Date of approval.
Date of revision.
Instructions for Temozolomide for Injection
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Temozolomide for Injection
English name: Temozolomide for Injection
Hanyu Pinyin：Zhusheyong Timozuo’an
Ingredients
Temozolomide is the active ingredient of this product.
Chemical name: 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d] 1,2,3,5-tetrazine-8-carboxamide
The chemical structure formula is
Molecular formula: C6H6N6O2
Molecular weight: 194.15
The excipients of this product are: mannitol, polysorbate 80 (for injection), cysteine hydrochloride, sodium citrate, hydrochloric acid.
Properties
This product is a white or off-white loose mass or (and) powder.
Indications】
This product is used for the treatment of.
-Newly diagnosed glioblastoma multiforme, started first in combination with radiotherapy and subsequently as maintenance therapy.
-Glioblastoma multiforme or mesenchymal astrocytoma that has recurred or progressed after conventional treatment.
【Specification】.
0.1g.
Dosage and Administration
1.Recommended dose and dose adjustment scheme.
The recommended dose of this product is the same as that of the oral capsule for 90-minute intravenous infusion. Only the bioequivalence of this product for 90 minutes intravenous infusion was determined. Dose administration needs to be adjusted based on the minimum neutrophil count and platelet count of the previous cycle and the neutrophil count and platelet count at the start of the next cycle. Calculation of the dose administered based on body surface area (BSA) is detailed in Table 4.
Adult patients with newly diagnosed glioblastoma multiforme.
Temozolomide is treated first in combination with local radiotherapy (concurrent radiotherapy phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (maintenance treatment phase).
Synchronous radiotherapy phase
Daily dose of 75 mg/m2 for 42 days in combination with local radiotherapy (60 Gy in 30 doses). Dosing may be suspended as tolerated by the patient, but no dose reduction is required. The product may be administered for 42 consecutive days up to a maximum of 49 days during the concurrent radiotherapy period if the following conditions are met: absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, and Common Toxicity Criteria (CTC)-non-hematologic toxicity ≤ grade 1 (except alopecia, nausea and vomiting). Weekly complete blood counts should be performed during treatment. The administration of this product should be suspended or discontinued during concurrent radiotherapy according to the hematologic and non-hematologic toxicity criteria shown in Table 1.
Table 1 Suspension or discontinuation of this product during concurrent radiotherapy
Toxicity Suspension of TMZa Termination of TMZ Absolute neutrophil count ≥ 0.5 × 109/L
and<1.5×109/L<0.5×109/L platelet count ≥10×109/L
and<100×109/L<10×109/L CTC-non-hematologic toxicity (except alopecia, nausea and vomiting) CTC Grade 2 CTC Grade 3 or 4a: Combined treatment with TMZ may be continued if the following criteria are met: absolute neutrophil count ≥ 1.5×109/L and platelet count ≥ 100×109/L, CTC-non-hematologic toxicity ≤ grade 1 (except alopecia, nausea and vomiting).
Maintenance treatment period.
Six cycles of monotherapy with this product were administered 4 weeks after the end of the concurrent radiotherapy period. The dose of this product in cycle 1 is 150 mg/m2/day once daily for 5 days, followed by 23 days of discontinuation. At the start of Cycle 2, the dose may be increased to 200 mg/m2/day if the non-hematologic toxicity of Cycle 1 CTC is ≤ Grade 2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L. If the dose is not increased in cycle 2, the dose should not be increased in subsequent cycles either. The dose is maintained at 200 mg/m2/day in subsequent cycles except in the event of toxicity. the dose should be reduced during treatment according to Tables 2 and 3.
During treatment, a complete blood count should be performed on day 22 (21 days after the first dose of this product). The dose should be reduced or the administration of this product should be discontinued according to Table 3.
Table 2 Dose levels for monotherapy with this product
Dose level Dose (mg/m2/day) Remarks – 1100 Dose reduction for earlier toxicity 0150 Dose for cycle 1 1200 Dose for cycles 2-6 when there is no toxicity
Table 3 Dose reduction or discontinuation during monotherapy
Toxicity TMZ dose reduction by one levela Termination of TMZ Absolute neutrophil count <1.0 x 109/L see footnote b Platelet count <50 x 109/L see footnote b CTC Non-hematologic toxicity
(except alopecia, nausea and vomiting) CTC Grade 3 CTC Grade 4 ba: See Table 2 for TMZ dose levels.
b: TMZ therapy should be discontinued if TMZ needs to be reduced to <100 mg/m2 or if the same grade 3 non-hematologic toxicity (except alopecia, nausea and vomiting) reoccurs after dose reduction.
Adult patients with glioblastoma multiforme or mesenchymal astrocytoma who have relapsed or progressed after conventional therapy.
For patients who have not received prior chemotherapy, the dose of this product is 200 mg/m2 daily for 5 days. Every 28 days is a cycle. For patients who have received prior chemotherapy, the starting dose is 150 mg/m2/day for 5 days. Every 28 days is a cycle. If the ANC is ≥1.5 x 109/L and platelet count is ≥100 x 109/L on the first day of the next cycle, the dose is increased to 200 mg/m2/day in cycle 2. The dose of this product should be adjusted according to the minimum ANC and platelet count values.
Laboratory Parameters for Dose Adjustment
The following laboratory parameters must be met to start the next cycle of dosing: ANC ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L. A complete blood count is performed on day 22 (21 days after the first dose) or within 48 hours of this date and weekly thereafter until ANC ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L. If ANC<1.0×109/L or platelet count<50×109/L in any cycle, the dose must be reduced by one level for the next cycle. Dose levels include 100 mg/m2, 150 mg/m2, and 200 mg/m2. The lowest recommended dose is 100 mg/m2.
In clinical trials, treatment was continued until progression of the lesion occurred, for a maximum of 2 years. However, the optimal duration of treatment is unknown.
Table 4 Calculation of daily dose administered based on body surface area
Overall surface area
(m2)75 mg/m2
(mg/d)150 mg/m2
(mg/d)200 mg/m2
(mg/d)1.0751502001.182.51652201.2901802401.397.51952601.41052102801.5112.52253001.61202403201.7127.52553401.81352703601. 9142.52853802.01503004002.1157.53154202.21653304402.3172.53454602.41803604802.5187.5375500
Special Populations
Pediatric patients
This product is intended for use only in pediatric patients 3 years of age or older with recurrent or progressive malignant glioma. There is limited clinical experience with the use of this drug in these children. The safety and efficacy of using this drug in children younger than 3 years of age has not been established.
In children 3 years of age or older, the recommended dose is 200 mg/m2/day for 5 days in 28-day cycles. For children who have received prior chemotherapy, the starting dose is 150 mg/m2/day for 5 days; if no toxicity occurs, the dose is increased to 200 mg/m2/day for the next cycle.
Elderly patients
Based on the results of a population pharmacokinetic analysis in patients aged 19-78 years, the clearance of TMZ was not affected by age. However, the risk of neutropenia and thrombocytopenia appears to be greater in elderly patients (>70 years).
Those with hepatic or renal impairment
Patients with normal hepatic function have similar pharmacokinetic results to those with mild to moderate abnormal hepatic function; there is no information on the use of temozolomide in patients with severe hepatic abnormalities (Child’s Class III) or renal abnormalities. Based on the pharmacokinetic profile of temozolomide, it is not necessary to reduce the dosage of temozolomide in patients with severe hepatic or renal insufficiency, but extra caution is required when applying it.
2. Preparation and Administration
This product must be administered by intravenous infusion. It cannot be administered by other routes, such as intrathecal, intramuscular or subcutaneous injection. This product may only be administered through the same intravenous infusion line as 0.9% saline injection. This product is not compatible with glucose solution.
Each vial contains sterile, pyrogen-free temozolomide lyophilized powder. After dissolution with 41 mL of sterile water for injection, the solution obtained contains 2.5 mg/mL temozolomide. Place the product at room temperature prior to dissolving with sterile water for injection. The preparation should be gently swirled and not shaken. Check the injection solution after preparation and do not use if there are obvious particles in the bottle. The prepared solution should not be diluted again. After preparation, store at room temperature (25°C [77°F]). Prepared solutions must be used within 14 hours, including injection time.
Using aseptic technique, draw 40 mL from each vial, prepare a complete dose according to Table 4, and inject into an empty, volume-appropriate infusion set. For clinical use, PVC infusion sets containing DEHP (di(2-ethylhexyl) phthalate) should not be used. This product should be administered intravenously via an infusion pump over a 90-minute dosing period. This product should be infused intravenously only. Flush the injection line before and after each infusion of this product.
Since there is no data on the compatibility of this product with other intravenous drugs or additives, other drugs should not be given simultaneously through the same intravenous line.
[Adverse Reactions].
Clinical trials of temozolomide capsules
Common adverse reactions reported in patients treated with TMZ, either in combination with radiotherapy, alone after radiotherapy in patients with newly diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, include: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were common in patients with newly diagnosed glioblastoma multiforme receiving monotherapy, and rash was common in patients with newly diagnosed glioblastoma multiforme receiving TMZ in combination with RT or monotherapy, and rash was common in patients with recurrent glioma. In both indications, most hematologic adverse reactions were common or very common (Tables 4 and 5); the incidence of grade 3-4 laboratory findings is indicated after each table.
In the tables, adverse reactions are categorized according to system organ class and incidence. Incidence subgroups were defined according to the following conventions: very common (≥1/10); common (≥1/100 to <1/10); occasional (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); and very rare (<1/10,000). Within each incidence subgroup, adverse reactions were listed in decreasing order of severity.
Newly diagnosed glioblastoma multiforme
Table 5 shows adverse events in patients with newly diagnosed glioblastoma multiforme during the concurrent radiotherapy and monotherapy periods (causality was not determined in the clinical trials).
Table 5 This product and radiotherapy: events occurring during the concurrent radiotherapy period and during monotherapy
Systemic systemic TMZ + radiotherapy
n=288*TMZ monotherapy
n=224 infections and infestations common: oral candidiasis, herpes simplex, infections, pharyngitis, wound infections oral candidiasis, infections occasional: herpes simplex, herpes zoster, flu-like symptoms blood and lymphatic system common: leukopenia, lymphopenia, neutropenia, thrombocytopenia anemia, febrile neutropenia, leukopenia, thrombocytopenia occasional: anemia Febrile neutropenia lymphopenia, petechiae Endocrine Occasional: Cushing-like syndrome Cushing-like syndrome Metabolic and nutritional Very common: loss of appetite Loss of appetite Common: hyperglycemia, weight loss Weight loss Occasional: hypokalemia, increased alkaline phosphatase, weight gain Hyperglycemia, weight gain Mental Common: anxiety, emotional instability, insomnia Anxiety, depression, emotional instability, insomnia Occasional. Agitation, emotional indifference, abnormal behavior, depression, hallucinations hallucinations, amnesia neurological very common: headache convulsions, headache common: convulsions, reduced consciousness, drowsiness, aphasia, balance disorders, dizziness, confusion, memory deficits, inability to concentrate, neuropathy, sensory abnormalities, speech disorders, tremor light hemiparesis, aphasia, balance disorders, drowsiness, confusion, dizziness, memory deficits, inability to concentrate Inability to concentrate, speech disorders, neurological disorders (NOS), neuropathies, peripheral neuropathies, sensory abnormalities, tremor Occasionally: persistent epilepsy, extrapyramidal disorders, mild hemiplegia, ataxia, cognitive impairment, speech difficulties, gait abnormalities, sensory hypersensitivity, hyperalgesia, neurological disorders (NOS), peripheral neuropathies ataxia, coordination abnormalities, gait abnormalities, hemiplegia, sensory hypersensitivity, sensory impairment Eye common: blurred vision blurred vision, diplopia, visual field defects occasional: eye pain, hemianopia, visual impairment, reduced vision, visual field defects eye pain, dry eyes, reduced vision ear and vagus common: hearing impairment hearing impairment, tinnitus occasional: ear pain, auditory hypersensitivity, tinnitus, otitis media deafness, ear pain, vertigo heart occasional: palpitations vascular common: swelling, swelling of lower extremities, hemorrhage swelling of lower extremities, hemorrhage, deep veins thrombosis occasional: hypertension, cerebral hemorrhage puffiness, peripheral puffiness, pulmonary embolism respiratory, thoracic and mediastinal common: cough, dyspnea cough, dyspnea occasional: pneumonia, upper respiratory tract infection, nasal congestion pneumonia, sinusitis, upper respiratory tract infection, bronchitis gastrointestinal very common: constipation, nausea, vomiting constipation, nausea, vomiting common: abdominal pain, diarrhea, dyspepsia, dysphagia, stomatitis Diarrhea, dyspepsia, dysphagia, dry mouth, stomatitis Occasionally: bloating, fecal incontinence, gastrointestinal disorders (NOS), gastroenteritis, hemorrhoids Skin and subcutaneous tissues Very common: alopecia, rash alopecia, rash Common: dermatitis, dry skin, erythema, pruritus Dry skin, pruritus Occasionally: photosensitivity reactions, abnormal pigmentation, skin shedding erythema, abnormal pigmentation, increased sweating Musculoskeletal and Connective tissue common: arthralgia, muscle weakness arthralgia, musculoskeletal pain, myalgia, muscle weakness occasional: back pain, musculoskeletal pain, myalgia, myopathy back pain, myopathy renal and urinary system common: urinary frequency, urinary incontinence incontinence occasional: urinary difficulty genital and breast occasional: impotence amenorrhea, breast pain, excessive menstruation, vaginal bleeding, vaginitis systemic and administration site very common: fatigue fatigue common. Fever, pain, allergic reactions, radiation damage, facial puffiness, abnormal taste Fever, pain, allergic reactions, radiation damage, abnormal taste Occasionally: flushing, hot flush, weakness, worsening condition, rigidity, tongue discoloration, olfactory inversion, thirst weakness, worsening condition, pain, rigidity, dental disease, facial puffiness Examination Common: Elevated ALT Elevated ALT Occasionally: Elevated gamma-glutamyl transferase, liver enzymes elevated, AST elevated *One patient randomly assigned to the radiotherapy group received this product + radiotherapy
Laboratory results: myelosuppression (neutropenia and thrombocytopenia) was observed, which is a dose-limiting toxicity for most cytotoxic agents, including this product. Pooled laboratory abnormalities and adverse events occurred during the concurrent radiotherapy and monotherapy phases of this product. Grade 3 or 4 neutrophil abnormalities (including neutropenia) occurred in 8% of patients; grade 3 or 4 platelet abnormalities (including thrombocytopenia) occurred in 14% of patients treated with this product.
Adult patients with glioma recurrence or progression
The most frequent treatment-related adverse reactions in clinical trials were gastrointestinal reactions, specifically nausea (43%) and vomiting (36%). These reactions were generally grade 1 or 2 (0-5 episodes of vomiting in 24 hours), self-limiting, or easily controlled with standard antiemetics. The incidence of severe nausea and vomiting was 4%. Table 6 includes adverse reactions reported in clinical trials and post-marketing for temozolomide in relapsed or progressive malignant glioma.
Table 6. Adverse reactions in patients with recurrent or progressive malignant glioma
Infections and Infections Rare: opportunistic infections, including Yersinia pneumonia (PCP) Blood and Lymphatic System Disorders Very common: neutropenia or lymphopenia (grade 3-4), thrombocytopenia (grade 3-4) Occasionally: complete blood cytopenia, anemia (grade 3-4), leukopenia Metabolic and Nutritional Disorders Very common: loss of appetite Common: weight loss Neurologic Disorders Very Common: headache Common: drowsiness, dizziness, sensory abnormalities Respiratory, thoracic, and mediastinal disorders Common: dyspnea Gastrointestinal disorders Very common: vomiting, nausea, constipation Common: diarrhea, abdominal pain, dyspepsia Skin and subcutaneous tissue disorders Common: rash, pruritus, alopecia Very rare: erythema multiforme, erythema, urticaria, eruption Systemic disorders and administration site conditions Very common: fatigue Common. Fever, weakness, rigidity, depression, pain, taste inversions very rare: allergic reactions, including anaphylaxis, angioedema laboratory findings: the incidence of grade 3 or 4 thrombocytopenia and neutropenia in glioma patients was 19% and 17%, respectively. Eight percent and 4% of glioma patients were hospitalized and/or discontinued from this product as a result. Myelosuppression is predictable (generally on days 21-28 of the first few cycles) and usually recovers rapidly within 1-2 weeks. Cumulative myelosuppression has not been observed. Pancytopenia, leukopenia and anemia have been reported; lymphocytopenia is also common.
Gender: An analysis of the different genders in the clinical trials showed that the number of people reaching the neutrophil nadir was 101 for women and 169 for men; the number of people reaching the platelet nadir was 110 for women and 174 for men. The incidence of grade 4 adverse reactions in the first cycle of treatment was higher in women than in men, with neutropenia (ANC<500 cells/μL) in 12% of women and 5% of men, and thrombocytopenia (<20,000 cells/μL) in 9% of women and 3% of men. In a group of 400 subjects with recurrent glioma, the incidence of grade 4 neutropenia in cycle 1 of treatment was 8% in women and 4% in men, while the incidence of grade 4 thrombocytopenia was 8% and 3%, respectively. In another trial of 288 subjects with newly diagnosed glioblastoma multiforme, the incidence of grade 4 neutropenia in the first cycle of treatment was 3% in women and 0% in men, and the incidence of grade 4 thrombocytopenia was 1% and 0%, respectively.
Clinical studies with intravenous infusion
Intravenous infusion of this product provides the same exposure to temozolomide and its active metabolite, MTIC, as the corresponding dose of temozolomide capsules (see [Pharmacokinetics] section for details). Adverse reactions that arose in two clinical studies of temozolomide injection and did not occur in clinical studies of temozolomide capsules were infusion site reactions, including pain, irritation, pruritus, burning, swelling, and rash, including hematoma.
Postmarketing Experience.
Few cases of opportunistic infections, including Yersinia pneumonia and initial and reactivated cytomegalovirus infections, have been reported during the marketing period of this product. Cases of hepatitis B reactivation, including some cases causing fatal outcomes, have also been reported. Cases of erythema multiforme, toxic epidermolysis bullosa, Stevens-Johnson syndrome, and allergic reactions (including allergic reactions) have been reported rarely. Cases of herpetic meningoencephalitis, including those causing fatal outcomes, have also been reported. Rare cases of interstitial pneumonia and pulmonary fibrosis have been reported. Rare cases of myelodysplastic syndrome (MDS) and secondary malignant diseases (including myeloid leukemia) have been reported in patients treated with this product. There have been reports of allogeneic cytopenia leading to aplastic anemia, and in some cases fatal consequences have occurred. There have been reports of uremia. Cases of hepatotoxicity have been reported including elevated liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis. Very few patients using temozolomide have developed liver injury, including fatal liver failure (see [Precautions] for details). Postmarketing reported serious adverse events are given in Table 7.
Table 7. Summary of postmarketing reported temozolomide adverse events
Infections and Infiltrations* Occasionally: cytomegalovirus infections, reinfections such as cytomegalovirus, hepatitis B virus#, herpes meningoencephalitis#, sepsis# Hematologic and lymphatic disorders Very rare: prolonged hematocrit of various kinds, aplastic anemia# Benign, malignant and neoplastic organisms of unknown nature Very rare: myelodysplastic syndromes (MDS), secondary malignant diseases including myeloid leukemia Endocrine disorders* occasional: uremia Respiratory, thoracic and mediastinal disorders very rare: interstitial pneumonia/pneumonitis, pulmonary fibrosis, respiratory failure # Hepatobiliary disorders* common: elevated liver enzymes occasional: hyperbilirubinemia, biliary depression, hepatitis, liver injury, liver failure # Skin and subcutaneous tissue disorders very rare: toxic epidermolysis bullosa, Stevens-Johnson syndrome* Incidence estimates based on relevant clinical trials.
# Includes cases that resulted in death.
There were no unintended adverse events in clinical studies conducted in China, and the overall results were similar to data reported abroad.
[Contraindication].
Contraindicated in persons with hypersensitivity to any of the components of this product or to dacarbazine (DTIC).
Contraindicated during pregnancy (see [Pregnancy and Lactation]).
Contraindicated in patients with severe bone marrow suppression.
[Precautions].
Pneumocystis jiroveci pneumonia.
In a small trial extending the duration of treatment to 42 days, patients receiving this product in combination with radiotherapy were at high risk for Pneumocystis carinii pneumonia (PCP). Therefore, regardless of lymphocyte counts, prevention of Pneumocystis carinii pneumonia is required for all patients receiving 42 days (up to 49 days) of combined therapy. If lymphopenia occurs, prophylaxis should be continued until lymphocytes return to ≤ grade 1.
The incidence of Pneumocystis carinii pneumonia may be higher during treatment with temozolomide in longer-term dosing regimens. Regardless of the regimen, the potential for Pneumocystis carinii pneumonia should be closely monitored in all patients treated with temozolomide, especially those receiving steroids. Cases of fatal respiratory failure have been reported in patients treated with temozolomide, especially when combined with dexamethasone or other steroids.
Hepatotoxicity.
Very few patients using temozolomide have developed liver injury, including fatal liver failure. Baseline liver function tests must be performed prior to treatment with this product. If baseline liver function is abnormal, physicians should perform a risk-benefit assessment prior to initiating temozolomide therapy, including an assessment of the potential risk of fatal liver failure. Liver function tests in the middle of the treatment cycle are required for patients undergoing a 42-day treatment cycle. For all patients, liver function tests must be performed after each treatment cycle. For patients with significant liver function abnormalities, physicians need to perform a risk-benefit assessment of whether to continue treatment. In addition, hepatotoxicity may occur several weeks or more after the use of this product.
In addition, some cases of death due to hepatitis caused by hepatitis B virus reactivation have been reported. Patients should be screened for hepatitis B virus infection prior to initiation of therapy. Monitor patients with pre-existing hepatitis B virus infection for clinical and laboratory indications of hepatitis B or HBV reactivation during TMZ treatment and for several months after the end of treatment. Treatment should be discontinued in patients with evidence of active hepatitis B infection.
Antiemetic therapy.
Nausea and vomiting are often associated with this product and antiemetics may be used before and after its use. Guidelines are.
In patients with newly diagnosed glioblastoma multiforme.
-Antiemetic prophylaxis is recommended prior to initiation of combined temozolomide therapy.
-Antiemetic prophylaxis is highly recommended during monotherapy.
Patients with recurrent or progressive glioma: Patients who have experienced severe (grade 3 or 4) vomiting during previous treatment cycles require antiemetic therapy.
Bone marrow suppression.
Patients treated with temozolomide may develop myelosuppression, including persistent reduction in whole blood cells, which may lead to aplastic anemia and, in some cases, has resulted in fatal outcomes. In some cases, concomitant administration of other drugs associated with aplastic anemia (including carbamazepine, phenytoin, and cotrimoxazole sulfamethoxazole) can make evaluation more difficult.
Male patients.
Male patients receiving temozolomide should use effective contraception. Temozolomide is genotoxic and therefore men should use contraception during treatment and for up to 6 months after the end of treatment. Because of the potential for irreversible infertility with temozolomide treatment, sperm should be cryopreserved prior to receiving this treatment.
Sodium
This product contains 2.4 mmol of sodium per vial. Caution is required for patients who require controlled sodium intake.
Timing of infusion.
Because bioequivalence has been established only for temozolomide Injection infusion over 90 minutes, infusion times that are too long or too short may result in poor efficacy; in addition, the possibility of increased adverse reactions associated with infusion cannot be ruled out.
Effects on the ability to drive and operate machinery
Temozolomide may cause fatigue and drowsiness. Effects on driving and operating machinery should be avoided.
Pregnant women and nursing mothers
Pregnancy
There are no data on the use of this product in pregnant women. In preclinical studies, rats and rabbits received 150 mg/m2 of TMZ and the results showed teratogenicity and/or fetal toxicity (see [Pharmacology and Toxicology]).
This product should not be used in pregnant women. If it must be used during pregnancy, patients should be informed of the potential risk to the fetus.
Lactation
It is not known whether TMZ is excreted via human milk and therefore breastfeeding should be discontinued while receiving TMZ therapy.
Women of Pregnant Age
Women of maternal age should be advised to use effective contraception to avoid pregnancy while receiving TMZ or for 6 months after termination of temozolomide therapy.
Male Fertility
TMZ may have genotoxic effects. Therefore, treated men should be advised to use contraception during treatment and for 6 months after receiving the last dose, and to cryopreserve sperm prior to treatment, as TMZ treatment may lead to irreversible infertility.
Pediatric Dosage]
There is no clinical experience with the use of this drug in children with glioblastoma multiforme under 3 years of age; there is limited clinical experience with the use of this drug in pediatric patients with glioma over 3 years of age.
Oral temozolomide has been studied in children (3-18 years of age) with recurrent brainstem glioma or recurrent high-grade astrocytoma; patients received temozolomide 160-200 mg/m2 daily for 5 days in a 28-day cycle. The tolerability of temozolomide in children is similar to that in adults.
[Geriatric Dosing].
Neutropenia and thrombocytopenia are more likely in older patients (> 70 years) compared to younger patients.
[Drug Interactions].
In a separate phase I study, concomitant administration of ranitidine did not alter the extent of absorption of temozolomide capsules or exposure to its active metabolite, monomethyltriazenylimidazolecarboxamide (MTIC).
According to a population pharmacokinetic analysis in a phase II trial, concomitant administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not affect the clearance of temozolomide. A mild but statistically significant decrease in temozolomide clearance was seen with concomitant administration of valproic acid.
No studies have examined the effect of temozolomide on the metabolism or elimination of other drugs. However, temozolomide is not metabolized by the liver and has low protein binding, so it is unlikely to affect the pharmacokinetics of other drugs.
Bone marrow suppression may be exacerbated when temozolomide capsules are combined with other drugs that can cause bone marrow suppression.
[Drug Overdose].
Clinical evaluations have been conducted in patients at doses of 500, 750, 1000, and 1250 mg/m2 (total dose per treatment cycle of 5 days of dosing). The dose-limiting toxicity was hematologic and was reported at any dose, but was more severe at higher doses. In one patient who was overdosed with 2000 mg per day for 5 days, the reported adverse events were complete cytopenia, fever, multi-organ failure, and death. Adverse events in patients who took the drug for more than 5 days (up to 64 days) included myelosuppression (with or without infection) and, in some severe and long-lasting cases, eventual death. In drug overdose events, a hematologic evaluation should be performed. Supportive measures should be taken if necessary.
[Clinical Trials].
Foreign capsule clinical trials.
Newly diagnosed glioblastoma multiforme
573 patients were randomized to receive temozolomide + local radiotherapy (n=287) or radiotherapy alone (n=286). Patients in the temozolomide + local radiotherapy group were given temozolomide 75 mg/m2 once daily for 42 days (up to 49 days) starting on the first day of radiotherapy. Temozolomide monotherapy was then started 4 weeks after the end of radiotherapy: a 28-day cycle of 150-200 mg/m2 daily on days 1-5 of each cycle for 6 cycles. Patients in the control group received radiotherapy only. Prophylaxis against Yersinia pneumonia (PCP) was required during radiotherapy and combination therapy with temozolomide and continued until lymphopenia returned to ≤ grade 1.
During follow-up, 161 of 282 patients (57 %) who received radiotherapy only and 62 of 277 patients (22 %) who received temozolomide + radiotherapy were re-treated with temozolomide.
The hazard ratio (HR) for overall survival was 1.59 (95 % CI 1.33-1.91), with a time-series test p <0.0001, favoring the temozolomide group. The 2-year survival rate was higher in the temozolomide + radiotherapy group than in the control group (26% vs. 10%). Patients with newly diagnosed glioblastoma multiforme treated with concurrent radiotherapy plus temozolomide monotherapy maintenance therapy showed a statistically significant improvement in overall survival time compared with radiotherapy alone. (Figure 1)
Figure 1 Kaplan-Meier curve of overall survival time (intention-to-treat population, ITT)
Malignant glioma with recurrence or lesion progression after conventional treatment
Clinical effectiveness data for patients with glioblastoma multiforme (Karnofsky physical status score ≥ 70) with recurrence or lesion progression after surgery or radiotherapy are from two clinical trials. One was an uncontrolled trial in 138 patients (29% of whom had received chemotherapy); the other was a randomized, controlled trial of temozolomide versus procarbazine (methylbenzylhydrazine) in 225 patients (67% of whom had received nitrosourea-based chemotherapy). The primary endpoint of these two trials was progression-free survival time (PFS), as judged by MRI scans or worsening neurological symptoms. In the uncontrolled trial, the 6-month PFS was 19%. The median PFS was 2.1 months and the median overall survival time was 5.4 months. the objective remission rate on MRI scan was 8%.
In the randomized, controlled study, the 6-month progression-free survival PFS was significantly higher in the temozolomide group than in the procarbazine group (21% versus 8%, chi-square test p = 0.008), with median PFS of 2.89 months and 1.88 months, respectively (time-series test p = 0.0063). The median survival time was 7.34 and 5.66 months in the temozolomide and procarbazine groups, respectively (time-series test p = 0.33). at 6 months, a significantly higher proportion of patients survived in the temozolomide group than in the procarbazine group, 60% and 44%, respectively, chi-square test p = 0.019. there was an improvement in Karnofsky’s physical status in patients who had previously received chemotherapy to 80 or more .
Data on time to worsening of neurological symptoms were also better in the temozolomide group than in the procarbazine group, as was data on time to worsening of physical status (KPS score remaining above 60 or at least decreasing by 30). For the median time to progression for these endpoints, the temozolomide group was 0.7-2.1 months longer than the procarbazine group (time-series test p ≤ 0.01 -0.03).
Mesenchymal astrocytoma
A global multicenter prospective, non-randomized phase II trial evaluating the safety and efficacy of oral temozolomide in patients with first recurrence of mesenchymal astrocytoma achieved a progression-free survival time of 6 months in 46% of patients. The median progression-free survival time was 5.4 months. The median overall survival time was 14.6 months. Based on a pooled evaluation of the ITT population, the remission rate was 35% with 13 CRs and 43 PRs. including 43 cases of persistent lesion remission, the remission rate was 61%. 6 months event-free survival was achieved in 44% of the ITT population, with a median event-free survival time of 4.6 months, similar to the progression-free survival time. Validity results were similar for those appropriate for histology. Patients who achieved objective radiographic remission or maintained progression-free status were able to improve and maintain their quality of life.
Domestic Capsules Clinical Trials
The registered clinical trials conducted in China in 2005 were multicenter, open, randomized, positive drug-parallel controlled trials. A study comparing the efficacy and safety of temozolomide and simustine in the treatment of glioblastoma or mesenchymal astrocytoma that has recurred or progressed after conventional therapy. A total of 144 subjects were enrolled in this study, 79 in the temozolomide group and 65 in the simustine group. The starting dose of temozolomide was 150 mg/m2/day (for those who had received chemotherapy) or 200 mg/m2/day (for those who had not received chemotherapy), administered orally for 5 consecutive days in 28-day cycles; the starting dose of simustine was 150 mg/m2/day in 1 dose, administered at 28-day intervals; the treatment period for both drugs was 2-6 months. The progression-free survival rates were 78.29% versus 55.08%, p=0.0384, for the temozolomide and control groups, respectively, and the overall clinical remission rates (including complete and partial remission) were 45.83% versus 21.27%, respectively, at 6 months of treatment.
The trial suggests that temozolomide may be superior to simustine in the treatment of recurrent glioblastoma (GBM) and mesenchymal astrocytoma (AA).
Pharmacology and Toxicology
Pharmacological effects
Temozolomide is an alkylating agent of imidazolotetrazine with antitumor activity. The cytotoxic effect of MTIC is mainly manifested by the alkylation of guanine at the 6th oxygen atom and the alkylation of nitrogen atom at the 7th position on the DNA molecule. The cytotoxic effect is exerted through the mismatch repair of methylated adducts.
Toxicological studies
Toxicological studies in rats and dogs have shown a low incidence of retinal hemorrhage, degeneration and necrosis at doses of temozolomide administered at ≥125 mg/m2 (equivalent to 0.63 times the maximum recommended daily human dose based on body surface area), with these changes occurring frequently at lethal doses.
Genotoxicity
Temozolomide is a mutagenic and disruptive agent, and the Ames test and human lymphocyte chromosome aberration test were positive.
Reproductive toxicity
Temozolomide may cause impairment of male fertility. Temozolomide at 50 mg/m2 and 125 mg/m2 (0.25 and 0.63 times the maximum recommended daily human dose based on body surface area) resulted in syncytiotrophoblast/immature sperm formation in rats and dogs, respectively. Temozolomide also caused testicular atrophy in dogs at 125 mg/m2 (0.63 times the maximum recommended human daily dose on a body surface area basis).
Oral administration of temozolomide at 75 mg/m2 and 150 mg/m2 (0.38 and 0.75 times the maximum recommended human daily dose on a body surface area basis) for 5 consecutive days during the organogenesis period in rats and rabbits, respectively, resulted in cosmetic, visceral, and skeletal malformations in fetuses. Temozolomide at 150 mg/m2 (0.75 times the maximum recommended human daily dose on a body surface area basis) resulted in increased fetal uptake and embryonic lethal effects in rats and rabbits.
Carcinogenicity
Temozolomide was carcinogenic in rats given less than the maximum recommended human daily dose. Temozolomide 25-125 mg/m2 (0.13-0.63 times the maximum recommended human daily dose based on body surface area) was administered orally to rats for 5 consecutive days in a 28-day cycle, and mammary carcinomas developed in both male and female rats after 6 cycles of administration. Temozolomide also caused fibrosarcoma in the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus and prostate at a dose equivalent to 0.5 times the maximum recommended human daily dose, leading to seminal vesicle carcinoma, cardiac nerve sheath tumor, optic nerve sheath tumor and Harder’s gland nerve sheath tumor, and adenomas in the skin, lung, pituitary gland and thyroid gland. Administration of temozolomide to rats for 3 cycles at the maximum recommended human daily dose resulted in mammary gland tumors.
Pharmacokinetics]
In an open double-crossover bioequivalence study of oral and intravenous TMZ in patients with CNS malignancies, the Cmax and AUC of TMZ and MTIC after 90-minute intravenous administration of temozolomide for injection were equivalent to those after oral temozolomide capsules at a dose of 150 mg/m2. The mean Cmax of TMZ and MTIC after 90-minute intravenous administration were 7.4µ g/ml and 320ng/ml, and the mean AUC (0→∞) was 25µg-h/ml and 1004ng-h/ml, respectively.
Absorption
After oral administration of temozolomide in adults, the drug is rapidly absorbed, with peak time being 20 minutes after administration (mean time between 0.5 and 1.5 hours). The average fecal excretion of 14C-temozolomide within 7 days of oral administration had a radioactivity of 0.8% of the total radioactivity, indicating complete absorption of the drug.
Distribution
Binding of TMZ to plasma proteins is low, approximately 10% to 20%. Not affected by substances with a high plasma protein binding rate.
Data from human PET studies and preclinical studies show that TMZ rapidly crosses the blood-brain barrier and is present in cerebrospinal fluid (CSF). Concentrations of TMZ in CSF were obtained from one patient, and TMZ exposure in CSF was approximately 30% of that in plasma, consistent with animal data.
Metabolism and clearance
Temozolomide is rapidly converted by spontaneous hydrolysis at physiological pH to the active product 3-methyl(triazin-1-yl)imidazole-4-carboxamide (MTIC). MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and methylhydrazine, which is considered to be the active fragment of alkylation. the cytotoxicity of MTIC results primarily from The alkylation of DNA guanine at the O6 and N7 positions. exposure to MTIC and AIC was 2.4% and 23%, respectively, compared to that of TMZ. In vivo, the half-life of MTIC is similar to that of TMZ at 1.8 h. The primary elimination route for 14C-temozolomide is the kidney. Approximately 5% to 10% of the dose is excreted in the urine as prodrug 24 hours after oral administration, with the remainder excreted as temozolomide acid, AIC and other monomeric metabolites.
In the therapeutic dose range of 75-250 mg/m2/day, plasma concentrations increase with increasing dose administration. Plasma clearance, volume of distribution and half-life are independent of the administered dose.
Special Populations
A population PK study of TMZ showed that plasma clearance of TMZ was independent of age, renal function and smoking status. In a separate PK study, plasma pharmacokinetic data from patients with mild to moderate hepatic impairment were similar to those from patients with normal liver function.
Exposure was higher in pediatric patients than in adults; however, the maximum tolerated dose per course was 1000 mg/m2 in both children and adults.
Storage】Store airtight at 2~8°C.
Package】Neutral borosilicate glass molded injection bottle, freeze-dried sterile powder for injection with PTFE/ethylene copolymer film chlorinated butyl rubber stopper, antibiotic bottle with aluminum-plastic combination cap. 1 bottle/box, 100 bottles/case.
Expiration date
24 months.
Execution standard
【Approval number】
【Manufacturing enterprise
Enterprise name: Jiangsu Hengrui Pharmaceutical Co.
Production Address: Lianyungang Economic and Technological Development Zone, Lingang Industrial Zone, Dongjin Road
Postal Code: 222047
Telephone number: 800-8283900 400-8283900
Fax number: 0518-85463261
Web
Address: http://www.hrs.com.cn