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PemetrexedALIMTA® pemetrexed for injection ALIMTA®, pemetrexed for injection, is an antifolate antineoplastic agent that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of C20H19N5Na2O6•7H2O and a molecular weight of 597.49. ALIMTA is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid. Each 500-mg vial of ALIMTA contains pemetrexed disodium equivalent to 500 mg pemetrexed and 500 mg of mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. Pharmacodynamics Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity 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), all folate-dependent enzymes involved in 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 converted to polyglutamate forms by the enzyme folyl polyglutamate synthase. 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, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells. 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, is inversely proportional to the systemic exposure of ALIMTA. 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 systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mg•hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures. Pharmacokinetics The pharmacokinetics of pemetrexed 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 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 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 clearance decreases, and exposure (AUC) increases, as renal function decreases. 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. 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. DRUG INTERACTIONS Chemotherapeutic Agents — Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed. Vitamins — Coadministration of oral folic acid or intramuscular vitamin B12 does not affect the pharmacokinetics of pemetrexed. Drugs Metabolized by Cytochrome P450 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. No studies were conducted to determine the cytochrome P450 isozyme induction potential of pemetrexed, because ALIMTA used as recommended (once every 21 days) would not be expected to cause any significant enzyme induction. Aspirin — Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown. Ibuprofen — Daily ibuprofen doses of 400 mg qid reduce 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 (see Drug Interactions under PRECAUTIONS). Special Populations The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single arm studies. Geriatric — No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years. Pediatric — Pediatric patients were not included in clinical trials. Gender — The pharmacokinetics of pemetrexed were not different in male and female patients. Race — The pharmacokinetics of pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups. Hepatic Insufficiency — There was no effect of elevated AST (SGOT), ALT (SGPT), or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted (see PRECAUTIONS). Renal Insufficiency — Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed in the presence of cisplatin decreases as renal function decreases, with increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min (see WARNINGS and DOSAGE AND ADMINISTRATION). CLINICAL STUDIES Malignant Pleural Mesothelioma — The safety and efficacy of ALIMTA have been evaluated in chemonaive patients with malignant pleural mesothelioma (MPM) in combination with cisplatin. Randomized Trial: A multi-center, randomized, single-blind study in 448 chemonaive patients with MPM compared survival in patients treated with ALIMTA in combination with cisplatin to survival in patients receiving cisplatin alone. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m2 and cisplatin was administered intravenously over 2 hours at a dose of 75 mg/m2 beginning approximately 30 minutes after the end of administration of ALIMTA. Both drugs were given on Day 1 of each 21-day cycle. After 112 patients were treated, white cell and GI toxicity led to a change in protocol whereby all patients were given folic acid and vitamin B12 supplementation. The primary analysis of this study was performed on the population of all patients randomly assigned to treatment who received study drug (randomized and treated). An analysis was also performed on patients who received folic acid and vitamin B12 supplementation during the entire course of study therapy (fully supplemented), as supplementation is recommended (see DOSAGE AND ADMINISTRATION). Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 1.
Table 2 summarizes the survival results for all randomized and treated patients regardless of vitamin supplementation status and those patients receiving vitamin supplementation from the time of enrollment in the trial.
Similar results were seen in the analysis of patients (N=303) with confirmed histologic diagnosis of malignant pleural mesothelioma. Exploratory demographic analyses showed no apparent differences in patients over or under 65. There were too few non-white patients to assess possible ethnic differences. The effect in women (median survival 15.7 months with the combination vs. 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 11 vs. 9.4 respectively). As with any exploratory analysis, it is not clear whether this difference is real or is a chance finding. Objective tumor response for malignant pleural mesothelioma is difficult to measure and response criteria are not universally agreed upon. However, based upon prospectively defined criteria, the objective tumor response rate for ALIMTA plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the ALIMTA plus cisplatin arm compared to the control arm. Patients who received full supplementation with folic acid and vitamin B12 during study therapy received a median of 6 and 4 cycles in the ALIMTA/cisplatin (N=168) and cisplatin (N=163) arms, respectively. Patients who never received folic acid and vitamin B12 during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for the ALIMTA/cisplatin and cisplatin arm, respectively). Patients receiving ALIMTA in the fully supplemented group received a relative dose intensity of 93% of the protocol specified ALIMTA dose intensity; patients treated with cisplatin in the same group received 94% of the projected dose intensity. Patients treated with cisplatin alone had a dose intensity of 96%. ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. DOSAGE AND ADMINISTRATIONALIMTA is for Intravenous Infusion Only Combination Use With Cisplatin Malignant Pleural Mesothelioma — The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive hydration consistent with local practice prior to and/or after receiving cisplatin. See cisplatin package insert for more information. 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, and the day after ALIMTA administration. Vitamin Supplementation — To reduce toxicity, patients treated with ALIMTA 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 first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mg, and the dose of vitamin B12 was 1000 mg. The most commonly used dose of oral folic acid in clinical trials was 400 mg (see WARNINGS). Laboratory Monitoring and Dose Reduction Recommendations Monitoring — Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. 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 is ³1500 cells/mm3, the platelet count is ³100,000 cells/mm3, and creatinine clearance is ³45 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 from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 5-7.
If patients develop nonhematologic toxicities (excluding neurotoxicity) Grade 3 (except Grade 3 transaminase elevations), ALIMTA should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 6.
In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 7. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.
ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions (except Grade 3 transaminase elevations) or immediately if Grade 3 or 4 neurotoxicity is observed. Elderly Patients — No dose reductions other than those recommended for all patients are necessary for patients ³65 years of age. Children — ALIMTA is not recommended for use in children, as safety and efficacy have not been established in children. Renally Impaired Patients — In clinical studies, patients with creatinine clearance ³45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min using the standard Cockcroft and Gault formula (below) or GFR measured by Tc99m-DPTA serum clearance method:
Caution should be exercised when administering ALIMTA concurrently with NSAIDs
to patients whose creatinine clearance is <80 mL/min (see Drug
Interactions under PRECAUTIONS).
Table 4 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.
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 ALIMTA plus cisplatin, the incidence of CTC Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater in patients 65 years or older as compared to patients younger than 65. No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%). ALIMTA 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 ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance ³80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ³45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min (see Dose Reduction Recommendations under DOSAGE AND ADMINISTRATION). One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. Bone Marrow Suppression ALIMTA can suppress bone marrow function, manifested by neutropenia, thrombocytopenia, and anemia (see ADVERSE REACTIONS); myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle (see Dose Reduction Recommendations under DOSAGE AND ADMINISTRATION). Need for Folate and Vitamin B12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity (see DOSAGE AND ADMINISTRATION). In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered. Pregnancy Category D ALIMTA may cause fetal harm when administered to a pregnant woman. Pemetrexed was fetotoxic and teratogenic in mice at i.v. doses of 0.2 mg/kg (0.6 mg/m2) or 5 mg/kg (15 mg/m2) when given on gestation days 6 through 15. Pemetrexed caused fetal malformations (incomplete ossification of talus and skull bone) at 0.2 mg/kg (about 1/833 the recommended i.v. human dose on a mg/m2 basis), and cleft palate at 5 mg/kg (about 1/33 the recommended i.v. human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. There are no studies of ALIMTA in pregnant women. Patients should be advised to avoid becoming pregnant. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking ALIMTA, the patient should be apprised of the potential hazard to the fetus. General ALIMTA 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 ALIMTA seen in clinical trials have been reversible. 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 (see DOSAGE AND ADMINISTRATION). The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration. Laboratory Tests Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. 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 is ³1500 cells/mm3, the platelet count is ³100,000 cells/mm3, and creatinine clearance is ³45 mL/min. 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, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. Pregnancy Pregnancy Category D (see WARNINGS). Nursing Mothers It is not known whether ALIMTA 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 ALIMTA, it is recommended that nursing be discontinued if the mother is treated with ALIMTA. Pediatric Use The safety and effectiveness of ALIMTA in pediatric patients have not been established. Geriatric Use Dose adjustments based on age other than those recommended for all patients have not been necessary (see Special Populations under CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Gender Dose adjustments based on gender other than those recommended for all patients have not been necessary (see Special Populations under CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Patients with Hepatic Impairment Patients with bilirubin >1.5 times the upper limit of normal were excluded from clinical trials of ALIMTA. Patients with transaminase >3.0 times the upper limit of normal were routinely excluded from clinical trials if they had no evidence of hepatic metastases. Patients with transaminase from 3 to 5 times the upper limit of normal were included in the clinical trial of ALIMTA if they had hepatic metastases. Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 6 (see Special Populations under CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidney. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment (see Special Populations under CLINICAL PHARMACOLOGY). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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