佩米替尼(pemigatinib)中文说明书

The R&D manufacturer is Incyte of the United States. In April 2020, the U.S. Food and Drug Administration (FDA) approved pemetinib for the treatment of advanced or metastatic cholangiocarcinoma with FGFR2 gene fusion or rearrangement. ‌

Indications of pemigatinib‌

1. Treatment of adult patients with previously treated unresectable locally advanced or metastatic cholangiocarcinoma confirmed by FDA-approved testing to have FGFR2 fusion or rearrangement. This indication received accelerated approval based on overall response rate and duration of response, with subsequent approval contingent on verification of clinical benefit in confirmatory trials.

2. Treatment of adult patients with relapsed or refractory FGFR1-rearranged myeloid/lymphoid neoplasms (MLNs).

The pictures are from public channels (such as the official website of the FDA, the official website of the original drug manufacturer, etc.) and are for reference only.

‌Usage and dosage of pemigatinib‌

‌1. Cholangiocarcinoma‌

Patients with FGFR2 gene fusion or rearrangement should undergo corresponding examination and confirmation before taking the drug.

The recommended dose of pemigatinib is 13.5 mg orally once a day, taken continuously for 14 days and then discontinued for 7 days (a cycle of 21 days) until disease progression or intolerable toxicity.

2‌.FGFR1-rearranged MLNs‌

The recommended dose of pemigatinib is 13.5 mg orally once daily (continuously taken) until disease progression or intolerable toxicity.

‌3. Medication Instructions‌

Pemigatinib needs to be swallowed whole and can be taken with food.

‌According to the severity of their renal function, patients with renal failure whose eGFR is less than or equal to 29 mL/min can have the original dose of 9 mg adjusted to an appropriate intermittent or continuous use regimen.

Based on severe hepatic insufficiency (especially an increase in total bilirubin more than 3 times the ULN), the initial dose of the drug should be reduced to 9 mg.

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‌Pemigatinib dosage forms and specifications‌

Three specifications of tablets: 4.5mg/9mg/13.5mg.

‌Contraindications of pemigatinib‌

None.

Precautions for pemigatinib‌

‌1. Ocular toxicity‌ may lead to retinal pigment epithelial detachment. Optical coherence tomography (OCT) examination is required before taking the drug, and should be reviewed every 2 months for 6 months before treatment, and every 3 months thereafter. Check immediately when visual symptoms appear.

‌2. Hyperphosphatemia and soft tissue calcification‌ According to the patient’s blood phosphorus level, we will adjust the dosage of the drug or discontinue the drug accordingly to try to keep it in a relatively stable state.

‌3. Embryo-fetal toxicity‌ has the risk of teratogenesis, and patients of childbearing age need to take effective contraceptive measures.

‌Adverse reactions of pemigatinib‌

‌1. Patients with cholangiocarcinoma (incidence ≥20%)

Hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, loss of appetite, vomiting, joint pain, abdominal pain, hypophosphatemia, back pain, and dry skin.

‌2.Patients with FGFR1 rearranged MLNs (incidence ≥20%)

Hyperphosphatemia, nail toxicity, alopecia, stomatitis, diarrhea, dry eye syndrome, fatigue, rash, abdominal pain, anemia, constipation, dry mouth, epistaxis, serous retinal detachment, limb pain, decreased appetite, dry skin, indigestion, back pain, nausea, blurred vision, peripheral edema, dizziness.

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‌Drug interactions of pemigatinib‌

(1)‌Strong/moderate CYP3A inducers‌

Combining pemigatinib with strong or moderate CYP3A inducers will reduce the plasma concentration of pemigatinib, which may lead to a decrease in efficacy. Coadministration of pemigatinib with strong or moderate CYP3A inducers should be avoided.

(2)‌Strong/moderate CYP3A inhibitors‌

Combining pemigatinib with strong or moderate CYP3A inhibitors will increase the plasma concentration of pemigatinib and may aggravate the incidence and severity of adverse reactions. Such combinations should be avoided. If this cannot be avoided, the dose of pemigatinib needs to be reduced.

‌Special population use of pemigatinib‌

1. Pregnancy‌

Based on the results of animal studies and its mechanism of action, the use of pemigatinib in pregnant women may cause fetal damage or miscarriage. There are currently no clinical data on the use of pemigatinib in pregnant women. Fetal malformations, growth retardation, and embryonic death were observed when pemetinib was administered to pregnant rats during the period of organogenesis (at plasma exposures below the human exposure at the clinical dose of 13.5 mg). Pregnant women should be informed of the potential risk to the fetus.

In the general U.S. population, the background risk of major birth defects in clinically confirmed pregnancies is 2%-4%, and the background risk of spontaneous abortion is 15%-20%.

‌2. Breastfeeding‌‌

There is no data on the content of pemetinib and its metabolites in breast milk and its effects on infants. Since pemigatinib may cause serious adverse reactions in breastfed children, it is recommended to stop breastfeeding during treatment and within 1 week after the last dose.

‌3. Women/men of childbearing potential‌

The use of pemigatinib in pregnant women may cause fetal damage.

Females should take effective contraceptive measures during treatment and within 1 week after the last dose.

Men and female partners of childbearing potential must use effective contraception during treatment and within 1 week after the last dose.

‌4. Medication in children‌

The safety and effectiveness of pemigatinib in pediatric patients have not been established.

‌5. Medication for the Elderly‌

There is no overall difference in safety and effectiveness between elderly patients and young patients.

‌6. Renal insufficiency‌

Patients with severe renal insufficiency (eGFR15-29mL/min/1.73m², estimated according to the MDRD equation) need to use reduced dosage. ‌

‌Mild to moderate renal insufficiency‌(eGFR30-89mL/min/1.73m²): No dose adjustment is required.

Patients with end-stage renal disease (eGFR<15mL/min/1.73m²) receiving intermittent hemodialysis: No dose adjustment is required.

‌7. Hepatic insufficiency‌

‌Severe hepatic insufficiency (total bilirubin >3×ULN with any AST elevation): Use in reduced dosage.

‌Mild to moderate hepatic insufficiency‌:

No dose adjustment is required for mild (total bilirubin > ULN to 1.5×ULN or AST > ULN) or moderate (total bilirubin > 1.5-3×ULN with any AST elevation).

‌Pemigatinib Storage

Store pemigatinib tablets at room temperature 20°C to 25°C; allow temperature fluctuation to 15°C to 30°C.

‌Pharmacokinetics of pemigatinib

With 13.5 mg taken orally once daily, the geometric mean (CV%) of steady-state AUC0-24h of pemigatinib is 2620nM·h (54%), and Cmax is 236nM (56%). Steady-state concentrations of pemigatinib increased proportionally over the dose range of 1 to 20 mg (0.07 to 1.5 times the recommended dose). Pemigatinib reached steady state within 4 days, with a median accumulation ratio of 1.63 (range, 0.63 to 3.28) after repeated once-daily dosing.

(1) Absorption

The median time to reach peak plasma concentration (Tmax) of pemigatinib is 1.13 (0.50-6.00) hours.

Effect of Food

Taking pemigatinib with a high-fat and high-calorie meal (approximately 1,000 calories, of which 150 calories from protein, 250 calories from carbohydrates, and 500-600 calories from fat) has no clinically significant effect on pemigatinib pharmacokinetics.

(2) Distribution

After an oral dose of 13.5 mg, the estimated apparent volume of distribution is 235L (60.8%). The protein binding rate of pemigatinib is 90.6% and is independent of in vitro concentration.

(3) Elimination

The geometric mean (%CV) elimination half-life (t½) of pemigatinib is 15.4 (51.6%) hours, and the geometric mean apparent clearance rate (CL/F) is 10.6L/h (54%).

(4) Metabolism

Pemigatinib is mainly metabolized by CYP3A4 in vitro. The major drug-related component in plasma was unchanged pemigatinib.

(5) Excretion

After a single oral administration of 11 mg of radiolabeled pemigatinib, 82.4% of the dose was recovered in the feces (1.4% unchanged) and 12.6% of the dose was recovered in the urine (1% unchanged).