Gliozomid

INSTRUCTIONS 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), red iron oxide (E 172), yellow iron oxide (E 172);

Capsule shell composition for 100 mg: gelatin, titanium dioxide (E 171), red iron oxide (E 172), indigocarmine FD&C Blue 2 (E 132);

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

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

Pharmaceutical form. Capsules.

Main physicochemical properties:

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

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

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

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

Pharmacotherapeutic group.

Antineoplastic agents. Alkylating agents. ATC code L01AX03.

Pharmacological Properties.

Pharmacodynamics.

Temozolomide is a triazene that undergoes rapid chemical conversion at physiological pH levels 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 adduct.

Pharmacokinetics.

Temozolomide undergoes spontaneous hydrolysis at physiological pH levels, primarily forming the active species 3-methyl-(triazene-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 elimination half-life (T1/2) of MTIC is similar to that of temozolomide—approximately 1.8 hours.

Absorption. After oral administration in adult patients, temozolomide is rapidly absorbed, with peak concentrations reached within 20 minutes after dose intake (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 shows low plasma protein binding (10–20%), so interactions with highly protein-bound substances are not expected.

Positron emission tomography (PET) studies 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 elimination half-life (T1/2) of temozolomide is approximately 1.8 hours. The primary route of 14C elimination is via the kidneys. After oral administration, approximately 5–10% of the dose is excreted unchanged in urine within 24 hours, with the remainder excreted as temozolomide acid, 5-aminoimidazole-4-carboxamide, or unidentified polar metabolites.

Plasma concentrations increase in a dose-proportional manner. Plasma clearance of temozolomide, volume of distribution, and T1/2 are independent of dose.

Special patient populations. Pharmacokinetic analysis of temozolomide has shown that its clearance is independent of age, renal function, or tobacco use. In a dedicated pharmacokinetic study, plasma pharmacokinetic profiles of the drug in patients with mild to 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) is the same for both pediatric and adult patients—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 children aged 3 years and older and adult patients with malignant glioma in the form of multiforme glioblastoma or anaplastic astrocytoma upon recurrence or disease progression after standard therapy.

Contraindications.

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

Special safety precautions.

Capsules must not be opened. If a capsule is damaged, contact with its contents should 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 capsules in a place inaccessible to children, preferably in a locked cabinet. Accidental ingestion may be fatal for a child.

Any unused medication or waste material should be destroyed in accordance with local regulations.

Interaction with other medicinal products and other types of interactions.

Interaction studies have been conducted only in adult patients.

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

Administration of Gliozomid with food resulted in 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 with food.

Concomitant use of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine H2-receptor antagonists, or phenobarbital does not alter the clearance of the drug. Concomitant use of valproic acid caused a mild but statistically significant reduction 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 agents that suppress bone marrow may increase the risk of developing myelosuppression.

Special precautions for use.

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

Herpes meningoencephalitis. Post-marketing cases of herpes 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 the 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 reaches 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 has been reported in patients with hepatitis B virus, 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. During treatment, patients should be monitored and appropriate decisions regarding therapy should be made.

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

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

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

Adult patients with newly diagnosed glioblastoma multiforme. Prophylaxis against vomiting is recommended prior to the first dose in 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 develop in patients receiving Gliozomid, which may lead to aplastic anemia, sometimes with fatal outcome. Assessment of some cases was complicated by concomitant use of drugs for treatment of aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim.

Prior to initiating Gliozomid treatment, the following laboratory parameters should be met: absolute neutrophil count ≥ 1.5 × 10⁹/L, 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 thereafter, and then weekly 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 childbearing 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 regarding sperm cryopreservation, as irreversible infertility may occur as a result of Gliozomid therapy.

Lactose. Since Gliozomid contains lactose, the product 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)/dose of sodium, i.e., essentially "sodium-free".

Capsules should not be opened. If a capsule is damaged, contact with the contents should 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 capsules in a place inaccessible to children, preferably in a locked cabinet. Accidental ingestion may be fatal for a child.

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 treatment is necessary during pregnancy, the woman should be informed of the potential risk to the fetus.

Women of childbearing 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 possibility of 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.

Dosage and Administration

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

Concomitant antiemetic therapy may be administered.

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 administration of the drug, a second dose should not be taken on the same day.

Adult patients with newly diagnosed multiform glioblastoma

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

Concomitant phase

Gliozomid is administered orally at a dose of 75 mg/m² once daily for 42 days, concurrently with focal radiotherapy (60 Gy in 30 fractions). Dose reduction is not recommended; decisions regarding treatment interruption or discontinuation of Gliozomid should be made weekly based on hematological and non-hematological toxicity criteria. Administration of the drug at the specified dose may be extended from 42 to 49 days of concomitant 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. Gliozomid administration should be interrupted or permanently discontinued during the concomitant treatment phase based on hematological and non-hematological toxicity criteria, as specified in Table 1.

Table 1

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

Toxicity	Temporary interruption of drug administration	Discontinuation of drug administration
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 of 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 of temozolomide plus 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/day if, during Cycle 1, non-hematological EORTC toxicity 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 should be administered at 200 mg/m²/day for the first 5 days 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 administration of the first dose). Dose reduction or discontinuation of the drug should be carried out according to Table 3.

Table 2

Gliozomid Dose Levels for Monotherapy

Level of dose	Dose (mg/m2/day)	Note
1	100	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 Gliozomide 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 Gliozomid are indicated in Table 2.

b Gliozomid 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, Gliozomid 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 in 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

Gliozomid is indicated in children aged 3 years and older only for the treatment of recurrent or progressive malignant glioma. Experience with 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 more than 5 days (up to 64 days), leading to bone marrow suppression (with or without infection), in some cases severe and prolonged, and resulting in death.

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 treatment during 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 parameter changes is presented after Table 4.

In patients with recurrent or progressive glioma, nausea (43%) and vomiting (36%) were generally 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 is 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 grouping, adverse reactions are listed in order of decreasing severity.

Table 4

Adverse reactions in patients receiving Gliozomid treatment

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-diabetic 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	behavior disorders, emotional lability, hallucinations, apathy
Nervous system disorders
Very common	seizures, hemiparesis, aphasia/dysphasia, headache
Common	ataxia, balance disorder, cognitive disorders, impaired concentration, decreased level of consciousness, dizziness, hypesthesia, memory impairment, neurological disorders, neuropathy4, paresthesia, somnolence, speech disorder, taste distortion, tremor
Uncommon	epileptic status, hemiplegia, extrapyramidal disorders, parosmia, gait disturbance, hyperesthesia, sensory disorders, 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	intracranial hemorrhage, blood flush, 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	liver 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 swelling, tongue discoloration, thirst, dental disorders
Investigations
Common	increased liver enzymes10, decreased body weight, increased body weight
Uncommon	increased gamma-glutamyl transferase (GGT) levels
Injury, poisoning and procedural complications
Common	radiation injury11

1Including pharyngitis, nasopharyngitis, streptococcal pharyngitis.

2Including gastroenteritis, viral gastroenteritis.

3Including Cushingoid, Cushing's syndrome.

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

5Including vision impairment, eye disorders.

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

7Including ear pain, ear discomfort.

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

9Including peripheral edema, peripheral swelling.

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

11Including radiation injury, radiation skin injury.

§Including cases with fatal outcome.

First-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, grade IV neutropenia (absolute neutrophil count < 0.5 × 10⁹/L) occurred in 12% of women and 5% of men; grade IV thrombocytopenia (< 20 × 10⁹/L) occurred in 9% of women and 3% of men. Data from 400 patients with recurrent glioma showed that during the first treatment cycle, grade IV neutropenia occurred 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, during the first treatment cycle, grade IV neutropenia was observed in 3% of women and 0% of men, and grade IV thrombocytopenia in 1% of women and 0% of men.

Pediatric population

Oral administration of temozolomide was studied in children (aged 3–18 years) with recurrent brainstem glioma or recurrent high-grade astrocytoma, administered on a schedule 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 medicine registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the appropriate reporting 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 box.

Prescription status. Prescription only.

Manufacturer.

Egen Pharma Limited.

Manufacturer's address and place of business.

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, 5B Brovarskyi Avenue, Kyiv, 02660, Ukraine, Tel./Fax +38 044 517-75-00, e-mail: [email protected]