Raltitrexide (Raltitrexidum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Antimetabolites

Included in the formulation
  • Tomoudex®
    lyophilizate in / in 
    AstraZeneca UK Ltd     United Kingdom
    • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    VED

    ONLS

    АТХ:

    L.01.B.A   Analogues of folic acid

    L.01.B.A.03   Raltitrexide

    Pharmacodynamics:Antimetabolite, has a cytostatic effect. Direct and specific inhibitor of thymidylate synthetaseTh - the key enzyme in the synthesis of thymidine triphosphatea, necessary for the formation of the DNA chain. Inhibition thymidylate synthetaseThreat leads to the fragmentation of the DNA molecule, which causes cell death. It is transported to the cell with the help of a restored folate transporter, extensively exposed to polyglutatimirsthrough the enzyme folyl polyglutamatetsmetetase to polyglutamate, which is retained in the cell and is a potent inhibitor thymidylate synthetaseThreat. PolyglutatimirsRaltithrexide enhances its inhibitory activity in relation to thymidylate synthetaseya and increases the durationThis action, and also contributes to increased toxicity due to the delay of the drug in normal tissues.
    Pharmacokinetics:After intravenous administration at a dose of 3 mg / m2, the "concentration-vr" curveemey "has 3 phases: peak concentration, determined at the end of the introduction,rapid initial concentration decrease, slow elimination phase; the maximum concentration is 656 ng / ml; AUC - 1841 ng h / ml; plasma clearance - 53.1 ml / min, renal clearance - 25.1 ml / min; the volume of distribution in the equilibrium state is 468 liters. The half-life for the second phase is 1.72 h, nElimination half-life for the terminal phase - 168 h. Binding to plasma proteins - 93%. It is excreted mainly by the kidneys in unchanged form, a significant part of the administered dose is retained in the tissues in the form of polyglutamate. When used in therapeutic doses (every 3 weeks), no cumulation was recorded. Violation of kidney function (creatinine clearance - 25-65 ml / min) leads to an increase inhalf-life approximately by 50%.
    Indications:Palliative treatment is widespreadabout colorectal cancer.
    ICD-10

    II.C15-C26.C18   Malignant neoplasm of colon

    II.C15-C26.C20   Malignant neoplasm of rectum

    XXI.Z40-Z54.Z51.5   Palliative Care

    Contraindications:Hypersensitivity, renal failure (creatinine clearance less than 25 ml / min), severe hepatic insufficiency (clinical jaundice, liver cirrhosis), children's age (safety and efficacy in children not defined).
    Carefully:Inhibition of bone marrow hematopoiesis (including on the background of concomitant radiation or chemotherapy), children's age (safety and efficacy in children not defined).
    Pregnancy and lactation:

    Category of recommendations FDA not defined. Controlled studies in humans have not been conducted. Possible development of fetal side effects observed in adults. When administered to rats raltitrexide causes fetal death and developmental abnormalities. It is necessary to exclude pregnancy before starting treatment with raltitreksidom. In the presence of indications, it is necessary to relate the risk and benefit and take into account the mutagenic and carcinogenic potential of these agents. In view of the potential threat to the fetus for women and men of childbearing age during treatment with raltitrexide and for 6 months. and more after its abolition, the use of contraceptives is recommended.

    Contraindicated in pregnancy.

    There is no information on the penetration into breast milk. In view of the excretion of other antitumor drugs with milk and the potential risk of unwanted effects on the child during raltiotrexide treatment, it is recommended that breastfeeding be discontinued.

    Dosing and Administration:

    Intravenous drip (for at least 15 minutes) is usually used at a dose of 3 mg / m2 (2 ml of substance is added to the vial, 4 ml of water for injection is added, the required dose is calculated, 50-250 ml of physiological saline or 5% glucose solution). Repeated administration - every 3 weeks. in the absence of toxic effect. With a creatinine clearance of 25-54 ml / min, the dose is reduced by 50%, with ground clearance creatinine 55-65 ml / min - by 25%, the interval between administrations is increased to 4 weeks.

    A dose reduction of 25% is performed with development in patients on the background of treatment of grade 3 neutropenia or thrombocytopenia (WHO scale), or diarrhea or grade II mucositis (WHO scale). Reduction of the dose by 50% - with the development of hematological toxicity of the IV degree (WHO scale) or gastrointestinal toxicity of the third degree (WHO scale). If the dose has been reduced once, all subsequent injections of the drug are given in this reduced dose. An increase in dose above 3 mg / m2 is not recommended, since it may be associated with life-threatening toxicity.

    Side effects:

    From the side nervous system and sense organs: headache, taste disorders, asthenia, conjunctivitis, hypertension of muscles, muscle cramps.

    From the side cardiovascular system and blood (hematopoiesis, hemostasis): anemia, leukopenia, thrombocytopenia.

    From the side bodies GIT: nausea, vomiting, diarrhea / constipation, anorexia; less often - abdominal pain; rarely - mucositis (inflammation of mucous membranes, stomatitis), dyspepsia, increased activity of hepatic transaminases and alkaline phosphatase.

    From the side skin integument: rash, sometimes in combination with itching, baldness, sweating.

    Other: arthralgia, fever, flu-like syndrome, exacerbation of chronic infection and sepsis against neutropenia, cellulite, dehydration, peripheral edema, weight loss, impaired fertility.

    Overdose:

    Symptoms: increased oppression of bone marrow hematopoiesis and severity of symptoms of dyspepsia.

    Development of toxicity of the IV degree (WHO scale) from the gastrointestinal tract (diarrhea or inflammation of the mucosa) or combination of third-degree toxicity (WHO scale) from the gastrointestinal tract with grade IV hematologic toxicity requires discontinuation of treatment.

    Treatment: in case of toxicity development it is necessary to start a standard maintenance therapy: intravenous hydration, myelopoiesis stimulants, leucovorin.

    Based on the clinical experience of using other antifolates, folic acid at a dose of 25 mg / m2 every 6 hours is recommended before the symptoms are removed. Antidote with proven clinical efficacy is unknown.

    Interaction:

    Warfarin. The study of the safety of raltitreksida administration against warfarin did not reveal a clinically significant interaction.

    Calcium folinate and vitamin preparations, its containing, reduce the effectiveness of raltitreksida, and therefore these drugs should not be used immediately before administration or during the administration of raltitreksida - simultaneous use is contraindicated.

    Folic acid. Folic acid and vitamin products containing it reduce the effectiveness of raltitreksida, and therefore these drugs should not be used immediately before administration or during the administration of raltitreksida - concurrent use is contraindicated.

    Fluorouracil. Patients with tumor progression after previous treatment of a common disease with chemotherapy with the inclusion of fluorouracil may be insensitive to the action of raltitrexide.

    Special instructions:

    Patients with tumor progression after previous treatment with fluorouracil may be insensitive to the action of raltitrexide.

    Raltithrexide is administered intravenously (short infusion for 15 min or more).

    Before intravenous administration, the contents of the vial containing 2 mg of raltitrexide are diluted with 4 ml of sterile water for injection, resulting in a solution of 0.5 mg / ml, which is then diluted with 50-250 ml of a 0.9% solution of sodium chloride or a 5% solution of dextrose.

    Before each introduction of raltitreksida requires monitoring of the clinical study of blood (with the leukocyte formula), the activity of hepatic transaminases, the concentration of bilirubin and the number of platelets. If the number of leukocytes is less than 4 × 109 / l, neutrophils to 2 × 109 / l or platelets to 100 × 109 / l, the next administration should be postponed.

    With the development of toxic effects, the drug is delayed until regression (especially until the regress of hematologic and gastrointestinal toxicity regresses, while peripheral blood monitoring is required at least once a week). With increasing transaminase activity, the next administration should be postponed until the regress of toxicity to grade II.

    Correction of the dose of raltitreksida depends on the severity of hematologic and gastrointestinal toxicity during the previous cycle (provided complete regression before the next administration). The dose in the subsequent treatment does not increase: hematological toxicity of the third degree (neutropenia or thrombocytopenia) or gastrointestinal toxicity of the second degree (diarrhea or stomatitis) - 75% of the previous dose, IV degree (neutropenia or thrombocytopenia) or gastrointestinal toxicity of the third degree (diarrhea or stomatitis) - 50% of the previous dose, Grade IV gastrointestinal toxicity (diarrhea or stomatitis) or a combination of grade III gastrointestinal toxicity and grade IV hematologic toxicity - treatment is discontinued.

    Impact on the ability to drive vehicles and manage mechanisms

    It is necessary to refrain from practicing potentially dangerous activities that require increased attention and speed of mental and motor reactions.

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