ALIMTA

Active material: Pemetrexed
When ATH: L01BA04
CCF: Anticancer drug. Antimetaʙolit
ICD-10 codes (testimony): C34, C45.0
When CSF: 22.02.01
Manufacturer: LILLY FRANCE S.A.S. (France)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Valium for solution for infusion from white to yellow or yellowish-green color.

Excipients: mannitol, hydrochloric acid solution 10% and / or sodium hydroxide solution 10% (to adjust the pH).

Bottles (1) – packs cardboard.

Pharmacological action

Anticancer drug, antimetaʙolit. Pemetrexed yavlyaetsya mnogotselevыm antifolatom, inhibiting thymidylate synthase (TC), digidrofolat-reduktazu (DGFR), Glycinamide ribonucleotide-formyltransferase (GARFT), which are key folate-dependent enzyme in the biosynthesis of thymidine and purine nucleotides. Pemetrexed enters cells via transporter of reduced folates and folate binding protein transport systems. Proceeding in a cage, pemetrexed quickly and efficiently converted to polyglutamate forms by the enzyme folil-polyglutamate synthetase.

Polyglutamate forms are retained in the cells and are more potent inhibitors of TS and GARFT. Polyglutamation – This process, time dependent and concentration, which occurs in tumor cells and, less, in normal tissues. For polyglutamate metabolites characterized by an increase in T_1/2, thereby increasing the effect of the drug on the tumor cells.

The combined use of pemetrexed and cisplatin in vitro studies observed antitumor effect of synergy.

Pharmacokinetics

Distribution

In the equilibrium sostoyaniiV_d Pemetrexed is 16.1 l. Binding to plasma proteins - about 81%.

Metabolism

Pemetrexed limited undergoes metabolism in the liver.

Deduction

First 24 hours after injection 70-90% the drug is excreted by the kidneys unchanged. The total plasma clearance of pemetrexed 92 ml / min, T_1/2 from plasma is 3.5 hours in patients with normal renal function.

Pharmacokinetics in special clinical situations

In renal failure, severe plasma protein binding is not changed.

Testimony

- Locally advanced or metastatic non-small cell lung cancer nonsquamous (adenocarcinoma, krupnokletochnыy cancer);

- Malignant pleural mesothelioma.

Dosage regimen

The drug is introduced into / in the drip for 10 m.

Locally advanced or metastatic non-small cell lung cancer nonsquamous (adenocarcinoma, krupnokletochnыy cancer)

The first line therapy. Combined treatment with cisplatin: The recommended dose of the drug Alimta ™ – 500 mg / m² the first day of each 21-day cycle. Cisplatin was administered at a dose of 75 mg / m² against the background of hydration approximately 30 min after administration Alimta ™ on the first day of each 21-day cycle.

The second line therapy. Monotherapy: The recommended dose of the drug Alimta ™ – 500 mg / m² the first day of each 21-day cycle.

Malignant pleural mesothelioma

Combined treatment with cisplatin: The recommended dose of the drug Alimta ™ – 500 mg / m² the first day of each 21-day cycle. Cisplatin was administered at a dose of 75 mg / m² against the background of hydration approximately 30 min after administration Alimta ™ on the first day of each 21-day cycle

Recommendations before the drug Alimta^™

Dexamethasone (or equivalent) dose 4 mg 2 times / day for 1 day before the start of treatment with Alimta^™, day after administration, and the day after administration Alimta^™ reduces the incidence and severity of skin reactions.

To reduce the toxicity of the drug to patients, receiving Alimta^™, should appoint folic acid or a multivitamin, folic acid at a daily dose of. Folic acid at a daily dose of (from 350 micrograms to 1000 g, average 400 g) should be administered at least 5 day within 7 days prior to the first administration of Alimta^™, and application of such doses should be continued during the entire treatment cycle and during 21 day after the last administration Alimta^™. Patients also need to enter a single vitamin B₁₂ dose 1000 ug / m during 7 days prior to the first administration of Alimta^™ and then every 3 cycle after treatment. Subsequent administration of vitamin B₁₂ in the same dose can be performed on the day of Alimta^™.

Recommendations to reduce Alimta dose^™

Dose adjustment to repeat courses should be based on the lowest threshold of hematological parameters or severe hematological toxicity as much as possible during the previous cycle of treatment.

Treatment may be delayed because of the toxicity. As the recovery should continue to be treated in accordance with the recommendations, shown in Tables 1-3 .

In the case of hematological toxicity recommended dose adjustment Alimta^™ and cisplatin, is shown in Table 1.

Table 1

^a These criteria are consistent with the definition of the degree of bleeding ≥ 2 in accordance with common Toxicity Criteria, version 2 (NCI 1998).

With the development of hematological toxicity (excluding neurotoxicity) ≥ 3 degrees (except transaminase elevations 3 degrees) introduction of Alimta^™ should be postponed until recovery indicators, corresponding to the level before treatment. Further, therapy should be continued in line with the recommendations, in the table 2.

Table 2

^a NCI CTC (Common Toxicity Criteria)

^b excluding neurotoxicity

^from with the exception of 3 degree transaminase elevations.

In the event of neurotoxicity recommended dose adjustment Alimta^™ and cisplatin, is shown in Table 3. If neurotoxicity 3 or 4 degree of treatment necessary to cancel.

Table 3

Alimta Treatment^™ should be abolished, if the patient is marked Non-hematological toxicity and hematological 3 or 4 degree after two dose reduction (except transaminase elevations 3 degrees) or immediately cancel the presence of neurotoxicity 3 or 4 degrees.

These increase the risk of side effects in patients aged 65 and older no. Dose reduction mode corresponds to the general guidelines.

In patients with impaired renal function at least QC 45 ml / min dose correction and mode of administration is not required. At CC less than 45 ml / min the use of Alimta^™ not recommended (due to insufficient data on the use of the drug in these patients).

Insufficient data on the use of the drug in patients with impaired liver function with an increase in bilirubin more, than 1.5 Downloads of the VGN, or increased activity of transaminases more than 3 Downloads of the VGN (in the absence of liver metastases), or more than 5 edited by VGN (in the presence of liver metastases).

Recommendations solution for infusion

As the solvent used only 0.9% sodium chloride solution.

For infusion solution contents of the vial (500 mg) dissolved in 20 ml 0.9% sodium chloride solution (without preservatives) before concentration 25 mg / ml. Each vial is gently agitated until complete dissolution of lyophilizate. The resulting solution should be clear; acceptable solution color change from colorless to yellow or greenish-yellow in color.

Next, an additional dilution. An appropriate volume of the resulting solution of pemetrexed should be further diluted to 100 ml 0.9% sodium chloride solution. Before the introduction of the drug solution should be inspected for the presence of particles and discoloration.

Unnecessarily. Alimta^™ and recommended the solvent does not contain antimicrobial preservatives, the resulting solution for injection should be used within 24 hours after reconstitution when stored at 2 ° to 8 ° C or 15 ° to 25 ° C.. Unused solution should be destroyed.

Side effect

Side effects, pemetrexed monotherapy observed with the addition of folic acid and vitamin B₁₂, presented in accordance with the following frequency: Often – ≥10%, often – ≥1% and <10%, infrequently – < 1% and ≥ 0.1%, rarely – ≤ 0.1%. In brackets the frequency of toxicity Percentage of all degrees / one 3-4 degree respectively.

From the hematopoietic system: Often – leukopenia (15.2%/5.4%), neutropenia (14.7%/8.2%), anemia (19.2%/4.2%); often – thrombocytopenia.

From the digestive system: Often – nausea (39.2%/2.6%), vomiting (19.6%/2.1%), anorexia (21.9%/1.9%), stomatitis / pharyngitis (15.4%/1.1%), diarrhea (15.2%/0.9%), increased ALT (15.6%/7%) IS (13.1%/4.4%); often – constipation, abdominal pain.

Dermatological reactions: Often – rash / desquamation (15.9%/0.2%); often – itching, alopecia; infrequently – erythema multiforme.

On the part of the peripheral nervous system: often – sensory or motor neuropathy.

From the urinary system: often – increased creatinine.

Cardio-vascular system: rarely – supraventricular tachycardia.

Other: Often – fatigue (34%/5.3%); often – fever, febrile neutropenia, allergic reactions and attaching secondary infections without neutropenia.

Side effects, observed with the combination of pemetrexed and cisplatin supplemented with folic acid and vitamin B₁₂, described below in accordance with the following frequency: Often – ≥10%, often – ≥1% and <10%, infrequently – < 1% and ≥ 0.1%, rarely – ≤ 0.1%. In brackets the frequency of toxicity Percentage of all degrees / one 3-4 degree respectively.

From the hematopoietic system: Often – leukopenia (53%/14.9%), neutropenia (56%/23.2%), anemia (33%/5.6%), thrombocytopenia (23.2%/5.4%).

From the digestive system: Often – nausea (82.1%/11.9%), vomiting (56.5%/10.7%), anorexia (26.6%/2.4%), stomatitis / pharyngitis (23.2%/3%), diarrhea (16.7%/3.6%), constipation (21%/0.8%); often – dyspepsia, increased ALT, IS, GGT.

Dermatological reactions: Often – rash / desquamation (16.1%/0.6%), alopecia (11.9%/0%).

On the part of the peripheral nervous system: Often – sensornaya neuropathy (10.1%/0%); often – taste disturbance; infrequently – motornaya neuropathy.

From the urinary system: Often – increased creatinine (10.7%/0.8%), decrease in QC (16.1%/0.6%); often – renal failure.

Cardio-vascular system: infrequently – arrhythmia.

The respiratory system: often – chest pain.

Other: Often – fatigue (47.6%/10.1%); often – conjunctivitis, dehydration, febrile neutropenia, infection, fever, hives.

Post-marketing data

The respiratory system: rarely – interstitial pneumonitis.

From the digestive system: rarely – kolity.

Contraindications

- Pregnancy;

- Lactation;

- Hypersensitivity to the drug.

Pregnancy and lactation

The drug is contraindicated during pregnancy and lactation.

Cautions

The drug Alimta^™ must appoint a physician, having experience of anticancer drugs.

Alimta^™ can inhibit bone marrow function, manifested neutropenia, thrombocytopenia and anemia; myelosuppression is usually dose-limiting toxicity manifestation.

Before each administration of Alimta^™ necessary to carry out a general analysis of blood leukocyte count and platelet count.

To evaluate renal and hepatic function should be periodically carried out biochemical analysis of blood.

Before the start of the drug absolute neutrophil count must be ≥1500 cells /, platelets ≥100 000 cells /.

Appointment of folic acid and vitamin B₁₂ reduces the toxicity of pemetrexed and the need for dose reduction in the hematological and hematological toxicity 3-4 degrees, such as, neutropenia, febrile neutropenia and infection with neutropenia 3-4 degrees.

Patients with symptomatic ascites and pleurisy effusion must be drained before use of pemetrexed, t. to. the impact of these conditions on the action of pemetrexed is unknown.

Use in Pediatrics

ALIMTA^™ not recommended for use in children, tk. safety and efficacy in children has not been established.

Overdose

Symptoms: possible bone marrow depression, manifested by neutropenia, thrombocytopenia and anemia. Also, there may be secondary infections accession, diarrhea, mucositis, rash.

Treatment: symptomatic, including the immediate application of leucovorin and thymidine.

Drug Interactions

The combined use of nephrotoxic drugs and / or substances, are excreted renally, may reduce the clearance of pemetrexed.

Results of in vitro studies indicates, that pemetrexed minimal interaction with drugs, которые метаболизируются CYP3A, CYP2D6, CYP2C9, CYP1A2.

The pharmacokinetics of pemetrexed do not change the application of folic acid inside, vitamin B₁₂ / m, and the combined use of cisplatin c. The total clearance of platinum is not affected by the use of pemetrexed.

Pemetrexed can be used in conjunction with ibuprofen (by 400 mg 4 times / day) in patients with normal renal function (KK≥80 ml / min). In the appointment of ibuprofen together with pemetrexed in patients with renal insufficiency, or mild to moderate severity (CC 45-79 ml / min) requires caution.

In patients with renal insufficiency of mild to moderate severity is not recommended the use of NSAIDs with a short T_1/2 during 2 days before applying Alimta^™, the day of application and during 2 days after application.

In the absence of data on the possible interaction between Alimta^™ and NSAIDs with greater than T_1/2, All patients, receiving NSAIDs, We should suspend their use at least 5 days before applying Alimta^™, the day of application and during 2 days after administration. If you want to co-administration of NSAIDs, patients requires strict monitoring of toxicity, especially myelosuppression and gastrointestinal toxicity from.

Pemetrexed is incompatible with Ringer's lactate and Ringer. Co-administration of pemetrexed with other drugs and solutions not studied and is not recommended.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored out of reach of children at temperature from 15 ° to 25 ° C. Shelf life – 2 year.

The prepared solution should be stored: at a temperature of from 2 ° to 8 ° C or 15 ° to 25 ° C max 24 no.