Temodal

General characteristics. Structure:

1 capsule contains:

Dosage of 5 mg
Active вещество:темозоломид 5 mg
Auxiliary 132,8 mg of a veshchestva:laktoz, carboxymethylstarch of sodium of 7,5 mg, silicon dioxide of colloid 0,2 mg, tartaric acid of 1,5 mg, stearic acid of 3,0 mg.
Structure of a cover of a kapsuly:titan dioxide of 1,093 mg, indigo carmine of 0,001 mg, dye ferrous oxide of yellow 0,059 mg, sodium lauryl sulfate of 0,070 mg, q.s gelatin.

Dosage of 20 mg
Active вещество:темозоломид 20 mg
Auxiliary 182,2 mg of a veshchestva:laktoz, carboxymethylstarch of sodium of 11,0 mg, silicon dioxide of colloid 0,2 mg, tartaric acid of 2,2 mg, stearic acid of 4,4 mg.
Structure of a cover of a kapsuly:titan dioxide of 1,174 mg, dye ferrous oxide of yellow 0,217 mg, sodium lauryl sulfate of 0,088 mg, q.s gelatin.

Dosage of 100 mg
Active вещество:темозоломид 100 mg
Auxiliary 175,7 mg of a veshchestva:laktoz, carboxymethylstarch of sodium of 15,0 mg, silicon dioxide of colloid 0,3 mg, tartaric acid of 3,0 mg, stearic acid of 6,0 mg.
Structure of a cover of a kapsuly:titan dioxide of 2,160 mg, dye ferrous oxide of red 0,029 mg, sodium lauryl sulfate of 0,106 mg, q.s gelatin.

Dosage of 250 mg
Active вещество:темозоломид 250 mg
Auxiliary 154,3 mg of a veshchestva:laktoz, carboxymethylstarch of sodium of 22,5 mg, silicon dioxide of colloid 0,7 mg, tartaric acid of 9,0 mg, stearic acid of 13,5 mg.
Structure of a cover of a kapsuly:titan dioxide of 3,045 mg, sodium lauryl sulfate of 0,136 mg, q.s gelatin.

The structure blackened for drawing a text on a cover of capsules: black color dye contains shellac, ethanol *, isopropanol *, butanol *, propylene glycol, the water purified *, ammonia water *, potassium hydroxide and dye ferrous oxide black.

* - are removed during production.

Pharmacological properties:

Pharmacodynamics. Темодал® is the imidazotetrazinovy alkylating drug having antineoplastic activity. At hit in system circulation, at physiological values рН it is exposed to bystry chemical transformation with formation of active connection of 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. Темодал® after intake it is quickly soaked up and also quickly brought out of an organism with urine. Темодал® quickly gets through a blood-brain barrier and gets to cerebrospinal fluid. 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. Plasma elimination half-life makes about 1,8 hours. The clearance, distribution volume in plasma and an elimination half-life do not depend on a dose. Темодал® poorly contacts proteins (12-16%). After oral administration of drug
Темодал® average extent of removal with excrements within 7 days made 0,8% that demonstrates full absorption of drug. The main way of removal of the drug Temodal® - through kidneys. In 24 hours after oral administration 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. Administration of drug of Temodal® together with food causes decrease in Cmax by 33% and reduction of the area under a curve "concentration time" (AUC) for 9%. The clearance of drug in plasma does not depend on age, function of kidneys or consumption of tobacco. A 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 (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;
- the widespread metastasizing malignant melanoma - as therapeutic means of the first row.

Route of administration and doses:

The drug Temodal® is accepted 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, and it is necessary to swallow 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. The drug Temodal® 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 1500/mkl, number of thrombocytes - not below 100000/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 Temodal at the combined treatment with radiation therapy

Criterion of toxicity	Having rummaged in administration of drug of Temodal®*	Termination of administration of drug of Temodal®
Absolute number of neutrophils	500/mkl, but <1500/mkl	<500/mkl
Number of thrombocytes	10000/mkl, but <100000/mkl	<10000/mkl
STS of not hematologic toxicity (except for an alopecia, nausea and vomiting)	Degree 2	Degree 3 or 4

* Resuming of administration of 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 below 100000/mkl, the general criterion of toxicity (STS) is not higher than degree 1 (except for an alopecia, nausea and vomiting).
Adjuvant therapy is appointed 4 weeks later after end of a combination therapy and is carried out in the form of 6 additional cycles. Cycle 1: The drug Temodal® is appointed in a dose of 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 a day provided that at the first cycle of treatment 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 below 100000/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 (21 days after reception of the first dose of the drug Temodal®) it is necessary to conduct a blood analysis with calculation of number of cells. Cancellation or a dose decline of the drug Temodal® should be carried out, being guided by table 3.

Table 2. Drug dosage steps Temodal at adjuvant therapy

Step	Dose (mg/m/day)	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 drug withdrawal Temodal at adjuvant therapy

Criterion of toxicity	To reduce Temodal's dose by 1 step (see tab. 2)	Termination of reception of Temodala®
Absolute number of neutrophils	<1000/mkl	*
Number of thrombocytes	<50000/mkl	*
STS of not hematologic toxicity (except for an alopecia, nausea and vomiting)	Degree 3	Degree 4 *

* The drug Temodal® should be cancelled 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, the drug Temodal® is appointed in a dose of 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/m a day within 5 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 100000/mkl.

Recommendations about modification of a dose of the drug Temodal® at treatment of the progressing or recurrent malignant glioma or a malignant melanoma
It is possible to begin treatment with the drug Temodal® only at absolute number of neutrophils ≥ 1500/mkl and thrombocytes ≥ 100000/mkl. Full clinical blood test has to be made for the 22nd day (21 days 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 100000/mkl. At absolute number of neutrophils lower than 1,0x109/l or thrombocytes lower than 50x109/l during any cycle of treatment, the dose in the following cycle has to be lowered on one step.
Possible doses: 100 mg/m 2, 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 signs of progressing of a disease treatment of the drug Temodal® should be stopped.

Features of use:

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. Antiemetic drugs can be accepted both to, and after administration of drug of Temodal®. Even if vomiting developed in the first 2 hours after administration of drug of Temodal®, 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 by the drug Temodal®, the increased vigilance concerning possible development of pneumocystic pneumonia should be shown concerning all patients receiving the drug Temodal®, especially in combination with glucocorticosteroids. Pharmacokinetic indicators of the drug Temodal® at persons with normal function of a liver and at patients with an abnormal liver function of weak or moderate severity, are close comparable. Data on use of the drug Temodal® for patients with the expressed abnormal liver function (a class III on classification of Chaylda-Pyyu) or a renal failure are not available. On the basis of data of studying of pharmacokinetic properties of the drug 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.
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 drug Temodal, to male patients before an initiation of treatment is in case of need recommended to discuss a possibility of a cryopreservation of sperm.
At hit of contents of the capsule (powder) on skin or mucous membranes they need to be washed out a large amount of water.

Influence on ability to manage vehicles, 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.

Side effects:

For the first time the revealed multiformny glioblastoma (adult patients).
In the table given below 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 specified during clinical tests. Distribution on the frequency of side effects is made according to the following gradation: very often (> 10%), it is frequent (from> 1% to <10%), infrequently (from> 0.1% to <1%).

Table 4

System of an organism	Reaction frequency	Nature of reaction
		the combined treatment phase (with radiation therapy) n = 288	adjuvant phase of treatment n=224
Mechanisms of resilience to infections	frequent	candidiasis of an oral cavity, herpes simplex, pharyngitis, wound fever, other infection	candidiasis of a mucous membrane of an oral cavity, other infection
	infrequent		herpes simplex, herpes zoster, grippopodobny syndrome
Blood and lymphatic system	frequent	leukopenia, lymphopenia, neutropenia, thrombocytopenia	anemia, febrile neutropenia, leukopenia, thrombocytopenia
	infrequent	anemia, febrile neutropenia	lymphopenia, petechias
Cardiovascular system	often	hypostases, including hypostases of legs, hemorrhages	hypostases of legs, hemorrhages, deep vein thrombosis
	infrequently	heartbeat, increase in arterial pressure, brain hemorrhage	hypostases, including peripheral hypostases, embolism of a pulmonary artery
Respiratory organs	often	cough, short wind	cough, short wind
	infrequently	pneumonia, upper respiratory tract infection, nose congestion	pneumonia, upper respiratory tract infection, sinusitis, bronchitis
Endocrine system	infrequent	cushingoid	cushingoid
Skin and hypodermic cellulose, grudnyezheleza	very often	alopecia, rash	alopecia, rash
	often	dermatitis, xeroderma, erythema, skin itch, face edema	dryness, skin itch
	infrequently	reactions of a photosensitization, pigmentation disturbance, exfoliation	erythema, pigmentation disturbance, the increased perspiration, pain in chest gland, a face edema
Nervous system	very often	headache	headache, spasms
	often	concern, emotional lability, sleeplessness, dizziness, disorder of balance, disturbance of concentration of attention, confusion and decrease in consciousness, spasm, memory impairment, neuropathy, paresthesias, drowsiness, alalia, tremor	concern, depression, emotional lability, sleeplessness, dizziness, balance disturbance, disturbance of concentration of attention, confusion of consciousness, alalia, hemiparesis, memory impairment, the neurologic frustration which are (not specified) neuropathy, paresthesias, drowsiness, a tremor
	infrequently	apathy, behavioural frustration, depression, hallucinations, perception disturbance, extrapyramidal frustration, a dysphasia, an ataxy, the gait disturbance, a hemiparesis, a hyperesthesia, a gipoyesteziya, neurologic frustration which are (not specified), the epileptic status, paresthesias, a parosmiya, thirst	hallucinations, ataxy, amnesia, gait disturbance, hemiplegia, hyperesthesia, disturbances from sense bodys
Basic motive device	often	arthralgia, muscular weakness	arthralgia, muscular skeletal pains, mialgiya, muscular weakness
	infrequently	dorsodynia, muscular skeletal pains, mialgiya, myopathy	dorsodynia, myopathy
Organ of sight	often	sight illegibility	sight illegibility, diplopia, restriction of fields of vision
	infrequently	eye pain, hemianopsia, vision disorder, decrease in visual acuity, restriction of fields of vision	eye pain, xerophthalmus, decrease in visual acuity
Urinogenital system	often	frequent urination, urine incontience	urine incontience
	infrequently	impotence	dysuria, amenorrhea, menorrhagia, vaginal bleeding, vaginitis
Acoustic organs and vestibular system	often	deterioration in hearing	deterioration in hearing, ring in ears
	infrequently	ear pain, hyperacusia, ring in ears, average otitis	deafness, ear pain, dizziness
Alimentary system	very often	anorexia, lock, nausea, vomiting	anorexia, lock, nausea, vomiting
	often	increase in activity ALT, hyperglycemia, body degrowth, abdominal pain, diarrhea, dyspepsia, dysphagy, stomatitis, taste disturbance	increase in activity of ALT, body degrowth, diarrhea, dyspepsia, dysphagy, stomatitis, dryness in a mouth, taste disturbance
	infrequently	hypopotassemia, increase in activity of an alkaline phosphatase, increase in body weight, language discoloration, increase in activity gamma глутамилтрансферазы, ACT, liver enzymes	hyperglycemia, increase in body weight, abdominal distention, incontience calla, hemorrhoids, gastroenteritis, diseases of teeth
Organism in general	very often	fatigue	fatigue
	often	fever, pain syndrome, radiation injury, allergic reaction	fever, pain syndrome, radiation injury, allergic reaction
	infrequently	"inflows" of heat to a body, an adynamy, an aggravation of symptoms, a fever	adynamy, aggravation of symptoms, fever

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).
The listed below undesirable phenomena noted at administration of drug of Temodal® are distributed on emergence frequency according to the following gradation: very often (≥10% of cases), it is frequent (from ≥ 1% to <10%), infrequently (from ≥ 0.1% to <1%), is rare (from ≥ 0.01% to <0.1%) and is very rare (<0.01%).
- From system of a hemopoiesis: very often - thrombocytopenia, a neutropenia, a lymphopenia; infrequently - a pancytopenia, a leukopenia, anemia. 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
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 marrow 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 system of digestion: very often - nausea, vomiting, a lock, anorexia; 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) degrees of manifestation and passed independently or were easily controlled by means of standard antiemetic therapy. Frequency of the expressed nausea and vomiting - 4%.
- From a nervous system: very often - a headache; often - drowsiness, dizziness, paresthesias, an adynamy.
- From skin and skin appendages: often - rash, an itch, an alopecia, petechias; very seldom - a small tortoiseshell, a dieback, an erythrosis, a multiformny erythema, a toxic epidermal necrolysis, Stephens-Johnson's syndrome.
- From immune system: very seldom - allergic reactions, including an anaphylaxis.
- Other: very often - increased fatigue; often - decrease in body weight, an asthma, fervescence, a fever, a febricula; infrequently - a hypopotassemia, increase in level of an alkaline phosphatase, increase in body weight; seldom - opportunistic infections, including the pneumonia caused by Pneumocystis carinii; development of a miyelodisplastichesky syndrome (MDS) and secondary malignant processes, including leukemia was very seldom noted, and also the Quincke's disease, development of a long pancytopenia with risk of development of aplastic anemia and irreversible infertility were noted.

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.
Joint reception with dexamethasone, prochlorperazine, Phenytoinum, carbamazepine, ondansetrony, antagonists of H2-histamine receptors or phenobarbital does not change clearance of a temozolomid. Joint reception with valproic acid involves 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;
- lactation 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 expressed renal or liver failure.

Overdose:

When using drug in doses 500, 750, 1000 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 longer 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 fatal outcome was noted.
Treatment. The antidote to the drug Temodal® is not known. Hematologic control and if necessary - symptomatic therapy is recommended.

Storage conditions:

At a temperature from 2 to 30 °C, in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules on 5 mg, 20 mg, 100 mg and 250 mg.
On 5 or 20 capsules in the bottles of dark glass which are screwing up the plastic cap having a waxed insert from soft polyethylene and sealing laying, and supplied with the device preventing opening of a bottle by children. Place the curtailed cotton wool lump in a bottle.
On 1 bottle together with the application instruction in a cardboard pack.
On 1 capsule in a sachet of white color from the aluminum foil covered from within with a layer of polyethylene of low density and outside a layer of polyethyleneterephthalate (PET). On 5 or 20 sachets together with the application instruction in a cardboard pack.