佩米替尼(pemigatinib)详细说明书:适应症、用法用量、副作用、注意事项

Pemetinib has clear therapeutic activity in patients with previously treated locally advanced/metastatic cholangiocarcinoma with FGFR2 fusion/rearrangement, as well as in patients with relapsed/refractory myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement.

1. Indications of pemigatinib

‌1.1 Cholangiocarcinoma‌

It is suitable for the treatment of adult patients with previously treated unresectable locally advanced or metastatic cholangiocarcinoma confirmed by FDA-approved testing to have fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangements.

Approval of this indication mainly depends on the overall response rate of the treatment regimen and its relative acceleration of the duration of response, and subsequent approval will also depend on the results of further confirmatory trials on its clinical benefit.

‌1.2 FGFR1 rearranged myeloid/lymphoid neoplasms‌

Pemigatinib is suitable for the treatment of adult patients with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.

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.

‌2. Usage and dosage of pemigatinib‌

‌2.1 Patient selection‌

‌ Cholangiocarcinoma patients‌ need to confirm FGFR2 fusion/rearrangement through FDA-approved testing methods.

‌Patients with FGFR1 rearranged MLNs‌ need to confirm the presence of FGFR1 rearrangement. There are currently no FDA-approved tests for screening patients with FGFR1 rearrangements who are treated with pemigatinib.

‌2.2 Recommended dose‌

(1)‌Dosage instructions‌:

Pemigatinib should be taken at about the same time every day, with food or on an empty stomach.

Swallow the tablet whole. Do not crush, chew, split or dissolve the tablet.

If a dose is missed for more than 4 hours or vomiting occurs, skip the dose and take the next dose as originally planned.

(2) Cholangiocarcinoma:

The recommended dose 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 the disease progresses or intolerable toxicity occurs.

(3) FGFR1-rearranged myeloid/lymphoid neoplasms:

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

‌2.3 Dose adjustment when used in combination with strong/moderate CYP3A inhibitors‌

Avoid coadministration of pemigatinib with strong or moderate CYP3A inhibitors. If coadministration cannot be avoided:

Adjust the initial dose of pemetinib from 13.5 mg to 9 mg.

If the original dose is 9 mg, then further reduce it to 4.5 mg

After discontinuing the strong/moderate CYP3A inhibitor (after 3 plasma half-lives of the inhibitor), return to the pemigatinib dose before combination.

‌2.4 Recommended dose for patients with severe renal insufficiency‌

For patients with severe renal insufficiency (eGFR15-29mL/min/1.73m², estimated using the MDRD formula):

The recommended dose is 9 mg, and should be used according to the intermittent or continuous dosage regimen corresponding to the indication.

‌2.5 Recommended dose for patients with severe hepatic impairment‌

For patients with severe hepatic impairment (total bilirubin >3×ULN with any AST elevation):

The recommended dose is 9 mg, and should be used according to the intermittent or continuous dosage regimen corresponding to the indication.

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‌3. Pemigatinib dosage forms and specifications‌

(1), 4.5 mg, round, white to off-white tablet, engraved with "I" on one side and "4.5" on the other side.

(2), 9 mg, oval, white to off-white tablets, engraved with "I" on one side and "9" on the other side.

(3), 13.5 mg, round, white to off-white tablets, engraved with "I" on one side and "13.5" on the other side.

‌4. Contraindications of pemigatinib‌

None.

5. Precautions for pemigatinib‌

‌5.1 Ocular toxicity‌

(1)‌Retinal pigment epithelial detachment (RPED)‌

Pemigatinib may cause RPED, with clinical manifestations of blurred vision, floaters or photopsias. Optical coherence tomography (OCT) was not routinely used to monitor asymptomatic RPED in pemigatinib clinical trials, so the incidence of asymptomatic RPED is unknown.

‌Monitoring requirements‌:

A comprehensive eye examination including OCT is required before taking the drug.

Reexamination every 2 months for the first 6 months of treatment and every 3 months thereafter.

Urgent ophthalmological evaluation is required when visual symptoms occur, and follow-up is required every 3 weeks until the symptoms are relieved or the medication is discontinued.

(2) ‌Dry Eye Syndrome‌

The incidence rate was 31% among 635 patients (Grade 3-4 accounted for 1.6%).

It is recommended to use oculardemulcents (eye lubricants) as needed for treatment.

5.2 Hyperphosphatemia and soft tissue calcification

Pemigatinib may cause hyperphosphatemia, leading to soft tissue calcification, skin calcification, calcinosis and non-uremic calciphylaxis. Increased serum phosphate is a pharmacodynamic effect of pemigatinib.

Monitoring and treatment:

Start a low-phosphate diet when blood phosphorus is >5.5 mg/dL;

Start phosphorus-lowering treatment immediately when blood phosphorus is >7 mg/dL.

Withhold/reduce/permanently discontinue medication based on duration and severity of hyperphosphatemia.

5.3 Embryo-fetal toxicity

(1) Mechanism of action:

As shown in animal studies, the administration of pemetinib to fetuses during the organ formation period can cause fetal malformations, growth retardation and even death. Its toxicity to the fetus is lower than the clinical safety AUC value of 13.5mg.

(2) Risk control measures:

Pregnant women should inform their fetuses of potential risks.

Women of childbearing potential need effective contraception during treatment and 1 week after the last dose.

Male patients with female partners of childbearing age need to take contraceptive measures during treatment and 1 week after the last dose.

6. Adverse reactions/side effects of pemigatinib

Ocular toxicity, hyperphosphatemia and soft tissue calcification.

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‌7. Drug interactions of pemigatinib‌

‌7.1 The effects of other drugs on pemigatinib Effects‌

(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.

‌8. Special population use of pemigatinib‌

‌8.1 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. Observations of pregnant rats during the organogenesis period at plasma exposure levels of pemetinib that were lower than the clinical human exposure of 13.5 mg still revealed a series of fetal abnormalities such as fetal malformation, growth retardation, and embryonic death. 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%.

‌8.2 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.

‌8.3 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.

‌8.4 Medication in Children‌

So far, the safety and effectiveness of pemetinib in children have not been fully studied and established.

‌8.5 Geriatric Medication‌

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

‌8.6 Renal insufficiency‌

Patients with severe renal insufficiency should use caution and reduce the dose. Patients with mild to moderate renal insufficiency do not need to adjust the dose of the drug.

No dose adjustment is required in patients with end-stage renal disease receiving intermittent hemodialysis.

‌8.7 Hepatic insufficiency‌

‌Patients with severe hepatic insufficiency (total bilirubin >3×ULN with any AST elevation) need to use reduced dosage.

‌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).

9. Description of pemigatinib

Pemigatinib is a kinase inhibitor with the chemical name 3-(2,6-di Fluoro-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. The molecular formula is C24H27F2N5O4 and the molecular weight is 487.5 g/mol.

Pemigatinib is a white to off-white solid. The solubility of pemigatinib is related to pH value, and the solubility decreases when the pH value increases. Pemigatinib tablets are uncoated tablets for oral administration. Tablets are available in sizes of 4.5 mg, 9 mg or 13.5 mg, and the active ingredient is pemigatinib. Inactive ingredients include magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

10. Clinical pharmacology of pemigatinib

10.1 Mechanism of action

Pemigatinib is a small molecule kinase inhibitor targeting FGFR1, 2 and 3 with an IC50 value of less than 2nM. The inhibitory effect of pemigatinib on FGFR4 is up to 100 times that of FGFR1, 2, and 3, and its inhibitory effect on FGFR4 can be clearly seen in in vitro experiments. Pemigatinib inhibits FGFR1-3 phosphorylation and signaling and reduces cell viability in cancer cell lines that harbor activated FGFR amplification and fusion, leading to constitutive activation of FGFR signaling. Constitutive FGFR signaling can support the proliferation and survival of malignant cells.

10.2 Pharmacodynamics

Serum phosphate

Pemigatinib causes an increase in serum phosphate levels due to FGFR inhibition. When the amount of Pemigatinib is gradually increased (i.e., within the daily dose range of 1 to 20 mg), its increase in serum phosphate is also proportional, and the risk of hyperphosphatemia in patients is also increased.

Cardiac Electrophysiology

Pemigatinib did not cause a large mean increase in the QTc interval (i.e., >20 msec) at doses 1.5 times the maximum recommended dose.

10.3 Pharmacokinetics

The geometric mean (CV%) of the steady-state AUC0-24h after oral administration is only 2620nM·h (54%), and the Cmax is only 236nM (56%), which obviously cannot achieve the expected effect. 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).

11. Non-clinical toxicology of pemigatinib

11.1 Carcinogenesis, mutagenicity, and impaired fertility

The carcinogenicity of pemigatinib has not been studied.

In the in vitro bacterial reverse mutation (Ames) test, pemigatinib has no mutagenicity; in the in vitro chromosomal aberration test and the in vivo rat micronucleus test, pemigatinib has no clastogenicity.

Fertility-specific studies with pemigatinib have not been conducted. Oral pemigatinib did not produce any dose-related effects that may lead to impairment of male or female reproductive organs.

12. How to store pemigatinib

Store pemigatinib tablets at room temperature 20°C to 25°C (68°F to 77°F); allow temperature fluctuations to 15°C to 30°C (59°F to 86°F)