Active substanceTemozolomideTemozolomide
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  • Dosage form: & nbspcapsules
    Composition:

    1 capsule contains:

    Capsules 5 mg

    Active substance - temozolomide 5.0 mg;

    Excipients - lactose 132.8 mg, silicon dioxide colloid 0.2 mg, carboxymethyl starch sodium 7.5 mg, tartaric acid 1.5 mg, stearic acid 3.0 mg. The composition of hard gelatin capsules:

    Body: gelatin (enough to 100%), titanium dioxide (E 171) (3,000%). Capsule: gelatin (enough to 100%), titanium dioxide (E 171) (0.8000%), brilliant blue (E 133) (0.0193%), quinoline yellow (E 104) (0.0176% ).


    Capsules 20 mg

    Active substance - Temozolomide 20.0 mg;

    Excipients - lactose 182.2 mg, silicon dioxide colloid 0.2 mg, carboxymethyl starch sodium 11.0 mg, tartaric acid 2.2 mg, stearic acid 4.4 mg. The composition of hard gelatin capsules:

    Body: gelatin (enough to 100%), titanium dioxide (E 171) (1.4100%). Capsule: gelatin (sufficient amount up to 100%), titanium dioxide (E 171) (1.4100%), dye sunset yellow (E 110) (0.0257%), quinoline yellow dye (E 104) (1.0000 %).

    Capsules 100 mg

    Active substance - temozolomide 100.0 mg;

    Excipients - lactose 175.7 mg, silicon colloidal dioxide 0.3 mg, sodium carboxymethyl starch 15.0 mg, tartaric acid 3.0 mg, stearic acid 6.0 mg. The composition of hard gelatin capsules:

    Body: gelatin (enough to 100%), titanium dioxide (E 171) (1.4100%). Cap: gelatin (enough to 100%), titanium dioxide (E 171) (1.5181%), iron oxide red (E 172) (0.0557%).

    Capsules 140 mg

    Active substance - temozolomide 140.0 mg;

    Excipients - lactose 246.0 mg, silicon dioxide colloid 0.4 mg, sodium carboxymethyl starch 21.0 mg, tartaric acid 4.2 mg, stearic acid 8.4 mg. The composition of hard gelatin capsules:

    Case: gelatin (enough to 100%), titanium dioxide (E 171) (1.7555%). Capsule: gelatin (sufficient amount up to 100%), titanium dioxide (E 171) (2.0000%), iron dye oxide black (E 172) (0.0320%), brilliant blue dye (E 133) (0.1800 %), the iron dye oxide is yellow (E 172) (0.0900%).

    Capsules 180 mg

    Active substance - temozolomide 180.0 mg;

    Excipients - lactose 316.3 mg, silicon dioxide colloid 0.5 mg, sodium carboxymethyl starch 27.0 mg, tartaric acid 5.4 mg, stearic acid 10.8 mg.

    The composition of hard gelatin capsules:

    Body: gelatin (enough to 100%), titanium dioxide (E 171) (1.4100%). Cap: gelatin (enough to 100%), titanium dioxide (E 171) (2.0000%), red dye (E 129) (0.1500%), dye sunset yellow (E 110) (0.4971 %).

    Capsules 250 mg

    Active substance - temozolomide 250.0 mg;

    Excipients - lactose 154.3 mg, silicon dioxide colloid 0.7 mg, carboxymethyl starch sodium 22.5 mg, tartaric acid 9.0 mg, stearic acid 13.5 mg.

    The composition of hard gelatin capsules:

    Body: gelatin (enough to 100%), titanium dioxide (E 171) (1.4100%).Cap: gelatin (enough to 100%), titanium dioxide (E 171) (1.4100%).

    Description:

    Capsules 5 mg: Hard gelatin capsules No. 3, with an opaque green lid and an opaque white casing.

    Capsules 20 mg: hard gelatin capsules No. 2, with an opaque yellow lid and an opaque white casing.

    Capsules 100 mg: hard gelatin capsules No. 1, with an opaque pink lid and an opaque white casing.

    Capsules 140 mg: hard gelatin capsules No. 0, with an opaque blue lid and an opaque white casing.

    Capsules 180 mg: Hard gelatin capsules No. 0, with an opaque orange lid and an opaque white casing.

    Capsules 250 mg: Hard gelatin capsules No. 0, with an opaque white lid and an opaque white casing.

    The contents of the capsules are powder from white to light pink.
    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 pH values, it 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. MTIC violates the structure and synthesis of DNA, the cell cycle.

    Pharmacokinetics:

    Suction: Temozolomide after intake is rapidly absorbed. Maximum concentration (Cmax) in plasma is achieved on average 0.5 - 1.5 hours (the earliest - in 20 minutes) after taking the drug. Taking temozolomide with food causes a decrease Stach by 33% and a decrease in the area under the "concentration-time" curve (AUC) on 9%. After oral administration of temozolomide, the average degree of excretion by the intestine for 7 days was 0.8%, indicating complete absorption of the drug. Distribution: Temozolomide quickly penetrates the blood-brain barrier and enters the cerebrospinal fluid. Volume of distribution (Vd) in plasma does not depend on the dose. Temozolomide weakly binds to plasma proteins (12-16%).

    Excretion: The half-life (T1/2) is about 1.8 hours.Clearance and half-life do not depend on the dose. The main way to remove temozolomide is through the kidneys. At 24 hours after oral administration, 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 as unidentified polar metabolites.

    Pharmacokinetics in special patient groups: The clearance of the drug does not depend on age, kidney function and tobacco consumption. The pharmacokinetic profile of temozolomide in patients with impaired liver function of mild or moderate severity is the same as in patients with normal liver function.

    In children, the indicator AUC higher than in adults. The maximum tolerable dose (MTD) 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) in the presence of relapse or disease progression after standard therapy;

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

    Contraindications:

    - Hypersensitivity to temozolomide or other components of the drug, as well as to dacarbazine (DTIK);

    - severe myelosuppression;

    - pregnancy;

    - the period of breastfeeding;

    - Children's age - up to 3 years (recurrent or progressive malignant glioma) or up to 18 years (newly diagnosed glioblastoma multiforme or malignant melanoma);

    - rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

    Carefully:

    - old age (over 70 years)

    - Children age over 3 years in the treatment of recurrent or progressive malignant glioma (glioblastoma multiforme or anaplastic astrocytoma) in case of recurrence or progression of the disease after standard therapy

    - renal or hepatic impairment of severe severity

    Pregnancy and lactation:

    Temozolomide is contraindicated during pregnancy and during breastfeeding.

    Dosing and Administration:

    Temozolomide is taken orally, on an empty stomach, not less than one 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 of adult patients (over 18 years).

    Primary treatment carried out 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 the 49th day, but only if all the conditions listed below are met: the absolute number of neutrophils is not lower than 1.5 x 109/ l, the number of platelets - not less than 100 x 109/ l, the general toxicity criterion (CTC) is not higher than degree 1 (except for alopecia, nausea and vomiting). During treatment, a blood test should be performed weekly, counting the number of cells.Recommendations for reducing the dose or withdrawal of temozolomide during the combined phase of treatment, see "Correction of the dosing regimen" (Table 1).

    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: the dose of temozolomide can be increased to 200 mg / m2 per day, provided that during the first cycle, the severity of non-hematologic toxicity (in accordance with the STS toxicity scale) did not exceed the grade 2 (except for alopecia, nausea and vomiting), while the absolute number of neutrophils was not lower than 1.5 x 109/ l, and the number of platelets - not less than 100 x 109/ l. If the dose of temozolomide has not been increased in cycle 2, it should not be increased in the following 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, the administration of temozolomide is carried out for 5 consecutive days with a subsequent 23-day break. Recommendations for dose reduction in the adjuvant phase of treatment are given in the section "Correction of the dosing regimen" (Tables 2 and 3).On the 22nd day of treatment (the 21st day after taking the first dose of the drug), a blood test should be performed to count the number of cells. The cancellation or reduction of the dose of the drug should be carried out, guided by Table 3.

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

    Patients who had not previously undergone chemotherapy, temozolomide appoint a dose of 200 mg / m2 once a 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 once a day; in the second cycle, the dose can be increased to 200 mg / m2 per day for 5 days, provided that on the first day of the next cycle the absolute number of neutrophils is not lower than 1.5 x 109/ l, and the number of platelets is not lower than 100 x 109/ l.

    Recommendations for modifying the dose of temozolomide in the treatment of progressive or recurrent malignant glioma or malignant melanoma.

    To begin treatment with temozolomide it is possible only at an absolute number of neutrophils> 1,5x109/ l and platelets> 100 x 109/ l. A complete clinical analysis of the blood should be performed on the 22nd day (the 21st day after taking the first dose), but not later than 48 hours after that day; further - weekly, until the absolute number of neutrophils becomes more than 1.5 x 109/ l, and the number of platelets does not exceed 100 x 109/ l. With an absolute number of neutrophils below 1.0 x 109/ l or platelets below 50 x 109/ l 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.

    Correction of the dosing regimen

    The newly discovered multiform glioblastoma (in patients older than 18 years) Recommendations for dose reduction or elimination of temozolomide during the combined phase of treatment are given in Table 1.

    Table 1. Recommendations for reducing the dose or elimination of temozolomide in combination treatment with radiotherapy.

    Criterion of toxicity

    Break in taking temozolomide *

    Termination of Temozolomide

    Absolute number of neutrophils

    > 0.5 x 109/ l, but <1.5 x 109/ l

    <0.5 x 109/ l

    Platelet count

    > 10 x 109/ l, but <100 x 109/ l

    <10x109/ l

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

    Degree 2

    Degree 3 or 4



    * Resumption of administration of temozolomide is possible if all the conditions listed below are met: absolute number of neutrophils not lower than 1.5 x 109/ l, the number of platelets - not less than 100 x 109/ l, the general toxicity criterion (CTC) is not higher than degree 1 (except for alopecia, nausea and vomiting).

    Recommendations for reducing the dose or elimination of temozolomide adjuvant therapy are given in Tables 2 and 3.

    Table 2. Dosage steps of the drug Temozolomide with adjuvant therapy.

    Step

    Dose (mg / m2/ day.)

    Note

    -1

    100

    Reduction of dose taking into account previous toxicity (see 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 reducing the dose or elimination of temozolomide with adjuvant therapy.

    Criterion of toxicity

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

    Termination of Temozolomide

    Absolute number of neutrophils

    <1 x 109/ l

    *

    Platelet count

    <50 x 109/ l

    *

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

    Degree 3

    Degree 4 *

    Based on the data on the study of the pharmacokinetic properties of temozolomide, it seems unlikely that patients with even a severe liver function disorder or with impaired renal function may need to reduce the dose of the drug. However, with the appointment of temozolomide, such patients should be cautious.

    In children, the indicator AUC higher than in adults. The maximum tolerable dose (MTD) in children and adults was the same and was 1000 mg / m2 for one treatment cycle. Elderly patients

    Based on the data obtained by pharmacokinetic analysis in patients aged 19-78 years, the clearance of temozolomide does not depend on age. However, elderly patients (over 70 years of age) are at increased risk for developing neutropenia and thrombocytopenia.

    * Temozolomide should be abolished if a dose reduction of <100 mg / m 2, and also in case of recurrence of non-hematological toxicity degree 3 (except for alopecia, nausea and vomiting) after dose reduction.

    Use in special patient groups

    Patients with hepatic or renal insufficiency

    Pharmacokinetic parameters of temozolomide in patients with normal liver function in patients with impaired liver function of mild or moderate severity are closely comparable.Data on the use of temozolomide in patients with severe hepatic dysfunction (class C on the Child-Pugh scale) or renal dysfunction.

    Side effects:

    The newly diagnosed multiform glioblastoma (adult patients)

    Below are the side effects noted in the treatment of patients with newly diagnosed multiform glioblastoma during the combined and adjuvant phases of treatment in clinical trials. Side effects are presented for organs and systems according to the frequency of their occurrence according to the recommendations of the World Health Organization: very often (> 10%), often (> 1% to <10%), infrequently (>> 0.1% to < 1), rarely (> 0.01% and <0.1%), very rarely (<0.01%).

    Combined phase of treatment (with radiotherapy)

    Infectious and parasitic diseases: often - candidiasis of the oral cavity, Herpes simplex, pharyngitis, wound infection, other infections;

    Violations from the blood and lymphatic system: often - leukopenia, lymphopenia, neutropenia, thrombocytopenia; infrequently - anemia, febrile neutropenia; Disorders from the endocrine system: infrequently - cushingoid;

    Disorders from the metabolism and nutrition: very often - anorexia; often hyperglycemia, weight loss; infrequently - hypokalemia, weight gain; Disorders of the psyche: often - anxiety, emotional lability, insomnia; infrequently - agitation, apathy, behavioral disorders, depression, hallucinations; Impaired nervous system: very often - headache; often - dizziness, aphasia, balance disorder, confusion and decreased consciousness, convulsions, memory impairment, neuropathy, paresthesia, drowsiness, speech disorder, impaired concentration, tremor; infrequent - extrapyramidal disorders, dysphasia, ataxia, impaired perception, gait disorders, hemiparesis, hyperesthesia, hypoesthesia, neurological disorders (unspecified), epileptic status, parosmia, thirst;

    Disorders from the side of the organ of vision: often - blurred vision; infrequently - pain in the eye, hemianopsia, impaired vision, reduced visual acuity, limiting visual fields;

    Hearing disorders and labyrinthine disturbances: often - hearing impairment, infrequently - earache, hyperacusis, otitis media, tinnitus;

    Heart Disease: infrequent - palpitation;

    Vascular disorders: often - swelling, including edema pog, hemorrhage; infrequently - increased blood pressure, cerebral hemorrhage;

    Disturbances from the respiratory system, chest and mediastinal organs often - cough, shortness of breath; infrequently - pneumonia, infections of the upper respiratory tract, nasal congestion;

    Violations from the e / seludo-intestinal tract: very often - constipation, nausea, vomiting; often - abdominal pain, diarrhea, dyspepsia, dysphagia, stomatitis, a taste disorder; infrequently - changing the color of the tongue;

    Disorders from the liver and bile ducts: often - increased activity of alanine aminotransferase (ALT); infrequently, an increase in the activity of alkaline phosphatase (APF), gamma-glutamyl transferase (GGT), aspartate aminotransferase (ACT), liver enzymes;

    Disturbances from the skin and subcutaneous tissues: very often - alopecia, rash; often - dermatitis, dry skin, erythema, itchy skin; infrequently - photosensitivity reactions, pigmentation disorders, exfoliation;

    Disturbances from the musculoskeletal and connective tissue: often - arthralgia, muscle weakness; infrequently - back pain, musculoskeletal pain, myalgia, myopathy;

    Disorders from the kidneys and urinary tract: often - frequent urination, urinary incontinence;

    Violations of the genitals and breast: infrequently - impotence; General disorders and disorders at the site of administration: very often fatigue; often - fever, pain syndrome, radiation damage, allergic reaction, edema of the face; infrequently - "hot flashes" of heat to the body, asthenia, worsening of the condition, chills.

    Adjuvant phase of treatment

    Infectious and parasitic diseases: often - candidiasis of the oral cavity, other infections; infrequently - Herpes simplex, Herpes zoster, influenza-like syndrome;

    Violations from the blood and lymphatic system: often - anemia, febrile neutropenia, leukopenia, thrombocytopenia; infrequently - lymphopenia, petechiae;

    Disorders from the endocrine system; infrequently - cushingoid;

    Disorders from the metabolism and nutrition; very often - anorexia; often - a decrease in body weight; infrequently hyperglycemia, weight gain;

    Disorders of the psyche: often - anxiety, depression, emotional lability, insomnia; infrequently - hallucinations, amnesia;

    Impaired nervous system: very often - headache, convulsions; often - dizziness, aphasia, imbalance, confusion, dysphasia, speech disorder, hemiparesis, memory impairment, impaired concentration, neurological disorders (unspecified), neuropathy, peripheral neuropathy, paresthesia, drowsiness, tremor; infrequent - gait disturbance, ataxia, coordination disorder, hemiplegia, hyperesthesia, sensitivity disorders;

    Disorders from the side of the organ of vision: often - blurred vision, diplopia, limitation of visual fields; infrequently - pain in the eye, dry eyes, decreased visual acuity;

    Hearing disorders and labyrinthine disturbances: often - hearing impairment, ringing in the ears, infrequently - deafness, pain in the ear, vertigo;

    Vascular disorders: often - swelling of the legs, hemorrhage, deep vein thrombosis;

    infrequently - edema, including peripheral edema, pulmonary embolism; Disturbances from the respiratory system, chest and mediastinal organs: often - cough, shortness of breath; infrequently - pneumonia, infection of the upper respiratory tract, sinusitis, bronchitis;

    Disorders from the gastrointestinal tract: very often - anorexia constipation, nausea, vomiting; often - diarrhea, dyspepsia, dysphagia, stomatitis, dry mouth, perversion of taste; infrequent abdominal distention, fecal incontinence, hemorrhoids, gastroenteritis, dental diseases, gastrointestinal disorders (unspecified); Disorders from the liver and e / selchevyvodayuschih ways: often - increased ALT activity;

    Disturbances from the skin and subcutaneous tissues: very often - alopecia, rash; often - dry skin, itchy skin; infrequently - erythema, a violation of pigmentation, increased sweating;

    Disturbances from the musculoskeletal and connective tissue: often - arthralgia, muscle weakness, myalgia, musculo-skeletal pains, infrequently - back pain, myopathy;

    Disorders from the kidneys and urinary tract: often - urinary incontinence; infrequently - dysuria;

    Violations of the genitals and milk e / seleza: infrequently - pain in the breast, amenorrhea, menorrhagia, vaginal bleeding, vaginitis;

    General disorders and disorders at the site of administration: very often fatigue; often - fever, pain syndrome, radiation damage, allergic reaction; infrequently - asthenia, edema of the face, worsening of the condition, chills.

    Laboratory and instrumental data: Myelosuppression (neutropenia and thrombocytopenia), is a dose-limiting side effect. Among patients in both groups (combined and adjuvant therapy), neutrophil changes, including neutropenia, were noted in 8% of cases, and platelet counts, including thrombocytopenia, in 14% of cases.

    Progressive or recurrent malignant glioma (adults and children over 3 years old) or malignant melanoma (adults)

    Side effects are presented for organs and systems according to the frequency of their occurrence according to the recommendations of the World Health Organization: very often (> 10%), often (> 1% to <10%), infrequently (>> 0.1% to < 1), rarely (> 0.01% and <0.1%), very rarely (<0.01%):

    Infectious and parasitic diseases: rarely opportunistic infections, including pneumocystis pneumonia;

    Violations from the blood and lymphatic system: Often - thrombocytopenia, neutropenia, lymphopenia; often - pancytopenia, leukopenia, anemia. In patients with glioma and metastatic melanoma, thrombocytopenia and grade 3 or 4 neutropenia were observed in 19% and 17%, respectively, in glioma and in 20% and 22%, respectively, in melanoma.Hospitalization of patients was required in this case in 8% and 4% of cases, respectively, with glioma and in 3% and 1.3% with melanoma. Oppression of the bone marrow developed 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. The presence of thrombocytopenia could increase the risk of bleeding, and the presence of neutropenia or leukopenia increased the risk of infectious complications.

    Disorders from the metabolism and nutrition: very often - anorexia; often - weight loss;

    Impaired nervous system: very often - headache; often - drowsiness, dizziness, paresthesia, peripheral neuropathy;

    Disturbances from the respiratory system, chest and mediastinal organs: often shortness of breath;

    Disorders from the gastrointestinal tract: very often - nausea, vomiting, constipation; often - diarrhea, abdominal pain, indigestion, taste perversion. The most frequent were nausea and vomiting. In most cases, these phenomena were 1-2 (from mild to moderate) severity and passed independently or were easily controlled with standard therapy. The incidence of severe nausea and vomiting was 4%. Disturbances from the skin and subcutaneous tissues: often - rash, itching, alopecia, petechiae; very rarely - hives, exanthema, erythroderma, erythema multiforme;

    General disorders and disorders at the site of administration: very often - increased fatigue; often - fever, chills, general malaise, asthenia, pain syndrome; very rarely - allergic reactions, including anaphylaxis, angioedema;

    Laboratory and instrumental data: cases of thrombocytopenia and neutropenia of grade 3 or 4 in 19% and 17%, respectively, in glioma and in 20% and 22% in melanoma, respectively, were observed in the treatment of patients with glioma and metastatic melanoma. Hospitalization of the patient and / or removal of temozolomide was required in 8% and 4% of cases, respectively, for glioma and 3% and 1.3% for melanoma. Myelosuppression progressed predictably, usually during the first few treatment cycles, with a maximum between 21 and 28 days; recovery occurred quickly, usually within 1-2 weeks. No evidence of cumulative myelosuppression was noted. The presence of thrombocytopenia could increase the risk of bleeding, and the presence of neutropenia or leukopenia increased the risk of infectious complications.

    Post-registration research data

    During postemergence studies of temozolomide, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and allergic reactions, including anaphylaxis, were very rare.

    Hepatotoxicity has been reported with an increase in hepatic enzyme activity, hyperbilirubinemia, cholestasis, hepatitis with hepatic impairment, including fatal cases.

    Opportunistic infections were rare, including pneumonia caused by Pneumocystis carinii; Very rarely reported cases of interstitial pneumonitis / pneumonitis, pulmonary fibrosis and fatal respiratory failure. Also, very rarely was the development of myelodysplastic syndrome (MDS) and secondary malignant processes, including leukemia; very rarely met the development of prolonged pancytopenia in several cases - with the development of lethal 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.A case of overdose (taking a dose of 2000 mg per day for 5 days), which resulted in the development of pancytopenia, pyrexia, multiple organ failure and death. When taking the drug for more than 5 days (up to 64 days), among other symptoms of overdose, hematopoiesis was suppressed, complicated or uncomplicated by the infection, in some cases prolonged and severe, with a fatal outcome.

    Symptoms: pancytopenia, hyperthermia, multiple organ failure,

    accompanied by infection or without infection, resulting in death.

    Treatment: antidote to temozolomide is not known. It is recommended hematological control and, if necessary, symptomatic therapy.

    Interaction:

    The administration of temozolomide together with ranitidine does not lead to a clinically significant change in the degree of absorption of temozolomide.

    Taking temozolomide together with food leads to a decrease in the maximum concentration (Cmax) temozolomide by 33% and a decrease in the area under the curve "concentration-time" (AUC) on 9%. It is impossible to exclude the clinical significance of this decrease Stach, so temozolomide should be taken on an empty stomach.

    Joint reception with dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine H2 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, was not carried out. Due to temozolomide not metabolized in the liver and weakly bound to proteins, its effect on the pharmacokinetics of other drugs is unlikely. The use of 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, against the background of treatment with temozolomide, nausea or vomiting occurs, it is recommended that antiemetic therapy be given in subsequent doses.Antiemetic drugs can be taken both before and after taking Temozolomide. Even if vomiting has developed in the first 2 hours after taking Temozolomide, it is not necessary to repeat the intake of the drug on the same day.

    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 periods of treatment with temozolomide, increased alertness to the possible development of PCP should be shown for all patients receiving temozolomide, especially in combination with glucocorticosteroids.

    Elderly patients

    Based on the data obtained by pharmacokinetic analysis in patients aged 19-78 years, the clearance of temozolomide does not depend on age. However, in elderly patients (over 70 years), the risk of developing neutropenia and thrombocytopenia is higher. Liver failure

    The pharmacokinetic parameters of temozolomide in individuals with normal liver function and in patients with impaired liver function of mild or moderate severity are comparable. Data on the use of temozolomide in patients with severe hepatic dysfunction (class C on the Child-Pugh scale) do not. Based on the data on the pharmacokinetic properties of temozolomide, it seems unlikely that patients with even a severe degree of impaired liver or kidney function may need to reduce the dose of the drug. However, when the drug is administered

    Temomide such patients should be cautious. Very rarely in treatment Temozolomide had hepatic insufficiency, including fatal cases. In this regard, it is recommended to perform an analysis of liver function before treatment with temozolomide. During treatment, the patient should also be under close medical supervision to assess the benefit / risk of continuing therapy.

    Myelosuppression, aplastic anemia

    In patients treated with temozolomide, myelosuppression may develop, including prolonged pancytopenia.Possible development of aplastic anemia, which in isolated cases led to a catabolic outcome. The development of aplastic anemia can also be associated with the use of a number of drugs, such as carbamazepine, phenytoin or sulfamethoxazole / trimethoprim, therefore, with the simultaneous use of temozolomide and these drugs, it is difficult to establish the cause of the development of aplastic anemia. To begin treatment with temozolomide it is possible only at an absolute quantity of neutrophils >1,5x109/ l and platelets> 100 x 109/ l. A complete clinical analysis of the blood should be performed on the 22nd day (the 21st day after the first dose), but no later than 48 hours after that day; further - weekly, until the absolute number of neutrophils is no higher than 1.5 x 109/ l, and the number of platelets does not exceed 100 x 109/ l. With an absolute number of neutrophils below 1.0 x 109/ l or platelets below 50 x 109/ l during any treatment cycle, the dose in the next cycle should be reduced by one step. Possible doses: 100 mg / m2, 150 mg / m2and 200 mg / m2. The minimum recommended dose is 100 mg / m2.

    Fertility and contraception

    Men and women of childbearing age during treatment with temozolomide and, at least, within 6 months after its termination should use reliable methods of contraception.

    Because of the risk of developing irreversible infertility with the treatment of temozolomide male patients before the start of treatment if necessary, it is recommended to discuss the possibility of cryopreservation of sperm.

    Precautions for use

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

    Effect on the ability to drive transp. cf. and fur:

    Some side effects of the drug on the part of the nervous system, such as drowsiness, fatigue, headache, dizziness and trouble

    concentration of attention, can adversely affect the ability of management

    vehicles or the performance of potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions. In this connection, when these symptoms appear, one should refrain from managing vehicles and mechanisms.

    Form release / dosage:

    Capsules of 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, 250 mg. 5 capsules in a contour mesh box made of PVC film and aluminum foil. For 1 or 4 contour packs with instructions for use in a pack of cardboard.

    Packaging:(5) - packings, cellular, outline (1) - packs, cardboard
    (5) - packings, cellular, outline (4) - packs, cardboard
    Storage conditions:

    Keep in dry the dark place at a temperature of no higher than 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002675
    Date of registration:24.10.2014
    The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia
    Manufacturer: & nbsp
    Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia
    Information update date: & nbsp14.09.2015
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