Tomoudex® (Tomudex®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceRaltitrexideRaltitrexide
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  • Tomoudex®
    lyophilizate in / in 
    AstraZeneca UK Ltd     United Kingdom
    • Dosage form: & nbsplyophosphate for solution for infusion
    Composition:

    1 bottle contains

    Active substance: Raltitrexide 2.0 mg

    Excipients: mannitol 203.0 mg, sodium phosphate bisubstituted 1.5 mg, sodium hydroxide to adjust pH 6.9-7.9, nitrogen, water for injection.

    Description:

    Liofilizat from white to white with a cream shade of color almost free of visible inclusions.

    Pharmacotherapeutic group:antitumour agent, antimetabolite
    ATX: & nbsp

    L.01.B.A   Analogues of folic acid

    L.01.B.A.03   Raltitrexide

    Pharmacodynamics:

    Raltitreksid is an analogue of folate and belongs to the class of antimetabolites. It is a direct and specific inhibitor of thymidylate synthetase (TC), a key enzyme in the synthesis of thymidine triphosphate, the nucleotide necessary for DNA synthesis. Inhibition of TS leads to DNA fragmentation and cell death. Raltitrexide is transported to the cell with a reconstituted folate transporter and then subjected to polyglutamation via a folyl-polyglutamate synthetase enzyme. Polyglutamination raltitrexide but enhances its inhibitory activity against TC and prolongs the duration of this action, which can potentially enhance the antitumor activity of the drug, as well as its toxicity,in connection with the delay of the drug in normal tissues.

    Pharmacokinetics:

    After intravenous administration at a dose of 3 mg / m2 curve "concentration-time" has a 3-phase character: peak concentration, defined at the end of drug administration, rapid initial decrease in the concentration of a slow elimination phase. The maximum plasma concentration was 656 ng / ml, area under the curve "concentration-time - 1856 ng / h / ml, volume of distribution at equilibrium concentrations - 468 ng / ml maximum concentration raltitreksida in plasma increased linearly with dose (. in the range of doses used).

    With repeated administrations with an interval of three weeks, clinically significant cumulation of raltitrexide in plasma in patients with normal renal function was not noted. Raltitrexide mainly excreted by the kidneys in an unchanged form (approximately 40-50%). 15% of raltitreksida is excreted with caloric masses.

    Plasma clearance of the drug is 51.6 ml / min; renal clearance - 25.1 ml / min. The half-life for the second phase was 1.79 hours, for the terminal phase - 168 hours.

    It is assumed that part of the administered dose of raltitrexide is retained in the tissues, probably in the form of polyglutamate. Trace amounts of radioactive label were detected in erythrocytes on day 29 of the study.

    The pharmacokinetics of raltitrexide does not depend on sex and age. The pharmacokinetics of raltitrexide in children has not been studied. Light and moderate liver dysfunction leads to a slight decrease in the clearance of raltitrexide (less than 25%).

    Mild and moderate impairment of renal function (creatinine clearance 25-65 ml / min) leads to a significant reduction (about 50%) of the clearance of raltitrexide from the plasma.

    Indications:

    Palliative treatment of advanced colorectal cancer.

    Contraindications:

    • increased sensitivity to raltitreksida and other components of the drug;

    • severe renal dysfunction (creatinine clearance <25 mL / min);

    • severe liver dysfunction;

    • pregnancy and lactation period

    Carefully:


    Dosing and Administration:

    Tomudex is administered intravenously in the form of a 15-minute infusion.

    Adults. The recommended dose of Tomudex is 3 mg / m2 1 time in 21 days.

    Increase in dose above 3 mg / m2 can lead to life threatening toxicity.

    Depending on the degree of toxicity (gastrointestinal and / or hematologic) observed with the previous administration of the drug, the following modification of doses is recommended for repeated administration:

    • reduction of the dose by 25% - with the 3 degree of hematological toxicity

    (neutropenia or thrombocytopenia) and / or 2 degrees of gastrointestinal toxicity (diarrhea or mucosal inflammation).

    • reduction of the dose by 50% - with 4 levels of hematological toxicity

    (neutropenia or thrombocytopenia) or 3 degrees of gastrointestinal toxicity (diarrhea or mucosal inflammation).

    • discontinuation of treatment - in case of development of the 4th degree of gastrointestinal

    toxicity (diarrhea or inflammation of the mucosa) or in the case of a combination of grade 3 gastrointestinal toxicity with a 4 degree of hematological toxicity

    If the dose has been reduced once, all subsequent drug administration should be carried out at this reduced dose.

    The elderly. Dosage and administration, both for adults. In elderly patients, Tomudex should be used with caution.

    Children. Tomudex is not recommended for use in children, since its safety and efficacy have not been studied in this group of patients.

    Impaired renal function. Before the first and subsequent administration of the drug, it is necessary to determine or calculate by the formula the clearance of creatinine. When creatinine clearance <65 ml / min,The dose of Tomudex should be reduced, in accordance with the recommendations below.

    Correction of the dose for renal failure.

    Creatinine clearance

    Dose (% of 3.0 mg / m2)

    Interval of administration

    more than 65 ml / min

    full dose (100%)

    every 3 weeks

    55-65 ml / min

    75%

    every 4 weeks

    25-54 ml / min

    50%

    every 4 weeks

    less than 25 ml / min

    treatment should be canceled

    treatment should be canceled

    Violation of the function of the liver. In patients with mild to moderate liver function impairment, dose adjustment is not required. However, treatment in this group of patients should be done with caution.

    In patients with severe impairment of liver function, clinical signs of jaundice or decompensated liver disease, Tom deck is not recommended.

    Rules for the preparation of solution. Tomudex is dissolved with water for injection to a concentration of 0.5 mg / ml and then diluted in 50-250 ml of 0.9% sodium chloride solution or 5% dextrose (glucose) solution immediately before intravenous infusion. Other drugs should not be mixed with Tomudex in one bottle. The dissolved preparation should be stored at a temperature of 2-8 ° C not more than 24 hours.It is recommended to start Thomuex infusion immediately after reconstitution.

    Tomudex diluted solution must be fully used within 24 hours or destroyed.

    There is no need to protect the dissolved and diluted drug from light.

    It is impossible to keep partially used drug vials or dissolved for further use.

    Side effects:

    On the part of the digestive system: nausea, vomiting, diarrhea, anorexia, mucositis, stomatitis, ulceration of the mucous membrane of the mouth, dyspepsia, constipation, gastrointestinal bleeding (in the background of inflammation slizistyyh membranes of the gastrointestinal tract (GIT) and / or thrombocytopenia), increase in activity " liver transaminases (ALT and ACT), Hyperbilirubinemia and increased alkaline phosphatase.

    Most often arise nausea (57%) and vomiting (35%). Typically, these events are mild to moderate harkter (1-2 degrees on the WHO scale). Diarrhea, which can occur at any time tomudeksa therapy, observed in 36% of cases and is also usually wears a light or moderate (grade 1-2 on the WHO scale).However, it is possible to develop severe diarrhea, especially severe when combined with hematotoxicity (in particular, with leukopenia).

    On the part of the hematopoiesis system: leukopenia, neutropenia, anemia,

    thrombocytopenia. Oppression of bone marrow hemopoiesis is usually observed in the first 2 weeks after the administration of Tomudex. It is possible to develop neutropenia and thrombocytopenia of the 4th degree of severity according to the WHO scale, which can be severe and life threatening, especially in combination with toxic phenomena on the part of the gastrointestinal tract.

    Metabolic disorders and eating disorders: weight loss, dehydration, peripheral edema.

    From the side of the musculoskeletal system: arthralgia.

    From the nervous system: increased muscle tone (usually in the form of convulsions), headache.

    From the skin and skin appendages: rash, sometimes accompanied by itching, desquamation of the epidermis, alopecia, increased sweating.

    From the sense organs: change in taste, conjunctivitis.

    Other: asthenia, fever, flu-like syndrome, less often - abdominal pain, pain of other localizations, attachment of secondary infections, superficial phlegmon and sepsis.

    Overdose:

    Expected symptoms: increased oppression of bone marrow hematopoiesis and

    severity of dyspepsia.

    Treatment. Antidote to raltitrexedu with proven clinical efficacy is not known. Taking into account the preclinical data, which testify to the reduction of toxic effect of Tomudex in the use of leucovorin, as well as the clinical experience with other antifolates, in case of an overdose, it is recommended to start folinic acid administration at a dose of 25 mg / m2 intravenously every 6 hours until symptoms resolve.

    In case of toxicity, supportive and symptomatic treatment should be used.

    Interaction:

    Leucovorin (folinic acid), folic acid and vitamin preparations containing them, reduce the effectiveness of Tomudex, and therefore, these drugs should not be used immediately before or during the administration of Tomudex. A study of the safety of raltitrexide administration against non-steroidal anti-inflammatory drugs or warfarin did not reveal a clinically significant interaction.

    Special instructions:

    Tomadex should be treated only under the supervision of a doctor who has experience with the use of antitumor drugs.

    Patients receiving Tomadex therapy should be carefully monitored for early detection of possible toxic and undesirable effects.

    When using Tomudex, special attention should be paid to the condition of patients with suppressed bone marrow function, poor general condition or after radiotherapy.

    Patients with tumor progression after previous treatment of a common disease with chemotherapy with the inclusion of 5-fluorouracil may also be insensitive to the action of Thomudex.

    Before each administration of the drug, control of the pattern of peripheral blood (including the blood formula and platelets), the activity of "liver" transaminases, the content of bilirubin and creatinine in the blood serum is necessary.

    The drug can be administered only at the following blood parameters: the number of white blood cells> 4000 / μl, the number of neutrophils> 2000 / μL, the number of platelets> 100,000 / μl. Repeated administration of the drug is possible only with the disappearance of all signs of toxicity (especially gastrointestinal and hematological).

    When signs of gastrointestinal toxicity appear,it is necessary to monitor the picture of peripheral blood (including the blood formula and platelets) at least 1 time per week to detect hematological toxicity.

    In the case of the development of 4 levels of gastrointestinal toxicity (diarrhea or mucosal inflammation) or in the case of a combination of grade 3 gastrointestinal toxicity with a 4 degree of hematological toxicity, Tomudex should be discontinued and immediately begin a standard maintenance therapy that includes intravenous fluids and therapeutic interventions to support bone marrow hematopoiesis. Possible intravenous administration of leucovorin (folinic acid) in a dose of 25 mg / m2 every 6 hours until the symptoms disappear. Further use of Thomudex in such patients is not recommended.

    Men and women of childbearing age should be treated with reliable contraceptive methods during treatment with TOMEX and at least 6 months after discontinuation of therapy.

    Tomudex belongs to the class of cytotoxic drugs and it is necessary to handle it according to the rules adopted for such substances.

    If the drug contacts the skin, immediately rinse it thoroughly with water.If the product gets into the eyes, they should be rinsed with clean water, opening the eyelids, for at least 10 minutes. Follow-up medical supervision is necessary.

    Some side effects of Tomudex, such as malaise and asthenia, can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and speed of psychomotor reactions.

    Form release / dosage:

    Lyophilizate for solution for infusion. 2 mg in a 5 ml glass vial with bromobutyl rubber stopper, aluminum crimp ring and plastic lid. Each bottle is packed in a cardboard box with instructions for use.

    Packaging:2 mg in a 5 ml glass vial with bromobutyl rubber stopper, aluminum crimp ring and plastic lid. Each bottle is packed in a cardboard box with instructions for use
    Storage conditions:

    At temperatures below 25 ° C, in a dark place out of the reach of children. The drug should not be used after the expiry date indicated on the package.

    Shelf life:3 years
    Terms of leave from pharmacies:On prescription
    Registration number:P N 013284/01
    Date of registration:18.05.2012
    The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom
    Manufacturer: & nbsp
    Information update date: & nbsp18.05.2012
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