Temozolomide accord

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Temozolomide Accord (Temozolomide Accord)

Composition:

Active substance: temozolomide;

1 capsule contains 20 mg, 100 mg, 140 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 for 20 mg: gelatin, purified water, titanium dioxide (E 171), yellow iron oxide (E 172);

capsule shell for 100 mg: gelatin, purified water, titanium dioxide (E 171), red iron oxide (E 172);

capsule shell for 140 mg: gelatin, purified water, titanium dioxide (E 171), FD&C Blue 2 (E 132);

capsule shell for 180 mg: gelatin, purified water, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172);

capsule shell for 250 mg: gelatin, purified water, titanium dioxide (E 171);

composition of black ink for printing markings on the cap and body of the capsule: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, concentrated ammonia solution, black iron oxide (E 172), potassium hydroxide, purified water.

Pharmaceutical form. Capsules.

Main physicochemical properties:

20 mg capsules: hard gelatin capsules of size "5" with the marking "TMZ" in yellow on the cap and "20" in white on the body, containing powder from white to light pinkish color;

100 mg capsules: hard gelatin capsules of size "3" with the marking "TMZ" in pink on the cap and "100" in white on the body, containing powder from white to light pinkish color;

140 mg capsules: hard gelatin capsules of size "1" with the marking "TMZ" in blue on the transparent cap and "140" in white on the body, containing powder from white to light pinkish color;

180 mg capsules: hard gelatin capsules of size "1" with the marking "TMZ" in dark red on the cap and "180" in white on the body, containing powder from white to light pinkish color;

250 mg capsules: hard gelatin capsules of size "0" with the marking "TMZ" in white on the cap and "250" in white on the body, containing powder from white to light pinkish color.

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 levels to the active metabolite 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is believed to be primarily due to alkylation of DNA at the O6 and N7 positions of guanine. The resulting cytotoxic lesions likely involve a mechanism of aberrant repair of the methyl group.

Pharmacokinetics.

Temozolomide undergoes spontaneous hydrolysis at physiological pH levels, primarily forming the active metabolite MTIC. MTIC in turn 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. Relative to the AUC of temozolomide, exposure to MTIC and AIC is approximately 2.4% and 23%, respectively. In vivo, the elimination half-life (t_1/2) 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: 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 weak binding to plasma proteins (10–20%), so interactions with highly protein-bound drugs 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 has been 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 t_1/2 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, while the remainder is 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 t_1/2 are independent of dose.

Special patient groups. Pharmacokinetic analysis of temozolomide has shown that its clearance is independent of patient age, renal function, or nicotine dependence. In a separate 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, plasma concentration (AUC) is higher than in adults. However, the maximum tolerated dose 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, in combination with radiotherapy and subsequently as monotherapy;
• of children aged 3 years and older and adult patients with malignant glioma in the form of multiforme glioblastoma or anaplastic astrocytoma in the presence of recurrence or disease progression after standard therapy.

Contraindications.

Temozolomide is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients or to dacarbazine; in patients with severe myelosuppression.

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 exposure of skin or mucous membranes to Temozolomide Accord, 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 medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adult patients.

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

Administration of temozolomide 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, Temozolomide Accord should not be taken during food intake.

Concomitant administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine H2-receptor antagonists, or phenobarbital does not alter temozolomide clearance. Concomitant administration of valproic acid caused a mild but statistically significant decrease 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 plasma protein binding, its influence on the pharmacokinetics of other medicinal products is unlikely.

The use of Temozolomide Accord with other agents that suppress bone marrow function may increase the risk of developing myelosuppression.

Special precautions for use.

Opportunistic infections and reactivation of infections. Opportunistic infections (e.g., 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 used concomitantly with steroids.

Pneumocystis jirovecii pneumonia. Patients receiving temozolomide in combination with radiotherapy according to an extended 42-day treatment schedule have a particular risk of developing Pneumocystis jirovecii-induced 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 longer treatment schedule. All patients receiving temozolomide, especially those taking corticosteroids, should be frequently monitored for the development of Pneumocystis jirovecii pneumonia, regardless of the treatment regimen. Fatal cases due to respiratory failure have been reported in patients treated with temozolomide, particularly in combination with dexamethasone or other corticosteroids.

Hepatitis B virus. Reactivation of hepatitis B virus has been reported in patients with positive serological markers for hepatitis B (including those with active disease), 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.

Hepatotoxicity. Hepatic 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 before initiating temozolomide, particularly considering the potential for fatal hepatic failure. For patients receiving the 42-day treatment cycle, liver function tests should be repeated at mid-cycle. Liver function should be monitored in all patients after each treatment cycle. The physician should reassess the benefit-risk ratio 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 rare cases of myelodysplastic syndrome and secondary malignant neoplasms, including myeloid leukemia, have been reported.

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

Adult patients with newly diagnosed glioblastoma multiforme. Prophylactic antiemetic therapy is recommended before 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 occur in patients treated with temozolomide and may lead 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.

Prior to initiating treatment with Temozolomide Accord, the following laboratory parameters should be met: absolute neutrophil count (ANC) ≥ 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 thereafter, and then weekly until ANC exceeds 1.5 × 10⁹/L and platelet count exceeds 100 × 10⁹/L. If ANC < 1.0 × 10⁹/L or platelet count < 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 daily dose is 100 mg/m².

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

Elderly patients. Elderly patients (aged 70 years and older) have a higher risk of developing neutropenia and thrombocytopenia compared to younger patients; therefore, Temozolomide Accord should be used with caution in elderly patients.

Female patients. Women of childbearing potential must use effective contraception to avoid pregnancy during treatment with temozolomide and for at least 6 months after completion of treatment.

Male patients. Temozolomide may have genotoxic effects. Men receiving temozolomide should not plan conception during treatment and for at least 3 months after the last dose. Sperm cryopreservation should be considered prior to starting treatment due to the potential for irreversible infertility associated with temozolomide therapy.

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

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

Use during pregnancy or breastfeeding.

Pregnancy. There are no data on the use of temozolomide in pregnant women. Preclinical studies in animals receiving a dose of 150 mg/m² showed evidence of teratogenic and/or fetal toxicity. Therefore, Temozolomide Accord 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 reproductive potential should be advised to use effective contraception to prevent pregnancy during treatment with Temozolomide Accord.

Breastfeeding. It is unknown whether temozolomide is excreted in human milk; therefore, breastfeeding must be discontinued during treatment with Temozolomide Accord.

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

Male fertility. Temozolomide may have genotoxic effects. Therefore, men using this medicinal product should use effective contraception. Planning conception is not recommended 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 caused by treatment with Temozolomide Accord.

Ability to affect reaction rate when driving or operating machinery.

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

Method of administration and dosage.

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

Concomitant antiemetic therapy may be administered.

Temozolomide Accord 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 glioblastoma multiforme

The medicinal product Temozolomide Accord should be administered in combination with focal radiotherapy (concomitant phase), followed by 6 cycles of monotherapy with temozolomide (monotherapy phase).

Concomitant phase

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

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

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

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

Table 1

Toxicity	Interrupt temozolomide administration	Discontinue temozolomide administration
ANC	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 II	CTC grade III or IV

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

Monotherapy Phase

Four weeks after completion of the combined treatment phase (temozolomide + radiotherapy), treatment with Temozolomide Accord should be continued 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 Temozolomide Accord in cycle 2 is increased to 200 mg/m² daily if, during cycle 1, non-hematological toxicity was ≤ Grade II (excluding alopecia, nausea, and vomiting), ANC ≥ 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 increased, the drug should be administered at a dose of 200 mg/m² daily on days 1–5 of each subsequent cycle, unless toxicity develops. Dose reduction or discontinuation of temozolomide 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 temozolomide should be performed according to Table 3.

Temozolomide Dose Levels for Monotherapy

Table 2

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

Reduction of dose or discontinuation of Temozolomide Accord during monotherapy

Table 3

Toxicity	Reduce dose of Temozolomide Accord by 1 levela	Discontinue Temozolomide Accord
ANC	< 1.0 × 109/L	see referenceb
Platelet count	< 50 × 109/L	see referenceb
CTC non-hematological toxicity (excluding alopecia, nausea and vomiting)	CTC Grade III	CTC Grade IV

a The dose levels of temozolomide are specified in Table 2.

b Treatment with Temozolomide Accord should be discontinued if dose level – 1 (100 mg/m²) continues to be associated with unacceptable toxicity or if grade III 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, Temozolomide Accord should be 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 liver 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 reduction 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 (aged 70 years and older) are at increased risk of developing neutropenia and thrombocytopenia.

Children

Temozolomide Accord may be administered to children aged 3 years and older only for the treatment of recurrent or progressive malignant glioma. Experience with temozolomide in this patient 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 mg/m², 750 mg/m², 1000 mg/m², and 1250 mg/m² (total dose over a five-day cycle) have been clinically evaluated. 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 necessary.

Adverse reactions.

Summary of safety profile

Clinical trial experience

In patients receiving Temozolomide Accord, the most commonly reported adverse reactions were nausea, vomiting, constipation, anorexia, headache, fatigue, seizures, 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 usually 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 temozolomide 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); frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Adverse reactions in patients receiving temozolomide therapy

Table 4

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
Neoplasms benign, malignant and unspecified
uncommon	myelodysplastic syndrome (MDS), secondary malignancy 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	diabetes insipidus
Metabolism and nutrition disorders
very common	anorexia
common	hyperglycemia
uncommon	hypokalemia, increased alkaline phosphatase levels
Psychiatric disorders
common	agitation, amnesia, depression, restlessness, confusion, insomnia
uncommon	behavioral disorders, emotional lability, hallucinations, apathy
Nervous system disorders
very common	convulsions, hemiparesis, aphasia/dysphasia, headache
common	ataxia, balance disorder, cognitive disorders, impaired concentration, decreased level of consciousness, dizziness, hypoesthesia, memory impairment, neurological disorders, neuropathy4, paresthesia, somnolence, speech disorder, taste alteration, tremor
uncommon	status epilepticus, hemiplegia, extrapyramidal disorders, parosmia, gait disturbance, hyperesthesia, sensory disturbances, coordination abnormality
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, arterial hypertension
uncommon	intracerebral hemorrhage, flushing, 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
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
Neoplasms benign, malignant and unspecified
uncommon	myelodysplastic syndrome (MDS), secondary malignancy 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	diabetes insipidus
Metabolism and nutrition disorders
very common	anorexia
common	hyperglycemia
uncommon	hypokalemia, increased alkaline phosphatase levels
Psychiatric disorders
common	agitation, amnesia, depression, restlessness, confusion, insomnia
uncommon	behavioral disorders, emotional lability, hallucinations, apathy
Nervous system disorders
very common	convulsions, hemiparesis, aphasia/dysphasia, headache
common	ataxia, balance disorder, cognitive disorders, impaired concentration, decreased level of consciousness, dizziness, hypoesthesia, memory impairment, neurological disorders, neuropathy4, paresthesia, somnolence, speech disorder, taste alteration, tremor
uncommon	status epilepticus, hemiplegia, extrapyramidal disorders, parosmia, gait disturbance, hyperesthesia, sensory disturbances, coordination abnormality
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, arterial hypertension
uncommon	intracerebral hemorrhage, flushing, 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§, hepatic injury, 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 disorder
frequency 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
frequency unknown	dysuria
Reproductive system and breast disorders
frequency unknown	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
frequency unknown	general deterioration in health, tremor, facial edema, tongue color change, thirst, dental disorders
Laboratory findings
common	elevated liver enzymes10, decreased body weight, increased body weight
frequency unknown	elevated gamma-glutamyl transferase (GGT) levels
Injury, poisoning and procedural complications
common	radiation injury11

1Including pharyngitis, nasopharyngeal pharyngitis, streptococcal pharyngitis.

2Including gastroenteritis, viral gastroenteritis.

3Including Cushingoid, Cushing's syndrome.

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

5Including visual 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, increased liver enzymes.

11Including radiation injury, including radiation injury of the skin.

§Including cases with fatal outcome.

First-diagnosed glioblastoma multiforme

Laboratory findings

Myelosuppression (neutropenia and thrombocytopenia) was observed, which is a manifestation of dose-dependent toxicity common to most cytotoxic agents, including temozolomide. During the combined treatment phase and temozolomide monotherapy, 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 the lowest levels between days 21 and 28) and recovery was rapid, 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.

Gender

According to population pharmacokinetic analysis, during the first treatment cycle, the highest incidence was grade IV neutropenia (absolute neutrophil count < 0.5 × 10⁹/L) in 12% of women and 5% of men, and grade IV thrombocytopenia (< 20 × 10⁹/L) 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 glioblastoma multiforme, 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.

Children

Oral administration of temozolomide was studied in children (aged 3–18 years) with recurrent brainstem glioma or recurrent high-grade astrocytoma using a regimen of daily dosing for 5 days every 28 days. Although data are limited, tolerability 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 continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: http://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep in the original packaging to protect from moisture. Store out of reach of children.

Packaging.

1 capsule in a sachet; 5 sachets in a pack.

Prescription status. Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Importer's Warehouse/Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and location of operations.

ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorization Holder. Accord Healthcare S.L.U./Accord Healthcare S.L.U.

Inquiries regarding poor-quality medicinal products, safety concerns, improper use of the medicinal product, or complaints are accepted 24/7 via phone: +380993100335 or by email at: [email protected].

Address of the Marketing Authorization Holder. World Trade Center, Moll de Barcelona, s/n, Edifici Est 6a planta, 08039 Barcelona, Spain.