Temovex-20/Temovex-100

Temovex-20/Temovex-100

temozolomide

Manufacturer:

Vexxa Lifesciences

Distributor:

VE Pharma
Full Prescribing Info
Contents
Temozolomide.
Description
TEMOVEX-20 (Temozolomide Capsules 20 mg) Each Hard gelatin capsule contains: Temozolomide 20 mg.
Approved colours used in capsule shells.
TEMOVEX-100 (Temozolomide Capsules 100 mg) Each Hard gelatin capsule contains: Temozolomide 100 mg.
Approved colours used in capsule shells.
Temozolomide is a White to light tan/light pink powder. Sparingly soluble in dimethyl sulphoxide and N,N-dimethyl formamide, slightly soluble in acetonitrile and water; very slightly soluble in methanol. Temozolomide is described chemically as 4-methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene- 9-carboxamide. The molecular formula is C6H6N6O2 and the molecular weight is 194.15.
Action
Pharmacotherapeutic group: Other alkylating agents. ATC code: L01A X03.
Pharmacology: Pharmacodynamics: Mechanism of Action: Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.
Paediatric population: Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance to TMZ is similar to adults.
Pharmacokinetics: Absorption: After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of 14C-labelled TMZ, mean faecal excretion of 14C over 7 days post-dose was 0.8 % indicating complete absorption.
Distribution: TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with highly protein-bound substances.
PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data.
Elimination: The half-life (t1/2) in plasma is approximately 1.8 hours. The major route of 14C elimination is renal. Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-carboxamide (AIC) or unidentified polar metabolites.
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.
Special populations: Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.
Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults
Indications/Uses
TEMOZOLOMIDE (TEMOVEX) used in the treatment of malignant gliomas such as glioblastoma multiforme and anaplastic astrocytoma, and malignant melanoma.
Dosage/Direction for Use
Adult patients with newly-diagnosed glioblastoma multiforme: TEMOZOLOMIDE (TEMOVEX) hard capsules is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).
Concomitant phase: TMZ is administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met: absolute neutrophil count (ANC) ≥1.5 x 10; thrombocyte count ≥100 x 10; common toxicity criteria (CTC) non-haematological toxicity ≤Grade 1 (except for alopecia, nausea and vomiting).
During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1. (See Table 1.)

Click on icon to see table/diagram/image

Monotherapy phase: Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m2 if the CTC nonhaematological toxicity for Cycle 1 is Grade ≤2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is ≥1.5 x 109/l, and the thrombocyte count is ≥100 x 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase should be applied according to Tables 2 and 3. (See Table 2.)

Click on icon to see table/diagram/image

During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TMZ). The dose should be reduced or administration discontinued according to Table 3 (see Table 3).

Click on icon to see table/diagram/image

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma: A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered orally at a dose of 200 mg/m2 once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 once daily, for 5 days if there is no haematological toxicity (see Adverse Reactions).
If vomiting occurs after the dose is administered, a second dose should not be administered that day.
Overdosage
Doses of 500, 750, 1,000, and 1,250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was hematologic and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2,000 mg per day for 5 days was taken by one patient and the adverse events reported were pancytopenia, pyrexia, multi-organ failure, and death. There are reports of patients who have taken more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity to dacarbazine (DTIC).
Severe myelosuppression.
Warnings
Patients treated with temozolomide capsules may experience myelosuppression. Prior to dosing, patients must have an absolute neutrophil count (ANC) ≥ 1.5 x 109/L and a platelet count ≥ 100 x 109/L. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 109/L and platelet count exceeds 100 x109/L.
Adverse Reactions
The most frequently occurring adverse effects were nausea, vomiting, headache, and fatigue. Most adverse effects were self limiting, and the nausea and vomiting were controlled with antiemetics. The incidence of grade 3 or 4 nausea occurred in 10%, and vomiting occurred in 6%. The dose-limiting toxicity of temozolomide is myelosuppression. The median nadirs in temozolomide studies occurred at 28 days (range 1 to 44 days) for neutrophils and 26 days (range 22 to 40 days) for platelets. The myelosuppression is the most common dose-limiting adverse event. The average time for the absolute neutrophil count (ANC) and platelet count to return to normal from the nadir was 14 days. Temozolomide may induce hypercoagulability. Pulmonary emboli and venous thrombosis were observed however, it is possible those events may have been associated with the disease being treated rather than the treatment.
Drug Interactions
Administration of valproic acid decreases oral clearance of temozolomide by about 5%. The clinical implication of this effect is not known.
Storage
Store at temperatures not exceeding 30°C. Protect from light and moisture.
Shelf Life: Two years from the date of Manufacturing.
ATC Classification
L01AX03 - temozolomide ; Belongs to the class of other alkylating agents. Used in the treatment of cancer.
Presentation/Packing
Temovex-20: Cap 20 mg (Caramel colored cap and Pink colored body hard gelatin capsules shell size "4" containing off white powder) x 5's.
Temovex-100: Cap 100 mg (Blue cap and white body hard gelatin capsule shell size "2" containing off white powder) x 5's.
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