Folotyn

[Drug name]

Common name: Pralatrexate Injection

Trade name: Pralatrexate Injection

English name: Pralatrexate Injection

Chinese Pinyin: Pulaqusha Zhusheye

[Characteristics]

This product is a yellow clear liquid.

[Indications]

This product is used to treat adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

Conditional approval for this indication is based on objective response rate results from a single-arm clinical trial. The clinical benefit in terms of progression-free survival or overall survival after treatment with this product has not been determined.

[Specifications]

1ml: 20mg

[Usage and Dosage]

Vitamin supplement before treatment

Folic acid: Patients should start taking folic acid 10 days before the first dose of pralatrexate, once a day, 1.0-1.25 mg each time. Folic acid supplementation should be continued throughout treatment until 30 days after the last dose of pralatrexate The Queen is over.

Vitamin B12: Patients should receive an intramuscular injection of vitamin B12 (1 mg) within 10 weeks before the first dose of pralatrexate and every 8-10 weeks thereafter. Follow-up vitamins B12 injections can be given on the same day as pralatrexate treatment.

The recommended dose of this product is 30 mg/m2, which should be injected intravenously through the side port of the intravenous infusion tube of 0.9% sodium chloride injection within 3-5 minutes, once a week, for 6 weeks of continuous administration, and one week of drug withdrawal. A course of treatment is given every week until disease progression or unacceptable toxicity occurs.

Monitoring and dose adjustment: When serious or intolerable adverse drug reactions occur, administration should be suspended, dose reduced, or treatment terminated.

Monitoring requires monitoring of complete blood count and severity of mucositis at baseline and weekly after dosing. Before the first and fourth dose of each course of treatment, blood biochemical tests, including liver and kidney function tests, should be performed.

Dosage adjustment is recommended before taking this product: mucositis should be ≤ grade 1.

The platelet count should be ≥ 100×109/L when taking the drug for the first time, and should be ≥ 50×109/L for subsequent doses.

The absolute neutrophil count (ANC) should be ≥ 1.0×109/L.

Dosing may be suspended or the dose may be reduced based on patient tolerance. The suspended dose must not be replenished at the end of the course; if the dose has been reduced due to toxicity, the dose must not be increased. For dose adjustments and dosing suspensions.

[Adverse Reactions]

Because clinical studies are conducted under a variety of different experimental conditions, the incidence of adverse reactions observed in the clinical studies of one drug cannot be directly compared with the incidence in the clinical studies of another drug, nor can it fully reflect the true incidence in clinical practice.

Overseas clinical trial experience

In the single-arm clinical study of PDX-008, the safety of 111 patients with relapsed or refractory PTCL who received pralatrexate monotherapy was evaluated. The starting dose of pralatrexate was 30 mg/m2, once a week, continuous administration for 6 weeks, one week off, a 7-week course of treatment. The median duration of treatment was 70 days (range, 1 - 540 days).

The most common adverse reactions

The most common adverse reactions (irrespective of causality) are mucositis, thrombocytopenia, nausea, anemia, fatigue, neutropenia, and epistaxis.

China’s clinical trial experience

A phase III single-arm clinical trial, FOT12-CN-301, conducted in China, evaluated 71 patients with relapsed or refractory peripheral T Safety of pralatrexate injection in patients with PTCL. These 71 patients received at least one pralatrexate injection, with a starting dose of 30 mg/m2, once a week, and continuous administration for 6 week, one week of drug withdrawal, and 7 weeks as a course of treatment. By the data cutoff date, all patients had completed 5 cycles of treatment, with an average treatment duration of 18.5 weeks and an average number of treatment cycles of 3.6. cycles, the average relative dose intensity was 80.4%. (The following data only represents FOT12-CN-301 from China Limited data from clinical studies. Due to the limited number of patients included in the study, it cannot represent the actual clinical drug use data after marketing).

Common adverse reactions (incidence ≥10%)

A total of 1569 TEAEs occurred in 70 (98.6%) subjects, most of which were CTCAE 1 or 2 class. The most common (incidence ≥10%) adverse reactions were oral mucositis (64.8%), anemia (45.1%), increased alanine aminotransferase (39.4%), decreased white blood cell count (36.6%), thrombocytopenia (36.6%), decreased platelet count (35.2%), neutropenia (31.0%), decreased neutrophil count (29.6 %), elevated aspartate aminotransferase (26.8%), nausea (26.8%), mucosal inflammation (21.1%), rash (19.7%), vomiting (19.7%), leukopenia Symptoms (18.3%), decreased appetite (14.1%), fever (14.1%), upper respiratory tract infection (14.1%), diarrhea (11.3%) and fatigue (11.3%).

Common adverse reactions of grade ≥3 (incidence rate ≥10%)

A total of 223 adverse reactions of grade 3 or above occurred in 52 patients (73.2%). Among them, the most common adverse reactions (incidence ≥10%) were decreased platelet count 23.9%, anemia 21.1%, thrombocytopenia 19.7%, oral mucositis 19.7%, neutropenia 16.9%, decreased white blood cell count 16.9%, decreased neutrophil count 12.7% and leukopenia 11.3%.

Serious adverse reactions

Serious adverse reactions occurred in 27 patients (38.0%). at least 2 of them Events that occurred in patients included decreased platelet count (14.1%), pulmonary infection (5.6%), thrombocytopenia (5.6%), pneumonia (4.2%), oral mucositis (4.2%), febrile neutropenia (2.8%), and pancytopenia (2.8%).

Result in dose reduction, suspension of administration, or discontinuation of treatment

32 Patients (45.1%) had pralatrexate dose reduction due to adverse events, of which the incidence was ≥2% and included oral mucositis (25.4%), mucosal inflammation (9.9%), alanine aminotransferase elevation (4.2%), thrombocytopenia (2.8%), and rash (2.8%).

55 Treatment with pralatrexate was suspended due to adverse events in 77.5% of patients. The most common (incidence ≥10%) adverse events were oral mucositis (47.9%), thrombocytopenia (18.3%), decreased platelet count (16.9%), mucosal inflammation (15.5%), and neutropenia (11.3%).

10 Patients (14.1%) discontinued treatment with pralatrexate due to adverse events. These adverse events were oral mucositis (4.2%), pulmonary infection (2.8%), decreased platelet count (2.8%), diarrhea (1.4%), and febrile neutropenia (1.4%). , gastrointestinal ulcer (1.4%), hypokalemia (1.4%), decreased neutrophil count (1.4%), pneumonia (1.4%), fever (1.4%) and decreased white blood cell count (1.4%).

[Precautions]

Myelosuppression

This product may cause bone marrow suppression manifested by thrombocytopenia, neutropenia and/or anemia. Complete blood count needs to be monitored and based on ANC before each dose (see Dosage and Administration). and platelet count, suspend administration and/or reduce dose. Administer vitamin B12 and instruct patients to take folic acid to reduce the risk of treatment-related hematologic toxicity (see Dosage and Administration and Adverse Reactions).

Mucositis

This product can cause mucositis. Mucositis should be monitored weekly and, if grade ≥ 2 mucositis occurs, dosing should be suspended and/or dose reduced. give vitamins B12 and instruct patients to take folic acid to reduce the risk of mucositis (see [Dosage and Dosage] and [Adverse Reactions]). Your mouth must be thoroughly examined before each pralatrexate treatment begins. Good oral hygiene (regular mouthwash, dental hygiene) must be maintained throughout treatment with pralatrexate. A comprehensive oral evaluation is recommended before high-dose chemotherapy to eliminate odontogenic and non-odontogenic sources of infection. Teeth should be brushed consistently with a soft-bristled toothbrush using warm water, two or three times a day. Toothbrushes should be replaced regularly, especially during periods of neutrophil depletion. Povidone-iodine solution can be used as a medicated mouthwash to prevent mouth ulcers. After the patient develops an ulcer, he should clean his mouth immediately after eating every day, use a small-head soft-bristled toothbrush and a toothpaste with less irritation. Use after meals 4% sodium bicarbonate gargle or 0.12% chlorhexidine gargle, 10 mL each time, gargle for 3-5 minutes, and then apply 0.1% triamcinolone acetonide oral ointment to the ulcer, 3 times/day to promote healing. Depending on the patient's condition, analgesics, anti-infectious drugs, etc. may be given.

Skin Reactions

This product can cause severe skin reactions, possibly leading to death. These skin reactions were reported in clinical studies (14/663 patients [2.1%]) and post-marketing experience, including exfoliative dermatitis, skin necrosis, ulceration, and toxic epidermal necrolysis (TEN). Patients with extensive skin involvement or a history of adverse cutaneous reactions are at greatest risk. The first signs usually appear early in treatment, and these symptoms may worsen or worsen with further treatment and may spread to the skin and subcutaneous sites where lymphoma is known. Patients should be closely monitored for skin reactions, and use of this product should be suspended or discontinued in severe cases.

Tumor lysis syndrome

This product can cause tumor lysis syndrome (TLS). Patients at increased risk for TLS need to be monitored and treated promptly. As of September 23, 2019, a total of 8 cases of tumor lysis syndrome (4 cases were from clinical studies and 4 cases were from post-marketing), of which 7 were serious cases. Among the 8 cases, the outcome was death in 1 case, recovery in 4 cases, no recovery in 1 case, and unknown outcome in 2 cases.

Pneumonia/Pulmonary Infection

Patients have developed pulmonary infection/pneumonia after using this product. All reported cases were confounded by medical history, concomitant chemotherapy, underlying disease, or age. In some cases the outcome is fatal.

Hepatotoxicity

This product can cause hepatotoxicity and abnormal liver function tests. Persistent liver function test abnormalities may indicate hepatotoxicity, requiring dose adjustment or discontinuation. Liver function test results need to be monitored, and administration should be suspended until resumption, dose adjustment, or treatment discontinuation based on the severity of hepatotoxicity. Mild liver damage recovers quickly after drug withdrawal. For severe cases that require hepatoprotective drug treatment, early acetyl cysteine ​​(NAC) scavenging for free radicals may be considered, and glucocorticoids must be carefully selected based on strict indications. From pralatrexate lymphoma clinical trials, patients with the following laboratory values ​​were excluded: Total bilirubin> 1.5 mg/dL; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN); AST or ALT > 5 times ULN (if there is a documented history of lymphoma with liver involvement) (see Dosage and Administration).

Risk of increased toxicity in patients with impaired renal function

Patients with moderate to severe renal impairment may be at greater risk for increased exposure and toxicity. Patients need to be monitored for renal function and systemic toxicity and the dose adjusted accordingly (see [Dosage and Administration]).

Patients with end-stage renal disease (ESRD) who are undergoing dialysis have experienced serious adverse drug reactions after receiving this product, including toxic epidermal necrolysis and mucositis. Patients with end-stage renal disease (including patients on dialysis) should avoid using this product unless the potential benefits outweigh the potential risks (see Adverse Reactions and Pharmacokinetics).

Effects on ability to drive and use machines

Relevant studies have not been conducted. Patients should be informed that they may experience fatigue, blurred vision, or dizziness during treatment with this product.

Patients should be advised not to drive or use machinery if experiencing any of the above adverse reactions.

Precautions for drug handling, preparation and administration Pralatrexate is a cytotoxic anticancer drug. Care should be taken when handling, preparing and administering drug solutions. It is recommended to wear gloves and other protective clothing. If the solution comes into contact with skin, wash immediately and thoroughly with soap and water. If contact with mucous membranes occurs, rinse thoroughly with water.

This product is a preservative-free, sterile, isotonic, pyrogen-free, clear yellow parenteral aqueous solution packaged in single-dose transparent glass bottles (Type I) for intravenous administration. Each 1 mL injection contains 20 mg Pralatrexate, sufficient sodium chloride to achieve an isotonic effect (280-300 mOsm), sufficient sodium hydroxide, and when necessary, hydrochloric acid can be added to adjust and maintain the pH at 7.5-8.5. This product does not contain preservatives and is intended for single use only. Calculate the required dose of pralatrexate and use it immediately after withdrawal by syringe in a sterile environment. This product must not be diluted. After withdrawing the required dose, the vial containing unused solution should be discarded.

When solution and container permit, injectable solutions should be visually inspected for particulate matter and discoloration before administration. Do not use if there are particles or discoloration.

Unopened vials are stable for up to 120 hours in a single storage at temperatures up to 30°C when removed from the refrigerator.

[Drug for pregnant and lactating women]

Drug for pregnancy

Embryo-fetal toxicity

Using this product by pregnant women may cause harm to the fetus. Studies in rats and rabbits indicate that pralatrexate is embryotoxic and fetotoxic. If the patient uses this product during pregnancy, or if the patient becomes pregnant while taking this product, the patient should be informed of the potential harm to the fetus.

Use during lactation

It is not known whether pralatrexate is excreted in breast milk. Because many drugs are excreted in breast milk and pralatrexate has potentially serious adverse effects in the infant, the importance of pralatrexate to the mother needs to be considered when deciding whether to discontinue breastfeeding or discontinue the drug.

[Pediatric use]

Children are not included in the clinical studies of this product. The safety and effectiveness of pralatrexate in pediatric patients have not been established.

There is no overall difference compared with age). Due to the promoting effect of renal excretion on the total clearance of pralatrexate (approximately 34%), age-related decline in renal function may result in reduced clearance and a corresponding increase in plasma exposure. In general, caution should be exercised in dose selection in elderly patients because they are more likely to have reduced hepatic, renal, or cardiac function, concomitant disease, or other medications. As older patients may be at higher risk, they should be monitored more closely. If exposure-related toxicity occurs, administration should be suspended, dosage should be adjusted subsequently, or treatment should be terminated (see [Usage and Dosage], [Precautions]).

[Drug Interactions]

Formal clinical evaluation of pharmacokinetic drug-drug interactions between pralatrexate and other drugs has not been performed.

In a phase I clinical study, the concomitant use of the uricosuric agent probenecid, an inhibitor of multiple transport systems, including multidrug resistance-associated proteins 2 (MRP2) efflux transporter) on the pharmacokinetics of pralatrexate. Coadministration of escalating doses of probenecid resulted in delayed clearance of pralatrexate and a corresponding increase in exposure.

Receiving probenecid or other drugs that may affect related transport systems (e.g. When pralatrexate is administered to patients with NSAIDs), patients need to be closely monitored for signs of systemic toxicity due to increased drug exposure. In vitro studies have shown that pralatrexate does not induce or inhibit CYP450 at concentrations reasonably expected clinically Isoenzyme activity.

In vitro studies have shown that at clinically reasonable expected concentrations, pralatrexate is a potent inhibitor of breast cancer resistance protein (BCRP), MRP2, multidrug resistance-related protein 3 (MRP3) and organic anion transporters. Substrate of the 1B3 (OATP1B3) transport system.

Platrexate is not a P-glycoprotein (P-gp), organic anion transporter 1B1 (OATP1B1), organic cation transporter 2 (OCT2), organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) transporter systems.

In vitro studies have shown that pralatrexate inhibits the MRP2 and MRP3 transporter systems ([I]/IC50 > 0.1) at concentrations reasonably expected clinically. MRP3 Is a transporter that may affect the transport of etoposide and teniposide.

In vitro studies show that pralatrexate does not significantly inhibit P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1 and OATP1B3 at concentrations reasonably expected clinically. transporter system.

【Drug overdose】

No specific information is available at this time regarding the treatment of overdose with this product. If overdose occurs, the attending physician should make a judgment and take necessary supportive measures. Based on the mechanism of action of pralatrexate, immediate administration of leucovorin may be considered for treatment.