Methotrexate-Teva - instructions for use, dose, side effects, contraindications

Composition:1 ml of solution for injection contains: active substance methotrexate 2.50 mg / 25.0 mg; Excipients: sodium chloride 8.5 mg / 6.0 mg, sodium hydroxide about 0.44 mg / about 4.4 mg, water for injection up to 1 ml / up to 1 ml.

Description:Transparent, from a yellow or orange to a brown solution.

Pharmacotherapeutic group:Antitumour agent, antimetabolite

ATX: & nbsp

L.01.B.A Analogues of folic acid

L.01.B.A.01 Methotrexate

Pharmacodynamics:

Antineoplastic, cytostatic agent of the group of antimetabolites-analogues of folic acid. Inhibits dihydrofolate reductase, which participates in the restoration of dihydrofolic acid to tetrahydrofolic acid (transporter carbon fragments required for synthesis of purine nucleotides and their derivatives).

It inhibits synthesis, DNA repair and cellular mitosis (in the S phase). Particularly sensitive: to the action of methotrexate tissue with high cell proliferation: tumor tissue, bone marrow, epithelial cells of mucous membranes, embryonic cells. Besides, methotrexate has immunosuppressive properties.

Along with the antitumor has an immunosuppressive effect.

Pharmacokinetics:

Time to reach the maximum concentration (Cmax) with intramuscular injection 30-60 minutes. The connection with plasma proteins is about 50%.

When taken in therapeutic doses, regardless of the route of administration, it practically does not penetrate the BBB (afterintrathecal injection in the cerebrospinal fluid reached high concentrations). Penetrates into breast milk.

Metabolized in the liver with the formation of pharmacologically active polyglutamine form, inhibiting dihydrofolate reductase and thymidine synthesis. The half-life in the initial phase is 2-4 hours, and in the final phase (which is prolonged) - 3-10 hours when using usual doses and 8-15 hours - when using high doses of the drug. In chronic renal failure, both phases of drug clearance can be significantly prolonged.

It is mainly excreted by the kidneys in unchanged form by glomerular filtration and tubular secretion (with IV administration 80-90% is excreted within 24 hours), with bile is excreted up to 10% (followed by reabsorption in the intestine). Removal of the drug in patients with impaired renal function, expressed ascites or transudate is significantly slowed down. With repeated administration, it accumulates in tissues in the form of metabolites.

Indications:

- Trophoblastic tumors;

- Acute leukemia (lymphoblastic and myeloblast variants);

- Neuroleukemia;

- non-Hodgkin's lymphomas, including lymphosarcomas;

- Breast cancer, squamous cell carcinoma of the head and neck, lung cancer, skin cancer, cervical cancer, vulvar cancer, esophageal cancer, kidney cancer, bladder cancer, testicular cancer, ovarian cancer, penile cancer, retinoblastoma, medulloblastoma;

- osteogenic sarcoma and soft tissue sarcomas;

- mushroom mycosis (far advanced stages);

- severe forms of psoriasis, psoriatic arthritis, rheumatoid arthritis, dermatomyositis, systemic lupus erythematosus, ankylosing spondylitis (if standard therapy is ineffective).

Contraindications:

- Hypersensitivity to methotrexate and / or any other component of the drug.

- Severe anemia, leukopenia, neutropenia, thrombocytopenia.

- Renal or hepatic impairment

- Pregnancy and the period of breastfeeding.

Carefully:In ascites, swelling in the pleural cavity, peptic ulcer of the stomach and duodenum, ulcerative colitis, dehydration, gout or nephrolithiasis in an anamnesis, previously conducted radiation therapy or chemotherapy, infectious diseases of a viral, fungal or bacterial nature.

Dosing and Administration:

Methotrexate is part of many chemotherapy regimens, therefore, when choosing the route of administration, regimen and dosage in each individual case, reference should be made to the literature.

Methotrexate for injection can be administered intramuscularly, intravenously, intraarterially or intrathecally.

The following dosing regimes are used:

Trophoblastic tumors: 15-30 mg intramuscularly, daily for 5 days with an interval of one or more weeks (depending on signs of toxicity). Or 50 mg once every 5 days with an interval of at least 1 month. Treatment rates are usually repeated 3 to 5 times to a total dose of 300-400 mg.

Solid tumors: in combination with other antitumor drugs 30-40 mg / m² intravenously sprayed once a week.

Leukemia and lymphoma: 200 - 500 mg / m² by intravenous infusion once every 2-4 weeks. Neuroleukemia: 12 mg / m² intrathecally for 15-30 seconds 1 or 2 times a week. In the treatment of children, the dose is selected depending on the age of the child: children under the age of 1 year are prescribed 6 mg, children aged 1 year 8 mg, children 2 years 10 mg, children 3 years and older 12 mg. Before administration, it is necessary to remove cerebrospinal fluid in a volume,approximately equal to the volume of the drug to be administered.

High-dose therapy: from 2 to 15 g / m² a 4-6 hour intravenous infusion at intervals of 1-5 weeks followed by optional introduction of calcium folinate which typically begin 24 hours after the start of infusion and methotrexate administered every 6 hours in a dose of 3-40 mg / m² (usually 15 mg / m²) and above, depending on the concentration of methotrexate in the blood serum for 48-72 hours (see Instructions for the use of calcium folinate).

Rheumatoid arthritis: the initial dose is usually 7.5 mg once a week, which is given either intravenously or intramuscularly, or 2.5 mg every 12 hours (3 doses in total). To achieve the optimal effect, a weekly dose can be increased, while it should not exceed 20 mg. When the optimal clinical effect is achieved, the dose should be reduced before reaching the lowest effective dose. The optimal duration of therapy is not known.

Psoriasis: intramuscularly or intravenously strontaneously at doses of 10-25 mg per week. The dose is usually increased gradually, when the optimal clinical effect is achieved, a dose reduction begins before the lowest effective dose is reached.

Mushroom mycosis: intramuscularly 50 mg once a week or 25 mg twice a week for several weeks or months. Dose reduction or withdrawal of drug administration is determined by the patient's reaction and hematological parameters.

Side effects:

From the hematopoiesis: leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia.

From the digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis, rarely - enteritis, diarrhea, erosive and ulcerative lesions and bleeding from the gastrointestinal tract, in some cases (with long-term daily use) - abnormal liver function, increased activity of "liver "Transaminase, periportal fibrosis and cirrhosis of the liver, liver necrosis, fatty liver, pancreatitis.

From the nervous system: encephalopathy, especially when administering multiple doses intrathecally, as well as in patients who received radiation therapy on the skull region. There are also reports of fatigue, weakness, confusion, ataxia, tremor, irritation, convulsions and coma. Acute side effects caused by intrathecal administration of methotrexate,may include dizziness, blurred vision, headache, back pain, stiff neck, convulsions, paralysis, hemiparesis.

From the respiratory system: rarely - interstitial pneumonitis, pulmonary fibrosis, exacerbation of pulmonary infections.

From the urinary system: cystitis, nephropathy, impaired renal function (increased level of creatinine, hematuria).

On the part of the reproductive system: violation of the process of oogenesis, spermatogenesis, decreased libido / impotence, changes in fertility, teratogenic effects.

From the skin and skin appendages: cutaneous erythema and / or rash, skin itching, urticaria, telangiectasia, furunculosis, depigmentation or hyperpigmentation, acne, skin peeling, folliculitis, alopecia (rarely), increased photosensitivity, exacerbation of radiation dermatitis.

From the sense organs: conjunctivitis, excessive lacrimation, cataract, photophobia, cortical blindness (at high doses), visual impairment.

Allergic reactions: fever, chills, rash, hives, anaphylaxis, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Other: immunosupression (reduced resistance to infectious diseases), malaise, osteoporosis, hyperuricemia, vasculitis, arthralgia / myalgia.

Overdose:

In case of accidental overdose of methotrexate, it is recommended to use a specific antidote - calcium folinate. The administration of calcium folinate should be started as soon as possible, preferably within the first hour, at a dose equal to or greater than the dose of methotrexate; subsequent doses are administered as needed depending on the concentration of methotrexate in the blood serum. To prevent precipitation of methotrexate and / or its metabolites in the renal tubules, hydration of the body and alkalinization of urine are carried out.

In case of an overdose with intrathecal injection, immediately after an overdose is detected, repeated lumbar punctures should be performed to ensure rapid drainage of cerebrospinal fluid, possibly neurosurgical intervention with ventricululumbral perfusion. All these procedures should be performed against a background of intensive maintenance therapy and systemic administration of large doses of calcium folinate.

Interaction:

The simultaneous use of high doses of methotrexate with various non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and other salicylates, azaprospan, diclofenac, indomethacin and ketoprofen the toxicity of methotrexate may increase, and in some cases a potentially toxic effect, sometimes even fatal, is possible. With special precautions and appropriate monitoring, the use of methotrexate in low doses (7.5-15 mg per week), in particular in the treatment of rheumatoid arthritis, in combination with NSAIDs is not contraindicated.

Simultaneous use of sulfonamides, derivatives of sulfonylurea, phenytoin, phenylbutazone, aminobenzoic acid, probenicide, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and lipid-lowering drugs (cholestyramine) increases the toxicity of methotrexate.

Retinoids, azathioprine, sulfasalazine increase the risk of hepatotoxicity. Parenteral use of acyclovir against the background of intrathecal administration of methotrexate increases the risk of developing neurological disorders.

Multivitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate therapy.

L-asparaginase is a methotrexate antagonist.

Anesthesia using dinitrogen oxide can lead to unpredictable severe myelosuppression and stomatitis.

Amiodarone can promote skin ulceration.

Methotrexate reduces the clearance of theophylline.

In several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (metoksalen and ultraviolet irradiation), skin cancer was detected.

Caution should be exercised with the simultaneous administration of erythrocyte mass and methotrexate.

The combination with radiotherapy can increase the risk of soft tissue necrosis.

Methotrexate may reduce the immunological response to vaccination. With simultaneous administration with a live vaccine, severe antigenic reactions can develop.

Special instructions:

Methotrexate is a cytotoxic drug, so care must be taken when handling it.

Dosage forms containing preservatives, in particular benzyl alcohol, are not allowed for intrathecal administration and for high-dosage therapy.

When high doses of methotrexate are administered, careful monitoring of the patient is needed to detect early signs of toxic reactions early.

High-dose therapy should be performed only by experienced chemotherapists under the control of methotrexate concentration in plasma under steady conditions under the cover of calcium folinate.

During therapy with methotrexate in elevated high doses, urine pH should be monitored: on the day of administration and for the next 2-3 days, the urine reaction should be alkaline. This is achieved by intravenous drip of a mixture consisting of 40 ml of 4.2% sodium hydrogen carbonate solution and 400-800 ml of 0.9% sodium chloride solution on the eve, on the day of treatment and in the next 2-3 days.

Treatment with methotrexate in high and high doses should be combined with increased hydration to 2 liters of fluid per day.

Introduction of methotrexate in a dose of 2 g / m² and above are carried out under the control of its concentration in blood serum. It is normal to reduce the content of methotrexate in the blood serum after 22 hours after the introduction of 2 times compared with the baseline. Increasing the level of creatinine by 50% or more of the original content and / or increasing the level of bilirubin requires intensive detoxification therapy.

Day of treatment of psoriasis methotrexate appoint only patients with severe disease that can not be treated by other types of therapy.

To prevent toxicity during the treatment with methotrexate, periodic blood testing (once a week), determination of the content of leukocytes and platelets, and performing of hepatic and renal functional tests are necessary.

With the development of diarrhea and ulcerative stomatitis, methotrexate therapy must be discontinued, otherwise it can lead to the development of hemorrhagic enteritis and to the death of the patient due to perforation of the intestine.

In patients with impaired liver function, the period of excretion of methotrexate is increased, therefore, in such patients therapy should be carried out with extreme caution, with the use of reduced doses.

Impaired renal function is dose dependent. Risk of impairment is elevated in patients with reduced renal function or with dehydration, as well as in patients taking other nephrotoxic drugs.

Men and women of childbearing age should be treated with methotrexate and at least 3 months after the use of reliable methods of contraception.

Effect on the ability to drive transp. cf. and fur:Some side effects of the drug may adversely affect the ability to drive and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Form release / dosage:Solution for injection 2.5 mg / ml and 25 mg / ml.

Packaging:

For a dosage of 2.5 mg / ml.

At 5 mg / 2 ml in bottles of colorless glass (type 1), sealed with rubber stoppers and crimped aluminum caps with a plastic cap made of colored polypropylene.

1 bottle, covered with a transparent film, along with instructions for use in a cardboard bundle.

For dosage of 25 mg / ml.

For 50 mg / 2 ml in bottles of colorless glass (type 1), sealed with rubber stoppers and crimped aluminum caps with a plastic lid of colored polypropylene.

1 bottle, covered with a transparent film of PVC or OPS, together with instructions for use in a cardboard bundle.

For 250 mg / 10 ml in bottles of colorless glass (type 1), sealed with rubber stoppers and crimped aluminum caps with a plastic cap made of colored polypropylene.

1 bottle, covered with a transparent film of PVC or OPS, together with instructions for use in a cardboard bundle.

For 500 mg / 20 ml in bottles of colorless glass (type 1), sealed with rubber stoppers and crimped aluminum caps with a plastic cap made of colored polypropylene.

1 bottle, covered with a transparent film of PVC or OPS, together with instructions for use in a cardboard bundle.

On 1000 mg / 40 ml in bottles of colorless glass (type 1), sealed with rubber stoppers and crimped with aluminum caps with a plastic cap made of colored polypropylene. 1 bottle, covered with a transparent film of PVC or OPS, together with instructions for use in a cardboard bundle.

Storage conditions:

Store at a temperature of no higher than 25 ° C in a dark place.

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:П N014895 / 01

Date of registration:14.03.2008 / 06.07.2017

Expiration Date:Unlimited

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

PHARMACHEMIE, B.V. Netherlands

Representation: & nbspTeva Teva Israel

Information update date: & nbsp11.05.2018

Illustrated instructions

Instructions

Methotrexate-Teva (Methotrexate-Teva)