Alimta - instructions for use, doses, side effects, contraindications

Excipients: mannitol - 106.4 mg, hydrochloric acid 10% solution and / or sodium hydroxide solution 10% (added in the production process for pH adjustment).

Description:Lyophilizate from white to yellowish or yellowish green in color.

Pharmacotherapeutic group:Antitumour agent, antimetabolite

ATX: & nbsp

L.01.B.A.04 Pemetrexed

Pharmacodynamics:Pemetrexed is a folic acid antagonist, acting on many targets of its metabolism and inhibiting in vitro thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycine amidobonucleotide formate transferase (GARFT), which are key folate-dependent enzymes in the biosynthesis of thymidine and purine nucleotides. Pemetrexed enters the cells with the help of a carrier of reduced folates and protein folate-binding transport systems. Entering the cage, pemetrexed quickly and efficiently converted to polyglutamate forms using folilpoliglutamatsintetazy enzyme. Polyglutamate forms are retained in cells and are more powerful inhibitors TS and GARFT. Polyglutamination is a process, dependent on time and concentration, which occurs in tumor cells and to a lesser extent in normal tissues. Have polyglutaminate metabolites increased half-life, as a result of which the effect of the drug in tumor cells increases.

With the combined use of pemetrexed and cisplatin in studies in vitro synergism of the antitumor effect was observed.

Pharmacokinetics:

The constant volume of distribution of pemetrexed is 9 l / m². About 81% of pemetrexed binds to plasma proteins. Binding is not impaired in severe renal failure. Pemetrexed is limitedly metabolized in the liver.

From 70 to 90% of the drug is excreted by the kidneys unchanged in the first 24 hours after administration.The total plasma clearance of pemetrexed is 92 ml / min, and the half-life from plasma is 3.5 hours in patients with normal renal function.

Indications:

Locally advanced or metastatic non-cell lung non-small cell lung cancer;
Malignant pleural mesothelioma.

Contraindications:

Hypersensitivity to pemetrexedum or excipients included in the preparation;
Myelosuppression (absolute the number of neutrophils <1500 / μL, platelets <100,000 / μL);
Pronounced renal insufficiency (creatinine clearance (CK) <45 ml / min);
Pregnancy, lactation;
Child age (lack of safety and efficacy data);
Simultaneous use with a vaccine for the prevention of yellow fever.

Carefully:

When the liver function is impaired;
In severe diseases of the cardiovascular system, including myocardial infarction and cerebral circulation disorders.

Pregnancy and lactation:Contraindicated.

Dosing and Administration:

Pemetrexed is administered intravenously drip for 10 minutes.

Locally or metastatic non-small cell non-small cell lung cancer

The first line of therapy. Combined treatment with cisplatin:

The recommended dose of ALIMTA® is 500 mg / m² on the first day of each 21-day cycle.

Cisplatin is administered at a dose of 75 mg / m against hydration (see instruction on the use of cisplatin) approximately 30 minutes after the administration of ALIMTA® on the first day of each 21-day cycle.

Supportive chemotherapy in patients with no progression after the first line of therapy based on derivatives of platinum. Monotherapy:

The recommended dose of ALIMTA® is 500 mg / m² on the first day of each 21-day cycle.

The second line of therapy. Monotherapy:

The recommended dose of ALIMTA® is 500 mg / m² on the first day of each 21-day cycle.

Malignant pleural mesothelioma

Combined treatment with cisplatin:

The recommended dose of ALIMTA® is 500 mg / m² on the first day of each 21-day cycle.

Cisplatin is administered at a dose of 75 mg / m against hydration (see instruction on the use of cisplatin) approximately 30 minutes after administration of ALIMTA® on the first day of each 21-day cycle.

Recommendations before starting the use of the drug ALIMTA®

The administration of dexamethasone (or analogue) at a dose of 4 mg 2 times a day, 1 day before the start of treatment with pemetrexed, on the day of administration and the day after administration of pemetrexed reduces the frequency and severity of skin reactions.

To reduce the toxicity of the drug to patients receiving pemetrexed, preparations of folic acid or multivitamins containing folic acid, providing its daily requirement, should be prescribed. Folic acid (from 350 μg to 1000 μg, an average of 400 μg) should be given for at least 5 days for 7 days before the first administration of pemetrexed, during the entire treatment cycle and for 21 days after the last administration of pemetrexed. Patients also need to once inject vitamin B12 at a dose of 1000 μg intramuscularly for 7 days before the first injection of pemetrexed and then every 3 cycles after the start of treatment. The subsequent administration of vitamin B12 at the same dose can be performed on the day of administration of pemetrexed.

Observation

For all patients receiving pemetrexed, it is recommended to observe before each injection of the drug for a general clinical analysis of blood, including the definition of the leukocyte formula and the number of platelets.To assess the function of the kidneys and liver, a biochemical blood test should be performed before each injection of pemetrexed. Before the beginning of each cycle of chemotherapy, the absolute number of neutrophils (ACH) should be ≥ 1500 cells / mm³, the number of platelets - ≥ 100,000 cells / mm³, the concentration of the total bilirubin ≤1.5 times the upper limit of the norm (HHV), alkaline phosphatase, aspartic and alanine aminotransferases ≤ 3 times from IGN or ≤ 5 times from IGN in the presence of metastases in the liver.

Recommendations for dose reduction.

Dose adjustment before repeated cycles should be carried out, based on the lowest of the hematological parameters or at the most pronounced non-hematologic toxicity during the previous treatment cycle. Treatment can be delayed in order to recover from manifestations of toxicity. As treatment is restored, treatment should be continued in accordance with the recommendations in Tables 1-3, which relate to the use pemetrexeda in monotherapy or in combination with cisplatin.

Table 1. Dosage regimen of pemetrexed (with monotherapy or combined therapy) and cisplatin
Hematological toxicity	Correction of dose (mg / m²)
The minimum neutrophil count <500 / μL and the minimum platelet count ≥50 000 / μL	75% of the previous dose (pemetrexed and cisplatin)
The minimum platelet count <50,000 / μl, regardless of the minimum neutrophil count	75% of the previous dose (pemetrexed and cisplatin)

^a These criteria are consistent with the definition bleeding ≥ 2 according with the criteria of general toxicity National Cancer Institute (NCI CTC).

With the development of non-hematological toxicity (excluding neurotoxicity) ≥3 degrees, treatment is necessary defer to restoration of indicators, corresponding to the value before the start of treatment. Further therapy should be continued in accordance with the recommendations given in Table 2.

Table 2. Dosage regimen of pemetrexed (with monotherapy or combined therapy) and cisplatin
Non-hematological toxicity^{a, b}	Dose of pemetrexed (mg / m²)	Dose of cisplatin (mg / m²)
Any toxicity of grade 3 or 4 with the exception of inflammation of the mucosa	75% of the previous dose	75% of the previous dose
Diarrhea requiring hospitalization and (regardless of degree) or grade 3 or 4 diarrhea	75% of the previous dose	75% of the previous dose
Inflammation	50% of	100% from
mucous	previous	previous
shell 3	dose	dose
or 4 degrees

^a According to the criteria NCI CTC;

^b Excluding neurotoxicity.

AT the case neurotoxicity, the recommended dose adjustment for pemetrexed and cisplatin is shown in Table 3. For neurotoxicity of grade 3 or 4, treatment should be discontinued.

Table 3. The dosage regimen of pemetrexed (with monotherapy or combined therapy) and cisplatin
Degree of neurotoxicity	Dose of pemetrexed (mg / m²)	Dose of cisplatin (mg / m²)
0-1	100% of the previous dose	100% of the previous dose
2	100% of the previous dose	50% of the previous dose

Treatment pemetrexed should be discontinued if the patient has hematologic and non-hematologic toxicity grade 3 or 4 after two decreases in doses or immediately reversed if neurotoxicity is 3 or 4 degrees.

Special patient groups

Elderly Patients: Data on The risk of side effects in patients 65 years of age or older is absent. Reduction mode doses meet the general recommendations.

Patients with impaired renal function: At QC values of at least 45 ml / min, dose adjustment and administration of the drug is not required. Patients with SC less than 45 ml / min pemetrexed is not recommended (due to insufficiency of data on the use of the drug in this category of patients).

Patients with impaired hepatic function: Insufficient data on the use of the drug in patients with impaired liver function with an excess of bilirubin concentration is more than 1.5 times the upper limit of the norm (UGN), or the excess of aminotransferase activity is more than 3 times that of UGH (in the absence of metastases in the liver), or more than 5 times from VGN (in the presence of metastases in the liver).

Recommendations for the preparation of a solution for infusions

1. Only 0.9 is used as a solvent % solution of sodium chloride.

2. For the preparation with a dosage of 100 mg: to obtain a solution for infusions, the contents of the vial (100 mg) are dissolved in 4.2 ml of 0.9% sodium chloride solution (without preservatives) 25 mg / ml (approximately). Each vial is gently shaken until completely dissolved lyophilisate.

The resulting solution should be clear; it is permissible to change the color of the solution from colorless to yellowish or greenish-yellow in color.

3. The corresponding volume of the obtained pemetrexed solution must be further diluted to 100 ml 0.9 % solution of sodium chloride.

4. Before administration, the drug solution should be inspected for particles and discoloration.

The solution for administration should be used immediately or within 24 hours if stored at 2-8 ° C, since pemetrexed and the recommended solvent not contain antibacterial preservatives. Unused solution must be disposed of.

Side effects:

Side effects observed with monotherapy pemetrexed (locally advanced or metastatic non-planocellular non-small cell lung cancer) with the addition of folic acid and vitamin B12, are described below according to the following frequency: very often (≥10%), often (<10% and ≥1%), infrequently (<1% and ≥0.1%), rarely (<0.1%):

On the part of the hematopoiesis system: very often - leukopenia, neutropenia, anemia; often - thrombocytopenia.

From the side of the digestive system: very often - nausea, vomiting, anorexia, stomatitis / pharyngitis, diarrhea; often - increase activity alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), constipation, abdominal pain.

From the skin and skin appendages: very often - rash / peeling; often - skin itching, alopecia, erythema multiforme.

From the peripheral nervous system: often a sensory or motor neuropathy.

From the urinary system: often - increase concentrations whey creatinine.

From the side of the cardiovascular system: infrequently - supraventricular arrhythmia. Other: Often - increased fatigue; often - fever, attachment of secondary infections without neutropenia, febrile neutropenia, allergic reactions.

Side effects observed with monetherapy with pemetrexed as maintenance therapy in patients with no progression after the first line (locally advanced or metastatic non-squamous non-small cell lung cancer) with the addition of folic acid and vitamin B12, are set out below according to the following frequency: very often (≥10%), often (<10% and ≥1%), infrequently (<1% and ≥0.1%), rarely (<0.1%):

On the part of the hematopoiesis system: very often - anemia; often - a leukopenia, neutropenia, thrombocytopenia.

From the side of the digestive system: very often - nausea, anorexia; often - vomiting, inflammation mucous membranes / stomatitis, diarrhea, constipation, increased ALT activity and ACT.

From the skin and skin appendages: often - rash / peeling, alopecia, itchy skin; infrequently, erythema multiforme.

From the peripheral nervous system: often - sensory and motor neuropathy.

From the urinary system: often - increase concentrations serum creatinine, reduced glomerular filtration, renal failure.

From the side of the cardiovascular system: infrequently - supraventricular arrhythmia.

Other: very often - increased fatigue; often - edema, pain syndrome, febrile neutropenia, attachment of secondary infections, fever without neutropenia, conjunctivitis, increased tear, dizziness; infrequently - allergic reactions, thromboembolism of the pulmonary artery.

Side effects observed with the use of pemetrexed in combination from cisplatin (malignant pleural mesothelioma) with the addition of folic acid and vitamin B12, are described below according to the following frequency: very often (≥10%), often (<10 % and ≥1%), infrequently (<1% and ≥0.1%), rarely (<0.1%):

On the part of the hematopoiesis system: very often - leukopenia, neutropenia. anemia, thrombocytopenia.

From the side of the digestive system: very often - nausea, vomiting, anorexia, stomatitis / pharyngitis, diarrhea, constipation; often - dyspepsia, increased activity of ALT, ACT and GGT.

From the skin and skin appendages: very often - a rash, alopecia.

From the peripheral nervous system: very often - sensory neuropathy; often - a violation of taste; infrequently - motor neuropathy.

From the urinary system: very often - an increase in the concentration of serum creatinine. decreased creatinine clearance; often - kidney failure.

From the side of the cardiovascular system: infrequent - arrhythmia.

On the part of the respiratory system: often - pain in the chest.

Other: very often - increased fatigue; often - conjunctivitis, dehydration, febrile neutropenia. attachment of secondary infections, fever, hives.

Side effects observed with the use of pemetrexed in other clinical research:

Serious cardiovascular and cerebrovascular adverse events, including myocardial infarction, angina pectoris. stroke, transient impairment of cerebral circulation, were infrequent when using pemetrexed in combination with other antitumor drugs; while mainly in patients with risk factors for cardiovascular disorders.

Also, cases of pancytopenia, esophagitis / radiation esophagitis were reported infrequently.

In rare cases, the development of hepatitis, a potentially severe degree, was noted. When using pemetrexed were cases of colitis (including intestinal and rectal bleeding, sometimes fatal, perforation of the intestinal wall, bowel necrosis, and inflammation of the caecum) and interstitial pneumonitis with respiratory failure, sometimes with a lethal outcome (infrequently) have been reported.

According to the results of clinical studies, approximately 1% of patients reported development of sepsis, in some cases with a fatal outcome.

Postmarketing data:

Infrequent - edema, limb ischemia, in some cases with the development of necrosis, acute renal failure, radiation pneumonitis; rarely - in patients previously receiving radiation therapy, there were cases of repeated development of skin reactions similar to radiation (anamnestic reaction to irradiation) with the subsequent appointment of pemetrexed; cases of bullous dermatitis, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have also been reported,in some cases fatal; rarely reported cases of development of hemolytic anemia, anaphylactic shock.

Overdose:

Expected complications of an overdose include oppression of bone marrow function, manifested by neutropenia, thrombocytopenia and anemia. Secondary infections, diarrhea, inflammation of the mucous membranes, rash may also occur.

In case of suspicion of an overdose of the drug should be regularly monitored by a general blood test. Treatment: symptomatic, including the immediate use of calcium folinata or folinic acid.

Interaction:

Research in vitro demonstrated that pemetrexed is actively secreted by OAT3 (a carrier of organic anions of human type 3).

Joint use with nephrotoxic drugs (such as aminoglycosides, looped diuretics, platinum-containing drugs, ciclosporin) and / or substances released by the kidneys through tubular secretion (eg, probenecid) can lead to a decrease in the clearance of pemetrexed. Research results in vitro evidence that pemetrexed minimally interacts with drugs that are metabolized by isoenzymes CYP3A. CYP2D6. CYP2C9, CYP1A2.

The pharmacokinetics of pemetrexed does not change when folic acid is administered orally. vitamin B12 intramuscularly and with combined use with cisplatin. The total clearance of platinum derivatives is not impaired by the use of pemetrexed.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) in high doses (eg, ibuprofen more than 1600 mg / day or acetylsalicylic acid more than 1,300 mg / day) concomitantly with pemetrexed therapy even in patients with normal kidney function (CC> 80 mL / min) may lead to reduce the clearance of pemetrexed and enhance its side effect.

Patients with mild and moderate renal insufficiency (CK 45-79 ml / min) are not recommended to use NSAIDs with a short half-life for 2 days before applying pemetrexed, on the day of application and for 2 days after applying pemetrexed.

In view of the lack of data on the possible interaction between pemetrexed and NSAID with a long half-life (piroxicam, rofecoxib), patients with mild or moderate renal failure receiving NSAIDs.should stop their use at least 5 days before the administration of pemetrexed, on the day of administration and within 2 days after the administration of pemetrexed. If the combined use of NSAIDs is required. patients need strict monitoring of toxicity, especially myelosuppression and gastrointestinal toxicity (GIT).

Pemetrexed is incompatible with Ringer's lactate solution and Ringer's solution. The combined use of pemetrexed with other drugs and solutions has not been investigated, and therefore is not recommended (with the exception of 0.9% sodium chloride solution).

When used simultaneously with live attenuated vaccines, it is possible to intensify the process of replication of the vaccine virus, increase its side / adverse effects and / or reduce the production of antibodies in the patient's body in response to the introduction of the vaccine.

When used concomitantly with oral anticoagulants, regular control International normalized ratio (INR).

Special instructions:

The drug ALIMTA® should be used under the supervision of a doctor who has an experience applications antitumor drugs. Myelosuppression is an dose-limiting toxicity pemetrexed.

Before each introduction of pemetrexed, it is necessary to perform a general blood test with counting the leukocyte formula and the number of platelets.

To assess the function of the kidneys and liver, it is necessary to periodically blood chemistry.

Before starting the drug, the absolute number of neutrophils should be ≥1 500 in μL, platelets ≥100,000 in μl.

The administration of folic acid and vitamin B12 reduces the toxicity of pemetrexed and the need for dose reduction for hematological and nonhematological toxicity of 3/4 degree, such as neutropenia, febrile neutropenia and infection with neutropenia of 3/4 degree.

The administration of dexamethasone (or its analogue) at a dose of 4 mg 2 times / day 1 day before the start of treatment with pemetrexed, on the day of administration and the day after administration of pemetrexed reduces the frequency and severity of dermatological reactions.

The effect of the presence of effusion in the serous cavities (ascites or pleurisy) on the action of pemetrexed is not completely known. In patients with effusion in serous cavities in a stable state, there was no difference in the concentrations of pemetrexed in plasma injected in a standard dose, or its clearance compared to patients without such effusion.Thus, the possibility of draining the effusion before starting treatment with pemetrexed should be considered, but this is not a prerequisite. During the treatment with pemetrexed and at least 6 months after it is necessary to use reliable methods of contraception.

Effect on the ability to drive transp. cf. and fur:The influence of pemetrexed on the ability to drive vehicles has not been studied. but pemetrexed can cause fatigue, so patients who are more fatigued, it is not recommended to drive vehicles and engage in other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Lyophilizate for the preparation of a solution for infusions of 100 mg in a vial.

Packaging:One bottle with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of 15 to 25 ° C.

Prepared solution: at temperature from 2 to 8 ° C not more than 24 hours.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:PL-000307

Date of registration:17.02.2011

Expiration Date:17.02.2016

The owner of the registration certificate:Eli Lilly East SAEli Lilly East SA Switzerland

Manufacturer: & nbsp

ELI LILLY & Company USA

Representation: & nbspELI LILLY EAST SA ELI LILLY EAST SA Switzerland

Information update date: & nbsp07.07.2017

Illustrated instructions

Instructions

Alimta® (Alimta)