Alimta

Mechanism Of Action

ALIMTA, pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

Pharmacodynamics

Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.

Absolute neutrophil counts (ANC) following single-agent administration of ALIMTA to patients not receiving folic acid and vitamin B12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, correlates with the systemic exposure, or area under the curve (AUC) of pemetrexed. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin Bi2 supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mcg•hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.

Pharmacokinetics

The pharmacokinetics of ALIMTA administered as a single-agent in doses ranging from 0.2 to 838 mg/m² infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.

Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.

Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The clearance decreases, and exposure (AUC) increases, as renal function decreases. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min).

The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single arm studies.

No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years.

The pharmacokinetics of pemetrexed were not different in male and female patients.

The pharmacokinetics of pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups.

There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

Pediatric patients were not included in clinical trials.

Ibuprofen doses of 400 mg four times a day reduce pemetrexed's clearance by about 20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown [see DRUG INTERACTIONS].

Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown.

Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.

Coadministration of oral folic acid or intramuscular vitamin Bi2 does not affect the pharmacokinetics of pemetrexed.

Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Clinical Studies

Non-Small Cell Lung Cancer (NSCLC) - Combination With Cisplatin

A multi-center, randomized, open-label study in 1725 chemonaive patients with Stage IIIb/IV NSCLC was conducted to compare the overall survival following treatment with ALIMTA in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m² with cisplatin administered intravenously at a dose of 75 mg/m² after ALIMTA administration, on Day 1 of each 21-day cycle. Gemcitabine was administered at a dose of 1250 mg/m² on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m² after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles, and patients in both treatment arms received folic acid, vitamin B12, and dexamethasone [see DOSAGE AND ADMINISTRATION].

Patient demographics of the intent to treat (ITT) population are shown in Table 9. The demographics and disease characteristics were well balanced.

Table 9: First-Line Therapy: Summary of Patient Characteristics in Study of NSCLC

Patients received a median of 5 cycles of treatment in both study arms. Patients treated with ALIMTA plus cisplatin received a relative dose intensity of 94.8% of the protocol-specified ALIMTA dose intensity and 95.0% of the protocol-specified cisplatin dose intensity. Patients treated with gemcitabine plus cisplatin received a relative dose intensity of 85.8% of the protocol-specified gemcitabine dose intensity and 93.5% of the protocol-specified cisplatin dose intensity.

The primary endpoint in this study was overall survival. The median survival time was 10.3 months in the ALIMTA plus cisplatin treatment arm and 10.3 months in the gemcitabine plus cisplatin arm, with an adjusted hazard ratio of 0.94.

Table 10: First-Line Therapy: Efficacy in NSCLC - ITT Population

Figure 1: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in NSCLC - ITT Population.

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 11. 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 [see Clinical Studies].

Table 11: First-Line Therapy: Overall Survival in NSCLC Histologic Subgroups

Figure 2: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in NSCLC - Nonsquamous NSClC and Squamous Cell NSCLC.

Non-Small Cell Lung Cancer - Maintenance

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. 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 Bi2, and dexamethasone [see DOSAGE AND ADMINISTRATION].

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 12. The demographics and baseline disease characteristics were well balanced between study arms.

Table 12: Maintenance Therapy: Summary of Patient Characteristics in Study of NSCLC

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. [see Clinical Studies]

Efficacy results for the overall patient population are presented in Table 13 and Figure 3, and efficacy results by pre-specified histologic subgroups are presented in Table 14 and Figure 4, below.

Table 13: Maintenance Therapy: Efficacy of ALIMTA versus Placebo in NSCLC - ITT Population

Table 14: Maintenance Therapy: Efficacy in NSCLC by Histologic Subgroupsa

Figure 3: Kaplan-Meier Curve for Overall Survival ALIMTA (A) versus Placebo (P) in NSCLC - ITT Population.

Figure 4: Kaplan-Meier Curves for Overall Survival ALIMTA versus Placebo in NSCLC - Nonsquamous NSCLC and Squamous Cell NSCLC.

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 Bi2. 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 (ITT) population are shown in Table 15.

Table 15: Second-Line Therapy: Summary of Patient Characteristics in NSCLC Study

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 (see Table 16). The study did not show an overall survival superiority of ALIMTA.

Table 16: Efficacy of ALIMTA versus Docetaxel in Non-Small Cell Lung Cancer - ITT Population

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 17. 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 [see Clinical Studies].

Table 17: Second Line Therapy: Overall Survival of ALIMTA versus Docetaxel in NSCLC by Histologic Subgroups

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 [see DOSAGE AND ADMINISTRATION]. Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 18.

Table 18: Summary of Patient Characteristics in MPM Study

Table 19 and Figure 5 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.

Table 19: Efficacy of ALIMTA plus Cisplatin versus Cisplatin in Malignant Pleural Mesothelioma

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.

Figure 5: Kaplan-Meier Estimates of Survival Time for ALIMTA plus Cisplatin and Cisplatin Alone in all Randomized and Treated Patients.

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 Bi2 during study therapy received a median of 6 and 4 cycles in the ALIMTA/cisplatin (N=168) and cisplatin (N=163) arms, respectively. Patients who never received folic acid and vitamin B12 during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for the ALIMTA/cisplatin and cisplatin arm, respectively). Patients receiving ALIMTA in the fully supplemented group received a relative dose intensity of 93% of the protocol specified ALIMTA dose intensity; patients treated with cisplatin in the same group received 94% of the projected dose intensity. Patients treated with cisplatin alone had a dose intensity of 96%.

ALIMTA®
(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:

• Malignant pleural mesothelioma. This cancer affects the inside lining of the chest cavity. ALIMTA is given with cisplatin, another anti-cancer medicine (chemotherapy).
• Nonsquamous non-small cell lung cancer. This cancer is a disease in which malignant (cancer) cells form in the tissues of the lung. If you are having initial treatment for your lung cancer, ALIMTA may be given alone or in combination with another chemotherapy drug. If this is the first time you have been treated for your lung cancer, ALIMTA may be given with another anti-cancer drug called cisplatin. If you have completed initial treatment for your lung cancer, ALIMTA may be given alone immediately following your initial treatment. If you are being treated because your cancer has come back or you had trouble tolerating a prior treatment, ALIMTA may be given alone. Your doctor will speak to you about whether ALIMTA is appropriate for your specific type of non-small cell lung cancer.

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. Corticosteroid medicines lower your chances of getting skin reactions with ALIMTA.

ALIMTA has not been studied in children.

What should I tell my doctor before taking ALIMTA?

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

• are pregnant or planning to become pregnant. ALIMTA may harm your unborn baby.
• are breastfeeding. It is not known if ALIMTA passes into breast milk. You should stop breastfeeding once you start treatment with ALIMTA.
• are taking other medicines, including prescription and nonprescription medicines, vitamins, and herbal supplements. ALIMTA and other medicines may affect each other causing serious side effects. Especially, tell your doctor if you are taking medicines called “nonsteroidal anti-inflammatory drugs” (NSAIDs) for pain or swelling. There are many NSAID medicines. If you are not sure, ask your doctor or pharmacist if any of your medicines are NSAIDs.

How is ALIMTA given?

• ALIMTA is slowly infused (injected) into a vein. The injection or infusion will last about 10 minutes. You will usually receive ALIMTA once every 21 days (3 weeks).
• If you are being treated with ALIMTA and cisplatin for the initial treatment of either mesothelioma or non-small cell lung cancer, ALIMTA will be given first as a 10 minute infusion into your vein and cisplatin (another anti-cancer drug) will also be given through your vein starting about 30 minutes after ALIMTA and ending about 2 hours later.
• If you have completed initial treatment for your non-small cell lung cancer, you may receive ALIMTA alone, given as a 10 minute infusion into your vein.
• If you are being treated because your non-small cell lung cancer has returned, you may receive ALIMTA alone, given as a 10 minute infusion into your vein.
• Your doctor will prescribe a medicine called a “corticosteroid” to take for 3 days during your treatment with ALIMTA. Corticosteroid medicines lower your chances for getting skin reactions with ALIMTA.
• It is very important to take folic acid and vitamin B12 during your treatment with ALIMTA to lower your chances of harmful side effects. You must start taking 350-1000 micrograms of folic acid every day for at least 5 days out of the 7 days before your first dose of ALIMTA. You must keep taking folic acid every day during the time you are getting treatment with ALIMTA, and for 21 days after your last treatment. You can get folic acid vitamins over-the-counter. Folic acid is also found in many multivitamin pills. Ask your doctor or pharmacist for help if you are not sure how to choose a folic acid product. Your doctor will give you vitamin B12 injections while you are getting treatment with ALIMTA. You will get your first vitamin Bi2 injection during the week before your first dose of ALIMTA, and then about every 9 weeks during treatment.
• You will have regular blood tests before and during your treatment with ALIMTA. Your doctor may adjust your dose of ALIMTA or delay treatment based on the results of your blood tests and on your general condition.

What should I avoid while taking ALIMTA?

• Women who can become pregnant should not become pregnant during treatment with ALIMTA. ALIMTA may harm the unborn baby.
• Ask your doctor before taking medicines called NSAIDs. There are many NSAID medicines. If you are not sure, ask your doctor or pharmacist if any of your medicines are NSAIDs.

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.

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

• Stomach upset, including nausea, vomiting, and diarrhea. You can obtain medicines to help control some of these symptoms. Call your doctor if you get any of these symptoms.
• Low blood cell counts:
  • Low red blood cells. Low red blood cells may make you feel tired, get tired easily, appear pale, and become short of breath.
  • Low white blood cells. Low white blood cells may give you a greater chance for infection. If you have a fever (temperature above 100.4°F) or other signs of infection, call your doctor right away.
  • Low platelets. Low platelets give you a greater chance for bleeding. Your doctor will do blood tests to check your blood counts before and during treatment with ALIMTA.
• Tiredness. You may feel tired or weak for a few days after your ALIMTA treatments. If you have severe weakness or tiredness, call your doctor.
• Mouth, throat, or lip sores (stomatitis, pharyngitis). You may get redness or sores in your mouth, throat, or on your lips.
• These symptoms may happen a few days after ALIMTA treatment. Talk with your doctor about proper mouth and throat care.
• Loss of appetite. You may lose your appetite and lose weight during your treatment. Talk to your doctor if this is a problem for you.
• Rash. You may get a rash or itching during treatment. These usually appear between treatments with ALIMTA and usually go away before the next treatment. Call your doctor if you get a severe rash or itching.

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.

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Especially, tell your doctor if you take:

• aspirin and other NSAIDs (non-steroidal anti-inflammatory drugs) such as:
  • celecoxib (Celebrex)
  • diclofenac (Cambia, Cataflam, Flector, Voltaren, Zipsor and others)
  • etodolac (Lodine)
  • ibuprofen (Advil, Motrin, Nuprin)
  • indomethacin (Indocin, Indocin SR)
  • ketoprofen (Orudis, Actron, Oruvail)
  • ketorolac (Toradol)
  • meloxicam (Mobic)
  • nabumetone (Relafen)
  • naproxen (Naprosyn)
  • naproxen sodium (Aleve, Anaprox, Naprelan)
  • oxaprozin (Daypro)
  • piroxicam (Feldene)

This is not a complete list of Alimta drug interactions. Ask your doctor or pharmacist for more information.

You should not receive this medication if you are allergic to pemetrexed.

To make sure pemetrexed is safe for you, tell your doctor if you have:

• kidney disease (especially if you take ibuprofen (Advil, Motrin) or other nonsteroidal anti-inflammatory drugs, or NSAIDs);

• liver disease;

• a weak immune system; or

• excess fluid in the space around your lung, liver, or other internal organs, including pleural effusion (fluid around the lungs) or ascites (fluid around the liver).

Do not use pemetrexed if you are pregnant. It could harm the unborn baby. Use effective birth control to avoid pregnancy during your treatment with pemetrexed. Follow your doctor's instructions about how long to prevent pregnancy after your treatment ends.

It is not known whether pemetrexed passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using pemetrexed.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• severe ongoing vomiting or diarrhea;

• bone marrow suppression--fever, swollen gums, painful mouth sores, cold or flu symptoms, sore throat, pale skin, easy bruising or bleeding, skin sores, red or pink urine, rapid heart rate, feeling light-headed or short of breath,

• kidney problems--swelling, rapid weight gain, little or no urinating;

• signs of dehydration--feeling very thirsty or hot, being unable to urinate, heavy sweating, hot and dry skin; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• tired feeling, loss of appetite, weight loss;

• upset stomach, nausea, vomiting, diarrhea;

• mild rash; or

• hair loss.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Absorption

Special Populations

In patients with renal impairment (Clcr 45–80 mL/minute), increased AUC.1

Distribution

Plasma Protein Binding

81%.1

Special Populations

Degree of renal impairment does not affect protein binding.1

Elimination

Metabolism

Not metabolized to an appreciable extent.1

Elimination Route

Principally eliminated in urine as unchanged drug.1

Half-life

3.5 hours.1

Special Populations

Clearance of pemetrexed decreases as renal function decreases.1

Age-related differences in pharmacokinetics not observed in adults 26–80 years of age.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.

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 (14.1, 14.2, 14.3)]

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 (5.1)].

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 (5.1)].

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 (5.1)].

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 (5.5)].

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.

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.

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.

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 (12.3)]. 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:

Caution should be exercised when administering Alimta concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

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 (15)].

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.

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.

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 (12.3)].

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.

Pemetrexed disodium heptahydrate has the chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. It is a white to almost-white solid with a molecular formula of C20H19N5Na2O6•7H2O and a molecular weight of 597.49. 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.

Non-Small Cell Lung Cancer (NSCLC) – Combination with Cisplatin

A multi-center, randomized, open-label study in 1725 chemonaive patients with Stage IIIb/IV NSCLC was conducted to compare the overall survival following treatment with Alimta in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). Alimta was administered intravenously over 10 minutes at a dose of 500 mg/m2 with cisplatin administered intravenously at a dose of 75 mg/m2 after Alimta administration, on Day 1 of each 21-day cycle. Gemcitabine was administered at a dose of 1250 mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2 after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles, and patients in both treatment arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.3)].

Patient demographics of the intent to treat (ITT) population are shown in Table 10. The demographics and disease characteristics were well balanced.

Patients received a median of 5 cycles of treatment in both study arms. Patients treated with Alimta plus cisplatin received a relative dose intensity of 94.8% of the protocol-specified Alimta dose intensity and 95.0% of the protocol-specified cisplatin dose intensity. Patients treated with gemcitabine plus cisplatin received a relative dose intensity of 85.8% of the protocol-specified gemcitabine dose intensity and 93.5% of the protocol-specified cisplatin dose intensity.

The primary endpoint in this study was overall survival. The median survival time was 10.3 months in the Alimta plus cisplatin treatment arm and 10.3 months in the gemcitabine plus cisplatin arm, with an adjusted hazard ratio of 0.94.

Figure 1: Kaplan-Meier Curves for Overall Survival Alimta plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in NSCLC – ITT Population.

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 [see Clinical Studies (14.2, 14.3)].

Figure 2: Kaplan-Meier Curves for Overall Survival Alimta plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in NSCLC – Nonsquamous NSCLC and Squamous Cell NSCLC.

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 [see Dosage and Administration (2.3)].

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.

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. [see Clinical Studies (14.1, 14.3)]

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.

Figure 3: Kaplan-Meier Curve for Overall Survival Alimta (A) versus Placebo (P) in NSCLC – ITT Population.

Figure 4: Kaplan-Meier Curves for Overall Survival Alimta versus Placebo in NSCLC – Nonsquamous NSCLC and Squamous Cell NSCLC.

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 [see Dosage and Administration (2.3)]. 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.

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.

Figure 5: Kaplan-Meier Curves for Overall Survival Alimta versus Placebo in Nonsquamous NSCLC Following Alimta Plus Cisplatin Induction Therapy.

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 (ITT) population are shown in Table 18.

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 (see Table 19). The study did not show an overall survival superiority of Alimta.

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 [see Clinical Studies (14.1, 14.2)].

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 [see Dosage and Administration (2.3)]. Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 21.

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.

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.

Figure 6: Kaplan-Meier Estimates of Survival Time for Alimta plus Cisplatin and Cisplatin Alone in all Randomized and Treated Patients.

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%.

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 (2.3) and Warnings and Precautions (5.1)].
• 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 (7.1)].

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:

• Malignant pleural mesothelioma. This cancer affects the inside lining of the chest cavity. Alimta is given with cisplatin, another anti-cancer medicine (chemotherapy).
• Nonsquamous non-small cell lung cancer. This cancer is a disease in which malignant (cancer) cells form in the tissues of the lung. If you are having initial treatment for your lung cancer, Alimta may be given alone or in combination with another chemotherapy drug. If this is the first time you have been treated for your lung cancer, Alimta may be given with another anti-cancer drug called cisplatin. If you have completed initial treatment for your lung cancer, Alimta may be given alone immediately following your initial treatment. If you are being treated because your cancer has come back or you had trouble tolerating a prior treatment, Alimta may be given alone. Your doctor will speak to you about whether Alimta is appropriate for your specific type of non-small cell lung cancer.

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:

• are pregnant or planning to become pregnant. Alimta may harm your unborn baby.
• are breastfeeding. It is not known if Alimta passes into breast milk. You should stop breastfeeding once you start treatment with Alimta.
• are taking other medicines, including prescription and nonprescription medicines, vitamins, and herbal supplements. Alimta and other medicines may affect each other causing serious side effects. Especially, tell your doctor if you are taking medicines called “nonsteroidal anti-inflammatory drugs” (NSAIDs) for pain or swelling. There are many NSAID medicines. If you are not sure, ask your doctor or pharmacist if any of your medicines are NSAIDs.

How is Alimta given?

• Alimta is slowly infused (injected) into a vein. The injection or infusion will last about 10 minutes. You will usually receive Alimta once every 21 days (3 weeks).
• If you are being treated with Alimta and cisplatin for the initial treatment of either mesothelioma or non-small cell lung cancer, Alimta will be given first as a 10 minute infusion into your vein and cisplatin (another anti-cancer drug) will also be given through your vein starting about 30 minutes after Alimta and ending about 2 hours later.
• If you have completed initial treatment for your non-small cell lung cancer, you may receive Alimta alone, given as a 10 minute infusion into your vein.
• If you are being treated because your non-small cell lung cancer has returned, you may receive Alimta alone, given as a 10 minute infusion into your vein.
• Your doctor will prescribe a medicine called a “corticosteroid” to take for 3 days during your treatment with Alimta.
• It is very important to take folic acid and vitamin B12 during your treatment with Alimta to lower your chances of harmful side effects. You must start taking 400-1000 micrograms of folic acid every day for at least 5 days out of the 7 days before your first dose of Alimta. You must keep taking folic acid every day during the time you are getting treatment with Alimta and for 21 days after your last treatment. You can get folic acid vitamins over-the-counter. Folic acid is also found in many multivitamin pills. Ask your doctor or pharmacist for help if you are not sure how to choose a folic acid product. Your doctor will give you vitamin B12 injections while you are getting treatment with Alimta. You will get your first vitamin B12 injection during the week before your first dose of Alimta, and then about every 9 weeks during treatment.
• You will have regular blood tests before and during your treatment with Alimta. Your doctor may adjust your dose of Alimta or delay treatment based on the results of your blood tests and on your general condition.

What should I avoid while taking Alimta?

• Women who can become pregnant should not become pregnant during treatment with Alimta. Alimta may harm the unborn baby.
• Ask your doctor before taking medicines called NSAIDs. There are many NSAID medicines. If you are not sure, ask your doctor or pharmacist if any of your medicines are NSAIDs.

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:

• Stomach upset, including nausea, vomiting, and diarrhea. You can obtain medicines to help control some of these symptoms. Call your doctor if you get any of these symptoms.
• Low blood cell counts:
  • Low red blood cells. Low red blood cells may make you feel tired, get tired easily, appear pale, and become short of breath.
  • Low white blood cells. Low white blood cells may give you a greater chance for infection. If you have a fever (temperature above 100.4°F) or other signs of infection, call your doctor right away.
  • Low platelets. Low platelets give you a greater chance for bleeding. Your doctor will do blood tests to check your blood counts before and during treatment with Alimta.
• Tiredness. You may feel tired or weak for a few days after your Alimta treatments. If you have severe weakness or tiredness, call your doctor.
• Redness or sores in your mouth, throat, on your lips, or in the tube that connects your throat and stomach (esophagus). Redness and sores may begin a few days after your Alimta treatment. Call your doctor if this happens, or if you have pain or trouble drinking or swallowing food.
• Loss of appetite. You may lose your appetite and lose weight during your treatment. Talk to your doctor if this is a problem for you.
• Rash. You may get a rash or itching during treatment. These reactions usually appear between treatments with Alimta and usually go away before the next treatment. Skin reactions or rashes that include blistering or peeling may be severe and could lead to death. Call your doctor if you have any of these symptoms.

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

You should not receive this medication if you are allergic to pemetrexed.

To make sure you can safely take pemetrexed, tell your doctor if you have other medical conditions, especially:

• kidney disease;
• liver disease;
• bone marrow suppression;
• a weak immune system; or
• excess fluid in the space around your lung, liver, or other internal organs, including pleural effusion (fluid around the lungs) or ascites (fluid around the liver).

FDA pregnancy category D. Do not use pemetrexed if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether pemetrexed passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using pemetrexed.

Do not use Alimta if you are pregnant. It could harm the unborn baby.

Before you receive Alimta, tell your doctor you have kidney or liver disease, bone marrow suppression, a weak immune system, or excess fluid in the space around your lung, liver, or other internal organs.

Tell your doctor about all other medicines you use, especially an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others.

To prevent certain side effects of Alimta, you will need to take folic acid supplements and receive vitamin B12 injections (starting 7 days before your first dose of Alimta). Take only the amount of folic acid that your doctor has prescribed.

Alimta can lower blood cells that help your body fight infections and help your blood to clot. Your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests. Avoid being near people who are sick or have infections. Avoid activities that may increase your risk of bleeding injury. Tell your doctor at once if you develop signs of infection.

Call your doctor at once if you have a serious side effect while using Alimta such as fever, flu symptoms, sore throat, mouth sores, pale skin, easy bruising or bleeding, ongoing vomiting or diarrhea, increased thirst, urinating less than usual, pounding heartbeats, and swelling or rapid weight gain.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

UK: Contraindicated AU, US: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comment: The effects in the nursing infant are unknown.