Active substanceTemozolomideTemozolomide
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  • Dosage form: & nbspcapsules
    Composition:

    1 capsule contains:

    active substance: temozolomide 140 mg and 180 mg

    Excipients: silicon colloidal dioxide 0.4 mg and 0.5 mg; tartaric acid 4.2 and 5.4 mg; sodium carboxymethyl starch 21 mg and 27 mg; lactose anhydrous 206 mg and 136.3 mg; stearic acid 8.4 mg and 10.8 mg.

    Capsule shell (for dosage of 140 mg):

    Cap and body: gelatin 82.60% and 84.60%, methylparahydroxybenzoate 0.118% and 0.176%, propyl parahydroxybenzoate 0.030% and 0.044%, silicon dioxide colloidal 0.123% and 0.183%, armolopol 0.012% and 0.018%, sodium lauryl sulfate 0.100% and 0.055%, glycerol 0.025% and 0.037%, titanium dioxide 0.369% and 0.549%, a brilliant blue dye of 0.061% and 0.091%.

    Capsule shell (for a dosage of 180 mg):

    Cap and body: gelatin 82.792% and 82.792%, sodium lauryl sulfate 0.100% and 0.100%, povidone 0.100% and 0.100%, bronopolum 0.100% and 0.100%, diamond brilliant blue 0.008% and 0.008%, azorubin dye 0.640% and 0.640%, dye quinoline yellow 0.340 % and 0.340%, titanium dioxide 1.520% and 1.520%.

    Description:

    Dosage of 140 mg:

    hard gelatin capsules No. 1, body and capsule capsules dark-blue color.

    Dosage of 180 mg:

    hard gelatin capsules No. 1, the case of a capsule of blue color, cap capsule white.

    The contents of all capsules are powder from white to light yellow with brown tint or light pink color.

    Pharmacotherapeutic group:antitumor agent, alkylating compound
    ATX: & nbsp

    L.01.A.X.03   Temozolomide

    Pharmacodynamics:Temozolomide is an imidazotetrazine alkylating drug with antitumor activity.When entering the systemic bloodstream, at physiological values, the pH undergoes a rapid chemical transformation to form the active compound - monomethyltriazenoimidazolecarboxamide (MTIK). It is believed that the cytotoxicity of MTIC is due primarily to the alkylation of guanine in position O6 and additional alkylation in the N7. Apparently, cytotoxic lesions resulting from this include (trigger) the mechanism of aberrant reduction of the methyl residue.
    Pharmacokinetics:

    Suction

    After oral administration temozolomide quickly absorbed. The maximum concentration (Сmах) in plasma is reached on the average in 0.5-1.5 h (the earliest - in 20 min) after taking the drug. Reception of the drug Temozolomide together with food causes a decrease in the maximum concentration (Cmax) by 33% and a decrease in the area under the "concentration-time" curve (AUC) on 9%. After oral administration of the drug Temozolomide the average degree of excretion with feces for 7 days was 0.8%, which indicates complete absorption of the drug.

    Distribution

    Temozolomide quickly penetrates the blood-brain barrier (BBB) ​​and enters the spinal cordliquid.

    Volume distribution of the drug (Va) does not depend on the dose. Temozolomide weakly binds to proteins (12-16%).

    Excretion

    Quickly excreted from the body by the kidneys. Half-life (T1 / 2) is approximately 1.8 hours. After 24 hours after ingestion, approximately 5-10% of the dose is determined unchanged in the urine; the remainder is deduced as 4-amino-5-imidazole carboxamide hydrochloride (APC), temozolomidic acid or unidentified polar metabolites. Clearance and T1 / 2 do not depend on the dose.

    Pharmacokinetics in special clinical cases

    The clearance of the drug in plasma does not depend on age, kidney function or smoking. Pharmacokinetic profile of the drug in patients with impaired liver function of mild or moderate degree is the same as in persons with normal liver function.

    In children, the indicator AUC higher than in adults.

    The maximum tolerated dose in children and adults was the same and was 1000 mg / m2 for one treatment cycle.

    Indications:

    - the newly discovered multiform glioblastoma - combined treatment with radiotherapy followed by adjuvant monotherapy;

    - malignant glioma (glioblastoma multiforme or anaplastic astrocytoma), with relapse or disease progression after standard therapy;

    - a common metastasizing malignant melanoma - as a first-line therapeutic agent.

    Contraindications:

    - hypersensitivity to temozolomide or other components of the drug, as well as to dacarbazine.

    - severe myelosuppression;

    - pregnancy;

    - lactation period (breastfeeding);

    - children under 3 years of age (recurrent or progressive malignant glioma) or up to 18 years (newly diagnosed glioblastoma multiforme or malignant melanoma);

    Carefully:

    FROM caution should be prescribed to patients older than 70 years, with severe renal or hepatic insufficiency, intolerance to galactose, a deficiency of lactase or glucose-galactose malabsorption.

    Pregnancy and lactation:contraindicated
    Dosing and Administration:

    Temozolomide is taken orally, on an empty stomach, no less than 1 hour before a meal. The prescribed dose should be taken using the lowest possible number of capsules. Capsules can not be opened or chewed, they should be swallowed whole, washed down with a glass of water.

    The newly discovered multiform glioblastoma (treatment adults over 18 years of age).

    Primary treatment conduct in combination with radiation therapy. Temozolomide is prescribed in a dose of 75 mg / m2 daily for 42 days at the same time as radiotherapy (30 fractions in a total dose of 60 Gy). Dose reduction is not recommended, but the drug may be interrupted depending on the tolerability. Renewal of the drug is possible during the entire 42-day period of combined treatment and up to 49 days, but only subject to all listed below

    Table 1. Recommendations for dose reduction or drug cancellation Temozolomide when combined with radiotherapy

    Criterion of toxicity

    Break in taking the drug Temozolomide

    Termination of the drug Temozolomide

    absolute number of neutrophils

    > = 500 / μL, but <1500 / μL

    <= 500 / μL

    platelet count

    > = 10 000 / μL, but <100 000 / μL

    <10 000 / μL

    CTC non-hematological toxicity (with the exception of alopecia, nausea and vomiting)

    Degree 2

    Degree 3 or 4

    Renewal of the drug Temozolomide subject to all the conditions listed below conditions: the absolute number of neutrophils is not lower than 1500 / μl, the number of platelets is not lower than 100,000 / μl, - the general toxicity criterion (common toxicity criteria (CTC)) not higher than degree 1 (with the exception of alopecia, nausea and vomiting).

    Adjuvant therapy is appointed 4 weeks after the completion of the combination therapy and is performed in the form of 6 additional cycles.

    Cycle 1: Temozolomide appoint a dose of 150 mg / m2 for 5 days followed by a 23-day interruption in treatment.

    Cycle 2: drug dose Temozolomide can be increased to 200 mg / m2/ day, provided that during the first cycle, the severity of non-hematologic toxicity (according to the STS toxicity scale) did not exceed degree 2 (with the exception of alopecia, nausea and vomiting), with the absolute number of neutrophils not lower than 1500 / μl, and the number of platelets - not less than 100 000 / mkl. If in cycle 2 the dose of the drug Temozolomide It has not been increased, it should not be increased in the next cycles. If in cycle 2 the dose was 200 mg / m2, in the same daily dose, the drug is prescribed and in the following cycles (in the absence of toxicity). In each cycle, taking the drug Temozolomide carry out for 5 consecutive days with a subsequent 23-day break.

    Recommendations for dose reduction or drug cancellation Temozolomide during the combined phase of treatment are given in the table Tables 2 and 3.On the 22nd day of treatment (the 21st day after taking the first dose of the drug) it is necessary to perform a general blood test> with the calculation of the formula and the number of platelets. The cancellation or reduction of the dose should be carried out according to Tables 2 and 3.

    Table 2. Dose levels of the drug Temozolomide with adjuvant therapy

    Step

    Dose

    (mg / m2/ day)

    Note

    -1

    100

    Dose reduction taking into account previous toxicity (see Fig.

    Table. 3)

    0

    150

    Dose during cycle 1

    1

    200

    The dose during cycles 2-6 (in the absence of toxicity)


    Table 3. Recommendations for dose reduction or drug cancellation Temozolomide with adjuvant therapy

    Criterion of toxicity

    Reduce the dose of the drug Temozolomide by 1 step (see Table 2)

    Termination of the drug Temozolomide

    absolute number of neutrophils

    <1000 / μL

    *

    platelet count

    <50 000 / μL

    *

    CTC non-hematological toxicity (with the exception of alopecia, nausea and vomiting)

    Degree 3

    Degree 4 *

    * Temozolomide should be abolished if a dose reduction of <100 mg / m is required, as well as in the case of recurrence of non-hematologic toxicity grade 3 (except for alopecia, nausea and vomiting) after dose reduction.

    Progressive or recurrent malignant glioma in the form of a multiform glioblastoma or anaplastic astrocytoma (treatment of adults and children older than 3 years). Common metastatic malignant melanoma (treatment of adults).

    Patients who had not previously undergone chemotherapy, Temozolomide appoint a dose of 200 mg / m2 1 time / day for 5 consecutive days, followed by a break in taking the drug for 23 days (the total duration of one treatment cycle is 28 days).

    For patients who had previously undergone chemotherapy, the initial dose is 150 mg / m2 1 time / day; in the second cycle, the dose can be increased to 200 mg / m2/ day, provided that on the first day of the next cycle the absolute number of neutrophils is not lower than 1500 / μl, and the number of platelets is not lower than 100,000 / μl.

    Recommendations by modifying the dose of the drug Temozolomide in the treatment of progressive or recurrent malignant glioma or malignant melanoma

    Start drug treatment Temozolomide is possible only with an absolute number of neutrophils> 1500 / μL and platelets> 100,000 / μL. A complete clinical blood test should be performed on the 22nd day (the 21st day after taking the first dose), but no later than 48 hours after that day; further - weekly, until the absolute number of neutrophils is higher than 1500 / μL, and the number of platelets does not exceed 100,000 / μl.With an absolute number of neutrophils below 1000 / μL or platelets below 50,000 / μL during any treatment cycle, the dose in the next cycle should be reduced by one step. Possible doses: 100 mg / m2, 150 mg / m2 and 200 mg / m2. The minimum recommended dose is 100 mg / m2.

    Duration of treatment is maximum 2 years. When there is a progression of the disease, the drug should be discontinued.

    Side effects:

    The following undesirable phenomena noted with the use of Temozolomide are distributed according to the frequency of occurrence in accordance with the following gradation: very often (> = 10%), often (> = 1%, <10%), infrequently (> = 0.1%, <1 %), rarely (> = 0.01%, <0.1%) and very rarely (<0.01%).

    On the part of the hematopoiesis system: often - thrombocytopenia, neutropenia, lymphopenia; infrequently - pancytopenia, leukopenia, anemia, febrile neutropenia. Oppression of the bone marrow developed usually during the first few cycles of treatment, with a maximum between 21 and 28 days; recovery occurred, usually within 1-2 weeks. No evidence of cumulative myelosuppression was noted.

    From the digestive system: very often - nausea, vomiting, anorexia, constipation; often - diarrhea, abdominal pain, indigestion, taste distortion, dysphagia, stomatitis, dry mouth; infrequently - flatulence, gastroenteritis.

    From the nervous system: very often - headache, convulsions; often - drowsiness / insomnia, dizziness, paresthesia, asthenia, imbalance, confusion, memory impairment, speech disorder, tremor, neuropathy, anxiety, depression, emotional lability; infrequently - hallucinations, amnesia, gait disturbance, hyperesthesia, hypoesthesia.

    From the cardiovascular system: often - peripheral edema, hemorrhage, deep vein thrombosis; infrequently - a feeling of palpitations, arterial hypertension, cerebral hemorrhage, embolism of the pulmonary artery.

    From the respiratory system; often - cough, shortness of breath; infrequently - sinusitis, bronchitis. From the genitourinary system: frequent - frequent urination; infrequently, impotence, dysuria, amenorrhea, menorrhagia, vaginal bleeding, vaginitis. Dermatological reactions: very often - alopecia, rash; often - skin itching, dryness, skin, erythema, dermatitis, petechiae; infrequently - a violation of pigmentation, photosensitivity, increased sweating; very rarely - hives, exanthema, erythroderma, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

    From the musculoskeletal system: often - arthralgia, muscle weakness, myalgia; infrequently - a pain in the back.

    From the side of the organ of vision: often - blurred vision, diplopia, narrowing of the fields of vision; infrequently - pain in the eye, dry eyes, decreased visual acuity.

    From the organ of hearing: often - hearing impairment, ringing in the ears; infrequently - pain in the ear.

    From the endocrine system: infrequently - Cushingoid.

    From the immune system: very rarely - allergic reactions, including anaphylaxis.

    From the laboratory indicators: often - hyperglycemia, increased activity of alanine aminotransferase (ALT); infrequently - hypokalemia, increased activity of aspartate aminotransferase (ACT), alkaline phosphatase and gamma-glutamyl transferase Other: very often - increased fatigue; often - weight loss, increased body temperature, general malaise; infrequently - weight gain, fever ("hot flashes"), chills, flu-like syndrome; rarely - the adherence of opportunistic infections, including pneumonia, caused by Pneumocystis carinii; very rarely observed the development of myelodysplastic syndrome and secondary malignant processes, including leukemia, as well as the development of prolonged pancytopenia with a risk of developing aplastic anemia.

    Overdose:

    When using the drug in doses of 500 mg / m2, 750 mg / m2, 1000 mg / m2 and 1250 mg / m2 (the total dose received for a 5-day treatment cycle), dose-limiting toxicity was hematologic toxicity, which was noted when taking any dose, but more pronounced - at higher doses. The case of overdose (taking a dose of 2 g / day for 5 days), as a result, which developed pancytopenia, pyrexia, multiple organ failure and death. When taking the drug for more than 5 days (up to 64 days), c. The number of other side effects noted oppression of hematopoiesis, complicated or uncomplicated by the infection, in some cases prolonged and severe, with a fatal outcome.

    Treatment: the antidote is unknown. It is recommended hematological control and, if necessary, symptomatic therapy.

    Interaction:

    Reception of the drug Temozolomide together with ranitidine does not lead to a clinically significant change in the degree of absorption of Temozolomide.

    Joint reception with dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine Hg-receptor blockers or phenobarbital does not change the clearance of temozolomide.

    Joint administration with valproic acid causes a mild but statistically significant decrease in the clearance of temozolomide.

    Studies aimed at elucidating the effects of temozolomide on metabolism and excretion of other drugs have not been conducted. Due to temozolomide It is not metabolized in the liver and weakly binds to proteins, its effect on the pharmacokinetics of other drugs is unlikely.

    Application of the drug Temozolomide together with other substances that depress the bone marrow, may increase the likelihood of myelosuppression.

    Special instructions:

    Prophylactic antiemetic therapy is recommended before the beginning of combined treatment (with radiotherapy) and is strongly recommended during adjuvant therapy for newly diagnosed multiform glioblastoma. If the background of drug treatment Temozolomide there is a nausea or vomiting in the subsequent receptions it is recommended to carry out antiemetic therapy. Antiemetic drugs can be taken both before and after taking the drug Temozolomide. Even if vomiting developed within the first 2 hours after taking the drug Temozolomide The same day should not be repeated.

    Due to the increased risk of developing pneumonia caused by Pneumocystis carinii, in patients receiving combined treatment with radiotherapy within 42 days (up to 49 days), such patients are recommended to carry out preventive treatment against the pathogen Pneumocystis carinii. Although the more frequent development of pneumonia caused by Pneumocystis carinii, is associated with longer durations of drug treatment Temozolomide, increased caution as to the possible development of PCP should be shown for all patients receiving Temozolomide, especially in combination with glucocorticosteroids. Pharmacokinetic parameters of the drug Temozolomide in individuals with normal liver function P in patients with impaired liver function of mild or moderate severity are comparable. Data on the use of the drug Temozolomide in patients with severe impaired liver function (class C on the Child-Pugh scale) or renal dysfunction is not available. Based on the data on the pharmacokinetic properties of Temozolomide, it seems unlikely that patients even with a marked impairment of liver or kidney function may need to reduce the dose of the drug. However, when the drug is administered Temozolomide such patients should be cautious.

    In elderly patients (over 70 years), the risk of developing neutropenia and thrombocytopenia is higher than in younger patients. Therefore, elderly patients Temozolomide should be administered with caution.

    Men and women of childbearing age during treatment with Temozolomide, and at least 6 months after graduation should use reliable methods of contraception.

    Because of the risk of irreversible infertility, against the background of treatment with Temozolomide, male patients before the start of treatment, if necessary, are advised to discuss the possibility of cryopreservation of sperm.

    If the contents of the capsule (powder) get on the skin or mucous membranes, rinse them with plenty of water.

    Use in Pediatrics

    Clinical experience of the drug Temozolomide with multiform glioblastoma in children under 3 years of age and with malignant melanoma in children and adolescents under the age of 18 is absent. There is limited experience with the use of Temozolomide in glioma in children older than 3 years.

    Effect on the ability to drive transp. cf. and fur:Some side effects of the drug, such as drowsiness and fatigue, can adversely affect the ability to drive vehicles or perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions.
    Form release / dosage:

    Capsules 140 mg, 180 mg

    5 or 20 capsules in a plastic bottle.

    1 bottle with instructions for use in a cardboard box.

    Packaging:(20) - plastic bottles (1) - packs cardboard
    (5) - plastic bottles (1) - packs cardboard
    Storage conditions:

    At a temperature of no higher than 30 ° C.

    Keep out of the reach of children.

    Shelf life:

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001771
    Date of registration:06.07.2012
    The owner of the registration certificate:ARS, LLC ARS, LLC Russia
    Manufacturer: & nbsp
    Representation: & nbspARS, LLCARS, LLC
    Information update date: & nbsp14.09.2015
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