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Alimta - Pemetrexed disodium



Main info

Pemetrexed disodium, powder for solution for infusion, vial 500 mg. Each vial contains 500 mg of pemetrexed as pemetrexed disodium. Each 500 mg vial must be reconstituted with 20 mL of 0.9 % Sodium Chloride Injection (preservative free). The reconstituted Alimta solution contains 25 mg/mL of pemetrexed.

Alimta is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid. Each 500-mg vial of Alimta contains pemetrexed disodium equivalent to 500 mg pemetrexed and 500 mg of mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.

Clinical pharmacology

Pharmacodynamics

Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides.

Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme 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, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

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

Absolute neutrophil counts (ANC) following single-agent administration of pemetrexed to patients not receiving folic acid and vitamin B 12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, is inversely proportional to the systemic exposure of Alimta. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin B 12 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 ghr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.

Pharmacokinetics

The pharmacokinetics of pemetrexed administered as a single agent in doses ranging from 0.2 to 838 mg/m 2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min).

The clearance decreases, and exposure (AUC) increases, as renal function decreases. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (C max ) 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.

Right usage of Alimta

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 for malignant pleural mesothelioma, Alimta is given in combination with cisplatin (another anti-cancer drug).Cisplatin is infused in your vein for about 2 hours starting about 30 minutes after 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 for getting skin reactions with Alimta.

It is very important to take folic acid and vitamin B 12 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 B 12 injections while you are getting treatment with Alimta. You will get your first vitamin B 12 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.

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 100.4F) 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.

Indications and usage

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.

Non-Small Cell Lung Cancer : Alimta as a single-agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy.

The effectiveness of Alimta in second-line NSCLC was based on the surrogate endpoint, response rate. There are no controlled trials demonstrating a clinical benefit, such as a favorable survival effect or improvement of disease-related symptoms.

Alimta therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions (except Grade 3 transaminase elevations) or immediately if Grade 3 or 4 neurotoxicity is observed.

Elderly Patients --No dose reductions other than those recommended for all patients are necessary for patients >/=65 years of age.

Children --Alimta is not recommended for use in children, as safety and efficacy have not been established in children.

Renally Impaired Patients --In clinical studies, patients with creatinine clearance >/=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-DPTA serum clearance method.

How supplied

Alimta , pemetrexed for injection is available in sterile single-use vials containing 500 mg pemetrexed.

NDC 0002-7623-01 (VL7623): single-use vial with flip-off cap individually packaged in a carton.

Storage

Alimta, pemetrexed for injection, should be stored at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].

Chemical and physical stability of reconstituted and infusion solutions of Alimta were demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8C (36-46F), or at 25C (77F), excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. When prepared as directed, reconstituted and infusion solutions of Alimta contain no antimicrobial preservatives. Discard unused portion.

Alimta is not light sensitive.

New Treatments For Mesothelioma

Earlier this year, the University of Chicago Cancer Research Center released the results of a yearlong clinical trial of Pemetrexed Disodium -- also known as Alimta. Researchers found that patients who combined Alimta with vitamin treatments and the chemotherapy drug, Cisplantin, lived longer and suffered less pain and difficulty breathing than those who only used chemotherapy.

Alimta is scheduled to go to the Federal Drug Administration for fast-track approval in 2003. Given the time it takes for an official FDA approval, the drug's maker, Eli Lilly, has arranged with the FDA to begin offering compassionate use of the drug in the interim. Patients who are currently not receiving treatment are eligible for the program.

Alimta must only be administered under the supervision of a physician qualified in the use of anti-cancer chemotherapy.

Malignant Pleural Mesothelioma

In patients treated for malignant pleural mesothelioma, the recommended dose of Alimta is 500mg/m2 of body surface area (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of cisplatin is 75mg/m2 BSA infused over two hours approximately 30 minutes after completion of the pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequate anti-emetic treatment and appropriate hydration prior to and/or after receiving cisplatin (see also cisplatin Summary of Product Characteristics for specific dosing advice).

Non-Small Cell Lung Cancer

In patients treated for non-small cell lung cancer, the recommended dose of Alimta is 500mg/m2 BSA administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

More info in Alimta official site Alimta.com

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