Temozolomide

TEMOZOLOMIDE

Complete information including dosage, side effects, interactions and pregnancy & breast feeding warnings for patient and professional use

Overview and uses

Temozolomide is an alkylating agent belonging to triazine class of compounds and are used for the treatment of cancer.

Indication (uses)

  • Newly Diagnosed Glioblastoma Multiforme
    • For the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.
  • Refractory Anaplastic Astrocytoma
    • For the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

Pharmacological classification

Alkylating agent (triazines) used for the treatment of cancer.

Brand names

TEMODAR, GLIOZ

Dosage form

  • Temozolomide is available in capsules for oral administration and injections in below mentioned strengths.
    • Capsules
      • Capsules are available in strengths of 5mg, 20 mg, 100 mg, 140 mg, 180 mg, 250 mg.
    • Injection
      • Available as 100 mg/vial powder for injection.

Mechanism of action

Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.

Dosage

The dosage of Temozolomide must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and the neutrophil and platelet counts at the time of initiating the next cycle.

  • Patients with Newly Diagnosed High-Grade Glioma
    • Concomitant Phase
      • TEMODAR is administered at 75 mg/m² daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) followed by maintenance TEMODAR for 6 cycles. Focal RT includes the tumor bed or resection site with a 2-to 3-cm margin. No dose reductions are recommended during the concomitant phase; however, dose interruptions or discontinuation may occur based on toxicity. The TEMODAR dose should be continued throughout the 42-day concomitant period up to 49 days if all of the following conditions are met: absolute neutrophil count greater than or equal to 1.5 x 109/L, platelet count greater than or equal to 100 x 109/L, common toxicity criteria (CTC) nonhematological toxicity less than or equal to Grade 1 (except for alopecia, nausea, and vomiting). During treatment, a complete blood count should be obtained weekly. Temozolomide dosing should be interrupted or discontinued during concomitant phase according to the hematological and nonhematological toxicity criteria as noted in Table 1. Pneumocystis pneumonia (PCP) prophylaxis is required during the concomitant administration of TEMODAR and radiotherapy and should be continued in patients who develop lymphocytopenia until recovery from lymphocytopenia (CTC Grade less than or equal to 1).

TABLE 1: Temozolomide Dosing Interruption or Discontinuation During Concomitant Radiotherapy and Temozolomide

Toxicity TMZ Interruption* TMZ Discontinuation
Absolute Neutrophil Count greater than or equal to 0.5 and less than 1.5 x 109/L less than 0.5 x 109/L
Platelet Count greater than or equal to 10 and less than 100 x 109/L less than 10 x 109/L
CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 2 CTC Grade 3 or 4
*Treatment with concomitant TMZ could be continued when all of the following conditions were met: absolute neutrophil count greater than or equal to 1.5 x 109/L; platelet count greater than or equal to 100 x 109/L; CTC nonhematological toxicity less than or equal to Grade 1 (except for alopecia, nausea, vomiting).

TMZ=temozolomide; CTC=Common Toxicity Criteria.

  • Maintenance Phase
    • Cycle 1
      • Four weeks after completing the TEMODAR+RT phase, TEMODAR is administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/m² once daily for 5 days followed by 23 days without treatment.
    • Cycles 2-6
      • At the start of Cycle 2, the dose can be escalated to 200 mg/m², if the CTC nonhematologic toxicity for Cycle 1 is Grade less than or equal to 2 (except for alopecia, nausea, and vomiting), absolute neutrophil count (ANC) is greater than or equal to 1.5 x 109/L, and the platelet count is greater than or equal to 100 x 109/L. The dose remains at 200 mg/m² per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles.
    • Dose Reduction or Discontinuation During Maintenance
      • Dose reductions during the maintenance phase should be applied according to Tables 2 and 3.
      • During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of TEMODAR) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 109/L (1500/μL) and the platelet count exceeds 100 x 109/L (100,000/μL). The next cycle of TEMODAR should not be started until the ANC and platelet count exceeds these levels. Dose reductions during the next cycle should be based on the lowest blood counts and worst nonhematologic toxicity during the previous cycle. Dose reductions or discontinuations during the maintenance phase should be applied according to Tables 2 and 3.

TABLE 2: Temozolomide Dose Levels for Maintenance Treatment

Dose Level Dose (mg/m²/day) Remarks
-1 100 Reduction for prior toxicity
0 150 Dose during Cycle 1
1 200 Dose during Cycles 2-6 in absence of toxicity

TABLE 3: Temozolomide Dose Reduction or Discontinuation during Maintenance Treatment

Toxicity Reduce TMZ by 1 Dose Level* Discontinue TMZ
Absolute Neutrophil Count less than 1.0 x 109/L See footnote†
Platelet Count less than 50 x 109/L See footnote†
CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 3 CTC Grade 4†
*TMZ dose levels are listed in Table 2.

†TMZ is to be discontinued if dose reduction to less than 100 mg/m² is required or if the same Grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.

TMZ=temozolomide; CTC=Common Toxicity Criteria.

  • Patients with Refractory Anaplastic Astrocytoma
    • For adults the initial dose is 150 mg/m² once daily for 5 consecutive days per 28-day treatment cycle. For adult patients, if both the nadir and day of dosing (Day 29, Day 1 of next cycle) ANC are greater than or equal to 1.5 x 109/L (1500/μL) and both the nadir and Day 29, Day 1 of next cycle platelet counts are greater than or equal to 100 x 109/L (100,000/μL), the TEMODAR dose may be increased to 200 mg/m²/day for 5 consecutive days per 28-day treatment cycle. During treatment, 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 (1500/μL) and the platelet count exceeds 100 x 109/L (100,000/μL). The next cycle of TEMODAR should not be started until the ANC and platelet count exceed these levels. If the ANC falls to less than 1.0 x 109/L (1000/μL) or the platelet count is less than 50 x 109/L (50,000/μL) during any cycle, the next cycle should be reduced by 50 mg/m², but not below 100 mg/m², the lowest recommended dose (see Table 4). TEMODAR therapy can be continued until disease progression. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known.

TABLE 4: Dosing Modification Table

temozolomide

Table 5: Daily Dose Calculations by Body Surface Area (BSA)

Total BSA (m²) 75 mg/m² (mg daily) 150 mg/m² (mg daily) 200 mg/m² (mg daily)
1.0 75 150 200
1.1 82.5 165 220
1.2 90 180 240
1.3 97.5 195 260
1.4 105 210 280
1.5 112.5 225 300
1.6 120 240 320
1.7 127.5 255 340
1.8 135 270 360
1.9 142.5 285 380
2.0 150 300 400
2.1 157.5 315 420
2.2 165 330 440
2.3 172.5 345 460
2.4 180 360 480
2.5 187.5 375 500

TABLE 6: Suggested Capsule Combinations Based on Daily Dose in Adults

Number of daily capsules by strength (mg)
Total daily dose (mg) 250 mg 180 mg 140 mg 100 mg 20 mg 5 mg
75 0 0 0 0 3 3
82.5 0 0 0 0 4 0
90 0 0 0 0 4 2
97.5 0 0 0 1 0 0
105 0 0 0 1 0 1
112.5 0 0 0 1 0 2
120 0 0 0 1 1 0
127.5 0 0 0 1 1 1
135 0 0 0 1 1 3
142.5 0 0 1 0 0 0
150 0 0 1 0 0 2
157.5 0 0 1 0 1 0
165 0 0 1 0 1 1
172.5 0 0 1 0 1 2
180 0 1 0 0 0 0
187.5 0 1 0 0 0 1
195 0 1 0 0 0 3
200 0 1 0 0 1 0
210 0 0 0 2 0 2
220 0 0 0 2 1 0
225 0 0 0 2 1 1
240 0 0 1 1 0 0
255 1 0 0 0 0 1
260 1 0 0 0 0 2
270 1 0 0 0 1 0
280 0 0 2 0 0 0
285 0 0 2 0 0 1
300 0 0 0 3 0 0
315 0 0 0 3 0 3
320 0 1 1 0 0 0
330 0 1 1 0 0 2
340 0 1 1 0 1 0
345 0 1 1 0 1 1
360 0 2 0 0 0 0
375 0 2 0 0 0 3
380 0 1 0 2 0 0
400 0 0 0 4 0 0
420 0 0 3 0 0 0
440 0 0 3 0 1 0
460 0 2 0 1 0 0
480 0 1 0 3 0 0
500 2 0 0 0 0 0

For more information on preparation and administration of Temozolomide, read the manufacturer’s package insert.

Renal dose adjustments

  • Data not available. Dose adjustments may be required.

Hepatic dose adjustments

  • Data not available. Dose adjustments may be required.

Geriatric dose adjustments

  • Data not available. Dose adjustments may be required.

Pediatric Use

  • Data not available. Dose adjustments may be required.

Overdosage

  • No specific antidote is known.
  • Symptoms of Overdosage includes
    • Pancytopenia
    • Pyrexia
    • multi-organ failure
    • death
  • Treatment of overdosage involves
  • General supportive measures.

Side effects or adverse effects

Side effects specific to Temozolomide

  • Myelosuppression
    • Myelosuppression including prolong pancytopenia which may result in aplastic anemia, which in some cases has resulted in the fatal outcome.
  • Myelodysplastic syndrome
    • Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia.
  • Pneumocystis pneumonia
  • hepatotoxicity
    • fatal and severe hepatotoxicity
  • Embryo fetal toxicities
    • Temozolomide can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose.

Other side effects

  • Bone marrow depression
    • Bone marrow depression is the most serious side effect/toxicity. It is also a limiting factor for the dose. Infections and bleeding are the common complications.
    • Bone marrow depression results in granulocytopenia, agranulocytosis, thrombocytopenia and aplastic anemia.
    • Consult your doctor as soon as possible if you observe any of the below-mentioned symptoms:
      • Sore throat
      • Chills
      • Sudden fever
      • Weakness in limbs
      • Mouth ulcers
      • Bleeding gums
      • Sore mouth
      • Fast heart rate
      • Low blood pressure
      • Sore gums
      • Skin abscesses
      • Rapid breathing
      • Rapid progression of infection of any organ
      • Rapid progression of Septicemia
    • Gastrointestinal side effects
      • Nausea and vomiting are commonly observed with anticancer medicines.
      • Mucositis – painful inflammation and ulceration of mucus membrane lining the digestive tract.
      • Diarrhea, shredding of mucosa and hemorrhage due to decreased rate of renewal of gastrointestinal mucosa lining.
    • Skin
      • Alopecia or hair loss.
      • Dermatitis
    • Oral side effects
      • Breaches during chewing.
      • Depression of immunity due to a reduction in the number of WBCs largely increases the risk of oral infections.
      • Bleeding gums
      • Rapid progression of dental caries.
    • Gonadal side effects
      • Infertility due to Oligozoospermia in males.
      • Impotence in males.
      • Loss or reduces sex drive.
      • Inhibition of ovulation in females
      • Amenorrhea in females.
      • Damage to germinal cells may lead to mutagenesis.
    • Lymphoreticular tissue
      • Lymphocytopenia (reduced number of lymphocytes)
      • Inhibition of lymphocyte function.
      • Suppression of immunity due to bone marrow depression and reduced lymphocyte function highly increases the risk of opportunistic infections like:
        • Candida and other infections causing deep mycosis.
        • Cytomegalo virus
        • Herpes zoster
        • Pneumocystis jiroveci
        • Toxoplasma
      • Fetal side effects
        • Use of anti-cancer medicines in pregnant women may cause fetal damage leading to:
          • Fetal death
          • Abortion
          • Teratogenesis
        • Renal side effects
          • Renal failure, Gout, and Urate stones may develop in the urinary tract.
        • Hyperuricemia
          • An elevated level of uric acid is common in leukemia and bulky lymphomas.
  • Please note: The side effects mentioned above are from the reported cases. However, side effects are not limited to above-mentioned conditions and symptoms. Consult your doctor as soon as possible if you feel or observe any symptoms that you relate to your treatment.

Warnings & Precautions

  • Temozolomide can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose.

Contraindications

  • Contraindicated in patients with previous hypersensitivity to Temozolomide.

Pregnancy & breast feeding warnings

  • Pregnancy
    • Category D, which means there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
  • Nursing
    • It is not known whether Temozolomide is excreted in human breast milk or not.
    • Since many drugs are excreted in milk and because of the potential for side effects in nursing infants, a decision should be made whether to discontinue drug or to discontinue nursing.

Interactions

Drug – drug interactions

  • Co-administration of valproic acid decreases the oral clearance of Temozolomide by 5%.
  • Concomitant use of Temozolomide with following drugs/medicines should be strictly avoided.
    • Leflunomide as it increases the risk of infections.
    • Adalimumab as it increases the risk of infections.
    • Teriflunomide as it increases the risk of infections.
    • Certolizumab as it increases the risk of infections.
    • Clozapine as it may lower the WBC count.
    • Tofacitinib as it increases the risk of infections.
    • Deferiprone as it may lower the WBC count.
    • Etanercept as it increases the risk of infections.
    • Fingolimod as it increases the risk of infections.
    • Anakinra as it increases the risk of infections.
    • Golimumab as it increases the risk of infections.
    • Infliximab as it increases the risk of infections.
    • Thalidomide may increase the risk of dangerous blood clots.
    • Lomitapide may cause liver problems and concomitant use with Temozolomide may increase that risk.
    • Talimogene may increase the risk of potentially life threatening herpes infection.
    • Nalidixic acid as the combination may cause unusual bruising or bleeding, nausea, stomach pain, unusual weakness, low fever and loss of appetite.
    • Natalizumab as it increases the risk of infections.
    • Thiotepa as it may affect the bone marrow function.
    • Brentuximab may cause liver problems and concomitant use with Temozolomide may increase that risk.
    • Doxorubicin may increase the side effects of Temozolomide, especially on bone marrow function.
    • Aldesleukin may increase the risk of tumor lysis syndrome, which is associated with certain electrolyte and chemical imbalances in the blood and kidney failure.
    • Alefacept as it increases the risk of infections.
    • Alemtuzumab as it increases the risk of infections.
    • Efalizumab as it increases the risk of infections.
    • Filgrastim as it may affect the effect of Temozolomide.
    • Fluorouracil as it may increase the side effect of Temozolomide.
    • Fludarabine as it may affect the bone marrow function.
    • Azathioprine as it increases the risk of infections.
    • Bedaquiline may cause liver problems and concomitant use with Temozolomide may increase that risk.
    • Etoposide as it may affect bone marrow function.
    • Efavirenz as it may increase the risk of liver toxicity.
    • Docetaxel as it may affect the bone marrow function.
    • Bendamustine may increase the side effects of Temozolomide, especially on bone marrow function.
    • Vinorelbine as it may affect the bone marrow function.
    • Busulfan may increase the side effects of Temozolomide, especially on bone marrow function.
    • Bleomycin may increase the side effects of Temozolomide, especially on bone marrow function.
    • Canakinumab as it increases the risk of infections.
    • Cisplatin may increase the side effects of Temozolomide, especially on bone marrow function.
    • Cladribine as it increases the risk of infections.
    • Clofarabine may increase the risk of liver toxicity.
    • Capecitabine may increase the side effects of Temozolomide, especially on bone marrow function.
    • Carboplatin may increase the side effects of Temozolomide, especially on bone marrow function.
    • Daunorubicin may increase the side effects of Temozolomide, especially on bone marrow function.
    • Imatinib as it may affect the bone marrow function.
    • Ifosfamide as it may affect the bone marrow function.
    • Idarubicin as it may affect the bone marrow function.
    • Mechlorethamine as it may affect the bone marrow function.
    • Melphalan as it may affect the bone marrow function.
    • Mitomycin as it may affect the bone marrow function.
    • Mitoxantrone as it may affect the bone marrow function.
    • Mercaptopurine as it may affect the bone marrow function.
    • Nelarabine as it may affect the bone marrow function.
    • Niraparib as it may potentiate the bone marrow toxicity.
    • Omacetaxine as it increases the risk of serious infections.
    • Oxaliplatin as it may affect the bone marrow function.
    • Olaparib as it increases the risk of bone marrow impairment which may lead to myelodysplastic syndrome or acute myeloid leukemia.
    • Ganciclovir may increase the side effects of Temozolomide, especially on bone marrow function.
    • Gemcitabine as it may affect the bone marrow function.
    • Temozolomide may increase the side effects of Carmustine, especially on bone marrow function.
    • Decitabine may increase the side effects of Temozolomide, especially on bone marrow function.
    • Dactinomycin may increase the side effects of Temozolomide, especially on bone marrow function.
    • Denosumab may increase the risk of serious infections involving the skin.
    • Ocrelizumab may increase the risk of serious infections.
    • Pentostatin as it may affect the bone marrow function.
    • Ruxolitinib as it may affect the bone marrow function.
    • Rilonacept as it increases the risk of serious infections.
    • Streptozocin as it may affect the bone marrow function.
    • Ustekinumab as it increases the risk of serious infections.
    • Topotecan as it may affect the bone marrow function.
    • Trabectedin as it may increase the risk of liver toxicity.

Click here to go to Temozolomide forums.

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Reference

  • Highlights of prescribing information: 1
By | 2017-08-11T14:04:46+00:00 August 11th, 2017|medicines|0 Comments

About the Author:

B. Pharm (K.L.E. society’s S.V.V. Patil College of Pharmacy, Bengaluru)
M. Pharm (Maharishi Arvind Institute of Pharmacy, Jaipur)

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