Pemex

Each vial contains Pemetrexed 100 mg and 500 mg.

Pharmacology: Pemetrexed 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.
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 ALIMTA 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 systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mcg·hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.
Pharmacokinetics: The following data are based on the results of studies conducted in foreign populations.
Absorption: The pharmacokinetics of ALIMTA 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) are increased 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.
Effect of Age: No effect of age on the pharmacokinetics of Pemetrexed was observed over a range of 26 to 80 years.
Effect of Gender: The pharmacokinetics of Pemetrexed were not different in male and female patients.
Effect of 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.
Effect of Hepatic Insufficiency: There was no effect of elevated AST, 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 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 Precautions and Dosage & Administration.)
Pediatric Patients: Pediatric patients were not included in clinical trials.
Effect of Ibuprofen: Ibuprofen doses of 400 mg four times a day 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 Interactions).
Effect of 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.
Effect of Cisplatin: Cisplatin does not affect the pharmacokinetics of Pemetrexed and the pharmacokinetics of total platinum are unaltered by Pemetrexed.
Effect of 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.
Toxicology: 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.
See Precautions for male fertility patient use, and see Use in Pregnancy & Lactation for female patient use.

Non-Small Cell Lung Cancer (NSCLC): Pemetrexed in combination with cisplatin is indicated for the first-line therapy of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.
Pemetrexed is indicated as a single-agent for the maintenance of patients with nonprogressive locally advanced or metastatic nonsquamous non-small cell lung cancer after 4 cycles first-line chemotherapy with platinum.
Pemetrexed 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.
Pemetrexed is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.
Malignant Pleural Mesothelioma: Pemetrexed in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma who is not eligible for surgery.

This product must be used under the guidance of a qualified physician having an experience of antineoplastic chemotherapy treatment. This product can only be used for intravenous infusion. Preparation of the solution must be carried out in accordance with the instruction of "Preparation for Intravenous Infusion Solution" as follows.
Combination use with Cisplatin: Malignant Pleural Mesothelioma and Nonsquamous Non-Small Cell Lung Cancer: The recommended dose of Pemetrexed is 500 mg/m² body surface area (BSA) 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 BSA, and the infusion time should be more than 2 hours. Cisplatin should be administered 30 minutes after finishing i.v. infusion of Pemetrexed of the first day of the 21-day cycle. Patients should receive appropriate hydration prior to and/or after receiving Cisplatin. See Cisplatin package insert for more information.
The single-agent use: Nonsquamous Non-Small Cell Lung Cancer: For patients with nonsquamous non-small cell lung cancer who have received prior chemotherapy, the recommended dose of Pemetrexed is 500 mg/m² BSA, administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.
Premedication Regimen: 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. In the former 7 days of the first time after administering Pemetrexed, folic acid must be taken once daily for at least 5 days, and dosing should continue during the full course of therapy and for 21 days after the last dose of Pemetrexed. Patients must also receive one intramuscular injection of vitamin B12 during the week preceding the first dose of Pemetrexed and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Pemetrexed. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 μg, and the dose of vitamin B12 was 1000 μg. The most commonly used dose of oral folic acid in clinical trials was 400 μg (see Precautions).
Corticosteroid Supplementation: 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 orally twice daily the day before, the day of, and the day after Pemetrexed administration (see Precautions).
Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations: 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 and on days 8 and 15 of each cycle. Periodic biochemistry tests should be performed to evaluate renal and hepatic function. Patients should not begin a new cycle of treatment unless the ANC is not less than 1500 cells/mm³, the platelet count is not less than 100,000 cells/mm³, creatinine clearance is not less than 45 mL/min, total bilirubin is not more than 1.5 ULN, alkaline phosphatase (AP), aspartic transaminase (AST or SGOT) and Alanine Aminotransferase (ALT or SGPT) are not more than 3 ULN. If liver is involved, alkaline phosphatase, AST and ALT not more than 5 ULN is accepted [see Precautions].
Dose Reduction Recommendations: Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum non-hematologic 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 1-3, which are suitable for using Pemetrexed as a single-agent or in combination with Cisplatin. (See Table 1.)

Click on icon to see table/diagram/image

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment 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 2. (See Table 2.)

Click on icon to see table/diagram/image

In the event of neurotoxicity, the recommended dose adjustments for Pemetrexed and Cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. (See Table 3.)

Click on icon to see table/diagram/image

Discontinuation Recommendation: Pemetrexed therapy 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.
Renally Impaired Patients: In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance less than 45 mL/min have been treated to make dosage recommendations for this group of patients [see Pharmacology: Pharmacokinetics under Actions]. Therefore, calculate creatinine clearance based on standard Cockcroft and Gault formula (as follows) or GFR measured by Tc99m-DPTA serum clearance method. Pemetrexed should not be administered to patients whose creatinine clearance is less than 45 mL/min. (See equation.)

Click on icon to see table/diagram/image

Be careful when administering Pemetrexed concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min (see Interactions).
Liver Impaired Patients: No pharmacokinetics relationship between AST (SGOT), ALT (SGPT) or total bilirubin and Pemetrexed is found. There is no special study conducted on liver impaired patients, such as total bilirubin >1.5 ULN or transaminase >3.0 ULN (No liver metastasis exist) or >5.0 ULN (Liver metastasis exist).
Precautions for Preparation and Administration: As with other potentially toxic anticancer agents, be careful in the handling and preparation of infusion solutions of Pemetrexed. The use of gloves is recommended. If a solution of Pemetrexed contacts the skin, wash the skin immediately and thoroughly with soap and water. If Pemetrexed contacts the mucous membranes, flush thoroughly with water.
Pemetrexed is not a vesicant. There is no specific antidote for extravasation of Pemetrexed. To date, there have been few reported cases of Pemetrexed extravasation, which were not assessed as serious by the investigator.
Pemetrexed extravasation should be managed with local standard practice for extravasation as with other non-vesicants.
Preparation for Intravenous Infusion Solution: (1). Use aseptic technique during redissolving and further dilution of Pemetrexed for intravenous infusion administration.
(2). Calculate the dose of Pemetrexed and determine the number of vials needed. The vials contain an excess of Pemetrexed to facilitate delivery of label amount.
(3). Reconstitute each 200-mg vial with 8 mL of 9 mg/mL (0.9%) Sodium Chloride Injection (preservative free). Reconstitution of either size vial gives a solution containing 25 mg/mL Pemetrexed. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted Pemetrexed solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.
(4). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.
(5). An appropriate quantity of the reconstituted Pemetrexed solution must be further diluted into a solution of 0.9% Sodium Chloride Injection (preservative free), so that the total volume of solution is 100 mL. Pemetrexed is administered as an intravenous infusion over 10 minutes.
(6). Chemical and physical stability of reconstituted and infusion solutions of Pemetrexed were demonstrated for up to 24 hours following initial reconstitution, when stored at refrigerated or ambient room temperature and lighting. When prepared as directed, reconstitution and infusion solutions of Pemetrexed contain no antimicrobial preservatives. Discard any unused portion.
(7). Prepared Pemetrexed is appropriate for PVC and intravenous injection bag.
(8). Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). Pemetrexed is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection (USP) and Ringer's Injection (USP) and therefore these should not be used. Co-administration of Pemetrexed with other drugs and diluents has not been studied, and therefore is not recommended.

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, CTC Grade 4 neutropenia lasting ≥ 3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m² intravenously once, followed by leucovorin, 50 mg/m² intravenously every 6 hours for 8 days.
The ability of Pemetrexed to be dialyzed is unknown.

Pemetrexed is contraindicated in patients who have a history of severe hypersensitivity reaction to Pemetrexed or to any other ingredient used in the formulation.
Contraindicate to inoculate yellow fever vaccine. (See Interactions.)

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 (see Dosage & 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.
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 (see Dosage & Administration).
Bone Marrow Suppression: Pemetrexed can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) (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 Dosage & Administration).
Decreased Renal Function: Pemetrexed is primarily eliminated unchanged by renal excretion. Decreased renal function can result in the decreased clearance and increased exposure (AUC) (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions). 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 (see Dosage & 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 Pemetrexed alone.
Pemetrexed combined with other drug or alone administrated, there was reported severe kidney accident, including acute renal failure. Many patients with the accidents have potential risk, including dehydration or original hypertension or diabetes mellitus. No study was conducted on Cisplatin with Pemetrexed administrated on patients with moderate renal impairment.
Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency: Caution should be taken when administering NSAIDs (including ibuprofen) concurrently with Pemetrexed to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) (see Interactions).
Liver Function impairment: High AST, ALT or total bilirubin can't influence the pharmacokinetics of Pemetrexed (see Pharmacology: Pharmacokinetics under Actions).
About liver function impairment in receiving Pemetrexed, the dosage adjustment see in Table 2 previously (see Dosage & Administration).
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 creatinine clearance is ≥45 mL/min (see Dosage & 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 embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833 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 (see Use Pregnancy & Lactation).
Pemetrexed can cause heredity toxicity. It is recommended that patients do not father a child during the treatment or within 6 months after the treatment. It is recommended to take contraceptive measures or avoid sexual activities. It is recommended to consider human sperm preservation before the treatment.
Gender: In the first-line treatment of non-small cell lung cancer trial, 70% of patients were males and 30% were females. The HR for overall survival was 0.97 (95% CI: 0.85, 1.10) for males and 0.86 (95% CI: 0.70, 1.06) for females in the intent to treat population.
In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. The HR for overall survival was 0.78 (95% CI: 0.63, 0.96) for males and was 0.83 (95% CI: 0.56, 1.21) for females in the intent to treat population.
In the second-line treatment of non-small cell lung cancer trial, 72% of patients were males and 28% females. The HR for overall survival was 0.95 (95% CI: 0.76, 1.19) for males and HR was 1.28 (95% CI: 0.86, 1.91) for females in the intent to treat population.
In the mesothelioma trial, 82% of patients were males and 18% females. The HR for overall survival was 0.85 (95% CI: 0.66, 1.09) in males and was 0.48 (95% CI: 0.27, 0.85) in females in the intent to treat population.
Race: In the first-line treatment of non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent to treat population.
In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others. For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.
In the second-line treatment of non-small cell lung cancer trial, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent to treat population.
In the mesothelioma trial, 92% of patients were Caucasians and 8% others. For Caucasians, the HR for overall survival was 0.77 (95% CI: 0.61, 0.97) and for others the HR was 0.86 (95% CI: 0.39, 1.90) in the intent to treat population.
Other: Because Pemetrexed co-administrate with Cisplatin has gastrointestinal toxic, even observe severe dehydration. Therefore, patients should receive adequate antiemetic and appropriate hydration before treatment and/or after treatment.
In Pemetrexed clinical research, few serious reports of cardiovascular accident including myocardial and cerebrovascular events were reported, except Pemetrexed was treated combination with other cytotoxic drugs. Most of patients who reported these accidents have known the cardiovascular risk.
Patients with radiotherapy before, during or after Pemetrexed treatment, were reported to radiation pneumonitis. Especially for these patients, it should be caution for using radical sensitizer. In the report of patients with radiotherapy several weeks ago or a few years ago, there is case of radical reminiscence injury.
Use in Children: The safety and effectiveness of pemetrexed for pediatric patients are unknown.
Use in Elderly: Pemetrexed is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug 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 of age or older (see Dosage & Administration).
In the first-line of treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with Pemetrexed plus Cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent to treat population.
In the maintenance non-small cell lung cancer trial 33.3% of patients treated with Pemetrexed were ≥65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.74 (95% CI: 0.58, 0.93) and for patients ≥65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent to treat population.
In the second-line treatment of non-small cell lung cancer trial, 29.7% patients treated with Pemetrexed were ≥65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients ≥65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent to treat population.
The mesothelioma trial included 36.7% patients treated with Pemetrexed plus cisplatin that were ≥65 years, and Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.71 (95% CI: 0.53, 0.96) and for patients ≥65 years, the HR was 0.85 (95% CI: 0.59, 1.22) in the intent to treat population.

Pregnancy: Based on its mechanism of action, Pemetrexed can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of Pemetrexed in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of Pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833 the recommended intravenous human dose on a mg/m² basis), and cleft palate (1/33 the recommended intravenous human dose on a mg/m² basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. 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 use effective contraceptive measures to prevent pregnancy during the treatment with Pemetrexed.
Nursing Mothers: 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 the drug, taking into account the importance of the drug for the mother.

Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
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.
Foreign Clinical Trials Experience: Non-Small Cell Lung Cancer (NSCLC) - Combination Use with Cisplatin: Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received pemetrexed plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B₁₂. (See Table 4.)

Click on icon to see table/diagram/image

No clinically relevant differences in adverse reactions were seen in patients based on histology.
In addition to the lower incidence of hematologic toxicity on the Pemetrexed and Cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the pemetrexed and cisplatin arm compared to the gemcitabine and cisplatin arm.
The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive pemetrexed plus cisplatin.
Incidence 1% to 5%: Body as a Whole: febrile neutropenia, infection, pyrexia.
General Disorders: dehydration.
Metabolism and Nutrition: increased AST, increased ALT.
Renal: creatinine clearance decrease, renal failure.
Special Senses: conjunctivitis.
Incidence Less than 1%: Cardiovascular: arrhythmia.
General Disorders: chest pain.
Metabolism and Nutrition: increased GGT.
Neurology: motor neuropathy.
Non-Small Cell Lung Cancer (NSCLC) - Maintenance: Table 5 provides the frequency and severity of adverse reactions reported in >5% of the 438 patients with NSCLC who received pemetrexed maintenance and the 218 patients with NSCLC who received placebo following a platinum-based induction therapy. All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B₁₂. (See Table 5.)

Click on icon to see table/diagram/image

No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).
Safety was assessed by exposure for patients who received at least one dose of pemetrexed (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of pemetrexed, and compared to patients who received >6 cycles of pemetrexed. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.
Consistent with the higher incidence of anemia (all grades) on the pemetrexed arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the pemetrexed arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).
The following additional adverse reactions were observed in patients with non-small cell lung cancer who received pemetrexed.
Incidence 1% to 5%: Dermatology/Skin: alopecia, pruritus/itching.
Gastrointestinal: constipation.
General Disorders: edema, fever (in the absence of neutropenia).
Hematologic: thrombocytopenia.
Renal: decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate.
Special Senses: ocular surface disease (including conjunctivitis), increased lacrimation.
Incidence Less than 1%: Cardiovascular: supraventricular arrhythmia.
Dermatology/Skin: erythema multiforme.
General Disorders: febrile neutropenia, allergic reaction/hypersensitivity.
Neurology: motor neuropathy.
Renal: renal failure.
Non-Small Cell Lung Cancer (NSCLC) - After Prior Chemotherapy: Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent pemetrexed with folic acid and vitamin B₁₂ supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy. (See Table 6.)

Click on icon to see table/diagram/image

No clinically relevant differences in adverse reactions were seen in patients based on histology.
Clinically relevant adverse reactions occurring in <5% of patients that received pemetrexed treatment but >5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% pemetrexed, 12.7% docetaxel).
The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive pemetrexed.
Incidence 1% to 5%: Body as a Whole: abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection.
Dermatology/Skin: erythema multiforme.
Neurology: motor neuropathy, sensory neuropathy.
Renal: increased creatinine.
Incidence Less than 1%: Cardiovascular: supraventricular arrhythmias.
Malignant Pleural Mesothelioma (MPM) - Combination Use with Cisplatin: Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and pemetrexed and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemo naive patients were fully supplemented with folic acid and vitamin B₁₂. (See Table 7.)

Click on icon to see table/diagram/image

The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive pemetrexed plus cisplatin.
Incidence 1% to 5%: Body as a Whole: febrile neutropenia, infection, pyrexia.
Dermatology/Skin: urticaria.
General Disorders: chest pain.
Metabolism and Nutrition: increased AST, increased ALT, increased GGT.
Renal: renal failure.
Incidence Less than 1%: Cardiovascular: arrhythmia.
Neurology: motor neuropathy.
Effects of Vitamin Supplementations on Toxicity: Table 8 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 pemetrexed plus cisplatin arm. (See Table 8.)

Click on icon to see table/diagram/image

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%).
Subpopulations: 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%).
Additional Experience Across Clinical Trials: Sepsis, which in some cases was fatal, occurred in approximately 1% of patients.
Esophagitis occurred in less than 1% of patients.
Postmarketing Experience in Foreign Countries: The following adverse reactions have been identified during post-approval use of pemetrexed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
These reactions occurred with pemetrexed when used as a single-agent and in combination therapies.
Gastrointestinal: colitis.
Disorders and Administration Site Conditions: edema.
Injury, poisoning, and procedural complications: Radiation recall has been reported in patients who have previously received radiotherapy.
Respiratory: interstitial pneumonitis.
Skin: Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal.
Experience of Chinese Patients: Table 9 provides Pemetrexed (ALIMTA) produced by LILLY did a research as second line drug for NSCLC (JMID). There were 106 Pemetrexed patients and 102 Docetaxel patients. The Incidence ≥2% may relate to patients in group is CTC Grade 3/4 toxic. (See Table 9.)

Click on icon to see table/diagram/image

Table 10 provides the frequency and severity of adverse reactions that have been reported in >5% of Chinese patients receiving pemetrexed (ALIMTA) for NSCLC maintain Globe clinical research for registering (JMEN) used CTCAE grades. (See Table 10.)

Click on icon to see table/diagram/image

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Ibuprofen: Although ibuprofen (400 mg, four times a day) can decrease the clearance of Pemetrexed, it can be administered with Pemetrexed in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be taken when administering high dose of Ibuprofen (>1600 mg/day). Caution should be taken when administering Ibuprofen concurrently with Pemetrexed to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). (see Pharmacology: Pharmacokinetics under Actions).
Other NSAIDs: Caution should be taken when high dose of NSAIDs or Aspirin combination with Pemetrexed on patients with normal renal function (creatinine clearance ≥80 mL/min).
NSAIDs with short elimination half-lives should be avoided for a period of 2 days before, the day of, and 2 days following administration of Pemetrexed on patients with mild and moderate function insufficient.
In the absence of data regarding potential interaction between Pemetrexed and NSAIDs with longer half-lives, patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following Pemetrexed administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.
Nephrotoxic Drugs: Pemetrexed is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs (such as aminoglycoside, loop diuretics, platinum compounds, cyclosporine) could result in delayed clearance of Pemetrexed. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of Pemetrexed. Caution should be taken when co-administration of previously mentioned drugs, it is necessary to monitor creatinine clearance.
Normal interaction of all cytotoxic drug: Because of risk of thrombus in cancer patients increasing, anticoagulant agent is often used. When patients use oral anticoagulant agent, variability of individual anticoagulant is high and oral anticoagulant has interaction with anti-cancer agent, so the INR monitoring frequency should increase.
Attenuated live vaccine: Immunosuppressive states are common in cancer patients, therefore, except for forbidden yellow fever vaccine, it is not recommended receiving attenuated live vaccine, because it may cause the fatal general disease risk.

Preserve in tightly closed and light-resistance containers, and store at temperature not exceeding 20°C.

Cytotoxic Chemotherapy

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

Rx