Description

Indication

• Newly diagnosed glioblastoma multiforme in adults, concomitantly with radiotherapy and then as maintenance treatment
• Refractory anaplastic astrocytoma in adults who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine

Dosage

• 100mg per square meter (m²) of body surface area, taken orally once daily
• Maximum duration of 42 to 49 days in combination with focal radiotherapy for treating certain types of brain cancer

Unique Information

• Temozolomide is a hazardous drug that requires special handling and disposal procedures
• The capsules are imported into Pakistan and may be subject to high prices, as reported by consumers
• Patients should consult with their oncologists to determine the appropriate treatment plan and obtain the necessary medication through proper channels
  

  Key Benefits of Temozolomide 100mg 5’ct Capsules

  Indication

  • Treats newly diagnosed glioblastoma multiforme in adults, used concomitantly with radiotherapy and then as maintenance treatment
  • Treats refractory anaplastic astrocytoma in adults who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine

  Dosage

  • Recommended dosage is 100mg per square meter (m²) of body surface area, taken orally once daily
  • Maximum duration of 42 to 49 days in combination with focal radiotherapy for treating certain types of brain cancer

  Unique Characteristics

  • Temozolomide is a hazardous drug that requires special handling and disposal procedures
  • The capsules are imported into Pakistan and may be subject to high prices, as reported by consumers
  • Patients should consult with their oncologists to determine the appropriate treatment plan and obtain the necessary medication through proper channels

  Key Ingredients

  The key ingredient in Temozolomide 100mg 5’ct Capsules is:

  • Temozolomide – A chemotherapy medication used to treat certain types of brain cancer, including glioblastoma multiforme and anaplastic astrocytoma.

  The capsules also contain the following excipient:

  • Lactose – A common filler and binder used in pharmaceutical capsules.
    

    Mechanism of Action of Temozolomide

    Temozolomide is an imidazotetrazine alkylating agent that undergoes rapid chemical conversion at physiologic pH to the active compound, 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).The cytotoxicity of MTIC is thought to be primarily due to DNA alkylation, mainly at the O6 and N7 positions of guanine, which causes DNA double strand breaks and results in programmed cell death.Temozolomide is not directly active but requires this conversion to MTIC to exert its antitumor effects.

  MTIC (5-(3-methyltriazen-1-yl)imidazole-4-carboxamide) plays a crucial role in the mechanism of action of Temozolomide. Here are the key points:

  1. Conversion to MTIC: Temozolomide is a prodrug that undergoes spontaneous nonenzymatic hydrolysis at physiological pH to form MTIC. This conversion occurs rapidly in the body, making MTIC the active metabolite of Temozolomide.
  2. DNA Alkylation: MTIC is a potent methylating agent that deposits methyl groups on DNA guanine bases. It primarily methylates DNA at the O6 and N7 positions of guanine, which leads to the formation of DNA nicks and ultimately apoptosis. This DNA alkylation is the primary mechanism by which Temozolomide exerts its cytotoxic effects.
  3. Repair Mechanisms: The repair of MTIC-induced DNA damage is crucial in determining the efficacy of Temozolomide. Cells with a functional O6-alkylguanine DNA alkyltransferase (AGT) enzyme, encoded by the MGMT gene, can repair the O6-methylguanine lesions, reducing the cytotoxicity of Temozolomide. Conversely, cells with deficient MGMT expression are more sensitive to Temozolomide due to their inability to repair the DNA damage.
  4. Resistance Mechanisms: The presence of mismatch repair (MMR) proteins can also influence the response to Temozolomide. Cells with intact MMR pathways can repair the DNA damage caused by Temozolomide, leading to resistance. However, cells with both MGMT deficiency and MMR deficiency are more susceptible to the cytotoxic effects of Temozolomide.

  The chemical structure of Temozolomide is:

  text

  Cn1c(=O)n2cnc(c2nn1)C(=O)N


  InChI: BPEGJWRSRHCHSN-UHFFFAOYSA-NThis structure is also validated by ChemSpider and PubChem, confirming the molecular formula as C₆H₆N₆O₂.                                                                Temozolomide is synthesized in the laboratory through the following key steps:

  1. Synthesis of Urea Intermediates: An alternate and scalable process for the synthesis of Temozolomide involves the synthesis of urea intermediates, as described in the ResearchGate article .
  2. Reaction with 4-Nitrophenyl Chloroformate: The process described in US Patent 6,844,434  involves reacting 5-amino-1H-imidazole-4-carboxamide hydrochloride (II) with 4-nitrophenyl chloroformate to afford an intermediate compound, which is then reacted with methyl hydrazine to obtain the corresponding compound (IV). This compound is then cyclized to yield Temozolomide.
  3. Reaction with Methyl Hydrazine: Another synthesis method, as outlined in US Patent Application 2002/0095036 , involves reacting an intermediate compound with methyl hydrazine to obtain Temozolomide.
  4. Crystallization and Purification: The synthesized Temozolomide is typically purified by crystallization from solvents like acetone, acetic acid, and water, as described in the various patent documents . This allows for the isolation of highly pure Temozolomide.

  Key Precautions

  Handling and Administration

  • Temozolomide is a hazardous drug that requires special handling and disposal procedures
  • Wear gloves when handling the capsules to avoid direct skin contact
  • Avoid opening or crushing the capsules to prevent inhalation of the powder
  • Administer the capsules immediately after transferring from the packaging to a disposable cup
  • Properly dispose of any used gloves, cups, and other contaminated materials

  Storage

  • Store Temozolomide at room temperature (68°F–77°F) in a dry location away from light
  • Keep the medication out of reach of children and pets

  Missed Doses

  • Do not take an extra dose or two doses at one time if a dose is missed
  • Simply take the next scheduled dose at the regular time

  Drug Interactions

  • Inform your healthcare providers of all medications, supplements, and vaccines you are taking
  • Consult your doctor or pharmacist before starting any new medications or supplements

  Disposal

  • Do not throw away unused Temozolomide in the trash or flush it down the sink/toilet
  • Consult your healthcare provider or pharmacist about the proper disposal method

  Pregnancy

  • Teratogenicity: Animal studies have shown that temozolomide can cause fetal malformations, including external organ, soft tissue, and skeletal defects. Embryolethality has also been observed in animal studies.
  • Human Data: There are no controlled data in human pregnancy, and the potential benefits of using temozolomide during pregnancy may not outweigh the risks.
  • Contraception: Females of reproductive potential should use effective contraception during treatment and for at least 6 months after the last dose.

  Breastfeeding

  • Contraindicated: Temozolomide is contraindicated for breastfeeding women due to the potential for serious adverse reactions in the breastfed child, including myelosuppression.
  • Breastfeeding Warnings: In Australia, the use of temozolomide is contraindicated during breastfeeding. In the UK and the US, breastfeeding is not recommended during use of this drug.

  Key Points

  • Pregnancy: Temozolomide can cause fetal harm and should not be used during pregnancy.
  • Breastfeeding: Temozolomide is contraindicated during breastfeeding due to potential harm to the breastfeeding infant.

  Some key points regarding diet and Temozolomide:

  • Food reduces the rate and extent of temozolomide absorption compared to the fasted state.
  • Mean peak plasma concentrations are reduced by 32% and the area under the curve (AUC) is reduced by 9% when temozolomide is administered with food.
  • To reduce nausea and vomiting, it is recommended to take temozolomide on an empty stomach, either 1 hour before or 2 hours after a meal.
  • Patients should maintain good nutrition while taking temozolomide.
  • Drink 2 to 3 quarts of fluid every 24 hours, unless fluid intake is restricted, to help decrease the chances of constipation and dehydration.

   key points about drug interactions:

  Drug Interactions

  • 261 drugs are known to interact with temozolomide, which can affect its efficacy and safety profile.
  • Valproic acid can interact with temozolomide, potentially reducing its effectiveness.
  • Vaccines may interact with temozolomide, and patients should consult their healthcare providers before receiving any vaccinations.

  Key Points

  • Consult your healthcare provider about any medications, supplements, or vaccines you are taking to ensure safe and effective treatment.
  • Inform your doctor if you are taking any other medications, as interactions can affect the efficacy and safety of temozolomide.

  Temozolomide has shown promising results in improving survival rates for certain types of brain cancer:

  Glioblastoma

  • When used alongside radiotherapy, temozolomide improved median overall survival to 15-16 months, with a 2-year survival rate of 27%.
  • The addition of tumor-treating fields to temozolomide further improved median overall survival to 20.9 months vs 16 months with temozolomide alone. At 2 years, overall survival was 43.1% vs 30.7% respectively.

  Anaplastic Glioma

  • In patients with anaplastic glioma without 1p/19q codeletion, the addition of adjuvant temozolomide to radiotherapy resulted in 5-year survival rates of 56% compared to 44% with radiotherapy alone.
  • Median time to disease progression was more than twice as long in the adjuvant temozolomide group (42.8 months vs 19 months).

  Recurrent Malignant Glioma

  • For recurrent malignant glioma, the 6-month progression-free survival rates were 41% and 18% for Grade 3 and Grade 4 tumors respectively. Median survival was 49 weeks.