Gliozomid

INSTRUCTION for medical use of the medicinal product GLIOZOMID (GLIOZOMID)

Composition:

Active substance: temozolomide;

1 capsule contains 20 mg, 100 mg, 180 mg, or 250 mg of temozolomide;

Excipients: anhydrous lactose, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), tartaric acid, stearic acid;

Capsule shell composition for 20 mg: gelatin, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172);

Capsule shell composition for 100 mg: gelatin, titanium dioxide (E 171), iron oxide red (E 172), indigocarmine FD&C Blue No. 2 (E 132);

Capsule shell composition for 180 mg: gelatin, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172), iron oxide black (E 172);

Capsule shell composition for 250 mg: gelatin, titanium dioxide (E 171).

Pharmaceutical form. Capsules.

Main physicochemical properties:

20 mg strength: hard gelatin capsules with orange cap and white body, marked with "20";

100 mg strength: hard gelatin capsules with purple cap and white body, marked with "100";

180 mg strength: hard gelatin capsules with brown cap and white body, marked with "180";

250 mg strength: hard gelatin capsules with white cap and white body, marked with "250".

Pharmacotherapeutic group.

Antineoplastic agents. Alkylating agents. ATC code L01A X03.

Pharmacological Properties

Pharmacodynamics

Temozolomide is a triazene that undergoes rapid chemical conversion at physiological pH to the active metabolite monomethyl triazenoimidazole carboxamide (MTIC). Cytotoxicity of MTIC is believed to be primarily due to alkylation at the O6 position of guanine, with additional alkylation occurring at the N7 position. The resulting cytotoxic lesions are thought to involve mechanisms of aberrant repair of the methyl group.

Pharmacokinetics

Temozolomide undergoes spontaneous hydrolysis at physiological pH levels, primarily forming the active species 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC then spontaneously hydrolyzes to 5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and methylhydrazine, which is likely the active alkylating species. The cytotoxicity of MTIC is believed to be primarily due to DNA alkylation, mainly at the O6 and N7 positions of guanine. Relative to the area under the concentration-time curve (AUC) of temozolomide, exposure to MTIC and AIC is approximately 2.4% and 23%, respectively. In vivo, the half-life (T_1/2) of MTIC is similar to that of temozolomide—about 1.8 hours.

Absorption. After oral administration in adult patients, temozolomide is rapidly absorbed, with peak concentrations achieved within 20 minutes after dose administration (median time: 0.5 to 1.5 hours). Following oral administration of ¹⁴C-labeled temozolomide, the mean fecal excretion of ¹⁴C over 7 days after dosing was 0.8%, indicating complete absorption.

Distribution. Temozolomide exhibits low plasma protein binding (10–20%), so interactions with highly protein-bound substances are not expected.

Studies using positron emission tomography (PET) in humans, as well as preclinical data, indicate that temozolomide rapidly crosses the blood-brain barrier and enters cerebrospinal fluid (CSF). In one patient, the presence of the drug in CSF was confirmed; CSF exposure, based on the AUC of temozolomide, was approximately 30% of plasma exposure.

Elimination. The plasma half-life (T_1/2) of temozolomide is approximately 1.8 hours. The primary route of ¹⁴C elimination is renal. After oral administration, approximately 5–10% of the dose is excreted unchanged in urine within 24 hours, with the remainder eliminated as temozolomide acid, 5-aminoimidazole-4-carboxamide, or unidentified polar metabolites.

Plasma concentrations increase in a dose-dependent manner. Plasma clearance of temozolomide, volume of distribution, and T_1/2 are independent of dose.

Special patient populations. Pharmacokinetic analysis of temozolomide has shown that its clearance is independent of age, renal function, or nicotine dependence. In a separate pharmacokinetic study, plasma pharmacokinetic profiles of the drug in patients with mild or moderate hepatic impairment were similar to those in patients with normal liver function.

In pediatric patients, AUC is higher than in adults. However, the maximum tolerated dose (MTD) for both pediatric and adult patients is the same—1000 mg/m² per treatment cycle.

Clinical characteristics.

Indications.

Treatment:

• of adult patients with newly diagnosed multiforme glioblastoma, concomitantly with radiotherapy, followed by monotherapy;
• of pediatric patients aged 3 years and older, and adult patients with malignant glioma in the form of multiforme glioblastoma or anaplastic astrocytoma, at the time of recurrence or disease progression after standard therapy.

Contraindications.

Hypersensitivity to the components of the medicinal product or to dacarbazine (DTIC). Severe myelosuppression.

Safety precautions.

Capsules must not be opened. If a capsule is damaged, contact with its contents must be avoided, particularly with skin or mucous membranes. In case of contact of Gliozomid with skin or mucous membranes, the affected area should be immediately and thoroughly washed with soap and water.

Patients should store the capsules in a place inaccessible to children, preferably in a locked cabinet. Accidental ingestion may be fatal for a child.

Any unused medicinal product or waste material must be disposed of in accordance with local regulations.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adult patients.

Concomitant administration of Gliozomid and ranitidine did not result in changes in the extent of temozolomide absorption or in exposure to its active metabolite – MTIC.

Administration of Gliozomid with food led to a 33% reduction in maximum concentration (Cmax) and a 9% reduction in AUC. Since a change in Cmax cannot be ruled out as being clinically significant, Gliozomid should not be taken during meals.

Concomitant use of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine H2-receptor antagonists, or phenobarbital does not alter the clearance of the medicinal product. Concomitant use of valproic acid caused a mild but statistically significant decrease in temozolomide clearance.

Studies assessing the effect of temozolomide on the metabolism or elimination of other drugs have not been conducted. However, since temozolomide is not metabolized in the liver and exhibits low protein binding, its influence on the pharmacokinetics of other medicinal products is unlikely.

Concomitant use of Gliozomid with other substances that suppress bone marrow function may increase the risk of developing myelosuppression.

Special precautions for use.

Opportunistic infections and reactivation of infections. Opportunistic infections (such as Pneumocystis jirovecii-induced pneumonia) and reactivation of infections such as hepatitis B and cytomegalovirus have been observed during treatment with temozolomide (see section "Adverse reactions").

Herpetic meningoencephalitis. Post-marketing cases of herpetic meningoencephalitis (including fatal cases) have been reported in patients receiving temozolomide in combination with radiotherapy, including when administered concomitantly with steroids.

Pneumocystis jirovecii pneumonia. Patients receiving Gliozomid in combination with radiotherapy according to an extended 42-day treatment schedule have a particular risk of developing Pneumocystis jirovecii pneumonia. Therefore, prophylaxis against Pneumocystis jirovecii pneumonia should be administered to all patients receiving concomitant temozolomide and radiotherapy according to the 42-day schedule (up to a maximum of 49 days), regardless of lymphocyte count. If lymphopenia occurs, prophylaxis should be continued until lymphopenia resolves to grade ≤ 1.

The incidence of Pneumocystis jirovecii pneumonia may be higher when temozolomide is administered according to a prolonged treatment schedule. All patients receiving temozolomide, especially those taking corticosteroids, should be regularly monitored for the development of Pneumocystis jirovecii pneumonia, regardless of the treatment regimen. Fatal cases due to respiratory failure have been reported in patients receiving temozolomide, particularly in combination with dexamethasone or other steroids.

Hepatitis B virus. Reactivation of hepatitis B virus infection has been reported, which in some cases led to fatal outcomes. Patients with positive serological markers for hepatitis B (including those with active disease) should receive consultation from a liver disease specialist prior to initiation of treatment. Patients should be monitored during treatment and appropriate decisions regarding antiviral therapy should be made accordingly.

Hepatotoxicity. Liver injury, including fatal hepatic failure, has been reported in patients receiving temozolomide. Baseline liver function tests should be performed before starting treatment. The physician must assess the benefit-risk ratio of treatment prior to initiating temozolomide, including the potential risk of fatal liver failure. Patients receiving the 42-day treatment cycle should have repeat liver function tests performed within the cycle. Liver function should be monitored after each treatment cycle in all patients. In patients with significant abnormalities in liver function, the physician should reassess the benefit-risk balance before continuing treatment. Hepatotoxic effects may occur several weeks (or later) after the last dose of temozolomide.

Malignant neoplasms. Very rare cases of myelodysplastic syndrome and secondary malignant neoplasms, including myeloid leukemia, have also been reported.

Antiemetic therapy. Nausea and vomiting are very common with Gliozomid administration; therefore, antiemetic therapy may be administered before or after drug administration.

Adult patients with newly diagnosed multiform glioblastoma. Prophylaxis against vomiting is recommended prior to the first dose during the combined treatment phase and is strongly recommended throughout the monotherapy phase.

Patients with recurrent or progressive malignant glioma. Antiemetic therapy may be necessary for patients who experienced severe vomiting (grade III or IV) in previous treatment cycles.

Laboratory parameters. Myelosuppression, including prolonged pancytopenia, may occur in patients receiving Gliozomid, which can lead to aplastic anemia, sometimes with fatal outcome. Assessment of some cases was complicated by concomitant use of drugs such as carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, which were used to treat aplastic anemia.

Prior to initiating Gliozomid treatment, the following laboratory parameters should meet the requirements: absolute neutrophil count ≥ 1.5 × 10⁹/L and platelet count ≥ 100 × 10⁹/L. A complete blood count with differential should be performed on day 22 (21 days after the first dose) or within 48 hours of that day, and then weekly thereafter until the absolute neutrophil count exceeds 1.5 × 10⁹/L and platelet count exceeds 100 × 10⁹/L. If the absolute neutrophil count is < 1.0 × 10⁹/L or platelet count is < 50 × 10⁹/L during any cycle, the dose in the next cycle should be reduced by one level. Available dose levels are 100 mg/m², 150 mg/m², and 200 mg/m² per day. The lowest recommended dose is 100 mg/m² per day.

Children. There is no clinical experience with the use of Gliozomid in children under 3 years of age. Experience in children aged 3 years and older is very limited.

Elderly patients. Elderly patients (over 70 years of age) have a higher risk of developing neutropenia and thrombocytopenia compared to younger patients. Therefore, Gliozomid should be used with caution in elderly patients.

Female patients. Women of reproductive potential must use effective contraception to prevent pregnancy during treatment with Gliozomid and for at least 6 months after completion of treatment.

Male patients. Gliozomid may exert genotoxic effects. Men receiving temozolomide therapy should not plan conception during treatment and for at least 6 months after the last dose. Prior to starting treatment, patients should be advised to consult on sperm cryopreservation due to the potential for irreversible infertility caused by Gliozomid therapy.

Lactose. Since Gliozomid contains lactose, it should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Sodium. This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Capsules should not be opened. If a capsule is damaged, contact of its contents with skin or mucous membranes should be avoided. If Gliozomid comes into contact with skin or mucous membranes, the affected area should be immediately and thoroughly washed with soap and water.

Patients should store capsules out of the reach of children, preferably in a locked cabinet. Accidental ingestion may be fatal in children.

Any unused medicine or waste material should be disposed of in accordance with local requirements.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no data on the use of the drug in pregnant women. Gliozomid should not be administered to pregnant women. If it is necessary to use the drug during pregnancy, the woman should be informed of the potential risk to the fetus.

Women of reproductive potential should be advised to use effective contraception to prevent pregnancy during treatment with Gliozomid and for at least 6 months after completion of treatment.

Lactation.

It is unknown whether temozolomide is excreted in human breast milk; therefore, breastfeeding should be discontinued during treatment with Gliozomid.

Male fertility. Gliozomid may exert genotoxic effects. Therefore, men receiving therapy with this drug should use effective contraception and are advised not to plan conception for at least 3 months after the last dose. Advice on sperm cryopreservation should be sought before starting treatment due to the potential for irreversible infertility resulting from Gliozomid therapy.

Ability to drive and use machines.

The ability to drive or operate machinery may be impaired during treatment with temozolomide due to possible development of fatigue and somnolence.

Method of administration and dosage.

Gliozomid should be prescribed only by a physician experienced in oncological therapy for brain tumors.

Anti-emetic therapy may be administered concomitantly.

Gliozomid capsules should be taken on an empty stomach.

The capsule should be swallowed whole with a glass of water. Capsules must not be opened or chewed.

If vomiting occurs after taking the medication, a second dose should not be taken on the same day.

Adult patients with newly diagnosed multiform glioblastoma

Gliozomid is used in combination with focal radiotherapy (combined phase), followed by 6 cycles of temozolomide monotherapy (monotherapy phase).

Combined phase

Gliozomid is administered orally at a dose of 75 mg/m² daily for 42 days concurrently with focal radiotherapy (60 Gy in 30 fractions). Dose reduction is not recommended; decisions regarding interruption or discontinuation of Gliozomid should be made weekly based on hematological and non-hematological toxicity criteria. Treatment with the specified dose may be extended from 42 to 49 days during combined therapy if all the following conditions are met:

• absolute neutrophil count ≥ 1.5×10⁹/L;
• platelet count ≥ 100×10⁹/L;
• Common Toxicity Criteria (CTC): non-hematological toxicity ≤ Grade 1 (excluding alopecia, nausea, and vomiting).

A complete blood count should be performed weekly during treatment. Administration of Gliozomid should be interrupted or permanently discontinued during the combined phase according to hematological and non-hematological toxicity criteria as specified in Table 1.

Table 1

Interruption or permanent discontinuation of Gliozomid during combined therapy (temozolomide + radiotherapy)

Toxicity	Temporary discontinuation of the drug	Permanent discontinuation of the drug
Absolute neutrophil count	³ 0.5 and < 1.5×109/l	< 0.5×109/l
Platelet count	³ 10 and < 100×109/l	< 10×109/l
CTC non-hematological toxicity (excluding alopecia, nausea and vomiting)	CTC grade 2	CTC grade 3 or 4

a The combined treatment phase (Gliozomid + focal radiotherapy) may be continued if all the following conditions are met: absolute neutrophil count ≥ 1.5×10⁹/L; platelet count ≥ 100×10⁹/L; EORTC: non-hematological toxicity ≤ Grade 1 (excluding alopecia, nausea, and vomiting).

Monotherapy Phase

Four weeks after completion of the combined treatment phase (temozolomide + radiotherapy), Gliozomid is administered for 6 cycles of monotherapy. The dose during cycle 1 (monotherapy) is 150 mg/m² once daily for 5 consecutive days, followed by a 23-day treatment-free period. The dose of Gliozomid in cycle 2 is increased to 200 mg/m² per day if non-hematological EORTC toxicity during cycle 1 was ≤ Grade 2 (excluding alopecia, nausea, and vomiting), absolute neutrophil count ≥ 1.5×10⁹/L, and platelet count ≥ 100×10⁹/L. If the dose was not increased in cycle 2, it should not be increased in subsequent cycles. If the dose was escalated, the drug is administered at 200 mg/m² per day on days 1–5 of each subsequent cycle, unless toxicity develops. Dose reduction or discontinuation of Gliozomid during adjuvant therapy should be performed according to Tables 2 and 3.

A complete blood count should be performed on day 22 (21 days after the first dose). Dose reduction or discontinuation of the drug should be performed according to Table 3.

Table 2

Dose levels of Gliozomid for monotherapy

Level of dose	Dose (mg/m2/day)	Note
1	100	Dose reduction due to prior toxicity
0	150	Dose during cycle 1
1	200	Dose during cycles 2-6 in the absence of toxicity

Table 3

Dose reduction or discontinuation of Gleozomide during monotherapy

Toxicity	Reduce temozolomide dose by 1 levela	Discontinue temozolomide
Absolute neutrophil count	< 1.0×109/l	see reference b
Platelet count	< 50×109/l	see reference b
CTC non-hematological toxicity (excluding alopecia, nausea and vomiting)	CTC grade 3	CTC grade 4

a The dose levels of Gleozomid are indicated in Table 2.

b Gleozomid should be discontinued if dose level –1 (100 mg/m²) continues to be associated with unacceptable toxicity or if grade 3 non-hematological toxicity (excluding alopecia, nausea, and vomiting) recurs after dose reduction.

Recurrent or progressive malignant glioma in adults and children aged 3 years and older

The treatment cycle is 28 days. For patients who have not previously received chemotherapy, Gleozomid is administered once daily at a dose of 200 mg/m² for 5 consecutive days, followed by a 23-day treatment-free interval. For patients who have previously received chemotherapy, the initial dose is 150 mg/m² once daily for 5 days; in cycle 2, the dose may be increased to 200 mg/m² once daily for 5 days, provided there is no hematological toxicity.

Special patient groups

Patients with hepatic or renal impairment

The pharmacokinetics of temozolomide are comparable in patients with normal hepatic function and those with mild to moderate hepatic impairment. There are no data on the use of temozolomide in patients with severe hepatic impairment (Child-Pugh class C) or in patients with renal impairment. Based on the pharmacokinetic properties of temozolomide, dose adjustment is unlikely to be necessary in patients with severe hepatic impairment or in those with any degree of renal impairment. However, temozolomide should be used with caution in such patients.

Elderly patients

Pharmacokinetic data from studies involving patients aged 19 to 78 years indicate that temozolomide clearance is not age-dependent. However, elderly patients (over 70 years of age) are at increased risk of developing neutropenia and thrombocytopenia.

Children

Gleozomid is indicated for children aged 3 years and older only for the treatment of recurrent or progressive malignant glioma. Experience with the use of the drug in this pediatric population is very limited. The safety and efficacy of temozolomide in children under 3 years of age have not been established. No data are available.

Overdose

Clinically evaluated doses of 500, 750, 1000, and 1250 mg/m² (total dose over a 5-day cycle) have been reported. Dose-dependent hematological toxicity occurred at all doses, but as expected, was more pronounced at higher doses. One patient received an overdose of 10,000 mg (total dose in one cycle over 5 days), resulting in pancytopenia, pyrexia, multi-organ failure, and fatal outcome. Cases have been reported of patients receiving recommended doses (150–200 mg/m²) for longer than 5 days (up to 64 days), leading to bone marrow suppression (with or without infection), in some cases severe and prolonged, with fatal outcomes.

In the event of overdose, hematological monitoring is recommended and supportive treatment should be administered as needed.

Adverse reactions

Summary of safety profile

In patients receiving Gliozomid during clinical studies, the most commonly reported adverse reactions were nausea, vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematological adverse reactions were reported with "frequent" incidence; the frequency of grade 3–4 laboratory abnormalities is presented after Table 4.

In patients with recurrent or progressive glioma, nausea (43%) and vomiting (36%) were generally of grade 1 or 2 (0–5 episodes within 24 hours) and resolved spontaneously or were easily controlled with standard antiemetic therapy. The incidence of severe nausea and vomiting was 4%.

The list of adverse reactions is provided in Table 4.

Adverse reactions reported during clinical studies and post-marketing use of Gliozomid are listed in Table 4. These adverse reactions are classified by system organ class and frequency. Frequency categories are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Table 4

Adverse reactions in patients receiving Gliozomid therapy

Infections and infestations
Common	infection, herpes simplex, pharyngitis1, oral candidiasis
Uncommon	opportunistic infections (including Pneumocystis carinii-induced pneumonia), sepsis§, herpes meningoencephalitis§, cytomegalovirus infection, cytomegalovirus reactivation, hepatitis B virus§, herpes simplex, reactivation of infections, wound infection, gastroenteritis2
Malignant and benign neoplasms, unspecified
Uncommon	myelodysplastic syndrome (MDS), secondary malignant neoplasm including myeloid leukemia
Blood and lymphatic system disorders
Common	febrile neutropenia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, anemia
Uncommon	prolonged pancytopenia, aplastic anemia§, pancytopenia, petechiae
Immune system disorders
Common	allergic reactions
Uncommon	anaphylaxis
Endocrine disorders
Common	Cushingoid3
Uncommon	non-insulin-dependent diabetes
Metabolism and nutrition disorders
Very common	anorexia
Common	hyperglycemia
Uncommon	hypokalemia, increased alkaline phosphatase levels
Psychiatric disorders
Common	agitation, amnesia, depression, restlessness, disorientation, insomnia
Uncommon	behavioral disorders, emotional lability, hallucinations, apathy
Nervous system disorders
Very common	seizures, hemiparesis, aphasia/dysphasia, headache
Common	ataxia, loss of balance, cognitive disorders, impaired concentration, decreased level of consciousness, dizziness, hypoesthesia, memory impairment, neurological disorders, neuropathy4, paresthesia, somnolence, speech disorder, taste distortion, tremor
Uncommon	epileptic status, hemiplegia, extrapyramidal disorders, parosmia, gait disturbance, hyperesthesia, sensory disturbances, coordination disorder
Eye disorders
Common	hemianopia, blurred vision, visual disturbance5, visual field defect, diplopia, eye pain
Uncommon	reduced visual acuity, dry eyes
Ear and labyrinth disorders
Common	deafness6, vertigo, tinnitus, ear pain7
Uncommon	hearing impairment, hyperacusis, otitis media
Cardiac disorders
Uncommon	palpitations
Vascular disorders
Common	hemorrhage, pulmonary embolism, deep vein thrombosis, hypertension
Uncommon	intracerebral hemorrhage, blood rush, hot flushes
Respiratory, thoracic and mediastinal disorders
Common	pneumonia, dyspnea, sinusitis, bronchitis, cough, upper respiratory tract infection
Uncommon	respiratory failure§, interstitial pneumonitis/pneumonitis, pulmonary fibrosis, nasal congestion
Gastrointestinal disorders
Very common	diarrhea, constipation, nausea, vomiting
Common	stomatitis, abdominal pain8, dyspepsia, dysphagia
Uncommon	abdominal distension, fecal incontinence, gastrointestinal disorders, hemorrhoids, dry mouth
Hepatobiliary disorders
Uncommon	hepatic failure§, liver damage, hepatitis, cholestasis, hyperbilirubinemia
Skin and subcutaneous tissue disorders
Very common	rash, alopecia
Common	erythema, dry skin, pruritus
Uncommon	toxic epidermal necrolysis, Stevens-Johnson syndrome, angioneurotic edema, erythema multiforme, erythroderma, skin exfoliation, photosensitivity reactions, urticaria, exanthema, dermatitis, increased sweating, pigmentation disorders
Unknown	drug reaction with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders
Common	myopathy, muscle weakness, arthralgia, back pain, musculoskeletal pain, myalgia
Renal and urinary disorders
Common	frequency of urination, urinary incontinence
Uncommon	dysuria
Reproductive system and breast disorders
Uncommon	vaginal bleeding, menorrhagia, amenorrhea, vaginitis, breast pain, impotence
General disorders and administration site conditions
Very common	fatigue
Common	fever, influenza-like symptoms, asthenia, malaise, pain, swelling, peripheral edema9
Uncommon	worsening of general condition, tremor, facial edema, tongue discoloration, thirst, dental disorders
Laboratory findings
Common	elevated liver enzymes10, decreased body weight, increased body weight
Uncommon	elevated gamma-glutamyltransferase (GGT) levels
Injury, poisoning and procedural complications
Common	radiation injury11

1 Including pharyngitis, nasopharyngeal pharyngitis, streptococcal pharyngitis.

2 Including gastroenteritis, viral gastroenteritis.

3 Including Cushingoid, Cushing's syndrome.

4 Including neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral motor neuropathy.

5 Including visual impairment, eye disorders.

6 Including deafness, bilateral deafness, sensorineural deafness, unilateral deafness.

7 Including ear pain, ear discomfort.

8 Including abdominal pain, lower abdominal pain, upper abdominal pain, abdominal discomfort.

9 Including peripheral edema, peripheral swelling.

10 Including increased liver function test results: increased alanine aminotransferase levels, increased aspartate aminotransferase levels, increased liver enzymes.

11 Including radiation injury, radiation skin injury.

§ Including cases with fatal outcome.

Newly diagnosed multiform glioblastoma

Laboratory findings

Myelosuppression (neutropenia and thrombocytopenia), which is a manifestation of dose-dependent toxicity observed with most cytotoxic agents including temozolomide, was reported. During the combined treatment phase and monotherapy with temozolomide, grade III or IV neutropenia was observed in 8% of patients, and grade III or IV thrombocytopenia in 14% of patients.

Recurrent or progressive malignant glioma

Laboratory findings

Grade III or IV thrombocytopenia and neutropenia were observed in 19% and 17% of patients, respectively, treated for malignant glioma. This led to hospitalization and/or discontinuation of temozolomide in 8% and 4% of patients, respectively. Myelosuppression was predictable (typically occurring during the first few cycles, with nadir between days 21 and 28) and rapidly reversible, usually within 1–2 weeks. There were no signs of cumulative myelosuppression. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Sex.

According to population pharmacokinetic analysis, during the first treatment cycle, the highest incidence was grade IV neutropenia (absolute neutrophil count < 0.5 × 10⁹/L), observed in 12% of women and 5% of men; grade IV thrombocytopenia (< 20 × 10⁹/L) occurred in 9% of women and 3% of men. In a study of 400 patients with recurrent glioma, grade IV neutropenia occurred during the first treatment cycle in 8% of women and 4% of men, and grade IV thrombocytopenia in 8% of women and 3% of men. In a study involving 288 patients with newly diagnosed multiform glioblastoma, grade IV neutropenia was observed during the first treatment cycle in 3% of women and 0% of men, and grade IV thrombocytopenia in 1% of women and 0% of men.

Children.

Oral administration of temozolomide has been studied in children (aged 3–18 years) with recurrent brainstem glioma or recurrent high-grade astrocytoma, using a regimen of 5 consecutive days every 28 days. Although data are limited, tolerability of the drug in children is expected to be similar to that in adults. The safety of temozolomide in children under 3 years of age has not been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are obliged to report any suspected adverse reactions through the appropriate system.

Shelf life. 2 years.

Storage conditions.

For 20 mg dosage: store at temperatures not exceeding 25 °C.

For 100 mg, 180 mg, and 250 mg dosages: store at temperatures not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging.

1 capsule in a sachet.

5 sachets in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Eugene Pharma Limited.

Manufacturer's address and location of its business operations.

Westside Business Park, Old Kilmeaden Road, Waterford, Ireland.

In case of adverse events, suspected adverse reactions, or lack of therapeutic effect, please report to Zentiva Ukraine LLC, 5I Brovarskyi Avenue, Kyiv, 02660, Ukraine; tel./fax +38 044 517-75-00; e-mail: [email protected]