Temozolomide

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Temozolomide: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. For violations of liver function
13. Use in the elderly
14. Drug interactions
15. Analogs
16. Terms and conditions of storage
17. Terms of dispensing from pharmacies
18. Reviews
19. Price in pharmacies

Latin name: Temozolomide

ATX code: L01AX03

Active ingredient: temozolomide (temozolomide)

Manufacturer: VMG Pharmaceuticals, Private Ltd. (India), JIANGSU TASLY DIYI PHARMACEUTICAL (China), Research Institute of Chemical Diversity, JSC (JSC "IIHR"), Pharmstandard-UfaVITA (Russia)

Description and photo update: 2018-21-11

Temozolomide is an antineoplastic drug.

Release form and composition

Temozolomide is available in the form of capsules: gelatinous solid, opaque, the body is white, the color of the cap depends on the dosage of the capsule: No. 3 (5 mg) - green, No. 2 (20 mg) - yellow, No. 1 (100 mg) - pink, No. 0 (140 mg) - blue, No. 0 (180 mg) - orange, No. 0 (250 mg) - white; inside capsules - powder from light pink to white (20 mg, 100 mg, 140 mg, 180 mg and 250 mg each - 5 or 20 pcs. in plastic bottles, in a cardboard box 1 bottle; 5 mg, 20 mg each, 100 mg, 140 mg, 180 mg and 250 mg - 5 pcs. In blisters, in a cardboard box 1 or 4 packs).

1 capsule contains:

active substance: temozolomide - 5 mg, 20 mg, 100 mg, 140 mg, 180 mg or 250 mg;
auxiliary components: lactose, tartaric acid, colloidal silicon dioxide, stearic acid, sodium carboxymethyl starch;
composition of the capsule body and cap: titanium dioxide (E171), gelatin.

In addition, the capsule cap contains:

5 mg capsules: dyes - brilliant blue (E133) and quinoline yellow (E104);
capsules of 20 mg: dyes - sunset yellow (E110) and quinoline yellow (E104);
100 mg capsules: iron dye red oxide (E172);
capsules of 140 mg: dyes - iron oxide black (E172), brilliant blue (E133) and iron oxide yellow (E172);
180 mg capsules: dyes - charming red (E129) and sunset yellow (E110).

Pharmacological properties

Pharmacodynamics

Temozolomide is an alkylating compound that has antitumor activity. Against the background of physiological acidity values, when it enters the systemic circulation, temozolomide is rapidly converted into monomethyltriazenoimidazolecarboxamide (MTIK). The cytotoxic effect of MTIK is primarily due to the alkylation of guanine at the O ⁶ position and additionally at the N ⁷ position, which promotes the triggering of the mechanism of aberrant reduction of the methyl residue. The resulting active compound (MTIK), being incorporated into the molecule, disrupts the structure and synthesis of DNA (deoxyribonucleic acid), the cell cycle.

Pharmacokinetics

After oral administration, temozolomide is absorbed quickly, its maximum concentration (_Cmax) in blood plasma is reached after 0.5-1.5 hours. Simultaneous food intake reduces C _max by 33% and the total concentration (AUC) of temozolomide in blood plasma by 9%.

Temozolomide quickly enters the cerebrospinal fluid, overcoming the blood-brain barrier. The volume of distribution in plasma is independent of dose.

Plasma protein binding - 12-16%.

Regardless of the dose taken, the half-life is 1.8 hours. The clearance of temozolomide is not affected by dose, age, renal function, or tobacco smoking. In case of mild to moderate liver dysfunction, the pharmacokinetic profile of temozolomide does not change.

Excretion of temozolomide occurs mainly through the kidneys. Part of the dose of temozolomide is excreted unchanged (5–10%), the second part in the form of temozolomidic acid, 4-amino-5-imidazole-carboxamide hydrochloride, unidentified polar metabolites.

AUC is higher in children than in adults. The maximum tolerated dose (MTD) for the treatment of children and adults per cycle is 1000 mg per 1 m ² of the patient's body surface.

Indications for use

advanced metastatic malignant melanoma as a first-line therapeutic agent;
newly diagnosed glioblastoma multiforme - as part of a combination treatment with radiation therapy and adjuvant monotherapy;
anaplastic astrocytoma, glioblastoma multiforme (malignant glioma) - with relapse or progression of the disease after standard therapy.

Contraindications

severe myelosuppression;
galactose intolerance, glucose-galactose malabsorption syndrome, lactase deficiency;
period of pregnancy;
breast-feeding;
age up to 3 years (for the treatment of recurrent or progressive malignant glioma);
age up to 18 years (for the treatment of newly diagnosed glioblastoma multiforme, malignant melanoma);
hypersensitivity to dacarbazine;
individual intolerance to the components of the drug.

Caution should be exercised when prescribing Temozolomide for severe renal or hepatic failure, in elderly patients (over 70 years old), in children (over 3 years old) in the treatment of recurrent or progressive glioblastoma multiforme or anaplastic astrocytoma after standard therapy.

Instructions for the use of Temozolomide: method and dosage

Capsules are taken orally, 1 hour before meals, swallowing whole with a glass of water.

The dose of Temozolomide should be prescribed using the smallest possible number of capsules.

Treatment with temozolomide can only be started when the absolute neutrophil count exceeds 1.5 x 10 ⁹ / l and the platelet count is more than 100 x 10 ⁹ / l.

Recommended dosage:

initially identified glioblastoma multiforme in patients older than 18 years: the rate of 75 mg per 1 m ² patient body surface daily in combination with radiotherapy (30 fractions at a total dose of 60 Gray). The duration of the course is 42 days. In case of poor tolerance, taking the capsules can be temporarily discontinued. It is necessary to resume treatment at the same dose. It is not recommended to reduce the dose during the course. During the course (up to the 49th day), the administration of Temozolomide can be resumed only with the following laboratory indicators: the absolute number of neutrophils is 1.5 x 10 ⁹ / l and above, the number of platelets is 100 x 10 ⁹/ l and above. At the same time, the general criterion of toxicity in accordance with the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) toxicity scale is not higher than the first degree (with the exception of alopecia, nausea, vomiting). Taking capsules should be accompanied by weekly blood cell counts. Six additional cycles of adjuvant therapy are prescribed 28 days after completion of the combination therapy. The cycle duration is 28 days, of which Temozolomide is taken for the first 5 days, then a break is taken. The first cycle of therapy is carried out in a daily dose of 150 mg per 1 m ², capsules are taken for 5 days, then there is a break for 23 days. In the second cycle, the dose of temozolomide can be increased to 200 mg per 1 m ²provided that during the first cycle the laboratory results corresponded to the indicators of the combined course with radiation therapy, and the non-hematological toxicity did not exceed grade 2 on the CTC scale (except for nausea, vomiting, alopecia). In the third and subsequent cycles, in the absence of toxicity, apply the dose of the second cycle. A blood test with counting the number of cells is carried out after 21 days of the cycle;
recurrent and progressive glioblastoma multiforme, anaplastic astrocytoma in patients older than 3 years, widespread metastatic malignant melanoma in adults: patients who have not previously undergone chemotherapy - at a dose of 200 mg per 1 m2 ^of body surface once a day for 5 days, followed by a break in admission for 23 days (1 cycle is 28 days); patients who have undergone a course of chemotherapy: the dose of the first cycle is 150 mg per 1 m ² once a day for 5 days, followed by a break of 23 days. In the second cycle, an increase in the daily dose to 200 mg per 1 m ^{2 is} performed if on the first day of the second cycle the absolute number of neutrophils is at least 1.5 x 10 ⁹/ l, platelets - not less than 100 x 10 ⁹ / l.

A complete CBC should be performed 21 days after taking the first dose, then weekly. If during any cycle of treatment the absolute number of neutrophils is less than 1 x 10 ⁹ / l or the number of platelets is less than 50 x 10 ⁹ / l, in the next cycle the dose must be reduced by one step. Temozolomide can be used in the following doses - 100 mg, 150 mg or 200 mg per 1 m ² of body surface. The maximum duration of therapy is up to 2 years. If the disease progresses during treatment, the capsules should be discontinued.

Dose reduction or discontinuation of Temozolomide in combination treatment of newly diagnosed glioblastoma multiforme with radiation therapy is performed taking into account the following toxicity criteria:

the absolute number of neutrophils: a break in admission - when the indicator is more than 0.5 x 10 ⁹ / l, but less than 1.5 x 10 ⁹ / l; discontinuation of intake - less than 0.5 x 10 ⁹ / l;
platelet count: break in admission - if the indicator is more than 10 x 10 ⁹ / l, but less than 100 x 10 ⁹ / l; discontinuation of admission - less than 10 x 10 ⁹ / l;
non-hematological toxicity on the CTC scale (except for nausea, vomiting, alopecia): interruption in admission - grade 2, withdrawal - grade 3 or 4.

With adjuvant therapy, 3 dosage steps are used - 100 mg, 150 mg and 200 mg per 1 m ² of body surface.

Dose reduction or withdrawal of Temozolomide during adjuvant therapy of newly diagnosed glioblastoma multiforme is performed taking into account the following toxicity criteria:

the absolute number of neutrophils is less than 1 x 10 ⁹ / l - decrease in the dose of temozolomide by 1 step;
the number of platelets is less than 50 x 10 ⁹ / l - decrease in the dose of temozolomide by 1 step;
non-hematological toxicity on the CTC scale (except for nausea, vomiting, alopecia): grade 3 - decrease in temozolomide dose by 1 step, grade 4 - discontinuation of temozolomide.

When treating patients over the age of 70 years, an increased risk of developing neutropenia and thrombocytopenia should be considered.

Side effects

In the course of clinical studies, the following incidence of side effects arising in patients during combined treatment with radiation therapy for newly diagnosed glioblastoma multiforme was recorded:

infections: often - oral candidiasis, herpes simplex, wound infection, pharyngitis, other types of infectious pathologies;
from the lymphatic system and blood: often - thrombocytopenia, lymphopenia, leukopenia, neutropenia; infrequently - febrile neutropenia, anemia;
from the endocrine system: infrequently - cushingoid;
from the gastrointestinal tract: very often - nausea, vomiting, constipation; often - taste disturbance, diarrhea, dyspepsia, dysphagia, abdominal pain, stomatitis; infrequently - a change in the color of the tongue;
from the side of metabolism and nutrition: very often - anorexia; often - hyperglycemia, decreased body weight; infrequently - hypokalemia, increased body weight;
mental disorders: often - emotional lability, anxiety, insomnia; infrequently - apathy, hallucinations, behavioral disorders, agitation, depression;
from the organ of hearing and labyrinth disorders: often - hearing loss; infrequently - tinnitus, ear pain, otitis media, hyperacusis;
on the part of the organ of vision: often - blurred vision; infrequently - decreased visual acuity, eye pain, visual impairment, hemianopsia, limitation of visual fields;
from the nervous system: very often - headache; often - drowsiness, dizziness, balance disorder, memory impairment, impaired concentration, confusion, aphasia, neuropathy, convulsions, speech disorder, tremor, paresthesia; infrequently - impaired perception, thirst, extrapyramidal disorders, ataxia, dysphasia, gait disturbance, hyperesthesia, hypesthesia, hemiparesis, neurological disorders, parosmia, status epilepticus;
from the side of the heart: infrequently - palpitations;
from the side of the vessels: often - edema, hemorrhage; infrequently - increased blood pressure (BP), cerebral hemorrhage;
from the respiratory system: often - shortness of breath, cough; infrequently - nasal congestion, upper respiratory tract infections, pneumonia;
from the hepatobiliary system: often - increased activity of alanine aminotransferase (ALT); infrequently - increased activity of liver enzymes, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), aspartate aminotransferase (ACT);
dermatological reactions: very often - rash, alopecia; often - dry skin, pruritus, erythema, dermatitis; infrequently - a violation of pigmentation, photosensitivity reactions, exfoliation;
from the urinary system: often - urinary incontinence, frequent urination;
from the musculoskeletal and connective tissue: often - muscle weakness, arthralgia; infrequently - musculoskeletal pain, back pain, myalgia, myopathy;
from the genitals and mammary gland: infrequently - impotence;
others: very often - fatigue; often - pain syndrome, fever, facial swelling, allergic reaction, radiation injury; infrequently - chills, asthenia, hot flashes to the body, deterioration.

In the course of clinical studies, the following incidence of side effects arising in patients during the adjuvant phase of treatment of newly diagnosed glioblastoma multiforme was recorded:

infections: often - oral candidiasis, other infectious pathologies; infrequently - flu-like syndrome, shingles, herpes simplex;
on the part of the blood and lymphatic system: often - leukopenia, anemia, thrombocytopenia, febrile neutropenia; infrequently - petechiae, lymphopenia;
from the endocrine system: infrequently - cushingoid;
from the side of metabolism and nutrition: very often - anorexia; often - a decrease in body weight; infrequently - weight gain, hyperglycemia;
mental disorders: often - emotional lability, insomnia, anxiety, depression; infrequently - amnesia, hallucinations;
from the nervous system: very often - convulsions, headache; often - drowsiness, confusion, dizziness, aphasia, dysphasia, imbalance, speech disorder, memory impairment, hemiparesis, impaired concentration, neuropathy, neurological disorders, peripheral neuropathy, tremor, paresthesia; infrequently - impaired sensitivity, ataxia, gait disturbance, lack of coordination, hyperesthesia, hemiplegia;
from the gastrointestinal tract: very often - nausea, vomiting, constipation, anorexia; often - dry mouth, diarrhea, taste perversion, stomatitis, dyspepsia, dysphagia; infrequently - bloating, dental disease, hemorrhoids, fecal incontinence, gastroenteritis, unspecified dysfunction of the gastrointestinal tract;
from the hepatobiliary system: often - an increase in ALT activity;
from the organ of hearing and labyrinth disorders: often - ringing in the ears, hearing impairment; infrequently - ear pain, deafness, vertigo;
on the part of the organ of vision: often - limitation of visual fields, diplopia, blurred vision; infrequently - dry eyes, decreased visual acuity, pain in the eye;
from the side of the vessels: often - hemorrhages, edema of the lower extremities, deep vein thrombosis; infrequently - pulmonary embolism, edema (including peripheral edema);
from the respiratory system: often - shortness of breath, cough; infrequently - sinusitis, upper respiratory tract infections, bronchitis, pneumonia;
dermatological reactions: very often - rash, alopecia; often - itching, dry skin; infrequently - increased sweating, pigmentation disorders, erythema;
on the part of musculoskeletal and connective tissue: often - muscle weakness, arthralgia, musculoskeletal pain, myalgia; infrequently - myopathy, back pain;
from the urinary system: often - urinary incontinence; infrequently - dysuria;
from the genitals and mammary gland: infrequently - vaginal bleeding, menorrhagia, amenorrhea, vaginitis, pain in the mammary gland;
others: very often - fatigue; often - pain syndrome, fever, allergic reaction, radiation injury; infrequently - facial edema, asthenia, chills, worsening of the condition.

When combined with radiation therapy and the adjuvant phase of treatment, the following changes in laboratory parameters were noted: myelosuppression (thrombocytopenia, neutropenia), neutropenia, grade 3 and 4 changes in neutrophils and platelets, thrombocytopenia.

In the course of clinical studies, the following incidence of side effects in patients with the treatment of progressive or recurrent malignant glioma in patients over 3 years of age and malignant melanoma in adults was recorded:

on the part of the blood and lymphatic system: very often - lymphopenia, thrombocytopenia, neutropenia; often - anemia, pancytopenia, leukopenia; cases have been reported - thrombocytopenia, neutropenia grade 3 or 4;
infections: rarely - opportunistic infections (including pneumocystis pneumonia);
from the side of metabolism and nutrition: very often - anorexia; often - a decrease in body weight;
from the gastrointestinal tract: very often - constipation, nausea, vomiting; often - taste perversion, abdominal pain, diarrhea, dyspepsia;
from the nervous system: very often - headache; often - dizziness, drowsiness, peripheral neuropathy, paresthesia;
from the respiratory system: often - shortness of breath;
dermatological reactions: often - itching, rash, petechiae, alopecia; very rarely - exanthema, urticaria, erythema multiforme, erythroderma;
others: very often - increased fatigue; often - general malaise, fever, pain syndrome, chills, asthenia; very rarely - reactions of allergic origin (including angioedema, anaphylaxis).

Overdose

Symptoms: hyperthermia, pancytopenia, multiple organ failure (with or without infection) with a fatal outcome.

Treatment: no special antidote; symptomatic therapy, hematological control is prescribed.

special instructions

Requires simultaneous prophylactic antiemetic therapy. It is recommended to take antiemetics before starting the use of the drug and during the entire period of therapy with Temozolomide.

If vomiting develops within the first two hours after taking the capsule, the drug should not be taken again on that day.

Due to the increased risk of Pneumocystis carinii pneumonia, when Temozolomide is combined with radiation therapy, concomitant prophylactic therapy against Pneumocystis carinii is recommended.

In addition, there is a high probability of developing pneumocystis pneumonia while taking temozolomide, especially when combined with glucocorticosteroids.

The development of hepatic failure (including severe forms) is possible, therefore, the analysis of liver function is recommended before and during treatment with temozolomide.

During the period of treatment with Temozolomide and at least 6 months after discontinuation of the drug, men and women of childbearing age should use reliable methods of contraception.

Before starting treatment, men should be informed about the risk of developing irreversible infertility after using the drug and about the possibility of sperm cryopreservation.

If the contents of the capsule accidentally get on the skin or mucous membranes, rinse them thoroughly with water.

Influence on the ability to drive vehicles and complex mechanisms

During the period of treatment, it is necessary to refrain from driving vehicles and complex mechanisms.

Application during pregnancy and lactation

The use of Temozolomide is contraindicated during gestation and breastfeeding.

Pediatric use

The use of the drug in children is contraindicated: under the age of 3 years - for the treatment of recurrent or progressive malignant glioma, under 18 years - for the treatment of newly diagnosed glioblastoma multiforme, malignant melanoma.

Care should be taken to prescribe Temozolomide to children over 3 years of age with relapse or progression of glioblastoma multiforme or anaplastic astrocytoma after standard therapy.

With impaired renal function

According to the instructions, Temozolomide should be used with caution in severe renal failure.

For violations of liver function

Capsules should be used with caution in severe hepatic impairment (class C on the Child-Pugh scale).

Use in the elderly

Caution should be exercised when treating patients over the age of 70, since the risk of developing neutropenia and thrombocytopenia in this category of patients is higher.

Drug interactions

With the simultaneous use of Temozolomide:

ranitidine does not cause a clinically significant change in the degree of drug absorption;
phenobarbital, dexamethasone, phenytoin, ondansetron, carbamazepine, histamine H ₂ receptor blockers, prochlorperazine do not affect the clearance of temozolomide;
valproic acid contributes to a clinically significant decrease in the clearance of the active substance of the drug;
drugs that suppress the bone marrow may increase the risk of myelosuppression.

Analogs

Temozolomide analogs are: Temozolomid-Rus, Temozolomid-Teva, Temozolomid-TL, Tezalom, Temodal, Temomid, Temtsital.

Terms and conditions of storage

Keep out of the reach of children.

Store at temperatures up to 30 ° C, protected from moisture and light.

The shelf life is 3 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Temozolomide

Reviews of Temozolomide are few. In them, patients report relatively mild side effects such as nausea and shortness of breath.

Experts consider the drug to be quite effective in the treatment of anaplastic astrocytoma, and for newly diagnosed glioblastoma multiforme, the drug is the first-line therapy.

The price of Temozolomide in pharmacies

The price of Temozolomide for a package containing 5 capsules at a dose of 140 mg can range from 37,970 rubles.

Maria Kulkes Medical journalist About the author

Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!