Pemetrexed - instructions for use, dose, side effects, contraindications

Active substancePemetrexedPemetrexed

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Pemetrexed

lyophilizate d / infusion

BIOCAD, CJSC Russia

Pemetrexed-native

lyophilizate d / infusion

NATIVA, LLC Russia

Dosage form: & nbsplyophilizate for solution for infusion

Composition:

1 bottle of 100 mg contains:

Active substance: pemetrexed disodium (in the form of hemipentahydrate) 121.4 mg, calculated as pemetrexed - 100 mg;

Excipients: mannitol - 106.4 mg, hydrochloric acid 10% solution and / or sodium hydroxide solution 10% to pH 7.0.

1 bottle of 500 mg contains:

Active substance: pemetrexed disodium (in the form of hemipentahydrate) 607.0 mg, in terms of pemetrexed - 500 mg;

Excipients: mannitol - 500.0 mg, hydrochloric acid solution 10% and / or sodium hydroxide solution 10% to pH 7.0.

Description:

The porous mass is from white to white with a yellowish tint of 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 amide 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 reduced folates and protein folate-binding transport systems. Entering the cage, pemetrexed quickly and effectively converted into polyglutamate forms with the help of 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. In poliglutaminirovannyh metabolites the half-life is increased, owing to what the action of a preparation in tumor cells increases. With the combined use of pemetrexed and cisplatin 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 pemetrexed or ancillary substances, included in the preparation;

- Myelosuppression (absolute number of neutrophils <1.5 ^x 10⁹ cells / l, platelets <100 x 10⁹ cells / l);

- Severe renal insufficiency (creatinine clearance (CK) <45 ml / min);

- Pregnancy, lactation;

- Child age (lack of safety and efficacy data);

- Simultaneous use with a vaccine to prevent yellow fever.

Carefully:

- If the liver function is impaired;

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

Pregnancy and lactation:

Women with preserved reproductive potential should use effective contraception during the treatment with pemetrexed. Pemetrexed can have genotoxic effect. Men are also encouraged to use contraception during treatment and within 6 months after completion of therapy.

Pregnancy

Data on the use of pemetrexed in pregnant women are absent. but pemetrexed, like other antimetabolites, can potentially cause serious birth defects of the fetus when it is used during pregnancy. In animal studies pemetrexed showed reproductive toxicity. Pemetrexed should not be used in pregnancy, unless a careful assessment of the benefit-risk relationship benefits the mother does not exceed the risk to the fetus.

Breastfeeding period

It is not known whether the blood is excreted pemetrexed with breast milk. However, it is impossible to exclude the development of unwanted reactions in children who are breastfeeding if the mother receives therapy with pemetrexed. Women receiving pemetrexed, it is necessary to refuse breastfeeding during the treatment period.

Fertility

There is a possibility of the development of irreversible infertility due to treatment with pemetrexed, and therefore it is recommended that men decide the cryopreservation of sperm samples before the beginning of therapy.

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 - 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 instructions for medical use of the drug 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 - 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 - 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 - 500 mg / m² on the first day of each 21-day cycle.

Recommendations before starting the use of the drug pemetrexed

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 during 21 days after the last administration of pemetrexed. Patients also it is necessary to inject vitamin B12 once in a dose of 1000 μg intramuscularly in the period of 7 days before the first administration 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 ≥ 1.5 * 10⁹ cells / l, platelets ≥100 * 10⁹ cells / l, the concentration of total bilirubin ≤ 1.5 times the upper limit of the norm (HHV), the activity of alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) ≤ 3 times from IGN or ≤ 5 times from IGN in the presence of metastases in the liver.

Correction of the dosing regimen

Dose adjustment before repeated cycles should be performed based on the lowest of hematological parameters or at the highest 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 that refer 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 content of neutrophils is <0.5 * 10⁹ cells / l and a minimum platelet count ≥50 * 10⁹ in μl	75% of the previous dose (pemetrexed and Cisplatinum)
The minimum content of platelets <50 * 10⁹ cells / l, regardless of the minimum content of neutrophils	75% of the previous dose (pemetrexed and Cisplatinum)
The minimum content of platelets <50 * 10⁹ cells / l with bleeding^a regardless of the minimum content of neutrophils	50% of the previous dose (pemetrexed and Cisplatinum)

^a - These criteria correspond to the definition of bleeding ≥ 2 degrees in accordance with the general toxicity criteria of the National Cancer Institute (NCI-CTC)
With the development of non-hematologic toxicity (excluding neurotoxicity) ≥3 degrees, treatment should be postponed until recovery of the indices,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. The dosage regimen of pemetrexed (with monotherapy or combined therapy) and cisplatin

Non-hematological toxicity ^a^{, b}	Dose of pemetrexed (mg / m²)	Dose 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 (regardless of grade) or grade 3 or 4 diarrhea	75% of the previous dose	75% of the previous dose
Inflammation of the mucous membrane of degree 3 or 4	50% of the previous dose	100% of the previous dose

^a - According to the criteria NCI-CTC

^b - Excluding neurotoxicity

In the case of 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 with pemetrexed should be discontinued if the patient has hematologic and non-hematologic toxicity grade 3 or 4 after two dose drops or immediately cancel if there is neurotoxicity of grade 3 or 4.

Use in special patient groups

Elderly patients: Data on the increased risk of side effects 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 the drug is not required. For patients with SC less than 45 ml / min, the use of pemetrexed is not recommended (due to insufficient 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 a violation of liver function with an excess of bilirubin concentration is more than 1.5 times the upper limit of the norm (VGN), or the excess of aminotransferase activity is more than 3 times higher than the IGN (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 infusion

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

2. For the preparation with a dosage of 100 mg: for the preparation of 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) 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; Allow opalescence of the solution and color change from colorless to yellowish or greenish-yellow color.

For the preparation with a dosage of 500 mg: for the preparation of a solution for infusions, 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 (approximately). Each vial is gently shaken until the lyophilizate is completely dissolved. The resulting solution should be clear; Allow opalescence of the solution and color change from colorless to yellowish or greenish-yellow color.

Do not apply the solution in the case of a different color change, other than yellowish or greenish-yellow, or the presence of visible particles in the solution.

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

4.Before administration, the drug solution should be inspected for particles and discoloration. Do not use the solution if there are visible particles in it.

5. 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 the solution must be destroyed.

Side effects:

The incidence of side effects is classified as follows: very often (> 10%), often (<10% and ≥ 1%), infrequently (<1% and ≥ 0.1%), rarely (<0.1%).

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:

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

Disorders from the gastrointestinal tract: very often - nausea, vomiting, anorexia, stomatitis / pharyngitis, diarrhea; often - increased activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT), constipation, abdominal pain.

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

Impaired nervous system: often - sensory or motor neuropathy.

Disorders from the kidneys and urinary tract: often - an increase in the concentration of serum creatinine.

Heart Disease: infrequently - supraventricular arrhythmia.

Other: very often - increased fatigue; often - fever, attachment of secondary infections without neutropenia, febrile neutropenia, allergic reactions.

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:

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, increased ALT activity and ACT; infrequently, an increase in the activity of gamma-glutamyl transferase (GGT).

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

Impaired nervous system: often - sensory neuropathy, taste disorder; infrequently - motor neuropathy.

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

Heart Disease: infrequent - arrhythmia;

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

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

Side effects observed with monetherapy with pemetrexed as 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:

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, mucositis / stomatitis, diarrhea, constipation, increased ALT activity and ACT.

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

Impaired nervous system: often - sensory neuropathy, motor neuropathy.

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

Heart Disease: infrequently - supraventricular arrhythmia.

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

Side effects observed with pemetrexed in combination with cisplatin (malignant pleural mesothelioma) from addition of folic acid and vitamin B12:

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, increased activity of ALT, ACT and GGT.

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

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

Disorders from the kidneys and urinary tract: very often - an increase in the concentration of serum creatinine, a decrease in the clearance of creatinine; often - kidney failure.

Heart Disease: infrequent - arrhythmia.

Disturbances from the respiratory system, chest and mediastinal organs: 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 pemetrexed in clinical studies for other indications:

Severe cardiovascular and cerebrovascular adverse events, including myocardial infarction, angina pectoris, stroke, transient cerebral circulation, were infrequent when pemetrexed was used 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. With the use of pemetrexed, cases of colitis have been reported (including intestinal and rectal bleeding, sometimes fatal, perforation of the intestinal wall, bowel necrosis and cecal inflammation) and interstitial pneumonitis with respiratory failure, sometimes fatal (infrequently).

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

Post-production data:

Infrequent - edema, limb ischemia, in some cases with the development of necrosisa, acute renal failure, radiation pneumonitis; rarely - in patients who had previously 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, in some cases fatal, have also been reported; 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 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 a decrease in the clearance of pemetrexed and an increase in its side effect.

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

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 or moderate renal failure receiving 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 e with other preparations and solutions has not been studied, 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 simultaneously with oral anticoagulants, the International Normalized Ratio (INR) should be monitored regularly.

Special instructions:

Pemetrexed 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, 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 perform a biochemical blood test.

Before starting the drug, the absolute number of neutrophils should be ≥ 1, 5 ^x 10⁹ cells / l, platelets ≥ 100 * 10⁹ cells / l.

The appointment of folic acid and vitamin B12 reduces the toxicity of pemetrexed and the need for dose reduction for hematologic and non-hematological toxicity 3/4 degree, such as neutropenia, febrile neutropenia and infection with neutropenia 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 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, 100 mg, 500 mg.

Packaging:

For 100 mg or 500 mg of pemetrexed in flasks of colorless neutral glass I of hydrolytic class, sealed with rubber stoppers with a rolling aluminum caps with a plastic lid type "flip-off". For each bottle stick the label self-adhesive.

1 bottle with instructions for use is placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of 15 to 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-004204

Date of registration:20.03.2017

Expiration Date:20.03.2022

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Information update date: & nbsp17.04.2017

Illustrated instructions

Instructions

Pemetrexed (Pemetrexed)