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Temozolomide Capsules (Diqing)

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Indications: This product is used to treat: newly diagnosed glioblastoma multiforme, starting with radiation therapy first, and then as an adjuvant treatment. Glioblastoma multiforme or anaplastic astrocytoma that relapses or progresses after conventional treatment.

Approval date: March 06, 2007

Revised Date: August 04, 2011 December 26, 2011 June 20, 2013 December 01, 2013 December 01, 2015

Please read the instructions carefully and use under the guidance of a physician

【Drug Name】

Common name: Temozolomide capsules

Product Name: Diqing

English name: Temozolomide Capsules

Phonetic script (Hanyu Pinyin): Timozuo'an Jiaonang

[Ingredients]

The main ingredient of this product is temozolomide

Chemical name: 3,4-dihydro-3-methyl-4-oxoimidazole [5,1-d] and 1,2,3,5-tetrazine-8-carboxamide.

Molecular formula: C 6 H 6 N 6 O 2

Molecular weight: 194.15

[Character]

This product is a hard capsule with a white powder content.

【specification】

5mg; 50mg; 100mg

【Dosage】

Adult patients with newly diagnosed glioblastoma multiforme:

Concurrent chemoradiotherapy

This product was taken orally at a daily dose of 75 mg / m 2 for a total of 42 days. At the same time, it received radiotherapy (60 Gy points 30 times); then it received 6 cycles of adjuvant treatment with this product. Medication can be suspended based on the patient's tolerance, but the dose need not be reduced. If the following conditions are met during concurrent chemoradiotherapy: absolute white blood cell count ≥1.5 × 10 9 / L, platelet count ≥100 × 10 9 / L, common toxicity standard (CTC)-non-hematological toxicity ≤ Grade 1 (except hair loss, nausea and Vomiting), this product can be used continuously for 42 days to 49 days. A full blood count should be performed weekly during treatment. Suspension or discontinuation of this product during concurrent chemotherapy should be based on hematological and non-hematological toxicity criteria (Table 1).

Table 1 Suspension or discontinuation of this product during combination with radiation therapy

toxicity

Suspend this product a

Termination of this product

Absolute neutrophil count

≥0.5 × 10 9 / L

And <1.5 × 10 9 / L

<0.5 × 10 9 / L

Platelet count

≥10 × 10 9 / L

And <100 × 10 9 / L

<10 × 10 9 / L

CTC non-hematological toxicity (except for hair loss, nausea and vomiting)

CTC Level 2

CTC level 3 or 4

a: If you meet the following criteria, you can continue to treat with this product at the same time: absolute white blood cell count ≥1.5x 10 9 / child, platelet count ≥100x10 9 / L, CTC-non-hematological toxicity ≤ Grade 1 (except hair loss, nausea and vomiting) ). CTC = Common Toxicity Rating Standard

Adjuvant treatment period:

4 weeks after the end of the concurrent chemoradiotherapy period, 6 cycles of adjuvant treatment with this product. The dose of this product in the first cycle is 150 mg / m 2 / day, once a day for 5 days, and then the drug is discontinued for 23 days. At the beginning of the second cycle, if the non-hematological toxicity of CTC in the first cycle is ≤ 2 (except for hair loss, nausea and vomiting), absolute white blood cell count (ANC) ≥ 1.5x 10 9 / L and platelet count ≥ 100 x 10 9 / L, the dose can be increased to 200mg / m 2 / day. If the dose is not increased in the second cycle, it should not be increased in subsequent cycles. With the exception of toxicity, the subsequent doses were maintained at 200 mg / m 2 daily. During treatment, the dose should be reduced according to Tables 2 and 3.

During the treatment, a complete blood cell count should be performed on day 22 (21 days after the first dose of this product). The dose should be reduced or discontinued according to Table 3.

Table 2 Dosage levels of monotherapy for this product

Dose level

Dose (mg / m 2 / day)

Remark

-1

100

Decrease due to earlier toxicity  

0

150

Dose for cycle 1  

1

200

Dose without toxicity during cycles 2-6  

Table 3.Dose reduction or discontinuation during monotherapy

toxicity

Reduce the dose of this product by one level

Termination of this product

Absolute neutrophil count

<1.0 × 10 9 / L

See footnote b

Platelet count

<50 × 10 9 / L

See footnote b

CTC non-hematological toxicity (except for hair loss, nausea and vomiting)

CTC Level 3

CTC Level 4

a: The dosage level of this product is shown in Table 2.

b: If this product needs to be reduced to <100 mg / m 2 or if the same grade 3 non-hematological toxicity reappears after reducing the dose (except for hair loss, nausea and vomiting), the treatment of this product should be terminated.

Adult patients with glioblastoma multiforme or anaplastic astrocytoma who have relapsed or progressed after routine treatment:

Adult patients:

The oral dose of this product is 200 mg / m 2 daily for every 28 days in patients who have not received chemotherapy before for 5 days. The starting dose of this product is 150mg / m 2 / day in patients who have previously received chemotherapy. If ANC ≥1.5 x 10 9 / L and platelet count ≥100x10 9 / L on the first day of the next cycle, the second cycle of The dose was increased to 200 mg / m2 / day. The dose of this product should be adjusted according to the minimum values of ANC and platelet count.

Child patient

In children 3 years old or older, the recommended oral dose of this product is 200 mg / m 2 / day for a total of 5 days per 28-day period. The starting dose of this product in children who have previously received chemotherapy is 150 mg / m 2 / day for a total of 5 days; if no toxicity occurs, the dose in the next cycle is increased to 200 mg / m 2 / day.

Treatment continues until the disease progresses, up to 2 years.

Laboratory parameters for dose adjustment

The following laboratory parameters must be met before administration: ANC ≥ 1.5 x 10 9 / L and platelet count ≥ 100 x 10 9 / L. On day 22 (21 days after the first dose) or within 48 hours of that day and weekly, a complete blood count must be checked until ANC ≥ 1.5 x 10 9 / L and platelet count ≥ 100 x 10 9 / L. If ANC <1.0x 10 9 / L or platelet count <50x10 9 / L in any one cycle, the dose in the next cycle must be reduced by one level. Dose levels include 100 mg / m 2 , 150 mg / m 2 and 200 mg / m 2 . The recommended minimum dose is 100 mg / m 2 .

All patients

This product should be taken on an empty stomach (at least one hour before a meal). Antiemetics can be used before and after taking this product. If vomiting occurs after taking the medicine, do not take the second dose on the day.

Do not open or chew this product and swallow it whole with a glass of water. If the capsule is damaged, contact of the skin or mucous membranes with the powdery contents of the capsule should be avoided.

【Adverse reactions】

Newly diagnosed glioblastoma multiforme

Table 4 shows the adverse events that occurred in patients with newly diagnosed glioblastoma multiforme in clinical studies abroad during the concurrent chemoradiotherapy and monotherapy periods (causality was not judged in clinical trials). The frequency of occurrence is indicated by extremely common (> 1/10), common (> 1/100, <1/10), and uncommon (> 1/1000, <1/100).

Table 4 Events during the concurrent chemoradiotherapy and adjuvant treatment of this product

* A patient randomly assigned to the radiotherapy group received this product + radiotherapy. NOST = Unspecified

Laboratory results: Myelosuppression (neutropenia and thrombocytopenia) was observed, which is the dose-limiting toxicity of most cytotoxic drugs (including this product). Laboratory abnormalities and adverse events occurred during both concurrent chemotherapy and adjuvant therapy. 8% of patients had grade 3 or 4 neutropenia (including neutropenia) events: 14% of patients receiving this product had grade 3 or 4 platelet abnormalities (including thrombocytopenia).

Adult patients with glioma recurrence or progression

In clinical trials, the most common adverse reactions are gastrointestinal reactions, especially nausea (43%) and vomiting (36%); generally grade 1 or 2, with self-limiting, or standard antiemetics are easy to control . The incidence of severe nausea and vomiting was 4%. Other frequently reported adverse events include fatigue (22%), constipation (17%), and headache (14%). Anorexia (11%), diarrhea (8%), rash, fever, weakness, and drowsiness were also reported as 6% each. Uncommon adverse events (2% -5%) in decreasing order of incidence are abdominal pain, pain, dizziness, weight loss, discomfort, dyspnea, hair loss, stiffness, itching, indigestion, abnormal taste, paresthesia, and petechiae .

Laboratory results: The incidence of grade 3 or 4 thrombocytopenia and neutropenia in glioma patients was 19% and 17%, respectively. 8% and 4% of glioma patients were hospitalized and / or discontinued. Myelosuppression is predictable (usually on days 21-28 of the first few cycles) and usually recovers quickly within 1-2 weeks. No cumulative bone marrow suppression was found. Pancytopenia, leukopenia, and anemia have been reported; lymphopenia is also common.

Analysis of the pharmacokinetic population in clinical trials showed that the number of neutrophils reached the lowest level, 101 women and 169 men; the number of platelets reached the lowest value, 110 women and 174 men. The incidence of Grade 4 adverse reactions in the first cycle of treatment was higher in women than men, among which neutropenia (ANC <500cells / uL) was 12% in women and 5% in men; thrombocytopenia (<20000 cells / L) was 9% in women. 3% for men.

In a group of 400 patients with recurrent glioma, the incidence of grade 4 neutropenia in the first cycle of treatment was 8% and 4% for women and men, respectively; and grade 4 thrombocytopenia The incidence rates were 8% and 3%, respectively. In another newly diagnosed multiline glioblastoma test involving 288 subjects, the incidence of grade 4 neutropenia in the first cycle of treatment was 3% for women and 0 for men. %; The incidence of grade 4 thrombocytopenia was 1% and 0%, respectively.

During the marketing period of this product, few cases of opportunistic infections were reported, including pneumocystis carinii pneumonia. Few cases of erythema erythematosus, toxic epidermal necrosis, Sjogger's syndrome, and allergies (including allergic reactions) are rarely 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 receiving this product. Reports of pancytopenia that can cause aplastic anemia are rare, and cases of liver toxicity have been reported including elevated liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.

[Taboo]

1. Those who are allergic to temozolomide capsules or dacarbazine (DTIC) are contraindicated.

2. Banned during pregnancy (see Medications for pregnant and lactating women).

3. Disabled in patients with severe bone marrow suppression.

【Precautions】

In a small-scale trial with treatment duration extended to 42 days, patients receiving concomitant therapy with this product and radiotherapy were at high risk for Pneumocystis carinii pneumonia (PCP). Therefore, for all patients who received concomitant treatment for 42 days (up to 49 days), it is necessary to prevent the occurrence of pneumocystis carinii pneumonia.

During longer-term dosing regimens, the incidence of Pneumocystis carinii pneumonia may be higher during temozolomide treatment. Regardless of the treatment plan, all patients treated with temozolomide (especially those receiving steroids) should be closely monitored for the possibility of developing pneumocystis carinii pneumonia.

       Antiemetic treatment: Nausea and vomiting are often related to this product. Antiemetics can be used before and after taking this product. The guiding principles are:

Patients with newly diagnosed glioblastoma multiforme:

-Before starting temozolomide combination therapy, antiemetic prophylaxis is recommended;

-During adjuvant therapy, antiemetic prophylaxis is strongly recommended.

Patients with glioma recurrence or progression: Patients who have experienced severe (grade 3 or 4) vomiting in a previous treatment cycle need antiemetic therapy.

Male patients: Male patients taking temozolomide should take effective contraception. Temozolomide is genotoxic, so men should have contraception during the course of treatment and within 6 months after the end of treatment. Because treatment with temozolomide may cause irreversible infertility, sperm should be stored frozen before receiving this treatment.

Patients with impaired liver function: Patients with normal liver function have similar pharmacokinetic results to patients with mild to moderate abnormal liver function; patients with severe liver dysfunction (Child's Class |||) or renal dysfunction have no data on taking temozolomide. According to the pharmacokinetic characteristics of temozolomide, it is not necessary to reduce the amount of temozolomide in patients with severe hepatic and renal dysfunction, but caution must be exercised when using it.

[Medication for pregnant and lactating women]

The safety and effectiveness of the drug in pregnant women have not been studied. In preclinical studies using rats and rabbits, teratogenic and / or fetal toxicity have been reported at 150 mg / m 2 . Therefore, temozolomide should not be routinely used in pregnant women. If the drug must be used during pregnancy, the patient should be informed of the potential risks to the fetus. Women who are likely to become pregnant should be discouraged from getting pregnant within 6 months of temozolomide treatment or termination of temozolomide treatment. Whether temozolomide can be secreted by breast milk is unknown, so temozolomide capsules should not be used in lactating women.

[Children's medication] There is no clinical experience of using the drug in children with glioblastoma multiforme under 3 years of age; for children with gliomas older than 3 years, the clinical experience of using the drug is limited.

[Medication for the elderly] Compared with young patients, elderly patients (> 70 years) are more likely to have neutropenia and thrombocytopenia.

【medicine interactions】

There was no clinical significance of the effect of concurrent taking ranitidine or food on the absorption of temozolomide capsules. Taking dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H 2 receptor antagonists, or phenobarbital at the same time did not affect the clearance of temozolomide. When taking valproic acid at the same time, temozolomide clearance was slightly reduced (statistically significant).

When temozolomide capsules are used in combination with other drugs that cause bone marrow suppression, bone marrow suppression may worsen.

[Drug overdose]

Clinical evaluations have been performed in foreign clinical studies at doses of 500, 750, 1000, and 1250 mg / m 2 (total dose of 5 days per treatment cycle). Dose-limiting toxicity is hematological toxicity, which has been reported at any dose, but is more severe at higher doses. One patient overdosed 2000 mg daily for 5 days. The reported adverse events were pancytopenia, fever, multiple organ failure, and death. Adverse events in patients taking the drug for more than 5 days (up to 64 days) included myelosuppression (with or without infection), and some severe and persistent cases eventually died. In the event of an overdose, a hematological evaluation should be performed. Supportive measures should be taken when necessary.

[Pharmacology and Toxicology]

Pharmacological action

Temozolomide is an alkylating agent with antitumor activity of imidazo tetrazines. At the physiological pH state of the systemic circulation, it is rapidly converted into the active product MTIC (3-methyl- (triazine-1-) imidazole-4-carboxamide). The cytotoxic effect of MTIC is mainly manifested by the alkylation of the guanine oxygen atom at the 6th position and the alkylation of the 7th nitrogen atom. Through the mismatch repair of methylated adducts, it exerts cytotoxicity.

Toxicology research

A single dose toxicity study of this product was performed in mice, rats and dogs. The oral LD 50 of rats is about 1900 mg / m 2 , which is higher than that of mice (about   1000mg / m 2 ). The minimum lethal dose to dogs is 600 mg / m 2 . In single-dose studies, clinical signs and death of toxicity generally appear later, indicating that it has a late toxic effect on tissues that cause rapid proliferation of organ damage; the toxic effect is consistent with the expected toxicity of alkylating agents.

After oral administration, the product is quickly absorbed and excreted into the urine. Human exposure to therapeutic doses is similar to that of rats and dogs. Toxicity studies in rats and dogs have been performed in 3 and 6 cycles, with one cycle consisting of 5 days of dosing and 23 days of discontinuation. In multi-cycle studies, the main toxic target organs are the bone marrow, lymphatic reticulum, testis, and gastrointestinal tract.

This product is more toxic to rats and dogs than to humans. Humans are well tolerated at the therapeutic dose (200 mg / m 2 ), but this dose is close to the lowest lethal dose of multiple doses in rats and dogs. Dose-related reductions in white blood cells and platelets are sensitive indicators for rats and dogs. During the treatment period, most hematological and biochemical indicators as well as histopathological changes can be significantly recovered. The tumor spectrum examined in the 6-cycle rat study includes breast cancer, keratoderma acanthoma, basal cell adenoma, and various stromal tumors. No tumors or precancerous changes were examined in the dog study. Considering that this product is a prodrug of the alkylating agent MTIC, it is expected to have a tumorigenic effect, which has been observed in other alkylating agents (including those that produce MTIC). The tumorigenic effect of this product on rats seems to be species-specific and has no significant difference from other chemotherapeutic drugs.

This product shows mutagenic effects in Ames / Salmonella and HPBL tests; and can cause chromosomal aberrations in human peripheral lymphocyte assays.

【Pharmacokinetics】

Preclinical data suggest that this product can quickly cross the blood-brain barrier and enter the cerebrospinal fluid. Adult patients are quickly absorbed after oral administration of this product, and peak plasma concentrations can be reached as early as 20 minutes after taking the drug (average time is 0.5-1.5 hours). Plasma clearance, volume of distribution, and half-life are independent of dose. This product has a low protein binding rate (10-20%), so it is estimated that it will not interact with drugs with high protein binding rate. Oral 14C-The 14C excreted in the feces within 7 days after this product is 0.8%, indicating that the drug is completely absorbed. After oral administration, the original drug in the urine for 24 hours accounts for about 5% -10% of the dose, and the rest is excreted into the urine as AIC (4-amino-5-imidazole-carboxamide hydrochloride) or other polar metabolites.

Analysis of population pharmacokinetics showed that plasma clearance of this product was not related to age, renal function, or smoking. The AUC of pediatric patients is higher than that of adult patients, but the maximum tolerated dose (MTD) per cycle for children and adults is 1000 mg / m 2 .

【Storage】

Shaded, sealed, and stored at 2-30 ° C.

[Packaging] Plastic bottle.

5mg, 5 capsules / bottle or 8 capsules / bottle

50mg, 5 capsules / bottle or 7 capsules / bottle

100mg, 5 capsules / bottle

[Validity] 36 months

[Executive Standards] 2015 Chinese Pharmacopoeia

【Approval Number】

5mg, Chinese Medicine Standard H20040636

50mg, Chinese Medicine Standard H20040637

100mg, Chinese medicine standard H20060880

【manufacturer】