Pemetrexed dr. varun
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Transcript of Pemetrexed dr. varun
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PEMETREXED
DR. VARUN GOELMEDICAL ONCOLOGIST
RAJIV GANDHI CANCER INSTITUTE, DELHI
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• Pemetrexed disodium heptahydrate – C20H19N5Na2O6•7H2O
• L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1Hpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate
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• ALIMTA – – white to either light yellow or green-yellow
lyophilized solid– intravenous infusion– single-dose vials– 100-mg or 500-mg vial
– contains pemetrexed disodium equivalent to 100 mg pemetrexed and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively.
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INDICATIONS
• Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin– initial treatment of locally advanced or metastatic
• Nonsquamous Non-Small Cell Lung Cancer – Maintenance• whose disease has not progressed after four cycles of platinum-based first-
line chemotherapy.
• Nonsquamous Non-Small Cell Lung Cancer – After Prior Chemotherapy– as a single-agent for locally advanced or metastatic
• Mesothelioma– in combination with cisplatin for malignant pleural mesothelioma
whose disease is unresectable
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DOSAGE AND ADMINISTRATION
• recommended dose of ALIMTA is 500 mg/m² administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.
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Premedication Regimen
• Vitamin Supplementation– low-dose oral folic acid preparation daily.
– At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA
– should continue during the full course of therapy and for 21 days after the last dose
– intramuscular injection of vitamin B12
– week preceding the first dose of ALIMTA and every 3 cycles thereafter.
– In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg
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• 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, and the day after ALIMTA administration
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Monitoring
• CBC– in the clinical study before each dose and on
days 8 and 15 of each cycle
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Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities
Nadir ANC <500/mm³ and nadir platelets >50,000/mm³.
75% of previous dose (pemetrexed and cisplatin).
Nadir platelets <50,000/mm³ without bleeding regardless of
nadir ANC.75% of previous dose
(pemetrexed and cisplatin).
Nadir platelets <50,000/mm³ with bleedinga, regardless of
nadir ANC.50% of previous dose
(pemetrexed and cisplatin).
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Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicities
DOSE OF ALIMTA
(MG/M²)
DOSE OF CISPLATIN (MG/M²)
Any Grade 3 or 4 toxicities except mucositis
75% of previous dose
75% of previous dose
Any diarrhea requiring hospitalization (irrespective of
Grade) or Grade 3 or 4 diarrhea75% of previous
dose75% of previous
dose
Grade 3 or 4 mucositis 50% of previous dose
100% of previous dose
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Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin – Neurotoxicity
CTC GRADE DOSE OF ALIMTA (MG/M²)
DOSE OF CISPLATIN (MG/M²)
0-1 100% of previous dose 100% of previous dose
2 100% of previous dose 50% of previous dose
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Discontinuation Recommendation
• should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity – after 2 dose reductions or – immediately if Grade 3 or 4 neurotoxicity is
observed
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Renally Impaired Patients
• In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments
• should not be administered to patients whose creatinine clearance is <45 mL/min
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• Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min
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Preparation and Administration Precautions
• use of gloves is recommended. – If a solution of ALIMTA contacts the skin, wash the skin
immediately and thoroughly with soap and water– not a vesicant. There is no specific antidote for
extravasation of ALIMTA. To date, there have been few reported cases of ALIMTA extravasation.
• Reconstitute each 100-mg vial with 4.2 ml and each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection 25 mg/mL
• ALIMTA is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection
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• Coadministration of ALIMTA with other drugs and diluents has not been studied, and therefore is not recommended
• ALIMTA is compatible with standard polyvinyl chloride (PVC) administration sets and intravenous solution bags.
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• further diluted into a solution of 0.9% Sodium Chloride Injection (preservative free), so that the total volume of solution is 100 ml. ALIMTA is administered as an intravenous infusion over 10 minutes.
• Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours following initial reconstitution, when stored at refrigerated or ambient room temperature
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SIDE EFFECTS
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DRUG INTERACTIONS
• ALIMTA is primarily eliminated unchanged by renal excretion
• Non-Steroidal Anti-Inflammatory Drugs– can decrease the clearance of pemetrexed
• Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min)
– NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of ALIMTA.
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• Nephrotoxic Drugs– Concomitant administration of nephrotoxic drugs
could result in delayed clearance of ALIMTA
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• There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed
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Pregnancy Category D
• Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice
• Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA
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• It is not known whether ALIMTA or its metabolites are excreted in human milk.
• Efficacy of ALIMTA in pediatric patients has not been demonstrated. – pediatric patients with recurrent solid tumors in a
Phase 1 study(32 patients) and a Phase 2 study (72 patients)
– No responses were observed in this Phase 2 trial.• No dose reductions other than those
recommended for all patients are necessary for patients 65 years of age or older
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• No carcinogenicity studies have been conducted with pemetrexed.
• Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests