Pemxcel

Pemetrexed.

Each vial of lyophilized powd for infusion contains pemetrexed disodium heptahydrate equivalent to pemetrexed 100 or 500 mg.
It has the chemical name disodium (2S)-2-[(4-[2-(2-amino-4-oxo-4,7-dihydro-lh-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] amino] pentanedioate heptahydrate.
It also has a molecular formula of C₂₀H₁₉N₅Na₂O₆·7H₂O and a molecular weight of 597.5.

Pharmacology: Pharmacodynamics: Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H. NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.
Absolute neutrophil counts (ANC) following single-agent administration of pemetrexed to patients not receiving folic acid and vitamin B12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, correlates with the systemic exposure or area under the curve (AUC) of pemetrexed. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin B12 supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.
Time to ANC nadir with pemetrexed AUC, varied between 8-9.6 days over a range of exposures from 38-316 mcg/hr/mL. Return to baseline ANC occurred 4.2-7.5 days after the nadir over the same range of exposures.
Mechanism of Action: 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 eg, 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 retain 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 (t_½) resulting in prolonged drug action in malignant cells.
Pharmacokinetics: Absorption: The pharmacokinetics of pemetrexed administered as a single-agent in doses ranging from 0.2-838 mg/m² infused over a 10-min period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed AUC and maximum plasma concentration (C_max) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.
Distribution: Pemetrexed has a steady-state volume of distribution (V_ss) of 16.1 L. 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 70-90% of the dose recovered unchanged within the first 24 hrs 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 t_½ of pemetrexed is 3.5 hrs in patient with normal renal function [creatinine clearance (CrCl) 90 mL/min].
The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single-arm studies.
Effect of Age: No effect on age on the pharmacokinetics of pemetrexed was observed over a range of 26-80 years.
Effect of Hepatic Insufficiency: There was no effect of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT) or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted.
Effect of Renal Insufficiency: Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed decreases as renal function decreases with a resultant increase in systemic exposure. Patients with CrCl 45, 50 and 80 mL/min had 65%, 54% and 13% increases respectively in pemetrexed AUC compared to patients with CrCl 100 mL/min.
Effect of Ibuprofen: Ibuprofen doses of 400 mg 4 times a day reduces pemetrexed's clearance by about 20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown.
Effect of Aspirin: Aspirin, administered in low to moderate doses (325 mg every 6 hrs) does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown.
Effect of Cisplatin: Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.
Effect of Vitamins: Co-administration of oral folic acid or vitamin B12 IM  does not affect the pharmacokinetics of pemetrexed.
Drugs Metabolized by Cytochrome P-450 Enzymes: Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9 and CYP1A2.

Nonsquamous Non-Small Cell Lung Cancer-Combination with Cisplatin: Initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.
Nonsquamous Non-Small Cell Lung Cancer-Maintenance: Maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after 4 cycles platinum-based first-line chemotherapy.
Nonsquamous Non-Small Cell Lung Cancer-After Prior Chemotherapy: Single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.
Pleural Mesothelioma: In combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are otherwise not candidates for curative surgery.
Limitations of Use: Pemxcel is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Combination Use with Cisplatin: Malignant Pleural Mesothelioma: Recommended Dose: 500 mg/m² administered as IV infusion over 10 min on day 1 of each 21-day cycle. Recommended Dose of Cisplatin: 75 mg/m² infused over 2 hrs beginning approximately 30 min after the end of pemetrexed administration. Patients should receive hydration consistent with local practice prior to and/or after receiving cisplatin.
Single-Agent Use: Nonsquamous Non-Small Cell Lung Cancer: Recommended Dose: 500 mg/m² administered as an IV infusion over 10 min on day 1 of each 21-day cycle.
Premedication Regimen: Corticosteroid skin rash has been reported more frequently in patients not pre-treated with a corticosteroid. Pre-treatment with dexamethasone (or equivalent) reduces the incidence and severity of ocutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before and the day after pemetrexed administration.
Vitamin Supplementation: To reduce toxicity, patients treated with pemetrexed must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the 1st dose of pemetrexed and dosing should continue during the full course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive 1 IM injection of vitamin B12 during the week preceding the 1st dose of pemetrexed. In clinical trials, the dose of folic acid studied ranged from 350-100 mcg and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic acid clinical trials was 400 mcg (see Warnings).
Monitoring: Complete blood cell counts, including platelet counts, should be performed on all patients receiving pemetrexed. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm¹, the platelet count is ≥100,000 cells/mm³ and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function.
Dose Reduction Recommendations: Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity form the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines as shown in Tables 1, 2 and 3.

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Administration: Reconstitute each 100 mg vial with 4.2 mL of sodium chloride 0.9% injection (preservative free).
Reconstitute each 500-mg vial with 20 mL of sodium chloride 0.9% injection (preservative free).
An appropriate quantity of reconstituted pemetrexed solution must be further diluted into a solution of sodium chloride 0.9% injection so that the total volume of solution is 100 mL. Pemetrexed is administered as an IV infusion over 10 min.

There have been few cases of pemetrexed overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia and anemia. In addition, infection with or without fever, diarrhea and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.
In clinical trials, leucovorin was permitted for CTC grade 4 leukopenia lasting ≥3 days and immediately for CTC grade 4 thrombocytopenia, bleeding associated with grade 3 thrombocytopenia or grade 3 or 4 mucositis. The following IV doses and schedules of leucovorin were recommended for IV use: 100 mg/m², IV once, followed by leucovorin 50 mg/m², IV every 6 hrs for 8 days.
The ability of pemetrexed to be dialyzed is unknown.

Hypersensitivity to pemetrexed or to any other excipients of Pemxcel.

Decreased Renal Function: Pemetrexed is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with CrCl >45 mL/min. Insufficient numbers of patients have been studied with CrCl <45 mL/min to give a dose recommendation. Therefore, pemetrexed should not be administered to patients whose CrCl <45 mL/min.
One (1) patient with severe renal impairment (CrCl 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of pemetrexed alone.
Use With Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency: Caution should be used when administering ibuprofen concurrently with Pemetrexed to patients with mild to moderate renal insufficiency (CrCl 45-79 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 is ≥1500 cells/mm³, the platelet count is >100,000 cells/mm³ and CrCl ≥45 mL/min. 
Use in pregnancy: 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 embryotoxic, fetotoxic and teratogenic in mice at >1/833rd the recommended human dose. If pemetrexed is used during pregnancy, or if the patient becomes pregnant while taking Pemxcel, the patients 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 should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Treatment-related adverse events of pemetrexed seen in clinical trials have been reversible. Skin rash has been reported more frequently in patients not pre-treated with a corticosteroid in clinical trials. Pre-treatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction (see Dosage & Administration). The effect of third-space fluid eg, 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.
Laboratory Tests: Complete blood cell counts including platelet counts and periodic chemistry tests should be performed on all patients receiving pemetrexed. Patients should be monitored for nadir and recovery which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC ≥1500 cells/mm³, the platelet count is ≥100,00 cells/mm³, and CrCl ≥45 mL/min.
Hepatic Impairment: There was no effect of elevated AST, ALT or total bilirubin on the pharmacokinetics of pemetrexed (see Pharmacology under Actions).
Dose adjustments based on hepatic impairment experienced during treatment with pemetrexed are shown in Table 2 (see Dosage & Administration).
Renal Impairment: Pemetrexed is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function (see Dosage & Administration). Cisplatin co-administration with pemetrexed has not been studied in patients with moderate renal impairment.
Carcinogenesis, Mutagenesis, Impairment of Fertility: 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 [Ames assay, chinese hamster ovary (CHO) cell assay]. Pemetrexed administered at IV doses of ≥0.1 mg/kg/day to male mice (about 1/1666 the recommended human dose on a mg/m² basis) resulted in reduced fertility, hypospermia and testicular atrophy.
Use in pregnancy: Teratogenic Effects: Pregnancy Category D: See Warnings.
Use in lactation: It is not known whether pemetrexed or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pemetrexed, a decision should be made to discontinue nursing or discontinue Pemxcel taking into account the importance of Pemxcel for the mother.
Use in children: The safety and effectiveness of pemetrexed in pediatric patients have not been established.
Use in the elderly: Pemetrexed is known to be substantially excreted by the kidney and the risk of adverse reactions to Pemxcel may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of pemetrexed. No dose reductions other than those recommended for all patients are necessary for patients ≥65 years (see Dosage & Administration).

Use in pregnancy: Teratogenic Effects: 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 embryotoxic, fetotoxic and teratogenic in mice at >1/833rd the recommended human dose. If pemetrexed is used during pregnancy, or if the patient becomes pregnant while taking Pemxcel, the patients 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.
Use in lactation: It is not known whether pemetrexed or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pemetrexed, a decision should be made to discontinue nursing or discontinue Pemxcel taking into account the importance of Pemxcel for the mother.

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with pemetrexed as a single-agent were fatigue, nausea and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with pemetrexed when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia and constipation.
Non-Small Cell Lung Cancer (NSCLC) - Combination with Cisplatin: See Table 4.

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The following adverse events were greater in the fully supplemented group compared to the never supplemented group: Hypertension (11%, 3%), chest pain (8%, 6%) and thrombosis/embolism (6%, 3%). For fully supplemented patients treated with pemetrexed plus cisplatin, the incidence of CTC grade 3/4 fatigue, leukopenia, neutropenia and thrombocytopenia were greater in patients ≥65 years as compared to patients <65. No relevant effect for pemetrexed safety due to gender or race was identified except an increased incidence of rash in men (24%) compared to women (16%).

Pemetrexed is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of pemetrexed. Concomitant administration of substances that are also tubularly secreted (eg, probenecid) could potentially result in delayed clearance of pemetrexed.
Although ibuprofen (400 mg four times daily) can be administered with pemetrexed in patients with normal renal function (CrCl ≥80 mL/min), caution should be used when administering ibuprofen concurrently with pemetrexed to patients with mild to moderate renal insufficiency (CrCl 45-79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination t_½ for a period of 2 days before, the day of, and 2 days following administration of pemetrexed.
Other Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination t_½ for a period of 306 of 2 days before, the day of, and 2 days following administration of Pemxcel injection. In the absence of data regarding potential interaction between Pemxcel injection and NSAIDs with longer t_½, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, 2 days following Pemxcel injection administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal and gastrointestinal toxicity.
Nephrotoxic Drugs: Pemxcel injection is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of Pemxcel injection. Concomitant administration of substances that are also tubularly secreted (eg, probenecid) could potentially result in delayed clearance of Pemxcel injection.

Store below 25°C, excursion permitted up to 30°C. Protect from light.

Cytotoxic Chemotherapy

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

POM

Powd for infusion (white to almost-white, lyophilized, in vial) 100 mg x 1's. 500 mg x 1's.