Pemetrexed-native - instructions for use, doses, side effects, contraindications

Active substance:	Amount, mg
Active substance:	100 mg	500 mg
Pemetrexed disodium heptahydrate	142,7	713,5
in terms of pemetrexed	100,0	500,0
Excipients:
Mannitol	100,0	500,0
Sodium hydroxide solution 1M or hydrochloric acid solution 1M	to a pH of 6.8 to 7.2	to a pH of 6.8 to 7.2

Description:

Porous amorphous mass from white to light yellow or light yellow with a greenish tinge. Caking is allowed.

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 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 reduced folates and protein folate-binding transport systems. Entering the cage, pemetrexed is rapidly and efficiently converted into polyglutamate forms by the enzyme folyl polyglutamate synthetase.

Polyglutamate forms are retained in cells and are more potent 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. Polyglutaminate metabolites have a half-life, which increases the effect of pemetrexed in tumor cells.

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

Pharmacokinetics:

Suction and distribution

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

Metabolism

Pemetrexed is limitedly metabolized in the liver.

Excretion

70 to 90 % pemetrexed 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 plasma half-life 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 pemetrexed or excipients included in the preparation;

- myelosuppression (absolute number of neutrophils <1,500 / μL, platelets <100,000 / μl);

- severe renal failure (creatinine clearance (CK) <45 mL / min);

- pregnancy, the period of breastfeeding;

- children's age (there are no data on safety and effectiveness of use);

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

Carefully:

- In violation of liver function;

- with severe diseases of the cardiovascular system, including myocardial infarction and cerebral circulation disorders.

Pregnancy and lactation:

A drug Pemetrexed-native contraindicated for use in pregnancy and in the period of breastfeeding.

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 the drug Pemetrexed-native - 500 mg / m² on the first day of each 21-day cycle.

Cisplatin is administered at a dose of 75 mg / m² on the background of hydration (see the instruction on the use of cisplatin) approximately 30 minutes after the administration of pemetrexed 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 derivatives. Monotherapy The recommended dose of the drug Pemetrexed-native - 500 mg / m² on the first day of each 21-day cycle.

The second line of therapy. Monotherapy

The recommended dose of the drug Pemetrexed-native - 500 mg / m² on the first day of each 21-day cycle.

Malignant pleural mesothelioma

Combined treatment with cisplatin

The recommended dose of the drug Pemetrexed-native - 500 mg / m² on the first day of each 21-day cycle.

Recommendations before using pemetrexed

The administration of dexamethasone (or its 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 dermatological reactions.

To reduce toxicity to patients receiving pemetrexed, folic acid medicines or multivitamins containing folic acid should be prescribed to ensure its daily requirement. 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 Pemetrexed-native on the 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 the number of neutrophils (ACH) should be ≥ 1,500 cells / mm³, the number of platelets - ≥ 100 000 cells / mm³, the concentration of total bilirubin is ≤1.5 times the upper limit of the norm (HHV), alkaline phosphatase, aspartic and alanine aminotransferases ≤ 3 times from IGN, or ≤ 5 times from IHH in the presence of liver metastases.

Recommendations for dose reduction

Correction of the dose of the drug Pemetrexed-native before repeated cycles should be carried out, based on the lowest of hematological parameters or on 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,as given in Tables 1-3, which relate to the use of pemetrexed in monotherapy or in combination with cisplatin.

Table 1.

The 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 Cisplatinum)
The minimum platelet count <50,000 / μl, regardless of the minimum neutrophil count	75% of the previous dose (pemetrexed and Cisplatinum)
The minimum platelet count <50 000 / μL with bleeding * regardless of the minimum neutrophil count	50% of the previous dose (pemetrexed and Cisplatinum)

* These criteria correspond to the definition of bleeding ≥ 2 degrees of severity in accordance with the criteria of general toxicity of the National Cancer Institute (NCI-CTC).

With the development of non-hematologic toxicity (excluding neurotoxicity) ≥3 degrees of severity, treatment should be postponed until the recovery of the values corresponding to the value before treatment begins. Further therapy should be continued in accordance with the recommendations given in Table 2.

Table 2.

The dosage regimen of pemetrexed (with monotherapy or combined therapy) and cisplatin
Non-hematological toxicity***	Dose of pemetrexed (mg / m²)	Dose of cisplatin (mg / m²)
Any toxicity of 3 or 4 severity, with the exception of inflammation of the mucosa	75% of the previous dose	75% of the previous dose
Diarrhea requiring hospitalization (regardless of the degree of severity), or diarrhea of 3 or 4 degrees of severity	75% of the previous dose	75% of the previous dose
Inflammation of mucosa 3 or 4 degrees of severity	50% of the previous dose	100% of the previous dose

* According to the criteria NCI-CTC.

** Excluding neurotoxicity.

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

Table 3.

The dosage regimen of pemetrexed (with monotherapy or combined therapy) and cisplatin
Power 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 with pemetrexed should be discontinued,if the patient has hematologic and non-hematologic toxicity of 3 or 4 severity after two dose decreases, or immediately cancel if there is a neurotoxicity of 3 or 4 severity.

Individual patient groups

Older and older patients

Data on the increased risk of developing adverse reactions in patients 65 years of age and older are not available. The dose reduction regimen corresponds to general recommendations.

Patients with impaired renal function

At QC values of at least 45 ml / min, dose adjustment and administration of pemetrexed are not required. In patients with SC less than 45 ml / min, the use of pemetrexed is not recommended (due to the lack of data on the use of pemetrexed in this category of patients).

Patients with hepatic impairment

There is insufficient data on the use of pemetrexed in patients with hepatic dysfunction with an excess of bilirubin concentration more than 1.5 times that of HHV, or exceeding the activity of aminotransferases more than 3 times that of HHV (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

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

- For the preparation by dosage 100 mg: 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 (approximately). 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.

- For the preparation by dosage 500 mg: to obtain a solution for infusion, the contents of the vial (500 mg) are dissolved in 20 ml of 0.9% sodium chloride solution (without 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.

Additional dilution is necessary

- The corresponding volume of the obtained pemetrexed solution should be further diluted to 100 ml with 0.9% sodium chloride solution.

- Before administration, the pemetrexed 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 do not contain antibacterial preservatives. Unused solution must be disposed of.

Side effects:

Side effects observed with monetherapy with pemetrexed (locally advanced or metastatic non-cell lung 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" (≥ 0.1% and < 1%), "rarely" (<0.1%):

Disorders from the blood and lymphatic system: very often - Lakopenia, neutropenia, anemia; often - thrombocytopenia.

Disorders from the gastrointestinal tract: very often - nausea, vomiting, anorexia, stomatitis / pharyngitis, diarrhea; often - Constipation, pain in the abdomen.

Disorders from the liver and bile ducts: often - increased activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT).

Disturbances from the skin and subcutaneous tissues: very often - rash / peeling; often - skin itching, alopecia, erythema multiforme.

Disorders from the nervous system: often - Sensory or motor neuropathy.

Disorders from the kidneys and urinary tract: often - Increased serum creatinine concentration.

Disorders from the heart: infrequently - supraventricular arrhythmia.

Disorders from the immune system: often - allergic reactions.

General disorders and disorders at the injection site: very often - increased fatigue; often - fever, attachment of secondary infections without neutropenia, febrile neutropenia.

Side effects observed with pemetrexed in combination with cisplatin (locally advanced or metastatic non-cell lung 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" (≥ 0.1% and < 1%), "rarely" (<0.1%):

Violations from the blood and lymphatic system: very often - leukopenia, neutropenia, anemia, thrombocytopenia.

Disorders from the gastrointestinal tract: very often - nausea, vomiting, anorexia, stomatitis / pharyngitis, diarrhea, constipation; often - dyspepsia, heartburn.

Disorders from the liver and biliary tract: often - increased ALT activity and ACT; infrequently - increase in activity of gamma-glutamyl transferase (GGT).

Disorders from the rut and subcutaneous tissues: very often - alopecia; often - rash / peeling.

Disorders from the nervous system: often - Sensory neuropathy, a taste disorder; infrequently - motor neuropathy.

Disorders from the kidneys and urinary tract: very often - increased serum creatinine concentration; often - decrease in creatinine clearance, renal failure.

Disorders from the heart: infrequently - arrhythmia.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - pain in the chest.

Disorders from the side of the organ of vision: often - conjunctivitis.

General disorders and disorders at the injection site: very often - increased fatigue; often - secondary infections, dehydration, febrile neutropenia, fever.

Side effects observed with monotherapy with pemetrexed inquality of maintenance therapy in patients with no progression after the first line (locally advanced or metastatic non-cell lung 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" (≥ 0.1% and < 1%), "rarely" (<0.1%):

Violations from the blood and lymphatic system: very often - anemia; often - leukopenia, neutropenia, thrombocytopenia.

Disorders from the gastrointestinal tract: very often - nausea, anorexia; often - vomiting, inflammation of the mucous membranes / stomatitis, diarrhea, constipation.

Disorders from the liver and biliary tract: often - increased ALT activity and ACT.

Disturbances from the skin and subcutaneous tissues: often - rash / peeling, alopecia, itchy skin; infrequently - erythema multiforme.

Disturbances from the nervous system: often - sensory and motor neuropathy.

Disorders from the kidneys and urinary tract: often - increased serum creatinine concentration, decreased glomerular filtration, renal failure.

Disorders from the heart: infrequently supraventricular arrhythmia.

Vascular disorders: infrequently - pulmonary embolism.

Disorders from the side of the organ of vision: often - conjunctivitis, increased lacrimation.

Immune system disorders: infrequently - Allergic reactions.

General disorders and disorders at the injection site: very often - increased fatigue; often - edema, pain syndrome, febrile neutropenia, attachment of secondary infections, fever without neutropenia, dizziness.

Side effects observed with pemetrexed in combination with cisplatin (malignant pleural mesothelioma) 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" (≥ 0.1% and < 1%), "rarely" (<0.1%):

Disorders from the blood and lymphatic system: very often - Lakopenia, neutropenia, anemia, thrombocytopenia.

Disorders from the gastrointestinal tract: very often - nausea, vomiting, anorexia, stomatitis / pharyngitis, diarrhea, constipation; often - dyspepsia.

Disorders from the liver and biliary tract: often - increased activity of ALT, ACT and GGT.

Disturbances from the skin and subcutaneous tissues: very often - rash, alopecia; often - hives.

Disorders from the nervous system: very often - sensory neuropathy; often - a taste disorder; infrequently - motor neuropathy.

Disorders from the kidneys and urinary tract: very often - Increased serum creatinine concentration, decreased creatinine clearance; often - renal insufficiency.

Disorders from the heart: infrequently - arrhythmia.

Disturbances from the respiratory, thoracic and mediastinal systems: often chest pain.

Disorders from the side of the organ of vision: often - conjunctivitis.

General disorders and disorders at the injection site: very often - increased fatigue; often - dehydration, febrile neutropenia, attachment of secondary infections, fever.

Side effects observed with pemetrexed in other clinical trials

Serious cardiovascular and cerebrovascular adverse events, including myocardial infarction, angina, stroke, transient ischemic attack,infrequently observed when using pemetrexed in combination with other anticancer 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. With the use of pemetrexed, cases of colitis have been reported (including intestinal and rectal bleeding, sometimes fatal, perforation of the intestinal wall, necrosis of the intestinal wall and inflammation of the caecum) and interstitial pneumonitis with respiratory failure, sometimes fatal (infrequently).

Based on the results of the kinetic studies, approximately 1 % patients noted the 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 have also been reported,including Stevens-Johnson syndrome and toxic epidermal necrolysis, in some cases fatal; rarely reported cases of development of hemolytic anemia, anaphylactic shock.

Overdose:

Symptoms

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

Treatment

Symptomatic, including the immediate use of calcium folinata or folinic acid.

In case of suspicion of an overdose of pemetrexed, a clinical blood test should be regularly monitored.

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 drugs released by the kidneys through tubular secretion (eg, probenecid),can lead to reduced 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 is administered intramuscularly and when combined 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 over 1600 mg / day or acetylsalicylic acid more than 1,300 mg / day) concomitantly with pemetrexed therapy even in patients with normal renal 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 NSAIDs with a long half-life (piroxicam, rofecoxib) patients with mild to moderate renal insufficiency who receive NSAIDs should discontinue 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 joint use of NSAIDs is required, patients need strict monitoring of toxicity, especially myelosuppression and gastrointestinal toxicity (GIT). Pemetrexed It 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 is therefore not recommended (with the exception of 0.9% sodium chloride solution).

With simultaneous use with live attenuated vaccines, it is possible to intensify the replication process of the vaccine virus, increase its unwanted reactions and / or reduce the production of antibodies in the patient's body in response to the introduction of the vaccine.

When used simultaneously with oral anticoagulants, the International Normalized Ratio (INR) should be monitored regularly.

Special instructions:

A drug Pemetrexed-native should be used under the supervision of a doctor who has experience in the use of antitumor drugs.

Myelosuppression is the dose-limiting toxicity of pemetrexed.

Before each introduction of pemetrexed, a clinical blood test should be performed to count the leukocyte count and the number of platelets.

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

Before starting the preparation Pemetrexed-native 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 hematologic and nonhematological toxicity of 3 and 4 severity, such as neutropenia, febrile neutropenia, and a neutropenia infection of 3 and 4 degrees of severity.

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 by Compared with 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 have increased fatigue, it is not recommended to drive vehicles and engage in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Lyophilizate for the preparation of a solution for infusions of 100 mg, 500 mg.

Packaging:

100 mg or 500 mg pemetrexed in 10 ml or 50 ml bottles of colorless glass of the first hydrolytic class, hermetically sealed with rubber stoppers covered with aluminum-plastic caps.

A label is attached to the vial.

On 1 bottle together with the instruction on application place in a pack a cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

The reconstituted solution of the drug should be stored at a temperature of 2-8 ° C not more than 24 hours.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-004216

Date of registration:28.03.2017

Expiration Date:28.03.2022

The owner of the registration certificate:NATIVA, LLC NATIVA, LLC Russia

Manufacturer: & nbsp

NATIVA, LLC Russia

Information update date: & nbsp22.04.2017

Illustrated instructions

Instructions

Pemetrexed-native (Pemetrexed-nativ)