Universal reference book for medicines
Name of the preparation: ALIMTA В® (ALIMTA В® )

Active substance: pemetrexed

Type: Antitumor drug.
Antimetabolite
Manufacturer: ELI LILLY VOSTOK (Switzerland) manufactured by ELI LILLY & Company (USA) packed LILLY FRANCE (France)
Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions
from white to yellowish or yellowish-green in color.

1 f.

pemetrexed (in the form of a pemetrexed disodium heptahydrate) 100 mg

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

Vials (1) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2013.

PHARMACHOLOGIC EFFECT

Antitumor drug, antimetabolite.
Pemetrexed is a folic acid antagonist acting on many targets of its metabolism and inhibiting in vitro thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide-ribonucleotide-formyl 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 reconstituted folate and protein folate-binding transport systems. Entering the cell, pemetrexed quickly and efficiently converted into polyglutamate forms with the enzyme folyl polyglutamate synthetase.
Polyglutamate forms are retained in cells and are more potent inhibitors of 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. In polyglutaminate metabolites, the half-life is increased, as a result of which the effect of the drug in tumor cells increases.
With the combined use of pemetrexed and cisplatin, an antitumor effect was observed in in vitro studies.

PHARMACOKINETICS

Distribution

In the equilibrium state
V d of pemetrexed is 9 l / m 2 . Binding to plasma proteins is about 81%.
Metabolism

Pemetrexed is limitedly metabolized in the liver.

Excretion

The total plasma clearance of pemetrexed is 92 ml / min, T 1/2 from plasma is 3.5 h in patients with normal renal function.
In the first 24 hours after the administration of 70-90% of the drug is excreted by the kidneys unchanged.
Pharmacokinetics in special clinical cases

In severe renal insufficiency, binding to plasma proteins does not change.

INDICATIONS

- locally advanced or metastatic non-cell lung non-small cell lung cancer;

malignant pleural mesothelioma.

DOSING MODE

The drug is injected / drip for 10 minutes.

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

The first line of therapy.
Combined treatment with cisplatin: the recommended dose of Alimta В® is 500 mg / m 2 on the first day of each 21-day cycle. Cisplatin is administered at a dose of 75 mg / m 2 on the background of hydration approximately 30 minutes after the administration of the AlimtaВ® preparation on the first day of each 21-day cycle.
Supportive chemotherapy in patients with no progression after the first line of therapy based on platinum drugs.
Monotherapy: the recommended dose of Alimta В® is 500 mg / m 2 on the first day of each 21-day cycle.
The second line of therapy.
Monotherapy: the recommended dose of Alimta В® is 500 mg / m 2 on the first day of each 21-day cycle.
Malignant pleural mesothelioma

Combined treatment with cisplatin: the recommended dose of Alimta В® is 500 mg / m 2 on the first day of each 21-day cycle.
Cisplatin is administered at a dose of 75 mg / m 2 on the background of hydration approximately 30 minutes after the administration of the AlimtaВ® preparation on the first day of each 21-day cycle.
Recommendations before using Alimta В®

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

To reduce the toxicity of the drug, patients receiving Alimt should be prescribed folic acid preparations or multivitamins containing folic acid in a daily dose.
Folic acid in a daily dose (from 350 Ојg to 1000 Ојg, an average of 400 Ојg) should be prescribed for at least 5 days for 7 days before the first administration of Alimta, during the entire treatment cycle and for 21 days after the last administration of Alimta. Patients also need to once inject vitamin B 12 at a dose of 1000 mcg IM for a period of 7 days before the first administration of Alimta and then every 3 cycles after the start of treatment. The subsequent administration of vitamin B 12 in the same dose can be carried out on the day of Alimta administration.
Observation

For all patients receiving pemetrexed, it is recommended to observe before each dose for a general clinical blood test, 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 should be? 1500 cells / μl, the platelet count should be ≥100,000 cells / μl, the total bilirubin level ≥ 1.5 times from the ВGN, the level of the ЩF, AST, ALT 3 3 times from the В или или or 3
5 times from VGN in the presence of metastases in the liver.
Recommendations for reducing the dose of Alimta В®

Dose adjustment before repeated courses should be performed taking into account the lowest threshold of hematologic indices or the maximum expressed nonhematological toxicity during the previous treatment cycle.

Treatment can be delayed because of toxicity.
As treatment is restored, treatment should be continued according to the recommendations in Tables 1-3, which refer to the use of pemetrexed in monotherapy or in combination with cisplatin.
In the case of hematological toxicity, the recommended dose adjustment for Alimta and cisplatin is shown in Table 1.

Dosage regimen of the drug Alimta В® (with monotherapy or combined therapy) and cisplatin

Hematologic toxicity

The minimum neutrophil count is <500 cells / Ојl and the minimum platelet count is 50,000 cells / Ојl 75% of the previous dose (both drugs)

The minimum platelet count is <50,000 cells / Ојl, regardless of the minimum neutrophil count of 75% of the previous dose (both drugs)

The minimum platelet count is <50,000 cells / ОјL with bleeding a, regardless of the minimum neutrophil count of 50% of the previous dose (both drugs)

Do these criteria correspond to the definition of bleeding?
grade 2 according to the criteria for total toxicity of the National Cancer Institute (NCI-CTC).
With the development of non-hematologic toxicity (excluding neurotoxicity)? 3 degrees (with the exception of an increase in the level of transaminases of grade 3), therapy should be postponed until the recovery of indicators corresponding to the level before the start of treatment.
Further therapy should be continued in accordance with the recommendations given in Table 2.
Dosage regimen of the drug Alimta В® (with monotherapy or combined therapy) and cisplatin

Non-hematological toxicity a, b Alimta dose (mg / m 2 ) Cisplatin dose (mg / m 2 )

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 (regardless of grade) or grade 3 or 4 diarrhea 75% of the previous dose 75% of the previous dose

Inflammation of the mucosa 3 or 4 degrees 50% of the previous dose 100% of the previous dose

a According to the NCI-CTC criteria

b excluding neurotoxicity

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

Dosage regimen of the drug Alimta В® (with monotherapy or combined therapy) and cisplatin

Degree of Neurotoxicity Dose of Alimta (mg / m 2 ) Cisplatin dose (mg / m 2 )

0-1 100% of the previous dose 100% of the previous dose

2 100% of the previous dose 50% of the previous dose

Treatment with Alimta should be discontinued if the patient has hematologic and non-hematologic toxicity of grade 3 or 4 after two dose decreases or immediately discontinued with neurotoxicity of grade 3 or 4.

Data on the increased risk of adverse events in patients aged 65 years and older are not available.
The dose reduction regimen corresponds to general recommendations.
In patients with impaired renal function with a QC of at least 45 ml / min, dose adjustment and administration of the drug is not required.
With SC less than 45 ml / min, the use of Alimta is not recommended (due to the lack of data on the use of the drug in this category of patients).
There is insufficient data on the use of the drug in patients with impaired hepatic function with an increase in bilirubin content by more than 1.5 times that of IGN, or an increase in the activity of transaminases more than 3-fold from IGN (in the absence of metastases in the liver), or more than 5 times from IGN (in the presence of metastases in the liver).

Recommendations for the preparation of a solution for infusions

As a solvent, only 0.9% sodium chloride solution is used.

To obtain a solution for infusion, the contents of the vial (100 mg) are dissolved in 4.2 ml of 0.9% sodium chloride solution (no preservatives) to a concentration of 25 mg / ml.
Each vial is gently shaken until the lyophilizate is completely dissolved. 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.
The corresponding volume of the obtained pemetrexed solution should be further diluted to 100 ml with 0.9% sodium chloride solution.

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

Because
Alimta В® and the recommended solvent do not contain antimicrobial preservatives, the resulting solution for administration should be used within 24 hours after reconstitution when stored at 2-8 В° C or 15-25 В° C. Unused solution must be disposed of.
SIDE EFFECT

Side effects observed with monotherapy with pemetrexed supplemented with folic acid and vitamin B 12 are presented according to the following frequency: very often (? 10%), often (? 1% and <10%), infrequently (<1% and? 0.1 %), rarely (<0.1%).

From the hemopoietic system: very often - leukopenia, neutropenia, anemia;
often - thrombocytopenia.
From the digestive system: very often - nausea, vomiting, anorexia, stomatitis / pharyngitis, diarrhea;
often - increased activity of ALT and AST, inflammation of the mucous membranes of the digestive tract, constipation, dyspepsia, abdominal pain; infrequently - increased activity of GGT, esophagitis; rarely - colitis, hepatitis.
Dermatological reactions: very often - rash / peeling;
often - itchy skin, alopecia, erythema multiforme.
From the side of the peripheral nervous system: often - sensory or motor neuropathy.

From the senses: often - a violation of taste.

From the urinary system: often - increased serum creatinine, decreased creatinine clearance, reduced glomerular filtration, renal failure.

From the cardiovascular system: infrequently - supraventricular arrhythmia.
Serious cardiovascular and cerebrovascular side effects, including myocardial infarction, angina pectoris, transient cerebral circulation, were infrequent when using pemetrexed in combination with other antitumor drugs, mainly in patients with risk factors for cardiovascular disorders.
Other: very often - increased fatigue;
often - fever, febrile neutropenia, fever, dehydration, swelling, conjunctivitis, increased lacrimation, allergic reactions and attachment of secondary infections, urticaria; infrequently, interstitial pneumonitis.
According to the results of clinical studies, approximately 1% of patients reported development of sepsis, in some cases with a fatal outcome.

Post-marketing data

Rarely: edema, in patients who received 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 were also reported some cases with a fatal outcome;
very rarely - limb ischemia, in some cases with the development of necrosis.
CONTRAINDICATIONS

- myelosuppression (absolute number of neutrophils <1500 / Ојl, platelets <100,000 / Ојl);

- severe renal failure (CC <45 ml / min);

- simultaneous use with a vaccine for the prevention of yellow fever;

- Pregnancy;

- lactation;

- Children's age (lack of data on safety and efficacy);

- Hypersensitivity to pemetrexedum or excipients included in the preparation.

With caution should apply the drug in violation of liver function;
with severe diseases of the cardiovascular system, incl. myocardial infarction and cerebral circulation disorders.
PREGNANCY AND LACTATION

The drug is contraindicated for use in pregnancy and lactation.

During therapy with Alimta В® and at least 6 months after the use of reliable methods of contraception.

APPLICATION FOR FUNCTIONS OF THE LIVER

To assess the function of the kidneys, it is necessary to periodically perform a biochemical blood test.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

To assess liver function, it is necessary to periodically perform a biochemical blood test.

APPLICATION FOR CHILDREN

It is not recommended to use Alimt in children.
safety and effectiveness of use in children is not established.
APPLICATION IN ELDERLY PATIENTS

Data on the increased risk of adverse events in patients aged 65 years and older are not available.
The dose reduction regimen corresponds to general recommendations.
SPECIAL INSTRUCTIONS

The drug Alimta В® should appoint a doctor who has experience in the use of antitumor drugs.

Myelosuppression is the dose-limiting toxicity of pemetrexed.

Before each introduction of Alimta it is necessary to carry out the general analysis of a blood with calculation of the leukocytic formula and quantity of thrombocytes.

To assess the function of the kidneys and liver, it is necessary to periodically perform a biochemical blood test.

Before using the drug, the absolute amount of neutrophils should be? 1500 / ОјL, platelets? 100,000 / ОјL.

The administration of folic acid and vitamin B12 reduces the toxicity of pemetrexed and the need for dose reduction for hematologic and nonhematological toxicity of grade 3-4, such as neutropenia, febrile neutropenia, and an infection with grade 3 neutropenia.

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.

Impact on the ability to drive vehicles and manage mechanisms

The influence of pemetrexed on the ability to drive vehicles has not been studied.
However, pemetrexed can cause increased fatigue, so patients should be careful when working, requiring increased concentration.
OVERDOSE

Symptoms: possibly oppression of bone marrow hematopoiesis, manifested by neutropenia, thrombocytopenia and anemia;
attachment of secondary infections, diarrhea, inflammation of the mucous membranes, rash.
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.

DRUG INTERACTION

In vitro studies
demonstrated that pemetrexed is actively secreted by OAT3 (a carrier of organic type 3 human anions).
Co-administration with nephrotoxic drugs (such as aminoglycosides, loop diuretics, platinum-containing drugs, cyclosporine) and / or substances released by the kidney via tubular secretion (eg probenecid) can lead to reduced clearance of pemetrexed.

Results of in vitro studies
suggest 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 B is administered at 12 v / m and when combined with cisplatin.The total clearance of platinum is not impaired when using pemetrexed.

The use of NSAIDs in high doses concomitantly with pemetrexed therapy even in patients with normal renal function (CC-80 ml / min) may lead to a decrease in the clearance of pemetrexed and an increase in its side effect.

In patients with mild to moderate renal insufficiency (CC 45-79 ml / min), NSAIDs with a short T 1/2 are not recommended for 2 days prior to application of Alimta, on the day of application and for 2 days after application.

In the absence of data on possible interaction between the NSAID and Alimta with large T 1/2 , all patients treated with NSAIDs, their use should terminate at least 5 days before use Alimta, the day of application and during two days after application. If required co-administration of NSAIDs, patients requires strict monitoring of toxicity, especially myelosuppression and gastrointestinal toxicity side.
While the use of live attenuated vaccines is possible intensification of replication of vaccine virus, increasing its side / adverse effects and / or reduce the production of antibodies in the patient's body in response to the vaccine.
In an application with oral anticoagulants should be monitored regularly MHO.
Pharmaceutical interaction

Pemetrexed is incompatible with Ringer's lactate and Ringer's solution.
Co-administration of pemetrexed with other drugs and solutions has not been studied and is not recommended.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at a temperature of 15 В° to 25 В° C.
Shelf life - 2 years.
The prepared solution should be stored at 2 В° to 8 В° C or from 15 В° to 25 В° C for up to 24 hours.

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