Temozolomide - instructions for use, dose, side effects, contraindications

Temozolomide is an imidazotetrazine alkylating compound with antitumor activity. Upon entering the systemic circulation, at physiological pH values, it undergoes a rapid chemical conversion to form the active compound monomethyltriazoimidazolecarboxamide (MTIC). 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. The maximum tolerable dose (MTD) in children and adults is the same and is 1000 mg / m² for one treatment cycle.

Pharmacokinetics:

Temozolomide after ingestion is rapidly absorbed and is also rapidly excreted from the body with urine. Temozolomide quickly penetrates the blood-brain barrier and enters the cerebrospinal fluid. The maximum concentration (C_max) in plasma is achieved on average 0.5-1.5 h (the earliest - in 20 minutes) after taking the drug. The half-life (T1 / 2) of plasma is approximately 1.8 hours. The clearance, the volume of distribution in the plasma and T1 / 2 are dose independent. Temozolomide weakly binds to proteins (12-16%). After oral administration of the drug, excretion with feces for 7 days is 0.8%, indicating that it is completely absorbed. 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 unidentified polar metabolites.

Admission together with food causes a decrease in C_max by 33% and a decrease in the area under the "concentration-time" curve (AUC) on 9%.

The clearance of the drug in plasma does not depend on age, kidney function or smoking. The pharmacokinetic profile of the drug in patients with impaired liver function of a mild to moderate degree is similar to that of individuals with normal liver function.

In children, the indicator AUC higher than in adults.

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;

- severe myelosuppression;

- pregnancy;

- lactation period;

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

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

Carefully:

- older age (over 70 years);

- marked renal or hepatic insufficiency.

Pregnancy and lactation:contraindicated

Dosing and Administration:

A drug Temozolomide taken orally, on an empty stomach, at least 1 hour before meals. 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 conduct in combination with radiotherapy. A drug Temozolomide applied at a dose of 75 mg / m²daily for 42 days at the same time as radiotherapy (30 fractions in a total dose of 60 Gy). Dose reduction is not recommended, however, the drug intake may be interrupted depending on tolerability. Renewal of the drug is possible during the entire 42-day period of combined treatment and up to 49 days, but only if all of the following conditions are met:

-absolute number of neutrophils is not less than 1500 / μl,

-the number of platelets - not less than 100,000 / μl,

-the general toxicity criterion (common toxicity criteria - CTC) not higher than 1 degree (except for alopecia, nausea and vomiting).

During treatment, a blood test should be performed weekly, counting the number of cells.

Recommendations for dose reduction or drug cancellation Temozolomide during the combined phase of treatment are shown in Table 1.

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

Criterion of toxicity	Break in taking the drug Temozolomide *	Termination of admission preparation Temozolomide
Absolute number of neutrophils	> 500 / μL, but <1500 / μl	<500 / μL
Platelet count	> 10000 / μL, but <100,000 / μL	<10000 / μL
CTC non-hematological toxicity (with the exception of alopecia, nausea and vomiting).	2 degree	3 or 4 degree

* Resumption of taking the drug Temozolomide it is possible if all the conditions listed below are met: the absolute number of neutrophils is not less than 1500 / μl, the number of platelets is not less than 100,000 / μl, the general toxicity criterion (CTC) is not higher than 1 degree (except for alopecia, nausea and vomiting).

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

1- th cycle: a drug Temozolomide applied at a dose of 150 mg / m² for 5 days followed by a 23-day interruption in treatment.

2- th cycle: dose of the drug Temozolomide can be increased to 200 mg / m² per day, with the proviso that when the first cycle of treatment severity nonhematologic toxicity (according to the scale CTC toxicity) does not exceed 2 degrees (except for alopecia, nausea and vomiting), and the absolute neutrophil count was at least 1500 / ml, and the number platelets - not less than 100000 / mkl. If in the 2nd cycle the dose of the drug Temozolomide It has not been increased, it should not be increased in subsequent cycles. If the 2nd cycle the dose was 200 mg / m, in the same daily dose of medication is assigned, and in subsequent cycles (no toxicity). In each cycle, taking the drug Temozolomide carry out for 5 consecutive days with a subsequent 23-day break. Recommendations for dose reduction in the adjuvant phase of treatmentI am given in Tables 2 and 3.

On day 22 of treatment (21 days after taking the first dose of the drug Temozolomide) it is necessary to conduct a blood test with counting the number of cells.

Abolition or reduction of the dose of the drug Temozolomide should be carried out, guided by Table 3.

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

Step	Dose (mg / m / day)	Note
-1	100	Dose reduction taking into account previous toxicity (see Table 3)
0	150	Dose during the 1st cycle
1	200 .	The dose during 2-6 cycles (in the absence of toxicity)

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

Criterion of toxicity	Reduce the dose of the drug Temozolomide for 1 step (see Table 2)	Termination of admission preparation Temozolomide
Absolute number of neutrophils	<1000 / μL	*
Platelet count	<50000 / μL	*
CTC non-hematological toxicity (with the exception of alopecia, nausea and vomiting)	3 degree	4 degree *

* A drug Temozolomide should be abolished if a dose reduction of <100 mg / m², and also in case of recurrence of non-hematological toxicity of the 3rd degree (except for alopecia, nausea and vomiting) after dose reduction.

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

Patients who had not previously undergone chemotherapy, the drug Temozolomide is prescribed in a dose of 200 mg / m² 1 time per day for 5 consecutive days, followed by a break in taking the drug for 23 days (the total duration of one treatment cycle is 28 days). For patients who had previously undergone chemotherapy, the initial dose is 150 mg / m² 1 per day; in the second cycle, the dose can be increased to 200 Mg / m² per day for 5 days, provided that in the 1 st day of the next cycle an absolute neutrophil count is not less than 1500 / L, and platelet count of at least 100,000 / L.

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

Start drug treatment Temozolomide it is possible only with an absolute number of neutrophils> 1500 / μL and platelets> 100,000 / μL. A complete clinical blood test should be performed on the 22nd day (the 21st day after taking the first dose), but no later than 48 hours after that day; then - weekly until the absolute number of neutrophils is above 1500 / μL, and the number of platelets does not exceed 100,000 / μl. When an absolute neutrophil count of less than 1000 / l or platelets less than 50,000 / microliter during any cycle of treatment, a dose in the next frame should be lowered by one stage. 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 are signs of progression of the disease, the drug treatment Temozolomide should be discontinued.

Side effects:

Glioblastoma multiforme (adult patients) was first detected.

The table below (Table 4) shows the side effects noted in the treatment of patients with newly diagnosed multiform glioblastoma during the combined and adjuvant phases of treatment during clinical trials of temozolamide.

The frequency distribution of side effects was made in accordance with the following gradation: very often> 10%, often> 1% and <10%, infrequently> 0.1% and <1%.

Table 4

System-Organ Class	Frequency reactions	The nature of the reaction
System-Organ Class	Frequency reactions	Combined phase of treatment (with radiotherapy) n = 288	adjuvant treatment phase n = 224
Infections and invasions	often	candidiasis of the oral mucosa, herpes simplex, pharyngitis, wound infection, other infection	Candidiasis of the oral mucosa, another infection
Infections and invasions	infrequently		herpes simplex, herpes zoster, influenza-like syndrome
Blood and lymphatic system	often	leukopenia, lymphopenia, neutropenia, thrombocytopenia	anemia, febrile neutropenia, leukopenia, thrombocytopenia
Blood and lymphatic system	infrequently	anemia, febrile neutropenia	lymphopenia, petechiae.
Cordially vascular system	often	edema, incl. lower limbs, hemorrhage	edema of the lower extremities, hemorrhage, deep vein thrombosis

	infrequently	heart beat, increased blood pressure, cerebral hemorrhage	edema, In TCH; peripheral, embolism of the pulmonary artery

Respiratory system	often	cough, dyspnea	cough, dyspnea
Respiratory system	infrequently	pneumonia, upper respiratory tract infection, nasal congestion	pneumonia, upper respiratory tract infection, sinusitis, bronchitis
Endocrine system	infrequently	Isenko-Kuschchyna syndrome	Isenko-Cushing syndrome
Skin, and subcutaneous fat, breast	highly often	alopecia, rash	alopecia, rash
	often	dermatitis, dry skin, erythema, skin itching, face swelling	dryness, itching of the skin
	infrequently	reactions photosensitivity, pigmentation disorder, exfoliation	erythema, impaired pigmentation, excessive sweating, pain in the chest, swelling of the face
Nervous system	highly often	headache	headache, convulsions
Nervous system	often	anxiety, emotional lability, insomnia, dizziness, balance disorder, impaired concentration, confusion and depression, convulsions, memory impairment, neuropathy, paresthesia, drowsiness, speech disorder, tremor	anxiety, depression, emotional lability, insomnia, dizziness, imbalance, violation of concentration of attention, confusion, speech disorder, hemiparesis. worsening, neurological. disorders (unspecified), neuropathy, paresthesia, drowsiness, tremor

	infrequently	apathy, behavioral disorders, depression, hallucinations, impairment	hallucinations, ataxia, amnesia, gait disturbance, hemiplegia,
		perception, extrapyramidal disorders, dysphasia, ataxia, gait disorders, hemiparesis, hyperesthesia, hypoesthesia, neurological disorders (unspecified), epileptic status, paresthesia, parosmia, thirst	hyperesthesia, sensitivity disorders / sensory disorders
Oporno motor staff	often	arthralgia, muscle weakness	arthralgia,. musculoskeletal pain, myalgia, muscle weakness
Oporno motor staff	infrequently	back pain, musculoskeletal pain, myalgia, myopathy	back pain, myopathy
Body of sight	often	blurred vision	blurred vision, diplopia, visual field limitation
Body of sight	infrequently	pain in the eye, hemianopsia, visual impairment, decreased visual acuity, limitation of visual fields	pain in the eye, dry eyes, decreased visual acuity
Genitourinary system	often	frequent urination, urinary incontinence	urinary incontinence
Genitourinary system	infrequently	impotence	dysuria, amenorrhea, menorrhagia, vaginal bleeding, vaginitis
The organ of hearing and balance	often	hearing impairment	hearing impairment, ringing in the ears
The organ of hearing and balance	infrequently	pain in the ear, hyperacia, ringing in the ears, otitis media	deafness, earache, dizziness
Digestive system	highly often	anorexia, constipation, nausea, vomiting	anorexia, constipation, nausea, vomiting
Digestive system	often	increased activity of alanine aminotransferase, abdominal pain, diarrhea, dyspepsia, dysphagia, stomatitis, impaired taste	increased activity of alanine aminotransferase, diarrhea, dyspepsia, dysphagia, stomatitis, dry mouth, impaired taste

	infrequently	increasing the activity of alkaline phosphatase, changing the color of the tongue,	bloating, fecal incontinence, hemorrhoids, gastroenteritis, diseases
		increased activity of gamma- glutamyltransferase,. aspartate aminotransferase, liver enzymes	teeth
Organism as a whole	highly often	Fatigue	Fatigue
	often	fever, pain syndrome, radiation damage, allergic reaction, hyperglycemia, weight loss	fever, pain syndrome, radiation damage, allergic reaction, weight loss
	infrequently	hypokalemia. "hot flashes", asthenia, worsening of the condition, chills, weight gain	hyperglycemia, weight gain, asthenia, worsening of the condition, chills

Laboratory indicators: Myelosuppression (neutropenia and thrombocytopenia) is a dose-limiting side effect. Among the patients of both groups (with combination therapy and adjuvant) toxicity of grade 3 and 4 by neutrophils, including neutropenia, observed in 8% of cases, and from the platelets, including thrombocytopenia, - in 14% of cases.

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

The following adverse events have been attributed to the occurrence frequency according to the following gradation: very often (> 10% of cases), often (> 1% and <10%), rare (> 0.1% and.<1%), rarely (> 0.01% and <0.1%) and very rarely (<0.01%).

On the part of the hematopoiesis system: very often - thrombocytopenia, neutropenia, lymphopenia; infrequently - pancytopenia, leukopenia, anemia. Oppression of bone marrow hematopoiesis developed usually during the first few cycles of treatment, with a maximum between 21 and 28 days; recovery occurred, usually within 1-2 weeks. Symptoms of cumulative myelosuppression. not noted.

Co side of the digestive system: very often - nausea, vomiting, constipation, anorexia; often - diarrhea, abdominal pain, indigestion, taste perversion. The most frequent were nausea and vomiting. In most cases, these events were 1-2 (from mild to moderate) severity and were treated independently or controlled with standard antiemetic therapy. The frequency of severe nausea and vomiting is 4%.

From the nervous system: very often - headache; often - drowsiness, dizziness, paresthesia, asthenia.

From the skin and subcutaneous adipose tissue: often - rash, itching, alopecia, petechiae; very rarely - hives, exanthema, erythroderma, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

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

Other: very often - increasedfluidity; often - weight loss, shortness of breath, fever, chills, general malaise; infrequently - hypokalemia, increased alkaline phosphatase activity, weight gain; rarely opportunistic infections, including pneumonia caused by Pneumocystis carinii; very rarely observed the development of myelodysplastic syndrome (MDS) and secondary malignant processes, including leukemia, and also noted angioedema, the development of prolonged pancytopenia with a risk of developing aplastic anemia and irreversible infertility.

Overdose:

When using the drug in doses of 500, 750, 1000 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 was more pronounced with higher doses.

A case of overdose (taking a dose of 2000 mg per day for 5 days) was described, which resulted in pancytopenia, pyrexia, multiple organ failure and death. When taking the drug for more than 5 days (up to 64 days), among other symptoms of an overdose, hematopoietic oppression was observed, complicated or uncomplicated by the infection, in some cases prolonged and. expressed, with a fatal outcome.

Treatment: the antidote of 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.

Joint reception with dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, blockers of H2-histamine receptors or phenobarbital does not change the clearance of temozolomide.

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

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

The use of temozolomide together with other drugs that inhibit bone marrow hematopoiesis may increase the likelihood of myelosuppression.

Special instructions:

Prophylactic antiemetic therapy is recommended before the start of combined treatment (with radiotherapy) and urgentlyIt is recommended during adjuvant therapy for the newly diagnosed multiform glioblastoma. If the background of drug treatment Temozolomide there is nausea or vomiting, then in the following receptions it is recommended to carry out anti-viral therapy. Antiemetic drugs can be taken both before and after taking the drug Temozolomide. Even if vomiting developed within the first 2 hours after taking the drug Temozolomide, repeat the reception of the drug on the same day should not be.

Due to the increased risk of developing pneumonia caused by Pneumocystis carinii, in patients receiving combined treatment with radiotherapy for 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 treatment with temozolomide, nevertheless, increased alertness to the possible development of PCP should be shown for all patients receiving the drug Temozolomide, especially in combination with glucocorticosteroids. The pharmacokinetic parameters of temozolomide in persons with normal liver function and in patients with impaired liver function are of moderate or moderate severity comparable.Data on the use of temozolomide in patients with severe impaired liver function (class C according to the Child-Pugh classification) or renal dysfunction is not available. Based on the data on the study of the pharmacokinetic properties of temozolomide, it seems unlikely that patients even with a marked impairment of liver or kidney function may need to reduce the dose of the drug. However, when the drug is used Temozolomide caution should be exercised in such patients.

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

Because of the risk of irreversible infertility, against the background of drug treatment Temozolomide, male patients before the start of treatment, if necessary, it is recommended to discuss the possibility of cryopreservation of sperm.

If the contents of the capsule (powder) get on the skin or mucous membranes, they should be washed with a large amount of water.

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

Form release / dosage:

Capsules of 20 mg, 100 mg and 250 mg.

5 capsules in a plastic bottle. 1 bottle with instructions for use in a cardboard box.

Packaging:(5) - plastic bottles (1) - packs cardboard

Storage conditions:Store at a temperature not higher than 25 ° C out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-008854/10

Date of registration:30.08.2010

The owner of the registration certificate:PSI-PHARMA, LLC PSI-PHARMA, LLC Russia

Manufacturer: & nbsp

PRECISE BIOPHARMA, (Pvt.) Ltd India

Representation: & nbspPSI-PHARMA, LLCPSI-PHARMA, LLC

Information update date: & nbsp16.09.2015

Illustrated instructions

Instructions

Temozolomide (Temozolomide)