatitis, vomiting

GU: ↑ serum creatinine, urinary tract infection

Hemat: anemia, leukocytosis, leukopenia, lymphocytopenia, thrombocytopenia

Metabolic: ↓ appetite, ↓ weight, hyperuricemia

MS: arthralgia, fractures

Neuro: dysgeusia, headache

Misc: fatigue

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

Strong CYP3A4 inhibitors, including itraconazole, and moderate CYP3A4 inhibitors, may ↑ levels and risk of toxicity; avoid concurrent use, if possible; if must use concurrently, ↓ pemigatinib dose.
Strong CYP3A4 inducers, including rifampin, and moderate CYP3A4 inducers may ↓ levels and effectiveness; avoid concurrent use.

Route/Dosage

Cholangiocarcinoma

PO (Adults): 13.5 mg once daily for 14 days, followed by 7 days off of therapy (21-day cycle). Continue 21-day cycles of therapy until disease progression or unacceptable toxicity. Concurrent use of strong or moderate CYP3A4 inhibitors: If previously taking 13.5 mg once daily, ↓ to 9 mg once daily. If previously taking 9 mg once daily, ↓ to 4.5 mg once daily.

Renal Impairment
PO (Adults): eGFR 15–29 mL/min/1.73 m² : 9 mg once daily for 14 days, followed by 7 days off of therapy (21-day cycle). Continue 21-day cycles of therapy until disease progression or unacceptable toxicity.

Hepatic Impairment
PO (Adults): Severe hepatic impairment (total bilirubin >3 times upper limit of normal [ULN]): 9 mg once daily for 14 days, followed by 7 days off of therapy (21-day cycle). Continue 21-day cycles of therapy until disease progression or unacceptable toxicity.

Myeloid/Lymphoid Neoplasms

PO (Adults): 13.5 mg once daily until disease progression or unacceptable toxicity. Concurrent use of strong or moderate CYP3A4 inhibitors: If previously taking 13.5 mg once daily, ↓ to 9 mg once daily. If previously taking 9 mg once daily, ↓ to 4.5 mg once daily.

Renal Impairment
PO (Adults): eGFR 15–29 mL/min/1.73 m² : 9 mg once daily until disease progression or unacceptable toxicity.

Hepatic Impairment
PO (Adults): Severe hepatic impairment (total bilirubin >3 times ULN): 9 mg once daily until disease progression or unacceptable toxicity.

Availability

Tablets: 4.5 mg, 9 mg, 13.5 mg

Assessment

Perform comprehensive ophthalmological exam, including OCT, before starting pemigatinib, every 2 mo for first 6 mo, and every 3 mo thereafter during therapy. If visual symptoms of retinal pigment epithelial detachment (blurred vision, visual floaters, photopsia) occur, refer patient for ophthalmologic evaluation urgently, with follow-up every 3 wk until resolution or discontinuation of pemigatinib. If asymptomatic and stable on serial examination, continue pemigatinib. If symptomatic or worsening on serial examination, hold pemigatinib. If asymptomatic and improved on subsequent examination, resume at a ↓ dose. If symptoms persist or do not improve, consider permanent discontinuation of pemigatinib.
Assess for dry eyes. Occurs frequently. Treat with ocular demulcents.

Lab Test Considerations:

Verify a negative pregnancy test before starting therapy.

Patient selection is based on presence of an FGFR2 fusion or rearrangement as detected by an FDA-approved test. Information is available athttp://www.fda.gov/CompanionDiagnostics .
Monitor for hyperphosphatemia periodically during therapy. Begin a low-phosphate diet when serum phosphate level >5.5 mg/dL. For serum phosphate level >7 mg/dL to ≤10 mg/dL, start phosphate-lowering therapy and monitor serum phosphate level weekly. If serum phosphate level ≥7 mg/dL within 2 wk of starting phosphate-lowering therapy, hold pemigatinib. When serum phosphate level <7 mg/dL, resume pemigatinib at same dose for 1st occurrence or at ↓ doses for subsequent occurrences. If serum phosphate level >10 mg/dL, start phosphate-lowering therapy and monitor serum phosphate level weekly. If serum phosphate level ≥10 mg/dL within 1 wk after starting phosphate-lowering therapy, hold pemigatinib. When serum phosphate level <7 mg/dL, resume pemigatinib at next lower dose. If serum phosphate level >10 mg/dL after two dose ↓, discontinue pemigatinib permanently.
May cause ↑ or ↓ leukocytes and ↓ hemoglobin, lymphocytes, and platelets.
May cause ↑ AST, ALT, alkaline phosphatase, and bilirubin and ↓ albumin.
May cause ↑ or ↓ calcium, glucose, and potassium, and ↓ sodium.
May cause ↑ uric acid and serum creatinine. Within first 21-day cycle, serum creatinine ↑ by a mean of 0.2 mg/dL, reached steady state by Day 8, and ↓ during 7 days off therapy. If ↑ serum creatinine persist, consider alternate measures of renal function. Calculate CCr using MDRD equation for dose adjustment.

Implementation

Recommended dose reductions: Cholangiocarcinoma with FGFR2 fusion or rearrangement 1st reduction: 9 mg once daily for first 14 days of each 21-day cycle 2nd reduction: 4.5 mg once daily for first 14 days of each 21-day cycle 3rd reduction: discontinue. Myeloid/lymphoid neoplasms with FGFR1 rearrangement 1st reduction: 9 mg once daily 2nd reduction: 4.5 mg once daily 3rd reduction: 4.5 mg once daily for first 14 days of each 21-day cycle. Permanently discontinue pemigatinib if unable to tolerate 4.5 mg once daily for 14 days of each 21-day cycle.
PO Administer once daily at the same time each day, without regard to food. DNC: Swallow tablet whole; do not break, crush, chew, or dissolve.

Patient/Family Teaching

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Instruct patient to take pemigatinib as directed at same time each day. If patient vomits or dose is missed by ≥4 hr, take next dose at scheduled time. Emphasize importance of frequent eye exams and lab test to monitor for side effects.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications. Advise patient to avoid grapefruit products.
Advise patient to notify health care professional immediately if visual changes (blurred vision, flashes of light, seeing black spots) or signs and symptoms of hyperphosphatemia (muscle cramps, numbness, tingling around mouth) occur.
Inform patient that nail disorders and dry eyes may occur. Artificial tear or substitutes and hydrating or lubricating eye gels may be used prevent or treat dry eyes.
Rep: May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception and to avoid breastfeeding during therapy and for 1 wk after last dose.

Evaluation/Desired Outcomes