Drug: Alimta

Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo1H-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. The structural formula is as follows: 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 100-mg or 500-mg vial of ALIMTA contains pemetrexed disodium equivalent to 100 mg pemetrexed and 106 mg mannitol or 500 mg pemetrexed and 500 mg mannitol, respectively. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.

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Clinical Trials Experience 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 ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥ 20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Small Cell Lung Cancer (NSCLC) – ALIMTA in Combination 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 ALIMTA 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. Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa
Reactionb ALIMTA/ cisplatin
(N=839) Gemcitabine/ cisplatin
(N=830) All Grades Toxicity (%) Grade 3-4 Toxicity (%) All Grades Toxicity (%) Grade 3-4 Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory   Hematologic     Anemia 33 6 46 10     Neutropenia 29 15 38 27     Leukopenia 18 5 21 8     Thrombocytopenia 10 4 27 13   Renal     Creatinine elevation 10 1 7 1 Clinical   Constitutional Symptoms     Fatigue 43 7 45 5   Gastrointestinal     Nausea 56 7 53 4     Vomiting 40 6 36 6     Anorexia 27 2 24 1     Constipation 21 1 20 0     Stomatitis/Pharyngitis 14 1 12 0     Diarrhea 12 1 13 2     Dyspepsia/Heartburn 5 0 6 0   Neurology     Neuropathy-sensory 9 0 12 1     Taste disturbance 8 0c 9 0c   Dermatology/Skin     Alopecia 12 0c 21 1c     Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.
bRefer to NCI CTC Criteria version 2.0 for each Grade of toxicity.
cAccording to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. 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 ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA 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 ALIMTA 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 ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction Therapy Table 5 provides the frequency and severity of adverse reactions reported in > 5% of the 438 patients with NSCLC who received ALIMTA 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. Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa Following Platinum-Based Induction Therapy
Reactionb ALIMTA
(N=438) Placebo
(N=218) All Grades Toxicity (%) Grade 3-4 Toxicity (%) All Grades Toxicity (%) Grade 3-4 Toxicity (%) All Adverse Reactions 66 16 37 4 Laboratory   Hematologic     Anemia 15 3 6 1     Neutropenia 6 3 0 0     Leukopenia 6 2 1 1   Hepatic     Increased ALT 10 0 4 0     Increased AST 8 0 4 0 Clinical   Constitutional Symptoms     Fatigue 25 5 11 1   Gastrointestinal     Nausea 19 1 6 1     Anorexia 19 2 5 0     Vomiting 9 0 1 0     Mucositis/stomatitis 7 1 2 0     Diarrhea 5 1 3 0 Infection 5 2 2 0 Neurology     Neuropathy-sensory 9 1 4 0 Dermatology/Skin     Rash/Desquamation 10 0 3 0 aFor the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.
bRefer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity. 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 ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤ 6 cycles of ALIMTA, and compared to patients who received > 6 cycles of ALIMTA. 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 ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transffusions 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 ALIMTA. Incidence 1% to 5% Dermatology/Skin — alopecia, pruritis/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 Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum Induction Therapy Table 6 provides the frequency and severity of adverse reactions reported in > 5% of the 500 patients with nonsquamous NSCLC who received at least one cycle of ALIMTA maintenance (n=333) or placebo (n=167) on the continuation maintenance trial. The median of maintenance cycles administered to patients receiving one or more doses of maintenance therapy was 4 on both the pemetrexed and placebo arms. Dose reductions for adverse events occurred in 3.3% of patients in the ALIMTA arm and 0.6% in the placebo arm. Dose delays for adverse events occurred in 22% of patients in the ALIMTA arm and 16% in the placebo arm. Patients in both study arms were supplemented with folic acid and vitamin B12. Table 6: Selecteda Adverse Reactionsb Occurring in ≥ 5% of Patients Receiving ALIMTA in Nonsquamous NSCLC Following ALIMTA Plus Cisplatin Induction Therapy
Adverse Reaction Organ System and Term ALIMTA
(N=333) Placebo
(N=167) All Gradesa Toxicity (%) Grade 3-4a Toxicity (%) All Gradesa Toxicity (%) Grades 3-4a Toxicity (%) All Adverse Reactions 53 17 34 4.8 Laboratory   Hematologic     Anemia 15 4.8 4.8 0.6     Neutropenia 9 3.9 0.6 0 Clinical   Constitutional Symptoms     Fatigue 18 4.5 11 0.6   Gastrointestinal     Nausea 12 0.3 2.4 0     Vomiting 6 0 1.8 0     Mucositis/stomatitis 5 0.3 2.4 0   General Disorders     Edema 5 0 3.6 0 aAdverse reactions of any severity (all grades) occurring more frequently ( ≥ 5%) or Grade 3-4 adverse reactions occurring more frequently ( ≥ 2%) in ALIMTA-treated patients compared to those receiving placebo.
bNCI CTCAE Criteria version 3.0 Administration of RBC (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0) were higher in the ALIMTA arm compared to the placebo arm. The following additional Grade 3 or 4 adverse reactions were observed more frequently in the ALIMTA arm. Incidence 1% to 5% Blood/Bone Marrow — thrombocytopenia General Disorders — febrile neutropenia Incidence Less than 1% Cardiovascular — ventricular tachycardia, syncope General Disorders — pain Gastrointestinal — gastrointestinal obstruction Neurologic — depression Renal — renal failure Vascular — pulmonary embolism Non-Small Cell Lung Cancer (NSCLC) – After Prior Chemotherapy Table 7 provides the frequency and severity of adverse reactions that have been reported in > 5% of 265 patients randomly assigned to receive single-agent ALIMTA 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. Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa
Reactionb ALIMTA
(N=265) Docetaxel
(N=276) All Grades Toxicity (%) Grades 3-4 Toxicity (%) All Grades Toxicity (%) Grades 3-4 Toxicity (%) Laboratory   Hematologic    Anemia 19 4 22 4    Leukopenia 12 4 34 27    Neutropenia 11 5 45 40    Thrombocytopenia 8 2 1 0   Hepatic    Increased ALT 8 2 1 0    Increased AST 7 1 1 0 Clinical   Gastrointestinal    Nausea 31 3 17 2    Anorexia 22 2 24 3    Vomiting 16 2 12 1    Stomatitis/Pharyngitis 15 1 17 1    Diarrhea 13 0 24 3    Constipation 6 0 4 0   Constitutional Symptoms    Fatigue 34 5 36 5    Fever 8 0 8 0   Dermatology/Skin    Rash/Desquamation 14 0 6 0    Pruritis 7 0 2 0    Alopecia 6 1c 38 2c aFor the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.
bRefer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0).
cAccording to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. 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 ALIMTA treatment but > 5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel). The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA. 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) Table 8 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 ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12. Table 8: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa
Reactionb ALIMTA/cisplatin
(N=168) Cisplatin
(N=163) All Grades Toxicity (%) Grade 3-4 Toxicity (%) All Grades Toxicity (%) Grade 3-4 Toxicity (%) Laboratory   Hematologic     Neutropenia 56 23 13 3     Leukopenia 53 15 17 1     Anemia 26 4 10 0     Thrombocytopenia 23 5 9 0   Renal     Creatinine elevation 11 1 10 1     Creatinine clearance decreased 16 1 18 2 Clinical   Eye Disorder     Conjunctivitis 5 0 1 0   Gastrointestinal     Nausea 82 12 77 6     Vomiting 57 11 50 4     Stomatitis/Pharyngitis 23 3 6 0     Anorexia 20 1 14 1     Diarrhea 17 4 8 0     Constipation 12 1 7 1     Dyspepsia 5 1 1 0   Constitutional Symptoms     Fatigue 48 10 42 9   Metabolism and Nutrition     Dehydration 7 4 1 1   Neurology     Neuropathy-sensory 10 0 10 1     Taste Disturbance 8 0c 6 0c   Dermatology/Skin     Rash 16 1 5 0     Alopecia 11 0c 6 0c aFor the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA.
bRefer to NCI CTC Criteria version 2.0 for each Grade of toxicity except the term “creatinine clearance decreased” which is derived from the CTC term “renal/genitourinary-other”.
cAccording to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA 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 9 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. Table 9: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence)
Adverse Eventa (%) Fully Supplemented Patients
(N=168) Never Supplemented Patients
(N=32) Neutropenia/granulocytopenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 aRefer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0). 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%). 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%). 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 The following adverse reactions have been identified during post-approval use of ALIMTA. 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 ALIMTA when used as a single-agent and in combination therapies. Blood and Lymphatic System — immune-mediated hemolytic anemia Gastrointestinal — colitis, pancreatitis General 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. Read the Alimta (pemetrexed) Side Effects Center for a complete guide to possible side effectsLearn More »

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Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or 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. See cisplatin package insert for more information. Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy 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. Premedication Regimen and Concurrent Medications Vitamin Supplementation Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see WARNINGS AND PRECAUTIONS]. Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see WARNINGS AND PRECAUTIONS]. Corticosteroids Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see WARNINGS AND PRECAUTIONS]. Laboratory Monitoring and Dose Reduction/Discontinuation 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 ≥ 1500 cells/mm³, 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 [see WARNINGS AND PRECAUTIONS]. 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 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin. Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin – Hematologic Toxicities
Nadir ANC < 500/mm³ and nadir platelets ?50,000/mm³ . 75% of previous dose (pemetrexed and cisplatin). Nadir platelets < 50,000/mm³ without bleeding regardless of nadir ANC. 75% of previous dose (pemetrexed and cisplatin). Nadir platelets < 50,000/mm³ with bleedinga, regardless of nadir ANC. 50% of previous dose (pemetrexed and cisplatin). aThese criteria meet the CTC version 2.0 (NCI 1998) definition of ≥ CTC Grade 2 bleeding. 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. Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin – Nonhematologic Toxicitiesa,b
  Dose of ALIMTA (mg/m²) Dose of Cisplatin (mg/m²) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea 75% of previous dose 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose aNCI Common Toxicity Criteria (CTC).
bExcluding neurotoxicity (see Table 3). In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin – Neurotoxicity
CTC Grade Dose of ALIMTA (mg/m²) Dose of Cisplatin (mg/m²) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA 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 below 45 mL/min have been treated to make dosage recommendations for this group of patients [see CLINICAL PHARMACOLOGY]. 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-DTPA serum clearance method: Males: (weight in kg) x (140 – age) (72) x serum creatinine (mg/100 mL) Females Estimated creatinine clearance for males × 0.85 Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is < 80 mL/min [see DRUG INTERACTIONS]. Preparation and Administration Precautions As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions of ALIMTA. The use of gloves is recommended. If a solution of ALIMTA contacts the skin, wash the skin immediately and thoroughly with soap and water. If ALIMTA contacts the mucous membranes, flush thoroughly with water. Several published guidelines for handling and disposal of anticancer agents are available [see REFERENCES]. ALIMTA is not a vesicant. There is no specific antidote for extravasation of ALIMTA. To date, there have been few reported cases of ALIMTA extravasation, which were not assessed as serious by the investigator. ALIMTA extravasation should be managed with local standard practice for extravasation as with other non-vesicants. Preparation for Intravenous Infusion Administration
  1. Use aseptic technique during the reconstitution and further dilution of ALIMTA for intravenous infusion administration.
  2. Calculate the dose of ALIMTA and determine the number of vials needed. Vials contain either 100 mg or 500 mg of ALIMTA. The vials contain an excess of ALIMTA to facilitate delivery of label amount.
  3. Reconstitute each 100-mg vial with 4.2 ml of 0.9% Sodium Chloride Injection (preservative free). Reconstitute each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection (preservative free). Reconstitution of either size vial gives a solution containing 25 mg/mL ALIMTA. 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 ALIMTA 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 ALIMTA 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. ALIMTA is administered as an intravenous infusion over 10 minutes.
  6. Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated. When prepared as directed, reconstitution and infusion solutions of ALIMTA contain no antimicrobial preservatives. Discard any unused portion.
Reconstitution and further dilution prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservative free). ALIMTA 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. Coadministration of ALIMTA with other drugs and diluents has not been studied, and therefore is not recommended. ALIMTA is compatible with standard polyvinyl chloride (PVC) administration sets and intravenous solution bags.

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Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥ 80 mL/min). No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function [see CLINICAL PHARMACOLOGY]. Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), 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 NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Nephrotoxic Drugs 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. Read the Alimta Drug Interactions Center for a complete guide to possible interactions Learn More »

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Nonsquamous Non-Small Cell Lung Cancer – Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. Nonsquamous Non-Small Cell Lung Cancer – Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Nonsquamous Non-Small Cell Lung Cancer – After Prior Chemotherapy ALIMTA 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. Mesothelioma 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. Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. [see Clinical Studies]

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ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. Last reviewed on RxList: 9/27/2013
This monograph has been modified to include the generic and brand name in many instances.

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There have been few cases of ALIMTA 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 ALIMTA to be dialyzed is unknown.

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Dosage Forms And Strengths ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed. ALIMTA, pemetrexed for injection, is available in sterile single-use vials containing 100 mg pemetrexed. NDC 0002-7640-01 (VL7640): single-use vial with ivory flip-off cap individually packaged in a carton. ALIMTA, pemetrexed for injection, is available in sterile single-use vials containing 500 mg pemetrexed. NDC 0002-7623-01 (VL7623): single-use vial with ivory flip-off cap individually packaged in a carton. Storage and Handling ALIMTA, pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Chemical and physical stability of reconstituted and infusion solutions of ALIMTA were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C (36-46°F). When prepared as directed, reconstituted and infusion solutions of ALIMTA contain no antimicrobial preservatives. Discard unused portion [see DOSAGE AND ADMINISTRATION]. ALIMTA is not light sensitive. REFERENCES 1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165. 2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html 3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193. 4. Polovich, M., White, J. M., & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society. Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA. Revised September 2013 Last reviewed on RxList: 9/27/2013
This monograph has been modified to include the generic and brand name in many instances.

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Requirement for Premedication and Concomitant Medication to Reduce Toxicity Vitamin Supplementation Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see DOSAGE AND ADMINISTRATION]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0]. Corticosteroids Administer dexamethasone the day before, the day of, and the day after ALIMTA administration [see DOSAGE AND ADMINISTRATION]. Bone Marrow Suppression ALIMTA 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 AND ADMINISTRATION]. Decreased Renal Function ALIMTA 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, ALIMTA should not be administered to patients whose creatinine clearance is < 45 mL/min [see 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. Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see DRUG INTERACTIONS]. Required Laboratory Monitoring Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a 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 AND ADMINISTRATION]. Pregnancy Category D Based on its mechanism of action, ALIMTA 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 1/833rd the recommended human dose. If ALIMTA 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 ALIMTA [see Use in Specific Populations]. Patient Counseling Information See FDA-Approved Patient Labeling (PPI)
  • Instruct patients to read the patient package insert before initiating ALIMTA.
  • Instruct patients on the need for folic acid and vitamin B12 supplementation to reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
  • Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia.
  • Instruct patients to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.
  • Instruct patients to inform their physician of all concomitant prescription or over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see DRUG INTERACTIONS].
Nonclinical 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. Use In Specific Populations Pregnancy Teratogenic Effects - Pregnancy Category D [see WARNINGS AND PRECAUTIONS] Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA 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 1/833rd the recommended intravenous human dose on a mg/m² basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m² basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA 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 ALIMTA. 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, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother. Pediatric Use Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m² and this dose (or 60 mg/kg for patients < 12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea. The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m² were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m²) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults. Geriatric Use ALIMTA 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. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see DOSAGE AND ADMINISTRATION]. Of 3,946 patients (34.0% ≥ 65) studied across the five clinical trials [see Clinical Studies], the effect of ALIMTA on survival was similar in patients < 65 compared to ≥ 65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia, fatigue, thrombocytopenia, hypertension, and neutropenia. Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see CLINICAL PHARMACOLOGY]. Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment. Gender Of 3,946 patients (Male 70.5%) studied across the five registration studies for ALIMTA indications [see Clinical Studies], the effect of ALIMTA on survival was similar in female and male patients. Race Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for ALIMTA indications [see Clinical Studies], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients. Last reviewed on RxList: 9/27/2013
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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