Pemetrexed Disodium for Injection

Pemetrexed disodium for Injection
 

General Name:Pemetrexed disodium for Injection
Brand name:JieBaiLi
Composition:
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5yl)ethyl]benzoyl]-, disodium salt

Chemical structure:

 
Molecular formula: C20H19N5O6Na2 · 2.5H2O
Strength: 0.5g
Description:JieBaiLi is sterile white-to-light yellow or green-yellow lyophilized powder
Indications:
JieBaiLi combinationwith cisplatin is indicatedfor the treatment of patients withmalignant pleural mesothelioma
whose disease is unresectable or who are otherwise not candidates for curative surgery.It is indicated in
combination with cispliatin therapy for the initial treatment of patients with locally advanced or metastatic
nonsquamous non-small lung cancer.
JieBaiLi itself is indicated for the maintenance treatment of patients with locally advanced or metastatic
nonsquamous non-small lung cancer whose disease has not progressed after four cycles of platinum-based
first-line chemotherapy.JieBaiLi is indicated as a single-agent for the treatment of patients with locally
advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. 
Dosage and Administration:
Pemetrexed should be applied under the guidance of doctors who have anti-tumor chemotherapy application
experiences. It can be only used for intravenous drip, the solution must be prepared according to introductions
given in "preparation of intravenous drip solution ".
Combination Use with Cispatin
Nonsquamous Non-small Cell Lung Cancer and Malignant Pleural Mesothelioma
The recommended dose of JieBaiLi is 500mg/m2 administered as an intravenous infusion over 10 minutes on
Day 1 of each 21-Day cycle. The recommended dose of cisplatin is 75mg/m2 infused over 2 hours beginning
approximately 30 minutes after the end of JieBaiLi administration. Patients should receive appropriate
hydration prior to and/or after receiving cisplatin. Seecisplatin package insert for more information.
Single-Agent Use
Nonsquamous Non-small Cell Lung Cancer
The recommended dose of JieBaiLi is 500mg/m2 administered as an intravenous infusion over 10 minutes on
Day 1 of each 21-Day cycle.
Premedication Regimen:
Corticosteroid--Skin rash has been reported more frequently in patients not pretreated with a corticosteroid.
Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction.
In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, the day after
JieBaiLi administration, continuously for three days.
Vitamin supplementation--to reduce toxicity, when pemetrexed is used, low-dose folic acid or multivitamin
preparations containing folic acid should be administrated at same time. Time of administration: At least 5
daily doses of folic acid should be given within 7 days of the first dose of  pemetrexed, then continued during
the treatment duration, and may be discontinued since 21 days after last dose of pemetrexed. Vitamin B12
should be given by intramuscular injection within 7 days before the first dose of pemetrexed, then
intramuscular injection is administrated once every three cycles, later, Vitamin B12 can be given on the
same day as pemetrexed is given. Dose of folic acid: 350-1000g, usual dose is 400g; dose of B12 is 1000g.
(see "Warnings" in "Precautions")
Laboratory monitoring and recommended dosage adjustment
Monitoring--all the patients ready to receive pemetrexed treatment, blood cell examination including platelet
counts should be taken before treatment, and lowest value of blood cell and recovery should be monitored
after administration, the items above should be tested at the beginning, 8th day and 15th day of each
treatment cycle.  Patients can't accept pemetrexed treatment until neutrophil ≥1500/mm3, blood platelet
≥100,000cells/mm3 and creatinine clearance ≥45ml/min. Biochemical test should be made on liver function
and renal function for each cycle of treatment.Recommended dosage adjustment--adjustment should be
made according to lowest value of blood cells and most serious non-hematological toxicity in past cycles.
If the patients not recovered from adverse reactions after 21 days, treatment should be delayed. After
patients are recovered, treatment can be given according to requirements described in Table 1, 2 and 3.


If non-hematological toxicity occurs with grade ≥3(not including neurotoxicity and grade 3 transaminase
elevation), Pemetrexed shouldn't be given till recovered to or lower than pre-treatment level.  Retreatment
should be given according to requirements described in Table 2.


In case of neurotoxicity, dosage adjustment of pemetrexed and cisplatin refers to Table 3. In case of grade 3
and grade 4 neurotoxicity, treatment should be stopped.



If patients have experienced dose adjustment for two times while grade 3/4 hematological toxicity or non-
hematological toxicity reoccurs (not including grade 3transaminase elevation), pemetrexed shouldn't be given,
if grade 3 or 4 neurotoxicity occurs, treatment should be stopped immediately. 
Geriatric Use--for patients not less than 65 years old, special adjustment is not necessary except for above
dose adjustment.
Pediatric Use--pemetrexed is not recommended for children, the safety and efficacy in pediatrics have not yet
been established.
Renal Impairment--for patients with creatinine clearance ≥45ml/min, dosage can be adjusted by referring to
dosage for general patients, special dosage adjustment is not necessary. Dosage adjustment hasn't been
established for patients with creatinine clearance below 45ml/min. Therefore, if creatinine clearance is
deemed less than 45ml/min when calculated by Cockcroft-Gault formula or calculated by glomerular filtration
rate using Tc99m-DPTA serum clearance method, pemetrexed should not be used for treatment.
Females: creatinine clearance rate for male×0.85
For patients with creatinine clearance rate less than 80ml/min, if pemetrexed is combined with non-steroid
anti-inflammatory drug, close monitoring should be performed. (see "Drug Interaction").
Hepatic Impairment--pemetrexed is not metabolized by liver, for patients with hepatic insufficiency, dosage
should be adjusted according to Table 2. (See "Renal Impairment" in "Precaution").

Precautions:
Pemetrexed is an antineoplastic agent, same as other antineoplastic agents with potential toxicity, special
attention should be paid in disposal and preparation, it is suggested to wear gloves.  If skin contacts with
Pemetrexed injection, please wash skin thoroughly with soap and water.  If mucosa contacts with Pemetrexed
injection, please wash mucosa thoroughly with water.  There are no recommended standards in disposal of
anti-cancer drugs.
Pharmacology and toxicology:
JieBaiLi, pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting
folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that
pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide
ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo
biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such
as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell,
pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The
polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time-
and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent,
in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting
in prolonged drug action in malignant cells.
Pharmacokinetics:
Absorption
The pharmacokinetics o administered as a single-agent in doses ranging from 0.2 to 838 mg/m2 infused over
a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed
total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose.
The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.
Distribution
Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed
is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
Metabolism and Excretion
Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to
90% of the dose recovered unchanged within the first 24 hours following administration. The clearance
decreases, and exposure (AUC) increases, as renal function decreases. The total systemic clearance of
pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal
renal function (creatinine clearance of 90 mL/min).The pharmacokinetics of pemetrexed in special populations
were examined in about 400 patients in controlled and single arm studies.
Storage:

Protect from light, and keep air-tightly

Packs:
Neutral borosilicate glass control injection vial, 0.5g/ vial, 1vial / box.

Shelf-life:24 months