Pemeta-100/Pemeta-500

Pemeta-100: White to off white lyophilised powder for concentrate for solution for infusion.
Each vial contains: Pemetrexed (as Disodium Heptahydrate) 100 mg.
Reconstituted solution contains 25 mg/mL of Pemetrexed.
Pemeta-500: White to off white lyophilised powder filled in 30 mL-capacity USP Type I glass vial with bromobutyl rubber and orange colour flip off seal.
For infusion.
Each vial contains: Pemetrexed Disodium eq. to Pemetrexed 500 mg.

Pharmacology: Pharmacodynamics: Pemeta-500: Mechanism of action: Pemeta-500 (pemetrexed) is a multi-targeted anti-cancer antifolate agent that exerts its action by disrupting crucial folate-dependent metabolic processes essential for cell replication.
Pharmacodynamic effects: In vitro studies have shown that pemetrexed behaves as a multitargeted antifolate by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumour cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
Pharmacokinetics: Pemeta-100/Pemeta-500: Pemetrexed has a plasma elimination half-life of 3.5hours in patients with normal renal function. In vitro data indicate that pemetrexed is about 81% bound to plasma proteins. It undergoes limited hepatic metabolism, and about 70 to 90% of a dose is eliminated unchanged in the urine within 24 hours.

Used in combination with Cisplatin, for initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. For the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer in patients whose disease has not progressed after four cycles of platinum-based first line chemotherapy.
For the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy. Used in combination with Cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

Pemetrexed in combination with cisplatin: The recommended dose of Pemetrexed is 500 mg/m² of body surface (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21 day cycle. The recommended dose of cisplatin is 75 mg/m² BSA over two hours approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21 day cycle. Patients must receive adequate anti-emetic.
Pemetrexed as single agent: In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of pemetrexed is 500 mg/m² BSA administered as an intravenous infusion over 10 minutes on the first day of each 21 day cycle.
Or as prescribed by the physician.

Reported symptoms of overdose include neutropenia, anemia, thrombocytopenia, mucositis, sensory polyneuropathy, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anaemia. In addition, infection with or without fever, diarrhoea, and/or mucositis may be seen. In the event of suspected overdose, patients should be monitored with blood counts and should receive supportive therapy as necessary. The use of calcium folinate/folinic acid in the management of pemetrexed overdose should be considered.

Pemetrexed is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. Breastfeeding and concomitant yellow fever vaccine.

Premedication Regimen: Need for Folate and Vitamin B12 Supplementation: Patients treated with Pemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and non-hematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pre-treatment with folic acid and vitamin B12 was administered.
Corticosteroid Supplementation: Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction.
Bone Marrow Suppression: Pemetrexed can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia); myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum non-hematologic toxicity seen in the previous cycle.
Decreased Renal Function: Pemetrexed is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance >45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, Pemetrexed should not be administered to patients whose creatinine clearance is <45 mL/min.
One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12.
Use with non-steroidal anti-inflammatory drugs with mild to moderate renal insufficiency: Caution should be used when administering ibuprofen concurrently with pemetrexed to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution.
Required Laboratory Monitoring: Patients should not begin a new cycle of treatment unless the ANC >1500 cells/mm³, the platelet count is >100,000 cells/mm³, and creatinine clearance is >45 mL/min.
Third space fluid: The effect of third space fluid, such as pleural effusion and ascites, on Pemetrexed is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to Pemetrexed administration.

Pregnancy Category D.
Based on its mechanism of action, Pemetrexed can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If Pemetrexed is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 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 Pemetrexed.

Pemetrexed may also cause fatigue, stomatitis, pharyngitis, dyspnoea, chest pain, and neuropathy. Rare cases of hepatitis, colitis, and intestinal pneumonitis have occurred; fatalities have been reported. Serious renal events, including acute renal failure, have been reported with pemetrexed when it was used either alone or with other cytotoxic drugs; most patients had underlying risk factors such as dehydration, hypertension, or diabetes. Cardiovascular events, including myocardial infarction and cerebrovascular events, have occurred rarely, when pemetrexed was used with other cytotoxic drugs. Cases of radiation pneumonitis and radiation recall have been reported in patients treated with radiotherapy. Hypersensitivity reactions may occur.
Complete blood cell counts should be monitored, and folate and vitamin B12 are given as prophylaxis against haematological and gastrointestinal toxicity during pemetrexed therapy. Pre-treatment with a corticosteroid, such as oral dexamethasone, reduces the incidence and severity of skin reactions.

Concomitant administration of nephrotoxic drugs (e.g. aminoglycosides, loop diuretics, platinum compounds, cyclosporin) could potentially result in delayed clearance of pemetrexed.
Concomitant administration of substances that are also tubularly secreted (e.g. probenecid, penicillin) could potentially result in delayed clearance of pemetrexed.
In patients with normal renal function (creatinine clearance ≥80 mL/min), high doses of non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen >1600 mg/day) and aspirin at higher doses (≥1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse events.
If concomitant administration of NSAIDs is necessary, patients should be monitored closely to toxicity, especially myelosuppression and gastrointestinal toxicity.
Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment is frequent. Require increased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.
Yellow fever vaccine: Risk of fatal generalised vaccine disease.
Live attenuated vaccines (except yellow fever, for which concomitant use is contraindicated): Risk of systemic, possibly fatal disease. The risk is increased in subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where it exists (poliomyelitis).

Preparation and administration precautions: Care should be exercised in handling and preparation of pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If pemetrexed solutions contact the mucous membranes, flush thoroughly with water. Pemetrexed is not a vesicant. There is not a specific antidote for extravasation of pemetrexed. There have been few reported cases of pemetrexed extravasation, which were not assessed as serious by the investigator. Extravasation should be managed by local standard practice as with other non-vesicants.
Direction for reconstitution: Reconstitute 500 mg vial with 20 mL Sodium Chloride Injection USP. Gently swirl each vial until the powder is completely dissolved.
Reconstituted solution contains 20 mL of 0.9% Sodium Chloride Injection USP (preservative free) into the vial to get a concentrate of 25 mg/mL of Pemetrexed.

Store at temperatures not exceeding 30°C.

Cytotoxic Chemotherapy

L01BA04 - pemetrexed ; Belongs to the class of antimetabolites, folic acid analogues. Used in the treatment of cancer.

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