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Alimta

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Alimta uses


1 INDICATIONS AND USAGE

Alimta® is a folate analog metabolic inhibitor indicated for:


Limitations of Use:

1.1 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.

1.2 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.

1.3 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.

1.4 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.

1.5 Limitations of Use

ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

2 DOSAGE AND ADMINISTRATION

2.1 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.

2.2 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.

2.3 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 .

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 .

Corticosteroids

Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after Alimta administration .

2.4 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 .

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.

a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.
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).

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.

a NCI Common Toxicity Criteria (CTC).
b Excluding neurotoxicity.
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

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.

Dose of Alimta Dose of Cisplatin
CTC Grade (mg/m2) (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 . 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: [140 - Age in years] × Actual Body Weight (kg) = mL/min
72 × Serum Creatinine (mg/dL)
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 .

2.5 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 .

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.

2.6 Preparation for Intravenous Infusion Administration


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.

3 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.

4 CONTRAINDICATIONS

Alimta is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

History of severe hypersensitivity reaction to pemetrexed. (4)

5 WARNINGS AND PRECAUTIONS

5.1 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 . 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 .

5.2 Bone Marrow Suppression

Alimta can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia ; 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 .

5.3 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 .

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.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs 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) .

5.5 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 .

5.6 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 .

6 ADVERSE REACTIONS

The most common adverse reactions with single-agent use are fatigue, nausea, and anorexia. Additional common adverse reactions when used in combination with cisplatin include vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

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.
b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity.
c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.
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

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%


Incidence Less than 1%


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.

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.
b Refer to NCI CTCAE Criteria version 3.0 for each Grade of toxicity.
Alimta

(N=438)

Placebo

(N=218)

Reactionb 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

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 (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 Alimta.

Incidence 1% to 5%


Incidence Less than 1%


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 non-squamous 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.

a Adverse 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.
b NCI CTCAE Criteria version 3.0
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

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%


Incidence Less than 1%


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.

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.
b Refer to NCI CTC Criteria for lab values for each Grade of toxicity (version 2.0).
c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.
Alimta

(N=265)

Docetaxel

(N=276)

Reactionb 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

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%


Incidence Less than 1%


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.

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.
b Refer 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”.
c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.
ALIMTA/cisplatin

(N=168)

Cisplatin

(N=163)

Reactionb 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

The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive Alimta plus cisplatin.

Incidence 1% to 5%


Incidence Less than 1%


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.

a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).
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

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.

6.2 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.

7 DRUG INTERACTIONS

7.1 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 .

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.

7.2 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects – Pregnancy Category D

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.

8.3 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.

8.4 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 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.

8.5 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 .

Of 3,946 patients (34.0% ≥65) studied across the five clinical trials , 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.

8.6 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 .

8.7 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 . Cisplatin coadministration with Alimta has not been studied in patients with moderate renal impairment.

8.8 Gender

Of 3,946 patients studied across the five registration studies for Alimta indications , the effect of Alimta on survival was similar in female and male patients.

8.9 Race

Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for Alimta indications , the effect of Alimta on survival was similar in the Caucasian and non-Caucasian patients.

10 OVERDOSAGE

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.

11 DESCRIPTION

Alimta heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-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:

A pre-specified analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 12. This difference in treatment effect for Alimta based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the single-agent, second-line study and the maintenance study .

a A HR that is less than 1.0 indicates that survival is better in the AC arm than in the GC arm. Alternatively, a HR that is greater than 1.0 indicates survival is better in the GC arm than in the AC arm.
b Unadjusted for multiple comparisons.
c HRs adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological).
d Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type.
e The subgroup of "other" represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.
Histology Subgroup Median Overall Survival in Months

(95% CI)

Unadjusted

Hazard Ratio (HR)a,b (95% CI)

Adjusted Hazard Ratio (HR)a,b,c

(95% CI)

Alimta plus Cisplatin Gemcitabine plus Cisplatin
Nonsquamous NSCLCd

(N=1252)

 11.0

(10.1-12.5)

 N=618 10.1

(9.3-10.9)

 N=634 0.84

(0.74-0.96)

 0.84

(0.74-0.96)
Adenocarcinoma

(N=847)

 12.6

(10.7-13.6)

 N=436 10.9

(10.2-11.9)

 N=411 0.84

(0.71-0.98)

 0.84

(0.71-0.99)
Large Cell

(N=153)

 10.4

(8.6-14.1)

 N=76 6.7

(5.5-9.0)

 N=77 0.68

(0.48-0.97)

 0.67

(0.48-0.96)
Othere

(N=252)

 8.6

(6.8-10.2)

 N=106 9.2

(8.1-10.6)

 N=146 1.12

(0.84-1.49)

 1.08

(0.81-1.45)
Squamous Cell

(N=473)

 9.4

(8.4-10.2)

 N=244 10.8

(9.5-12.1)

 N=229 1.22

(0.99-1.50)

 1.23

(1.00-1.51)
Figure 1 Figure 2

14.2 Non-Small Cell Lung Cancer – Maintenance

Alimta Maintenance Following Non-ALIMTA Containing Platinum-Based, Induction Therapy

A multi-center, randomized, double-blind, placebo-controlled study was conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients who did not progress were randomized 2:1 to receive Alimta or placebo immediately following platinum-based chemotherapy. Of the randomized patients, 47.2% versus 52.7% achieved a complete or partial response to induction therapy and 51.9% versus 47.3% had stable disease after induction therapy in the Alimta and placebo arms, respectively. Alimta was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle, until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone .

The study was designed to demonstrate superior progression-free survival and overall survival of Alimta over placebo. Progression-free survival (PFS) was assessed by independent review. Patient characteristics of the intent to treat (ITT) population are shown in Table 13. The demographics and baseline disease characteristics were well balanced between study arms.

a Stage at Entry was not reported for all randomized patients. Percentages are representative of N=440 for the Alimta arm and N=222 for the placebo arm.
b Includes patients with adenocarcinoma, large cell, and other histologic diagnoses.
c The subgroup of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
d Eastern Cooperative Oncology Group Performance Status (ECOG PS) was not reported for all randomized patients. Percentages are representative of N=439 for the Alimta arm, and N=222 for the placebo arm.
e Smoking history was not reported for all randomized patients. Percentages are representative of N=437 for the Alimta arm and N=221 for the placebo arm.
Patient characteristic Alimta

(N=441)

Placebo

(N=222)

Age (yrs)
Median (range) 60.6 (25.6-82.6) 60.4 (35.4-78.5)
Gender
Male/Female 73.0%/27.0% 72.5%/27.5%
Ethnic Origin
Caucasian 279 (63.3%) 149 (67.1%)
East Asian 104 (23.6%) 50 (22.5%)
Other 58 (13.2%) 23 (10.4%)
Stage at Entry a
IIIb/IV 18.0%/82.0% 21.2%/78.8%
Histology (%)
Nonsquamous NSCLCb 325 (73.7%) 156 (70.3%)
Adenocarcinoma 222 (50.3%) 106 (47.7%)
Large cell 10 (2.3%) 10 (4.5%)
Otherc 93 (21.1%) 40 (18.0%)
Squamous 116 (26.3%) 66 (29.7%)
ECOG PSd
0/1 40.1%/59.9% 38.3%/61.7%
Smoking Historye
Ever/never smoker 74.1%/25.9% 71.5%/28.5%
Time from start of induction therapy to study randomization (months)
Median (range) 3.25 (1.6-4.8) 3.29 (2.7-5.1)

Patients received a median of 5 cycles of Alimta and 3.5 cycles of placebo. Patients randomized to Alimta received a relative dose intensity of 95.7%. A total of 213 patients (48.3%) completed ≥6 cycles and a total of 98 patients (22.6%) completed ≥10 cycles of treatment with Alimta.

In the overall study population, Alimta was statistically superior to placebo in terms of overall survival (OS) (median 13.4 months versus 10.6 months, HR=0.79 (95% CI: 0.65-0.95), p-value=0.012) and PFS (median 4.0 months versus 2.0 months, HR=0.60 (95% CI: 0.49-0.73), p-value<0.00001). A difference in treatment outcomes was observed according to histologic classification. For the population of patients with nonsquamous NSCLC, Alimta was superior to placebo for OS (median 15.5 months versus 10.3 months, HR=0.70 (95% CI: 0.56-0.88)) and PFS (median 4.4 months versus 1.8 months, HR=0.47 (95% CI: 0.37-0.60)). For the population of patients with squamous NSCLC, Alimta did not improve OS compared to placebo (median 9.9 months versus 10.8 months, HR=1.07 (95% CI: 0.77-1.50)) or PFS (median 2.4 months versus 2.5 months, HR=1.03 (95% CI: 0.71-1.49)). This difference in treatment effect for Alimta based on histology demonstrating lack of benefit in squamous cell histology was also observed in the first-line and second-line studies.

Efficacy results for the overall patient population are presented in Table 14 and Figure 3, and efficacy results by pre-specified histologic subgroups are presented in Table 15 and Figure 4, below.

a PFS and OS were calculated from time of randomization, after completion of 4 cycles of induction platinum-based chemotherapy.
b Values for PFS given based on independent review (ALIMTA N=387, Placebo N=194).
c Unadjusted hazard ratios are provided. A HR <1.0 indicates that the result is better in the Alimta arm than in the placebo arm.
Efficacy Parametera,b Alimta

(N=441)

Placebo

(N=222)

Median overall survivalc (95% CI) 13.4 mos (11.9-15.9) 10.6 mos (8.7-12.0)
Hazard ratio (HR)c (95% CI) 0.79 (0.65-0.95)
p-value p=0.012
Median progression-free survival (95% CI) 4.0 mos (3.1-4.4) 2.0 mos (1.5-2.8)
Hazard ratio (HR)c (95% CI) 0.60 (0.49-0.73)
p-value p<0.00001
a PFS and OS were calculated from time of randomization, after completion of 4 cycles of induction platinum-based chemotherapy. All results unadjusted for multiple comparisons.
b Values for PFS are given based on independent review (ALIMTA N=387, Placebo N=194).
c Unadjusted hazard ratios are provided. A HR <1.0 indicates that the result is better in the Alimta arm than in the placebo arm. A HR >1.0 indicates that the result is better in the placebo arm than in the Alimta arm.
d Includes patients with adenocarcinoma, large cell carcinoma, and other histology.
e The subgroup of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
Overall Survival Progression-Free Survivalb
Alimta Placebo Alimta Placebo
Median (months) Median (months) Median (months) Median (months)
HRc (95% CI) HRc (95% CI)
Nonsquamous NSCLCd 15.5 10.3 4.4 1.8
N=481 0.70 (0.56-0.88) 0.47 (0.37-0.60)
Adenocarcinoma 16.8 11.5 4.6 2.7
N=328 0.73 (0.56-0.96) 0.51 (0.38-0.68)
Large cell carcinoma 8.4 7.9 4.5 1.5
N=20 0.98 (0.36-2.65) 0.40 (0.12-1.29)
Othere 11.3 7.7 4.1 1.6
N=133 0.61 (0.40-0.94) 0.44 (0.28-0.68)
Squamous cell 9.9 10.8 2.4 2.5
N=182 1.07 (0.77-1.50) 1.03 (0.71-1.49)
Figure 3 Figure 4

Continuation of Alimta as Maintenance Following Alimta Plus Platinum Induction Therapy

A multi-center, randomized, double-blind, placebo-controlled study was conducted to evaluate continuation of Alimta in patients with Stage IIIb/IV nonsquamous NSCLC. Patients completing induction treatment of four cycles of Alimta plus cisplatin with stable disease or better and PS 0/1 were randomized (2:1) to maintenance treatment with Alimta or placebo. Randomization was stratified by response to induction (complete response (CR)/partial response (PR) versus stable disease (SD)), disease stage (IIIb versus IV), and ECOG performance status (0 versus 1). Alimta was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle and continued until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone . The main efficacy outcome was investigator-assessed progression-free survival.

A total of 539 patients were randomized; all completed four cycles of Alimta and cisplatin induction prior to randomization. Of the randomized patients, 44% versus 42% achieved a complete or partial response to induction therapy and 53% versus 53% had stable disease after induction treatment in the Alimta or the placebo arms respectively.

Patient demographics of the intent to treat (ITT) population are shown in Table 16.

a Histological or cytological diagnosis of NSCLC defined as other than predominantly squamous cell histology (squamous cell and/or mixed small cell, non-small cell histology were not permitted on this study).
b The subcategory of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma or large-cell carcinoma.
c Smoking history was not reported for all randomized patients.
Patient characteristic Alimta

(N=359)

Placebo

(N=180)

Age (yrs)
Median 61.0 62.4
Range 31.9-78.7 34.9-83.3
Gender (%)
Male 201 (56%) 112 (62%)
Female 158 (44%) 68 (38%)
Ethnic Origin (%)
Caucasian 339 (94%) 171 (95%)
Asian 16 (4.5%) 8 (4.4%)
African 4 (1.1%) 1 (0.6%)
Stage at Entry
IIIb 31 (9%) 18 (10%)
IV 328 (91%) 162 (90%)
Histology (%)
Nonsquamous NSCLCa
Adenocarcinoma 310 (86%) 161 (89%)
Large cell 24 (7%) 12 (7%)
Otherb 25 (7%) 7 (3.9%)
ECOG PS (%)
0 113 (32%) 60 (33%)
1 245 (68%) 118 (66%)
Smoking History c
Ever 274 (76%) 144 (80%)
Never smoker 83 (23%) 34 (19%)

Patients received a median of four cycles of Alimta maintenance or placebo. The percentages of patients that received post-study treatment were similar (64% in the Alimta arm and 72% in the placebo arm).

The trial showed a statistically significant improvement in progression-free survival and in overall survival for patients randomized to Alimta maintenance. Efficacy results are presented in Table 17 and Figure 5.

a PFS and OS were calculated from time of randomization, after completion of 4 cycles of Alimta plus cisplatin induction therapy.
b Values for PFS given based on investigator assessment.
c A hazard ratio of less than 1 indicates that the maintenance treatment with pemetrexed is associated with lower risk of progression or death compared to treatment with placebo.
Efficacy Parametera,b Alimta

(N=359)

Placebo

(N=180)

Median overall survivalc (95% CI) 13.9 mos (12.8-16.0) 11.0 mos (10.0-12.5)
Hazard ratio (HR)c (95% CI) 0.78 (0.64-0.96)
p-value p=0.02
Median progression-free survival (95% CI) 4.1 mos (3.2-4.6) 2.8 mos (2.6-3.1)
Hazard ratio (HR)c (95% CI) 0.62 (0.49-0.79)
p-value p<0.0001
Figure 5

14.3 Non-Small Cell Lung Cancer – After Prior Chemotherapy

A multi-center, randomized, open label study was conducted in patients with Stage III or IV NSCLC after prior chemotherapy to compare the overall survival following treatment with Alimta versus docetaxel. Alimta was administered intravenously over 10 minutes at a dose of 500 mg/m2 and docetaxel was administered at 75 mg/m2 as a 1-hour intravenous infusion. Both drugs were given on Day 1 of each 21-day cycle. All patients treated with Alimta received vitamin supplementation with folic acid and vitamin B12. The study was intended to show either an overall survival superiority or non-inferiority of Alimta to docetaxel. Patient demographics of the intent to treat population are shown in Table 18.

a Performance status was not reported for all randomized patients. Percentages are representative of N=264 for the Alimta arm and N=274 for the docetaxel arm.
Patient characteristic Alimta

(N=283)

 Docetaxel

(N=288)
Age (yrs)
Median (range) 59 (22-81) 57 (28-87)
Gender (%)
Male/Female 68.6/31.4 75.3/24.7
Stage at Entry (%)
III/IV 25.1/74.9 25.3/74.7
Diagnosis/Histology (%)
Adenocarcinoma 154 (54.4) 142 (49.3)
Squamous 78 (27.6) 94 (32.6)
Bronchoalveolar 4 (1.4) 1 (0.3)
Other 47 (16.6) 51 (17.7)
Performance Status (%)a
0-1 234 (88.6) 240 (87.6)
2 30 (11.4) 34 (12.4)

The primary endpoint in this study was overall survival. The median survival time was 8.3 months in the Alimta treatment arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99. The study did not show an overall survival superiority of Alimta.

Alimta

(N=283)

 Docetaxel

(N=288)
Median overall survival (95% CI) 8.3 mos (7.0-9.4) 7.9 mos (6.3-9.2)
Hazard ratio (HR) (95% CI) 0.99 (0.82-1.20)
Median progression-free survival (95% CI) 2.9 mos (2.4-3.1) 2.9 mos (2.7-3.4)
Hazard ratio (HR) (95% CI) 0.97 (0.82-1.16)
Overall response rate (95% CI) 8.5% (5.2-11.7) 8.3% (5.1-11.5)

A retrospective analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 20. This difference in treatment effect for Alimta based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the first-line combination study and in the maintenance study .

a A HR that is less than 1.0 indicates that survival is better in the ALIMTA arm than in the docetaxel arm. Alternatively, a HR that is greater than 1.0 indicates survival is better in the docetaxel arm than in the ALIMTA arm.
b Unadjusted for multiple comparisons.
c HRs adjusted for ECOG PS, time since prior chemotherapy, disease stage, and gender.
d Includes adenocarcinoma, large cell, and other histologies except those with squamous cell type.
e The subgroup of “other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.
Histology Subgroup Median Overall Survival in Months

(95% CI)

Unadjusted Hazard Ratio (HR)a,b

(95% CI)

Adjusted Hazard Ratio (HR)a,b,c

(95% CI)

Alimta Docetaxel
Nonsquamous NSCLCd

(N=399)

 9.3

(7.8-9.7)

 N=205 8.0

(6.3-9.3)

 N=194 0.89

(0.71-1.13)

 0.78

(0.61-1.00)
Adenocarcinoma

(N=301)

 9.0

(7.6-9.6)

 N=158 9.2

(7.5-11.3)

 N=143 1.09

(0.83-1.44)

 0.92

(0.69-1.22)
Large Cell

(N=47)

 12.8

(5.8-14.0)

 N=18 4.5

(2.3-9.1)

 N=29 0.38

(0.18-0.78)

 0.27

(0.11-0.63)
Othere

(N=51)

 9.4

(6.0-10.1)

 N=29 7.9

(4.0-8.9)

 N=22 0.62

(0.32-1.23)

 0.57

(0.27-1.20)
Squamous Cell

(N=172)

 6.2

(4.9-8.0)

 N=78 7.4

(5.6-9.5)

 N=94 1.32

(0.93-1.86)

 1.56

(1.08-2.26)

14.4 Malignant Pleural Mesothelioma

A multi-center, randomized, single-blind study in 448 chemonaive patients with malignant pleural mesothelioma (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 117 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 . Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 21.

a Only 67% of the patients had the histologic diagnosis of malignant mesothelioma confirmed by independent review.
b Karnofsky Performance Scale.
Randomized and Treated Patients Fully Supplemented Patients
Patient characteristic ALIMTA/cis

(N=226)

 Cisplatin

(N=222)

 ALIMTA/cis

(N=168)

 Cisplatin

(N=163)
Age (yrs)
Median (range) 61 (29-85) 60 (19-84) 60 (29-85) 60 (19-82)
Gender (%)
Male 184 (81.4) 181 (81.5) 136 (81.0) 134 (82.2)
Female 42 (18.6) 41 (18.5) 32 (19.0) 29 (17.8)
Origin (%)
Caucasian 204 (90.3) 206 (92.8) 150 (89.3) 153 (93.9)
Hispanic 11 (4.9) 12 (5.4) 10 (6.0) 7 (4.3)
Asian 10 (4.4) 4 (1.9) 7 (4.2) 3 (1.8)
African descent 1 (0.4) 0 1 (0.6) 0
Stage at Entry (%)
I 16 (7.1) 14 (6.3) 15 (8.9) 12 (7.4)
II 35 (15.6) 33 (15.0) 27 (16.2) 27 (16.8)
III 73 (32.4) 68 (30.6) 51 (30.5) 49 (30.4)
IV 101 (44.9) 105 (47.2) 74 (44.3) 73 (45.3)
Unspecified 1 (0.4) 2 (0.9) 1 (0.6) 2 (1.2)
Diagnosis/Histologya (%)
Epithelial 154 (68.1) 152 (68.5) 117 (69.6) 113 (69.3)
Mixed 37 (16.4) 36 (16.2) 25 (14.9) 25 (15.3)
Sarcomatoid 18 (8.0) 25 (11.3) 14 (8.3) 17 (10.4)
Other 17 (7.5) 9 (4.1) 12 (7.1) 8 (4.9)
Baseline KPSb (%)
70-80 109 (48.2) 97 (43.7) 83 (49.4) 69 (42.3)
90-100 117 (51.8) 125 (56.3) 85 (50.6) 94 (57.7)

Table 22 and Figure 6 summarize 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.

a p-value refers to comparison between arms.
Randomized and Treated Patients Fully Supplemented Patients
Efficacy Parameter ALIMTA/cis

(N=226)

 Cisplatin

(N=222)

 ALIMTA/cis

(N=168)

 Cisplatin

(N=163)
Median overall survival 12.1 mos 9.3 mos 13.3 mos 10.0 mos
(95% CI) (10.0-14.4) (7.8-10.7) (11.4-14.9) (8.4-11.9)
Hazard ratio 0.77 0.75
Log rank p-valuea 0.020 0.051

Similar results were seen in the analysis of patients (N=303) with confirmed histologic diagnosis of malignant pleural mesothelioma. There were too few non-white patients to assess possible ethnic differences. The effect in women (median survival 15.7 months with the combination versus 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 11 versus 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%.

Figure 5

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Alimta, pemetrexed for injection, is available in sterile single-use vials containing 100 mg pemetrexed.

NDC 0002-7640-01 : 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.

16.2 Storage and Handling

Alimta, pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

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 .

Alimta is not light sensitive.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (PPI)

Instruct patients to read the patient package insert before initiating Alimta.


Marketed by: Lilly USA, LLC

Indianapolis, IN 46285, USA

Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.

PV 8927 AMP

PATIENT INFORMATION

Alimta® (uh-LIM-tuh)

(pemetrexed for injection)

Read the Patient Information that comes with Alimta before you start treatment and each time you get treated with Alimta. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about Alimta.

What is Alimta?

Alimta is a treatment for:


To lower your chances of side effects of Alimta, you must also take folic acid and vitamin B12 prior to and during your treatment with Alimta. Your doctor will prescribe a medicine called a “corticosteroid” to take for 3 days during your treatment with Alimta.

In children, Alimta has not been shown to be effective. No important differences in side effects were seen in children compared to adults (see “What are the possible side effects of Alimta?”).

What should I tell my doctor before taking Alimta?

Tell your doctor about all of your medical conditions, including if you:


How is Alimta given?


What should I avoid while taking Alimta?


What are the possible side effects of Alimta?

Most patients taking Alimta will have side effects. Sometimes it is not always possible to tell whether Alimta, another medicine, or the cancer itself is causing these side effects. Call your doctor right away if you have a fever, chills, diarrhea, or mouth sores. These symptoms could mean you have an infection which may be severe and could lead to death.

The most common side effects of Alimta when given alone or in combination with cisplatin are:


Talk with your doctor, nurse, or pharmacist about any side effect that bothers you or that doesn't go away.

These are not all the side effects of Alimta. For more information, ask your doctor, nurse, or pharmacist.

General information about Alimta

Medicines are sometimes prescribed for conditions other than those listed in patient information leaflets. Alimta was prescribed for your medical condition.

This leaflet summarizes the most important information about Alimta. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Alimta that is written for health professionals. You can also call 1-800-LILLY-RX (1-800-545-5979) or visit www. ALIMTA.com.

Revised September 2013

Marketed by: Lilly USA, LLC

Indianapolis, IN 46285, USA

www. ALIMTA.com

Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.

PX 0040 AMP

PACKAGE CARTON – Alimta 100 mg single-use vial

NDC 0002-7640-01

Single-Use Vial

VL7640

Alimta®

pemetrexed for injection

100 mg

For intravenous use only.

Rx only

www. ALIMTA.com

Lilly

PACKAGE CARTON – Alimta 500 mg single-use vial

Single-Use Vial

NDC 0002-7623-01

VL7623

Alimta®

pemetrexed for injection

500 mg

For intravenous use only.

Rx only

www. ALIMTA.com

Lilly

PACKAGE CARTON – Alimta 100 mg single-use vial PACKAGE CARTON – Alimta 500 mg single-use vial

Alimta pharmaceutical active ingredients containing related brand and generic drugs:


Alimta available forms, composition, doses:


Alimta destination | category:


Alimta Anatomical Therapeutic Chemical codes:


Alimta pharmaceutical companies:


References

  1. Dailymed."ALIMTA (PEMETREXED DISODIUM) INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION [ELI LILLY AND COMPANY]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."PEMETREXED DISODIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Pemetrexed". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Alimta?

Depending on the reaction of the Alimta after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Alimta not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Alimta addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Alimta, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Alimta consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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