Темодал®

General characteristics. Structure:

Active ingredient: 100 mg of a temozolomid in 1 bottle.

Excipients: Mannitolum, threonine, polysorbate 80, citrate sodium a dihydrate, Acidum hydrochloricum concentrated.

Pharmacological properties:

Pharmacodynamics. Antineoplastic drug, derivative imidazotetrazine, is the alkylating means. At hit in a system blood stream, at physiological values рН 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.

Pharmacokinetics. Distribution. Temozolomid quickly gets through GEB and gets to cerebrospinal fluid. Vd does not depend on a dose. Temozolomid poorly contacts proteins (12-16%).

Removal. T1/2 makes about 1.8 h of plasma. The main way of removal of a temozolomid - a kidney. By 24 h after intake about 5-10% of a dose is defined in not changed look in urine; other part is removed in a look a 4-amino-5-imidazole-karboksamida of a hydrochloride (AIK), temozolomidovy acid or not identified polar metabolites. The clearance and T1/2 do not depend on a dose.

Pharmacokinetics in special clinical cases. The clearance of drug in plasma does not depend on age, function of kidneys or smoking.

Pharmacokinetic profile of drug at patients with an abnormal liver function of weak or moderate degree same, as at persons with normal function of a liver.

At children the indicator of AUC is higher, than at adults.

The maximum tolerable dose 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;

— the widespread metastasizing malignant melanoma - as therapeutic means of the first row.

Route of administration and doses:

For the first time the revealed multiformny glioblastoma. Treatment of adult patients is more senior than 18 years. Primary treatment is carried out to combinations with radiation therapy. ^{Темодал®} appoint in a dose 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 use of drug can be interrupted depending on portability. Resuming of use of drug is possible throughout all 42-day period of the combined treatment and up to 49 days, but only at observance of all listed below conditions: the absolute number of neutrophils are not lower 1500/mkl, number of thrombocytes — not lower than 100 000/mkl, 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 drug withdrawal ^{of Temodal®} during the combined phase of treatment are given in table 1.

Table 1. Recommendations about a dose decline or drug withdrawal ^{of Temodal®} at the combined treatment with radiation therapy.

* Resuming of use ^{of the drug Temodal®} is possible at observance of all listed below conditions: the absolute number of neutrophils are not lower 1500/mkl, number of thrombocytes — not lower than 100 000/mkl, the general criterion of toxicity (STS) is not higher than degree 1 (except for an alopecia, nausea and vomiting).

Adjuvant therapy is appointed in 4 weeks after end of a combination therapy and is carried out in the form of 6 additional cycles.

Tsikl1: ^{Темодал®} appoint in a dose 150 ^mg/sq.m within 5 days with the subsequent 23-day break in treatment.

Cycle 2: the dose ^{of the drug Temodal®} can be increased to 200 ^mg/sq.m/days 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 1500/mkl, and number of thrombocytes - not lower than 100 000/mkl. If in a cycle 2 the dose ^{of the drug Temodal®} 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 administration of drug ^{of Temodal®} 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 made in tables 2 and 3. For the 22nd day of treatment (the 21st day after reception of the first dose of drug) it is necessary to conduct a blood analysis with calculation of number of cells. Cancellation or a dose decline of drug should be carried out, being guided by table 3.

Table 2. ^{Drug Temodal®} dosage steps at adjuvant therapy.

Table 3. Recommendations about a dose decline or drug withdrawal ^{of Temodal®} at adjuvant therapy.

* ^{Темодал®} it is necessary to cancel if the dose decline to <100 ^mg/sq.m, 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.

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

To the patients who were earlier not exposed to chemotherapy, ^Temodal® appoint in a dose 200 ^mg/sq.m of 1 times/days for 5 days in a row with the subsequent break in administration of drug within 23 days (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 of 1 times/days; in the second cycle the dose can be raised to 200 ^mg/sq.m/days provided that in the first day of the following cycle the absolute number of neutrophils are not lower 1500/mkl, and the number of thrombocytes are not lower 100 000/mkl.

Recommendations about modification of a dose ^{of the drug Temodal®} at treatment of the progressing or recurrent malignant glioma or a malignant melanoma. At the patients receiving ^Temodal® the miyelosupressiya, including a long pancytopenia can develop. Development of aplastic anemia which in isolated cases led to a fatal 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 the drug Temodal®} and these drugs it is difficult to establish the reason of development of aplastic anemia.

It is possible to begin treatment ^{with the drug Temodal®} only at absolute number of neutrophils 1500/mkl and thrombocytes ≥100 000/mkl. Full clinical blood test has 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 1500/mkl, and the number of thrombocytes will not exceed 100 000/mkl. At absolute number of neutrophils below 1000/mkl or thrombocytes lower than 50 000/mkl 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.

Rules of preparation of solution for infusions. Preparation of solution for infusions should be carried out in strictly aseptic conditions.

For dissolution of drug add 41 ml of water for injections to a bottle. Dissolution is carried out by rotation of bottles, without allowing stirring. Concentration of the received solution makes 2.5 mg/ml of a temozolomid.

Bottles with the solution containing visible mechanical inclusions cannot be used. The recovered solution should be used during 14 h, including infusion time.

Calculate the solution volume necessary for introduction. In aseptic conditions from each bottle move up to 40 ml of solution to empty capacity for infusions with a capacity of 250 ml.

Solution needs to be entered in/in within 90 min.

Solution is allowed to be entered in one infusional system with chloride sodium solution 0.9%. Drug is not compatible to dextrose solutions. Since researches of compatibility of a temozolomid, lyophilisate for preparation of solution for infusions, with others in/in drugs or excipients were not conducted, it is not necessary to carry out their simultaneous joint infusion, using one system.

Features of use:

Use at pregnancy and feeding by a breast. Use of the drug Temodal® is contraindicated at pregnancy and in the period of a lactation (breastfeeding).

Men and women of childbearing age during treatment by the drug Temodal®, and, at least, within 6 months after the termination have to use reliable methods of contraception.

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

Use at abnormal liver functions. With care it is necessary to appoint drug at the expressed liver failure.

Use at renal failures. With care it is necessary to appoint drug at the expressed renal failure.

Use for children. It is contraindicated at 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).

Use for elderly patients. With care patients should appoint more senior drug than 70 years.

Special instructions. 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 nausea arises the drug Temodal® or vomiting at the subsequent receptions is recommended to carry out antiemetic therapy.

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 Pneumocystis carinii is recommended to such patients. Though more frequent development of the pneumonia caused by Pneumocystis carinii is associated with more long terms of treatment by the drug Temodal®, the increased vigilance concerning possible development of pneumocystic pneumonia should be shown concerning all patients receiving Temodal®, especially in combination with GKS.

Pharmacokinetic indicators of the drug Temodal® at persons and at patients with an abnormal liver function of weak or moderate severity are close comparable to normal function of a liver. Data on use of the drug Temodal® for patients with the expressed abnormal liver function (a class C on a scale of Chayld-Pyyu) or a renal failure are not available. On the basis of data of studying of pharmacokinetic properties of Temodal it is represented improbable that even with the expressed abnormal liver function or kidneys the drug dose decline can be required by patients. Nevertheless, at purpose of the drug Temodal® such patients should show care.

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

Use in pediatrics. Clinical experience of use of the drug Temodal® at a multiformny glioblastoma at children under 3 years and at a malignant melanoma at children and teenagers aged up to 18 years is absent. There is a limited experience of use of Temodal at a glioma for children 3 years are more senior.

Influence on ability to driving of motor transport and to driving. Some side effects of drug, such as drowsiness and feeling of fatigue, 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.

Side effects:

For the first time the revealed multiformny 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 provided during clinical trials below. Determination of frequency of side effects: very often (≥1/10), it is frequent (from ≥1/100 to <1/10), infrequently (from ≥1/1000 to <1/100).

At the combined treatment phase (with radiation therapy). The majority of side effects are caused by radiation therapy and not connected using drug.

Infectious and parasitic diseases: often — oral cavity candidiasis, a herpes simplex, pharyngitis, a wound fever, other infection.

From system of a hemopoiesis: often - a leukopenia, a lymphopenia, a neutropenia, thrombocytopenia; infrequently - anemia, a febrile neutropenia.

From endocrine system: infrequently — cushingoid.

From a metabolism: very often - anorexia; often - a hyperglycemia, a body degrowth; infrequently - a hypopotassemia, increase in activity of ShchF, increase in body weight.

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

From a nervous system: very often - a headache; often — spasms, consciousness oppression, drowsiness, aphasia, balance disturbance, dizziness, confusion of consciousness, a memory impairment, concentration disturbance, a neuropathy, paresthesias, an alalia, a tremor; infrequently - the epileptic status, extrapyramidal frustration, a hemiparesis, an ataxy, perception disturbance, a dysphasia, the gait disturbance, a hyperesthesia, a hypesthesia, neurologic frustration which are (not specified) a peripheral neuropathy.

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

From an acoustic organ and labyrinth disturbances: often - deterioration in hearing; infrequently - average otitis, a ring in ears, a hyperacusia, ear pain.

From cardiovascular system: often - hemorrhages, hypostases, including hypostases of legs; infrequently - heartbeat, brain hemorrhage, arterial hypertension.

From respiratory system: often - short wind, cough; infrequently - pneumonia, an upper respiratory tract infection, a nose congestion.

From the alimentary system: very often - a lock, nausea, vomiting; often - stomatitis, diarrhea, an abdominal pain, dyspepsia, a dysphagy.

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

From a musculoskeletal system: often - muscular weakness, an arthralgia; infrequently - a myopathy, a dorsodynia, musculoskeletal pains, a mialgiya.

From an urinary system: often - a frequent urination, an urine incontience.

From a reproductive system: infrequently - impotence.

General frustration: very often - fatigue; often - allergic reaction, fever, radiation injury, a face edema, a pain syndrome, a food faddism; infrequently - an adynamy, reddening, inflows, an aggravation of symptoms, a fever, disturbance of coloring of language, a perversion of sense of smell, thirst.

Laboratory researches: often - increase in activity of ALT; infrequently — increase in activity of enzymes of a liver, GGT, nuclear heating plant.

At an adjuvant phase of treatment.

Infectious and parasitic diseases: often - candidiasis of a mucous membrane of an oral cavity, other infection; infrequently - the herpes simplex, herpes surrounding grippopodobny symptoms.

From system of a hemopoiesis: often - a febrile neutropenia, thrombocytopenia, anemia, a leukopenia; infrequently - a lymphopenia, petechias.

From endocrine system: infrequently - cushingoid.

From a metabolism: very often - anorexia; often - a body degrowth; infrequently - a hyperglycemia, increase in body weight.

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

From a nervous system: very often - spasms, a headache; often - a hemiparesis, aphasia, balance disturbance, drowsiness, consciousness oppression, dizziness, confusion of consciousness, a memory impairment, concentration disturbances, a dysphasia, neurologic frustration, a neuropathy, a peripheral neuropathy, paresthesias, an alalia, a tremor; infrequently - a hemiplegia, an ataxy, decrease in coordination, gait disturbance, a hyperesthesia, touch disturbances.

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

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

From cardiovascular system: often - hemorrhages, a deep vein thrombosis, hypostases of legs; infrequently - a pulmonary embolism, hypostasis, peripheral hypostasis.

From respiratory system: often - short wind, cough; infrequently - pneumonia, sinusitis, an upper respiratory tract infection.

From the alimentary system: very often - a lock, nausea, vomiting; often - stomatitis, diarrhea, dyspepsia, a dysphagy, dryness of mucous membranes of an oral cavity; infrequently - abdominal distention, an incontience a calla, the gastrointestinal frustration which is (not specified) a gastroenteritis, hemorrhoids.

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

From a musculoskeletal system: often - muscular weakness, an arthralgia, musculoskeletal pains, a mialgiya; infrequently - a myopathy, a dorsodynia.

From an urinary system: often - an urine incontience, infrequently - a dysuria.

From reproductive system: infrequently - vaginal bleeding, a menorrhagia, an amenorrhea, a vaginitis, mammary gland pains.

General frustration: very often - fatigue; often — allergic reaction, fever, radiation injury, a pain syndrome, a food faddism; infrequently - an adynamy, a face edema, pain, an aggravation of symptoms, a fever, disturbances from teeth, a food faddism.

Laboratory researches: often - increase in activity of ALT.

Laboratory indicators. 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)

Determination of frequency of side effects: very often (≥1/10), it is frequent (from ≥1/100 to <1/10), infrequently (from ≥1/1000 to <1/100), is rare (<1/1000).

Infectious and parasitic diseases: seldom — the infections caused by opportunistic flora including pneumocystic pneumonia.

From system of a hemopoiesis: very often - a neutropenia or a lymphopenia (3-4 degrees), thrombocytopenia (3-4 degrees); infrequently - a pancytopenia, anemia (3-4 degrees), a leukopenia. At treatment of patients with a glioma and the metastasizing 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 drug withdrawal of Temodal® 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. Oppression of a marrowy hemopoiesis developed usually 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.

From a metabolism: very often - anorexia; often - a body degrowth.

From a nervous system: very often — a headache; often - drowsiness, dizziness, paresthesia.

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

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

From skin and skin appendages: often - rash, an itch, an alopecia; very seldom - a mnogoformny erythema, an erythrosis, a small tortoiseshell, a dieback.

General frustration: very often - fatigue; often - fever, an adynamy, a fever, feeling of alarm, pain, a food faddism; very seldom - allergic reactions, including an acute anaphylaxis, a Quincke's edema.

During the post-marketing period it was very seldom reported about cases of a mnogoformny erythema, a toxic epidermal necrolysis, Stephens-Johnson's syndrome and allergic reactions, including an anaphylaxis. Also messages on hepatotoxic cases, including increase in activity of enzymes of a liver, a hyperbilirubinemia, a cholestasia and hepatitis were received.

It was in rare instances reported about opportunistic infections, including the pneumonia caused by Pneumocystis carinii. It was very seldom reported about cases of development of an intersticial pneumonitis / pneumonitis, a miyelodisplastichesky syndrome, metastatic malignant new growths, including a myeloleukemia. It was reported about cases of a long pancytopenia. Development of aplastic anemia which isolated cases led to a lethal outcome is possible.

Interaction with other medicines:

Combined use 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 the drug Temodal® together with other substances oppressing marrow can increase probability of a miyelosupressiya.

Contraindications:

— the expressed miyelosupressiya;

— pregnancy;

— period of a lactation (breastfeeding);

— 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);

— hypersensitivity to drug components;

— hypersensitivity to a dakarbazin.

With care patients should appoint more senior drug than 70 years, at the expressed renal or liver failure.

Overdose:

Symptoms: during clinical trials use of 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) was studied. 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 2 g/days 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 side effects the hemopoiesis oppression complicated or not complicated by an infection, in certain cases long and expressed, with a lethal outcome was noted.

Treatment: the antidote is unknown. Hematologic control and if necessary - symptomatic therapy is recommended.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature from 2 °C to 8 °C. Not to freeze the Period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

Bottles of colourless glass with a capacity of 100 ml (1) - a pack cardboard.