Temomedak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TEMOMEDAC (TEMOMEDAC)

Composition:

Active substance: temozolomide;

1 capsule contains 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide;

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

Capsules 5 mg: titanium dioxide (E 171), gelatin, shellac, propylene glycol, indigocarmine (E 132), yellow iron oxide (E 172);

Capsules 20 mg: titanium dioxide (E 171), gelatin, shellac, propylene glycol, yellow FCF (E 110);

Capsules 100 mg: titanium dioxide (E 171), gelatin, shellac, propylene glycol, yellow iron oxide (E 172), red iron oxide (E 172);

Capsules 140 mg: titanium dioxide (E 171), gelatin, shellac, propylene glycol, indigocarmine (E 132);

Capsules 180 mg: titanium dioxide (E 171), gelatin, shellac, propylene glycol, red iron oxide (E 172);

Capsules 250 mg: titanium dioxide (E 171), gelatin, shellac, propylene glycol, black iron oxide (E 172).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules. The capsules contain a powder ranging from white to light yellowish-brown/light pink in color. Two stripes are printed on the opaque cap of the capsules, and the markings "T 5 mg", "T 20 mg", "T 100 mg", "T 140 mg", "T 180 mg", or "T 250 mg" are printed on the opaque body. The color of the stripes and markings, as well as the capsule size, corresponds to the dosage: green for 5 mg; orange for 20 mg; pink for 100 mg; blue for 140 mg; red for 180 mg; black for 250 mg.

Pharmacotherapeutic group.

Antineoplastic agents. Alkylating agents. ATC code L01AX03.

Pharmacological Properties

Pharmacodynamics

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

Pharmacokinetics

Temozolomide undergoes spontaneous hydrolysis at physiological pH levels, primarily forming 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 cytotoxic effect of MTIC is believed to result primarily from DNA alkylation, mainly at the O6 and N7 positions of guanine. Relative to the AUC of temozolomide, exposure to MTIC and AIC is approximately 2.4% and 23%, respectively. In vivo, the half-life (T1/2) of MTIC is similar to that of temozolomide—1.8 hours.

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

Distribution. Temozolomide exhibits weak 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). The presence of the drug in CSF was confirmed in one patient; CSF exposure, based on the AUC of temozolomide, was approximately 30% of plasma exposure, consistent with data obtained from animal studies.

Elimination. The plasma elimination half-life (t1/2) of temozolomide is approximately 1.8 hours. The primary route of 14C excretion is renal. 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-dependent manner. Drug clearance in plasma, volume of distribution, and elimination half-life 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 dedicated pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were comparable to those in patients with normal liver function.

In pediatric patients, plasma concentration (AUC) is higher than in adults. However, the maximum tolerated dose (MTD) for both pediatric and adult patients is the same, at 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 with disease recurrence or progression after standard therapy.

Contraindications.

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

Special safety precautions.

Capsules must not be opened. If a capsule is damaged, contact between the powder content and skin or mucous membranes must be avoided. If Temodal comes into contact with skin or mucous membranes, the affected area should be immediately and thoroughly washed with soap and water.

Patients should be advised to store capsules out of reach of children, preferably in a closed cabinet. Accidental ingestion may be fatal for children.

Any unused product or waste materials must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other types of interactions.

Interaction studies have been conducted only in adult patients.

Co-administration of Temodal with ranitidine did not result in changes in the extent of temozolomide absorption or exposure to its active metabolite—monomethyl triazenoimidazole carboxamide (MTIC).

Administration of Temodal with food resulted in a 33% reduction in Cmax and a 9% reduction in the area under the curve (AUC). Since a change in Cmax cannot be ruled out as being clinically significant, Temodal should not be taken with food.

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

Studies to determine 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.

The use of Temodal with other agents that suppress bone marrow function may increase the likelihood of developing myelosuppression.

Special precautions for use.

Opportunistic infections and reactivation of infections. Opportunistic infections (including pneumonia caused by Pneumocystis jirovecii) and reactivation of infections (such as cytomegalovirus and hepatitis B).

Pneumonia caused by Pneumocystis jirovecii. Patients who received treatment with Temodar in combination with radiotherapy according to the extended 42-day treatment regimen had a particular risk of developing pneumonia caused by Pneumocystis jirovecii. Therefore, prophylaxis against Pneumocystis jirovecii-induced pneumonia should be administered to all patients receiving concomitant temozolomide and radiotherapy according to the 42-day regimen (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-induced pneumonia may be higher when temozolomide is administered according to a prolonged treatment regimen. All patients receiving temozolomide, and particularly those receiving concomitant corticosteroids, should be closely monitored for the development of Pneumocystis jirovecii-induced 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 corticosteroids.

Hepatitis B. Hepatitis due to reactivation of hepatitis B virus (HBV) has been reported, with some cases resulting in fatal outcomes. Consultation with a liver disease specialist is required before initiating treatment in patients with positive serological tests for hepatitis B (including those with active disease). Appropriate monitoring should be performed during treatment.

Herpes meningoencephalitis.

Herpes meningoencephalitis (including fatal cases) has been observed in patients treated with Temodar in combination with radiotherapy, including cases with concomitant use of corticosteroids.

Hepatotoxicity.

Liver injury, including fatal hepatic failure, has been reported in patients receiving temozolomide. Baseline liver function tests should be performed before initiating treatment. The physician must assess the benefit-risk ratio before starting temozolomide therapy, particularly considering the potential for 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 reassess the benefit-risk ratio in patients with marked abnormalities in liver function before continuing treatment. Hepatotoxic effects may occur several weeks (or later) after the last course of temozolomide.

Malignant neoplasms.

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

Antiemetic therapy.

Nausea and vomiting are very common with temozolomide. Antiemetic therapy may be administered before or after drug administration.

For patients with newly diagnosed multiform glioblastoma:

antiemetic prophylaxis is recommended prior to the initial dose of concomitant Temodar therapy and is strongly recommended during monotherapy.

For patients with recurrent or progressive 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 treated with Temodar, potentially leading to aplastic anemia, sometimes with fatal outcome. Assessment of some cases was complicated by concomitant use of drugs for the treatment of aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim. Before initiating Temodar therapy, the following laboratory parameters must be met: absolute neutrophil count ≥ 1.5 × 10⁹/L, platelet count ≥ 100 × 10⁹/L. A complete blood count 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.

Elderly patients.

Elderly patients (aged 70 years and older) have an increased risk of developing neutropenia and thrombocytopenia compared to younger patients. Therefore, Temodar should be used with caution in elderly patients.

Male patients.

Temodar may have genotoxic effects. Men receiving temozolomide therapy should not plan conception during treatment and for 6 months after the last dose. Sperm cryopreservation should be discussed before starting treatment due to the potential for irreversible infertility associated with Temodar therapy.

Lactose.

This medicinal product contains lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Temodar medicinal product contains sodium

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

The excipient Yellow FCF (E 110) present in the capsule coating may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy. There are no data on the use of the medicinal product in pregnant women. Animal studies at a dose of 150 mg/m² showed evidence of teratogenic and/or fetal toxicity. Therefore, Temodar should not be administered to pregnant women. If treatment during pregnancy is necessary, 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 Temodar.

Breastfeeding. It is unknown whether Temodar is excreted in human breast milk; therefore, breastfeeding should be discontinued during treatment.

Male fertility. Temodar may have genotoxic effects. Men receiving therapy with this medicinal product should be advised not to plan conception for 6 months after the last dose and to seek advice on sperm cryopreservation prior to starting treatment due to the potential for irreversible infertility caused by Temodar therapy.

Ability to affect reaction speed when driving or operating machinery.

The ability to drive or operate machinery may be slightly impaired during treatment with Temodar due to the possible occurrence of fatigue and somnolence.

Method of administration and dosage.

Temodal should be prescribed only by a physician experienced in oncological therapy for brain tumors. Temodal 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. Antiemetic therapy may be administered concomitantly.

Adult patients with newly diagnosed glioblastoma multiforme.

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

Concomitant treatment phase with Temodal accompanied by radiotherapy.

Temodal is administered orally at a dose of 75 mg/m² daily for 42 days, concomitantly with radiotherapy (60 Gy in 30 fractions). Dose reduction is not recommended; decisions regarding interruption or discontinuation of Temodal should be made weekly based on hematological and non-hematological toxicity criteria. The use of Temodal at this dose may be extended from 42 to 49 days if all of 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 Temodal should be interrupted or permanently discontinued during the concomitant phase according to hematological and non-hematological toxicity criteria (see Table 1).

Interruption or discontinuation of Temodal during concomitant therapy (Temodal + radiotherapy)

Table 1

Toxicity	Temporary interruption* of administration	Discontinuation of administration
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

* – Treatment with Temomedac is resumed 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.

Four weeks after completion of the "Temomedac + radiotherapy" treatment phase, Temomedac is administered for an additional 6 cycles of therapy. The dose during Cycle 1 (monotherapy) is 150 mg/m² once daily for 5 days of a 28-day cycle (5 days of Temomedac administration, followed by a 23-day treatment-free period). The dose of Temomedac is increased to 200 mg/m²/day in Cycle 2 if, during Cycle 1, the following criteria are met: EORTC non-hematological toxicity ≤ Grade 2 (excluding alopecia, nausea, and vomiting), absolute neutrophil count ≥ 1.5 × 10⁹/L, and platelet count ≥ 100 × 10⁹/L. If the dose increase did not occur in Cycle 2, the dose should not be increased in subsequent cycles. The dose of 200 mg/m²/day during the first 5 days of each subsequent cycle is maintained unless toxicity develops. In each cycle, Temomedac is administered consecutively for 5 days, followed by a 23-day break. Dose reduction or discontinuation of Temomedac during monotherapy 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 Temomedac should be carried out according to Table 3.

Dosage of Temomedac for Monotherapy

Table 2

Dose level	Dose (mg/m2/day)	Notes
1	100	Reduction for prior toxicity
0	150	Dose during Cycle 1
1	200	Dose during Cycles 2-6 in the absence of toxicity

Dose reduction or discontinuation of Temomedac during monotherapy

Table 3

Toxicity	Dose reduction by 1 levela	Discontinuation
Neutrophil count	< 1.0 × 109/l	b
Platelet count	< 50 × 109/l	b
CTC: non-hematological toxicity (excluding alopecia, nausea and vomiting)	CTC, grade 3	CTC, grade 4b

a – the dosing regimen for Temomedac is specified in Table 2;

b – Temomedac 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, Temomedac 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 populations

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 reduction is unlikely to be necessary in patients with severe hepatic impairment or any degree of renal impairment. However, temozolomide should be used with caution in such patients.

Elderly patients

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

Children

Temomedac 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 group 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

Doses of 500, 750, 1000, and 1250 mg/m² (total dose over a 5-day cycle) have been clinically evaluated. Dose-dependent hematological toxicity occurred at all administered 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, with fatal outcomes.

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

Adverse Reactions

Clinical Trials

In patients receiving temozolomide in clinical trials, the most commonly observed adverse reactions were nausea, vomiting, constipation, anorexia, headache, fatigue, seizures, and rash. Most expected hematological adverse reactions reported as frequent or very frequent are listed in Tables 4–5. The incidence of Grade III–IV laboratory abnormalities is provided below Table 4.

In patients with recurrent or progressive malignant glioma, nausea (43%) and vomiting (36%) were particularly common. These events were usually Grade I or II (0–5 episodes of vomiting within 24 hours), were self-limiting, or were easily managed with standard antiemetic therapy. The incidence of severe nausea and vomiting was 4%.

List of adverse reactions in tabular form

The adverse reactions observed in clinical trials and reported during the post-marketing period of temozolomide use are listed in Table 4.

Adverse reactions are classified by system organ class and frequency of occurrence. The frequency of adverse effects is defined according to the following categories: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated based on available data).

Table 4. Adverse reactions in patients receiving temozolomide
Infections and infestations	common	infection, herpes simplex, pharyngitis, oral candidiasis
	uncommon	opportunistic infection (including Pneumocystis carinii pneumonia), sepsis†, herpes encephalitis†, CMV infection, CMV reactivation, hepatitis B virus†, herpes simplex, infection reactivation, wound infection, gastroenteritis
Benign, malignant and unspecified neoplasms	uncommon	myelodysplastic syndrome (MDS), secondary malignant neoplasms including myeloid leukemia
Blood and lymphatic system disorders	common	febrile neutropenia, neutropenia, thrombocytopenia, lymphopenia, anemia
	uncommon	prolonged pancytopenia, aplastic anemia†, pancytopenia, petechiae
Immune system disorders	common	allergic reactions
	uncommon	anaphylactic reactions
Endocrine disorders	common	Cushingoid features
	uncommon	diabetes insipidus
Metabolism and nutrition disorders	very common	anorexia
	common	hyperglycemia
	uncommon	hypokalemia, increased alkaline phosphatase levels
Psychiatric disorders	common	anxiety, amnesia, depression, restlessness, confusion, insomnia
	uncommon	behavioral disorders, emotional lability, hallucinations, apathy
Nervous system disorders	very common	convulsions, hemiparesis, aphasia/dysphasia, headache
	common	ataxia, impaired balance, cognitive disturbances, decreased concentration, decreased level of consciousness, tremor, hypesthesia, memory impairment, neurological disorders, neuropathyd, paresthesia, somnolence, speech disorder, dysgeusia
	uncommon	epileptic status, hemiplegia, extrapyramidal disorders, parosmia, gait disturbance, hyperesthesia, sensory disturbances, coordination disorder
Eye disorders	common	hemianopia, blurred vision, visual disturbancee, visual field defect, eye pain, diplopia
	uncommon	decreased visual acuity, dry eyes
Ear and labyrinth disorders	common	deafnessf, vertigo, tinnitus, ear paine
	uncommon	hearing impaired, otitis media, hyperacusis
Cardiac disorders	uncommon	palpitations
Vascular disorders	common	hemorrhage, pulmonary embolism, deep vein thrombosis, hypertension
	uncommon	intracranial hemorrhage, hot flushes
Respiratory, thoracic and mediastinal disorders	common	pneumonia, dyspnea, cough, bronchitis, upper respiratory tract infections
	uncommon	respiratory failure†, interstitial pneumonitis, pulmonary fibrosis, nasal congestion
Gastrointestinal disorders	very common	diarrhea, constipation, nausea, vomiting
	common	stomatitis, abdominal painn, dyspepsia, dysphagia
	uncommon	abdominal distension, fecal incontinence, gastrointestinal disorders, hemorrhoids, dry mouth
Hepatobiliary disorders	uncommon	hepatic failure†, hyperbilirubinemia, cholestasis, hepatitis, hepatic injury
Skin and subcutaneous tissue disorders	very common	rash, alopecia
	common	dry skin, erythema, pruritus
	uncommon	toxic epidermal necrolysis, Stevens-Johnson syndrome, angioneurotic edema, erythema multiforme, erythroderma, skin exfoliation, photosensitivity reaction, urticaria, exanthema, dermatitis, increased sweating, abnormal pigmentation
	Frequency unknown	drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
Musculoskeletal and connective tissue disorders	common	myopathy, muscle weakness, arthralgia, bone pain, myalgia
Renal and urinary disorders	common	frequency, 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, worsening of general condition, asthenia, anxiety, pain, edema, peripheral edemai
	uncommon	worsening of general condition, tremor, facial swelling, tongue color change, thirst, dental disorders
Investigations	common	increased enzyme levelsj, increased body weight, decreased body weight
	uncommon	increased gamma-GT levels
Injury, poisoning and procedural complications	common	radiation therapy injurieks

a Includes pharyngitis, nasopharyngitis, streptococcal pharyngitis

b Includes gastroenteritis, viral gastroenteritis

c Includes Cushingoid, Cushing's syndrome

d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral motor neuropathy

e Includes vision disorders, eye disorders

f Includes deafness, bilateral deafness, sensorineural deafness, unilateral deafness

g Includes ear pain, ear discomfort

h Includes abdominal pain, lower abdominal pain, lower abdominal pain, abdominal discomfort

i Includes peripheral edema, peripheral edema

j Includes increased liver function, increased alanine aminotransferase, increased aspartate aminotransferase, increased liver enzymes

k Includes radiation injury, radiation skin injury

† Including cases with fatal outcome

First diagnosis of multifocal glioblastoma

Laboratory findings

Myelosuppression (neutropenia and thrombocytopenia), which is a manifestation of dose-dependent toxicity common to most cytotoxic agents, including temozolomide, was observed. 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, receiving treatment for malignant glioma. This led to hospitalization and/or discontinuation of temozolomide in 8% and 4% of patients, respectively. Myelosuppression was predictable (usually occurring during the first few cycles, with nadir between days 21 and 28) and rapidly reversible, typically 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. During studies, women experienced a slightly higher incidence of grade IV neutropenia and thrombocytopenia during the first treatment cycle compared to men.

Children.

Oral administration of temozolomide was studied in children (aged 3–18 years) with recurrent brainstem glioma or recurrent high-grade astrocytoma using 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 suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via national reporting systems.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30°C in the original tightly closed amber glass bottle to protect from moisture.

Keep out of the reach of children.

Packaging.

5 mg, 20 mg, 100 mg capsules: 5 or 20 capsules in a bottle made of amber glass with a screw cap; 1 bottle in a carton.

140 mg, 180 mg, 250 mg capsules: 5 capsules in a bottle made of amber glass with a screw cap; 1 bottle in a carton.

Prescription status. Prescription only.

Manufacturer.

Medac Gesellschaft für klinische Spezialpräparate mbH, Germany / Medac Gesellschaft fur klinische Spezialpraparate m.b.H., Germany.

Manufacturer's address and location of operations.

Theaterstrasse 6, 22880 Wedel, Germany / Theaterstrasse 6, 22880 Wedel, Germany.