Temozolomid

General characteristics. Structure:

Active ingredients: 5 mg, 20 mg, 100 mg, 140 mg, 180 mg or 250 mg of a temozolamid.

Auxiliary veshchesva: lactose, silicon dioxide colloid, sodium carboxymethylstarch, tartaric acid, stearic acid.

Structure of solid gelatin capsules: case: gelatin (enough to 100%), titanium dioxide (Е 171) (1,4100%). Lid: gelatin (enough to 100%), titanium dioxide (Е 171) (1,4100%).

Pharmacological properties:

Pharmacodynamics. Temozolomid - the imidazotetrazinovy alkylating drug having antineoplastic activity. At hit in a system blood stream, at physiological PH values it is exposed to bystry chemical transformation with formation of active connection - a monometiltriazenoimidazolkarboksamid (MTIK). It is considered that cytotoxicity of MTIK is caused first of all by alkylation of guanine in situation O6 and additional alkylation in situation N7. Apparently, the cytotoxic damages arising thereof include (start) the mechanism of aberrant recovery of the methyl rest. MTIK breaks structure and synthesis of DNA, a cellular cycle.

Pharmacokinetics. Absorption: Temozolomid after intake is quickly soaked up. The maximum concentration (Cmax) in plasma is reached on average in 0,5 - 1,5 hours (the earliest - in 20 minutes) after administration of drug. Reception of a temozolomid with food causes decrease Stakh for 33% and reduction of the area under a curve "concentration time" (AUC) for 9%. After oral administration of a temozolomid average extent of removal by intestines within 7 days made 0,8% that demonstrates full absorption of drug. Distribution: Temozolomid quickly gets through a blood-brain barrier and gets to cerebrospinal fluid. The volume of distribution (Vd) in plasma does not depend on a dose. Temozolomid poorly contacts proteins of plasma (12 - 16%).

Removal: The elimination half-life (T1/2) makes about 1,8 h. The clearance and an elimination half-life do not depend on a dose. The main way of removal of a temozolomid - through kidneys. In 24 hours after oral administration about 5%-10% of a dose is defined in not changed look in urine; the rest is removed in a look a 4-amino-5-imidazole-karboksamida of a hydrochloride (agrarian and industrial complex), temozolomidovy acid or in the form of not identified polar metabolites.

Pharmacokinetics in special groups of patients: The clearance of drug does not depend on age, function of kidneys and consumption of tobacco. A pharmacokinetic profile of a temozolomid at patients with an abnormal liver function easy or moderate severity same, as well as at persons with normal function of a liver.

At children the indicator of AUC is higher, than at adults. The Maximum Tolerable Dose (MTD) at children and adults was identical and made 1000 mg/sq.m on one cycle of treatment.

Indications to use:

- for the first time the revealed multiformny glioblastoma - the combined treatment with radiation therapy with the subsequent adjuvant monotherapy;

- a malignant glioma (a multiformny glioblastoma or an anaplastic astrocytoma) in the presence of a recurrence or progressing of a disease after standard therapy;

- a widespread metastatic malignant melanoma - as therapeutic means of the first row.

Route of administration and doses:

Temozolomid accept inside, on an empty stomach, not less, than in one hour prior to meal.

The appointed dose has to be accepted with use of minimum possible number of capsules. Capsules cannot be opened or chewed, they should be swallowed entirely, washing down with a glass of water.

For the first time the revealed multiformny glioblastoma. Treatment of adult patients (18 years are more senior).

Primary treatment is carried out to combinations with radiation therapy. Temozolomid is appointed in a dose of 75 mg/sq.m daily within 42 days along with performing radiation therapy (30 fractions in a total dose of 60 Gr.

The dose decline is not recommended, however administration of drug can be interrupted depending on portability. Resuming of administration of drug is possible throughout all 42-day period of the combined treatment and up to the 49th day, but only at observance of all listed below conditions: the absolute number of neutrophils are not lower 1,5 x 109/l, number of thrombocytes - not lower than 100 x 109/l, the general criterion of toxicity (STS) is not higher than degree 1 (except for an alopecia, nausea and vomiting). During treatment it is necessary to conduct weekly a blood analysis with calculation of number of cells. Recommendations about a dose decline or cancellation of a temozolomid during the combined treatment phase see in the section "Correction of the Mode of Dosing" (tab. 1).

Adjuvant therapy is appointed in 4 weeks after end of a combination therapy and is carried out in the form of 6 additional cycles. Cycle 1: Temozolomid appoint in a dose 150 mg/sq.m within 5 days with the subsequent 23-day break in treatment. Cycle 2: the dose of a temozolomid can be increased to 200 mg/sq.m a day provided that at the first cycle expressiveness of not hematologic toxicity (according to a scale of toxicity of STS) did not exceed degree 2 (except for an alopecia, nausea and vomiting), at the same time the absolute number of neutrophils was not lower than 1,5 x 109/l, and number of thrombocytes - not lower than 100 x 109/l. If in a cycle 2 the dose of a temozolomid was not increased, it should not be increased also in the following cycles. If in a cycle 2 the dose was 200 mg/sq.m, in the same daily dose drug is appointed also in the following cycles (in the absence of toxicity). In each cycle reception of a temozolomid is carried out within 5 days in a row with the subsequent 23-day break. Recommendations about a dose decline in an adjuvant phase of treatment are provided in the section "Correction of the Mode of Dosing" (tab. 2 and 3). For the 22nd day of treatment (the 21st day after reception of the first dose of drug) needs to be spent blood test with calculation of number of cells. Cancellation or a dose decline of drug should be carried out, being guided by table 3.

The progressing or recurrent malignant glioma in the form of a muljtiformny glioblastoma or an anaplastic astrocytoma (treatment of adults and children is more senior than 3 years). Widespread metastatic malignant melanoma (treatment of adults).

To the patients who were earlier not exposed to chemotherapy темозоломид appoint in a dose 200 mg/sq.m for 5 days in a row with the subsequent break in administration of drug within 23 days once a day (the general duration of one cycle of treatment makes 28 days). For the patients who were earlier taking a chemotherapy course, the initial dose makes 150 mg/sq.m once a day; in the second cycle the dose can be raised to 200 mg/sq.m a day within 5 days provided that in the first day of the following cycle the absolute number of neutrophils are not lower 1,5 x 109/l, and the number of thrombocytes are not lower than 100 x 109/l.

Recommendations about modification of a dose of a temozolomid at treatment of the progressing or recurrent malignant glioma or a malignant melanoma.

It is possible to begin treatment temozolomidy only at absolute number of neutrophils> 1,5x109/l and thrombocytes> 100 x 109/l. The integrated clinical analysis крови_должен to be made for the 22nd day (the 21st day after reception of the first dose), but no later than 48 h after this day; further - weekly until the absolute number of neutrophils becomes higher than 1,5 x 109/l, and the number of thrombocytes will not exceed 100 x 109/l. At absolute number of neutrophils lower than 1,0 x 109/l or thrombocytes lower than 50 x 109/l during any cycle of treatment, the dose in the following cycle has to be lowered on one step. Possible doses: 100 mg/sq.m, 150 mg/sq.m and 200 mg/sq.m. The minimum recommended dose makes 100 mg/sq.m. Duration of treatment makes at most 2 years. At emergence of progressing of a disease treatment of drug should be stopped.

Correction of the mode of dosing. For the first time the revealed multiformny glioblastoma (at patients 18 years are more senior) Recommendations about a dose decline or cancellation of a temozolomid during the combined phase of treatment are given in table 1.

Table 1. Recommendations about a dose decline or cancellation of a temozolomid at the combined treatment with radiation therapy.

 

Criterion of toxicity	Having rummaged in reception of a temozolomid *	Termination of reception of a temozolomid
Absolute number of neutrophils	> 0,5 x 109/l, but <1,5 x 109/l	<0,5 x 109/l
Number of thrombocytes	> 10 x 109/l, but <100 x 109/l	<10x109/l
STS of not hematologic toxicity (except for an alopecia, nausea and vomiting)	Degree 2	Degree 3 or 4

* Resuming of reception of a temozolomid is possible at observance of all listed below conditions: the absolute number of neutrophils are not lower 1,5 x 109/l, number of thrombocytes - not lower than 100 x 109/l, the general criterion of toxicity (STS) is not higher than degree 1 (except for an alopecia, nausea and vomiting).

Recommendations about a dose decline or cancellation of a temozolomid at adjuvant therapy are provided in tables 2 and 3.

Table 2. Drug dosage steps Temozolomid at adjuvant therapy.

Step	Dose (mg/sq.m/days)	Note
- 1	100	Reduction of a dose taking into account the previous toxicity (see tab. 3)
0	150	Dose during a cycle 1
1	200	Dose during cycles 2-6 (in the absence of toxicity)

Table 3. Recommendations about a dose decline or cancellation of a temozolomid at adjuvant therapy.

 

Criterion of toxicity	To reduce a dose of a temozolomid by 1 step (see tab. 2)	Termination of reception of a temozolomid
Absolute number of neutrophils	<1 x 109/l	*
Number of thrombocytes	<50 x 109/l	*
STS of not hematologic toxicity (except for an alopecia, nausea and vomiting)	Degree 3	Degree 4 *

On the basis of data of studying of pharmacokinetic properties of a temozolomid it is represented improbable that even with an abnormal liver function of heavy degree or with a renal failure the drug dose decline can be required by patients. Nevertheless, at purpose of a temozolomid such patients should show care.

At children the indicator of AUC is higher, than at adults. The Maximum Tolerable Dose (MTD) at children and adults was identical and made 1000 mg/sq.m on one cycle of treatment. Patients of advanced age

On the basis of the data obtained by method of the pharmacokinetic analysis at patients of 19-78 years, the clearance of a temozolomid does not depend on age. However at patients of advanced age (70 years are more senior) the risk of development of a neutropenia and thrombocytopenia increases.

* Temozolomid it is necessary to cancel if the dose decline to <100 mg/m 2, and also in case of a recurrence of not hematologic toxicity of degree 3 (except for an alopecia, nausea and vomiting) after a dose decline is required.
Use for special groups of patients

Patients with a liver or renal failure. Pharmacokinetic indicators of a temozolomid at persons at patients to an abnormal liver function easy or moderate severity are close comparable to normal function of a liver. There are no data on use of a temozolomid for patients with an abnormal liver function of heavy degree (a class C on a scale of Chayld-Pyyu) or and a renal failure.

Features of use:

Pregnancy and lactation. Temozolomid is contraindicated during pregnancy and during breastfeeding.

Performing preventive antiemetic therapy is recommended before the combined treatment (with radiation therapy) and is strongly recommended during adjuvant therapy for the first time of the revealed multiformny glioblastoma.

If against the background of treatment temozolomidy there is nausea or vomiting at the subsequent receptions is recommended to carry out antiemetic therapy. Antiemetic drugs can be accepted both to, and after reception of a temozolomid. Even if vomiting developed in the first 2 hours after reception of a temozolomid it is not necessary to repeat administration of drug on the same day.

Due to the increased risk of development of the pneumonia caused by Pneumocystis carinii at the patients receiving the combined treatment with radiation therapy within 42 days (up to 49 days), performing preventive treatment against the Pneumocystis carinii activator is recommended to such patients. Though more frequent development of the pneumonia caused by Pneumocystis carinii is associated with more long terms of treatment temozolomidy, the increased vigilance concerning possible development of pneumocystic pneumonia should be shown concerning all patients receiving темозоломид, especially in combination with glucocorticosteroids.

Patients of advanced age. On the basis of the data obtained by method of the pharmacokinetic analysis at patients of 19-78 years, the clearance of a temozolomid does not depend on age. However at patients of advanced age (70 years are more senior) the risk of development of a neutropenia and thrombocytopenia increases above. Liver failure

Pharmacokinetic indicators of a temozolomid at persons and at patients to an abnormal liver function easy or moderate severity are comparable to normal function of a liver. There are no data on use of a temozolomid for patients with an abnormal liver function of heavy degree (a class C on a scale of Chayld-Pyyu). On the basis of data of studying of pharmacokinetic properties of a temozolomid it is represented improbable that even with heavy degree of an abnormal liver function or kidneys the drug dose decline can be required by patients. Nevertheless, at purpose of drug

Temomid such patients should show care. Very seldom at treatment temozolomidy the liver failure, including cases from the death was noted. In this regard, it is recommended to carry out the analysis of function of a liver before an initiation of treatment temozolomidy. During treatment the patient also has to be under careful observation of the doctor for assessment of advantage/risk of continuation of therapy.

Miyelosupressiya, aplastic anemia. At the patients receiving treatment temozolomidy the miyelosupressiya, including a long pancytopenia can develop. Development of aplastic anemia which brought in isolated cases to a kletalny outcome is possible. Development of aplastic anemia can be also connected using a number of drugs, such as carbamazepine, Phenytoinum or sulfamethoxazole/Trimethoprimum therefore at simultaneous use of a temozolomid and these drugs it is difficult to establish the reason of development of aplastic anemia. It is possible to begin treatment temozolomidy only at absolute quantity of neutrophils> 1,5x109/l and thrombocytes> 100 x 109/l. The integrated clinical analysis кровщдолжен to be made for the 22nd day (the 21st day after reception of the first dose), but no later than 48 h after this day; further - weekly until the absolute quantity of neutrophils becomes higher than 1,5 x 109/l, and the quantity of thrombocytes will not exceed 100 x 109/l. At absolute quantity of neutrophils lower than 1,0 x 109/l or thrombocytes lower than 50 x 109/l during any cycle of treatment, the dose in the following cycle has to be lowered on one step. Possible doses: 100 mg/sq.m, 150 mg / м2и 200 mg/sq.m. The minimum recommended dose makes 100 mg/sq.m.

Fertility and contraception. Men and women of childbearing age during treatment temozolomidy and, at least, within 6 months after its termination have to use reliable methods of contraception.

Because of risk of development of irreversible infertility against the background of treatment temozolomidy male patients before an initiation of treatment are in case of need recommended to discuss a possibility of a cryopreservation of sperm.

Precautionary measures at use. At hit of contents of the capsule (powder) on skin or mucous membranes it is necessary to wash out their large number waters.

Influence on ability to manage vehicles and mechanisms. Some side effects of drug from a nervous system, such as drowsiness, feeling of fatigue, headache, dizziness and disturbance of concentration of attention, can negatively influence ability of control of vehicles or performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. In this regard, at emergence of these symptoms it is necessary to refrain from control of vehicles and mechanisms.

Side effects:

For the first time the revealed muljtiformny glioblastoma (adult patients). The side effects noted at treatment of patients with for the first time revealed multiformny glioblastomy during the combined and adjuvant phases of treatment are included below during clinical trials. Side effects are presented on bodies and systems according to the indication of frequency of their emergence according to recommendations of World Health Organization: very often (> 10%), it is frequent (from> 1% to <10%), infrequently (from> 0,1% to <1), is rare (> 0,01% and <0,1%), is very rare (<0,01%).

The combined treatment phase (with radiation therapy). Infectious and parasitic diseases: often - candidiasis of an oral cavity, Herpes simplex, pharyngitis, a wound fever, other infections.

Disturbances from blood and lymphatic system: often - a leukopenia, a lymphopenia, a neutropenia, thrombocytopenia; infrequently - anemia, a febrile neutropenia; Disturbances from endocrine system: infrequently - cushingoid.

Disturbances from a metabolism and food: very often - anorexia; often - a hyperglycemia, a body degrowth; infrequently - a hypopotassemia, increase in body weight.

Disturbances of mentality: often - concern, emotional lability, sleeplessness; infrequently - agitation, apathy, behavioural frustration, a depression, hallucinations.

Disturbances from a nervous system: very often - a headache; often - dizziness, aphasia, disorder of balance, confusion and decrease in consciousness, a spasm, a memory impairment, neuropathy, paresthesias, drowsiness, an alalia, disturbance of concentration of attention, a tremor; infrequently - extrapyramidal frustration, a dysphasia, an ataxy, perception disturbance, gait disturbance, a hemiparesis, a hyperesthesia, a hypesthesia, neurologic frustration (not specified), epileptic status, a parosmiya, thirst.

Disturbances from an organ of sight: often - a sight illegibility; infrequently - eye pain, a hemianopsia, a vision disorder, decrease in visual acuity, restriction of fields of vision.

Disturbances from an acoustic organ and labyrinth disturbances: often - deterioration in hearing, infrequently - ear pain, a hyperacusia, average otitis, a sonitus.

Disturbances from heart: infrequently - a heart consciousness.

Disturbances from vessels: often - hypostases, including hypostases пог, hemorrhages; infrequently - increase in arterial pressure, a hematencephalon.

Disturbances from respiratory system, bodies of a thorax and a mediastinum it is frequent - cough, short wind; infrequently - pneumonia, upper respiratory tract infections, a nose congestion.

Disturbances from digestive tract: very often - a lock, nausea, vomiting; often - an abdominal pain, diarrhea, dyspepsia, a dysphagy, stomatitis, taste disturbance; infrequently - language discoloration.

Disturbances from a liver and biliary tract: often - increase in activity of alaninaminotranspherase (ALT); infrequently - increase in activity of the alkaline phosphatase (AP), gamma глутамилтрансферазы (GGT), aspartate aminotransferases (ACT), liver enzymes.

Disturbances from skin and hypodermic fabrics: very often - an alopecia, rash; often - dermatitis, a xeroderma, an erythema, a skin itch; infrequently - reactions of a photosensitization, pigmentation disturbance, exfoliation.

Disturbances from skeletal and muscular and connecting fabric: often - an arthralgia, muscular weakness; infrequently - a dorsodynia, musculoskeletal pains, a mialgiya, a myopathy.

Disturbances from kidneys and urinary tract: often - the speeded-up urination, an urine incontience.

Disturbances from generative organs and a mammary gland: infrequently - impotence.

The general frustration and disturbances in an injection site: very often - fatigue; often - fever, a pain syndrome, radiation injury, allergic reaction, a face edema; infrequently - "inflows" of heat to a body, an adynamy, an aggravation of symptoms, a fever.

Adjuvant phase of treatment. Infectious and parasitic diseases: often - oral cavity candidiasis, other infections; infrequently - Herpes simplex, Herpes zoster, a grippopodobny syndrome.

Disturbances from blood and lymphatic system: often - anemia, a febrile neutropenia, a leukopenia, thrombocytopenia; infrequently - a lymphopenia, petechias.

Disturbances from endocrine system; infrequently - cushingoid.

Disturbances from a metabolism and food; very often - anorexia; often - a body degrowth; infrequently - a hyperglycemia, increase in body weight.

Disturbances of mentality: often - concern, a depression, emotional lability, sleeplessness; infrequently - hallucinations, amnesia.

Disturbances from a nervous system: very often - a headache, spasms; often - dizziness, aphasia, balance disturbance, confusion of consciousness, a dysphasia, an alalia, a hemiparesis, a memory impairment, disturbance of concentration of attention, the neurologic frustration which are (not specified), neuropathy, peripheral neuropathy, paresthesias, drowsiness, a tremor; infrequently - gait disturbance, an ataxy, a lack of coordination, a hemiplegia, a hyperesthesia, sensitivity disturbances.

Disturbances from an organ of sight: often - a sight illegibility, a diplopia, restriction of fields of vision; infrequently - eye pain, a xerophthalmus, decrease in visual acuity.

Disturbances from an acoustic organ and labyrinth disturbances: often - deterioration in hearing, a ring in ears, infrequently - deafness, ear pain, вертиго.

Disturbances from vessels: often - hypostases of legs, hemorrhages, a deep vein thrombosis; infrequently - hypostases, including peripheral hypostases, an embolism of a pulmonary artery; Disturbances from respiratory system, bodies of a thorax and a mediastinum: often - cough, short wind; infrequently - pneumonia, an infection of upper parts of respiratory tracts, sinusitis, bronchitis.

Disturbances from digestive tract: very often - anorexia lock, nausea, vomiting; often - diarrhea, dyspepsia, a dysphagy, stomatitis, dryness in a mouth, a food faddism; infrequently - abdominal distention, an incontience a calla, hemorrhoids, a gastroenteritis, diseases of teeth, disturbances from digestive tract (not specified).

Disturbances from a liver and e/selchevyvodyashchy ways: often - increase in activity of ALT.

Disturbances from skin and hypodermic fabrics: very often - an alopecia, rash; often - a xeroderma, a skin itch; infrequently - an erythema, pigmentation disturbance, the increased perspiration.

Disturbances from skeletal and muscular and connecting fabric: often - an arthralgia, muscular weakness, a mialgiya, musculoskeletal pains, infrequently - a dorsodynia, a myopathy.

Disturbances from kidneys and urinary tract: often - an urine incontience; infrequently - a dysuria.

Disturbances from generative organs and a milk e/seleza: infrequently - pain in chest gland, an amenorrhea, a menorrhagia, vaginal bleeding, a vaginitis.

The general frustration and disturbances in an injection site: very often - fatigue; often - fever, a pain syndrome, radiation injury, allergic reaction; infrequently - an adynamy, a face edema, an aggravation of symptoms, a fever.

Laboratory and tool data: Miyelosupressiya (a neutropenia and thrombocytopenia), is dozolimitiruyushchy side effect. Among patients of both groups (at the combined and adjuvant therapy) changes 3 and 4 degrees from neutrophils, including a neutropenia, are noted in 8% of cases, and from thrombocytes, including thrombocytopenia, - in 14% of cases.

The progressing or recurrent malignant glioma (adults and children are more senior than 3 years) or malignant melanoma (adults). Side effects are presented on bodies and systems according to the indication of frequency of their emergence according to recommendations of World Health Organization: very often (> 10%), it is frequent (from> 1% to <10%), infrequently (from> 0,1% to <1), is rare (> 0,01% and <0,1%), is very rare (<0,01%):

Infectious and parasitic diseases: seldom - opportunistic infections, including pneumocystic pneumonia.

Disturbances from blood and lymphatic system: very often - thrombocytopenia, a neutropenia, a lymphopenia; often - a pancytopenia, a leukopenia, anemia. At treatment of patients with a glioma and a metastatic melanoma cases of thrombocytopenia and a neutropenia 3 or 4 degrees at 19% and 17% were noted, respectively, at a glioma and at 20% and 22%, respectively, at a melanoma. Hospitalization of patients was required at the same time in 8% and 4% of cases, respectively, at a glioma and in 3% and 1,3% at a melanoma. Oppression of marrow developed during the first several cycles of treatment, with a maximum between 21 and 28 days; recovery happened, as a rule, within 1-2 weeks. Signs of a cumulative miyelosupressiya are noted. Existence of thrombocytopenia could increase risk of bleedings, and existence of a neutropenia or leukopenia increased risk of infectious complications.

Disturbances from a metabolism and food: very often - anorexia; often - decrease in body weight.

Disturbances from a nervous system: very often - a headache; often - drowsiness, dizziness, paresthesias, peripheral neuropathy.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: often - an asthma.

Disturbances from digestive tract: very often - nausea, vomiting, a lock; often - diarrhea, an abdominal pain, dyspepsia, a food faddism. Nausea and vomiting were the most frequent. In most cases these phenomena were 1-2 (from weak to moderated) severity and passed independently or were easily controlled by means of standard therapy. Frequency of the expressed nausea and vomiting made 4%.

Disturbances from skin and hypodermic fabrics: often - rash, an itch, an alopecia, petechias; very seldom - a small tortoiseshell, a dieback, an erythrosis, a multiformny erythema.

The general frustration and disturbances in an injection site: very often - increased fatigue; often - fervescence, a fever, a febricula, an adynamy, a pain syndrome; very seldom - allergic reactions, including an anaphylaxis, a Quincke's disease.

Laboratory and tool data: at treatment of patients with a glioma and a metastatic melanoma cases of thrombocytopenia and a neutropenia 3 or 4 degrees at 19% and 17% respectively - were noted at a glioma and at 20% and 22% respectively - at a melanoma. Hospitalization of the patient or/and cancellation of a temozolomid at the same time was required in 8% and 4% of cases respectively at a glioma and in 3% and 1,3% - at a melanoma. Miyelosupressiya developed predictably, usually during the first several cycles of treatment, with a maximum between 21 and 28 days; recovery happened quickly, as a rule, within 1-2 weeks. Signs of a cumulative miyelosupressiya are noted. Existence of thrombocytopenia could increase risk of bleedings, and existence of a neutropenia or leukopenia increased risk of infectious complications.

Data of post-registration researches. During the post-registration researches of a temozolomid the multiformny erythema, a toxic epidermal necrolysis, Stephens's syndrome - Johnson, and also allergic reactions, including an anaphylaxis very seldom met.

Hepatotoxic cases with increase in activity of liver enzymes, hyperbilirubinemias, a cholestasia, hepatitis with an abnormal liver function, including cases with a lethal outcome are declared.

Seldom opportunistic infections, including the pneumonia caused by Pneumocystis carinii met; it was very seldom reported about cases of an intersticial pneumonitis / pneumonitis, a pneumosclerosis and fatal respiratory insufficiency. Also, development of a miyelodisplastichesky syndrome (MDS) and secondary malignant processes, including leukoses was very seldom noted; very seldom development of a long pancytopenia in several cases - met development of lethal aplastic anemia.

Interaction with other medicines:

Reception of a temozolomid together with ranitidine does not lead to clinically significant change of extent of absorption of a temozolomid.

Reception of a temozolomid together with food is led to reduction of the maximum concentration (Cmax) of a temozolomid by 33% and reduction of the area under a curve by "concentration time" (AUC) for 9%. It is impossible to exclude the clinical importance of such reduction Stakh therefore темозоломид it is necessary to accept on an empty stomach.

Joint reception with dexamethasone, prochlorperazine, Phenytoinum, carbamazepine, ondansetrony, blockers of histamine H2 receptors or phenobarbital does not change clearance of a temozolomid.

Joint reception with valproic acid causes poorly expressed, but statistically significant decrease in clearance of a temozolomid.

The researches directed to clarification of impact of a temozolomid on metabolism and removal of other drugs were not conducted. Because темозоломид it is not metabolized in a liver and poorly contacts proteins, its action on pharmacokinetics of other medicines is improbable. Use of a temozolomid together with other substances oppressing marrow can increase probability of a miyelosupressiya.

Contraindications:

- Hypersensitivity to a temozolomid or other components of drug, and also to a dakarbazin (DTIK);

- the expressed miyelosupressiya;

- pregnancy;

- breastfeeding period;

- children's age - up to 3 years (the recuring or progressing malignant glioma) or up to 18 years (for the first time the revealed multiformny glioblastoma or a malignant melanoma);

- rare hereditary diseases, such as intolerance of a galactose, deficit of lactase or glyukozo-galaktozny malabsorption.
 
With care:
- advanced age (70 years are more senior)

- the children's age is more senior than 3 years at treatment of the recuring or progressing malignant glioma (a multiformny glioblastoma or an anaplastic astrocytoma) in case of a recurrence or progressing of a disease after standard therapy

- renal or liver failure of heavy severity

Overdose:

When using drug in doses of 500 mg/sq.m, 750 mg/sq.m, 1000 mg/sq.m and 1250 mg/sq.m (the total dose received for a 5-day cycle of treatment) dozolimitiruyushchy toxicity was hematologic toxicity which was noted at reception of any dose, but is more expressed - at higher doses. The overdose case (reception of a dose of 2000 mg a day within 5 days) is described as a result of which the pancytopenia, a pyrexia, multiorgan insufficiency and death developed. At administration of drug more than 5 days (up to 64 days), among other symptoms of overdose the hemopoiesis oppression complicated or not complicated by an infection, in certain cases long and expressed, with a lethal outcome was noted.

Symptoms: the pancytopenia, a hyperthermia, multiorgan insufficiency which are followed by an infection or without infection, coming to an end with death.

Treatment: the antidote to a temozolomid is not known. Hematologic control and if necessary - symptomatic therapy is recommended.

Storage conditions:

To store in the dry place protected from light at a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Capsules on 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, 250 mg. On 5 capsules in a blister strip packaging from a film of PVC and aluminum foil. On 1 or 4 blister strip packagings together with the application instruction in a pack from a cardboard.