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temozolomide
Temozolomide is an imidazotetrazine derivative of the alkylating agent dacarbazine. It undergoes rapid chemical conversion in the systemic circulation at physiological pH to the active compound, MTIC (monomethyl triazeno imidazole carboxamide). Temozolomide exhibits schedule-dependent antineoplastic activity by interfering with DNA replication.
Oral absorption: yes, 100 % (rapidly absorbed). Administration of temozolomide with food may decrease AUC.
Plasma concentrations are dose-dependent, while plasma clearance, volume of distribution and half-life are independent of dose. No accumulation with multiple dosing.
| Cross blood brain barrier? | Yes |
| PPB | 10-20% |
Temozolomide undergoes spontaneous hydrolysis to MTIC at physiological pH (7.4) with subsequent formation of a reactive methyl-diazonium species, and followed by further degradation to 4-amino-5-imidazole-carboxamide.
| Active metabolites | MTIC and others |
| Inactive metabolites | AIC, temozolomide acid metabolite and others |
Plasma clearance of temozolomide is independent of age, renal function, hepatic function or tobacco use. Temozolomide is eliminated primarily in the urine
| Urine | primary |
| Feces | minor |
| Half-life | 1.2 hours |
- Treatment of adult patients with glioblastoma multiforme or anaplastic astrocytoma, and documented evidence of recurrence or progression after standard therapy.
- Treatment of patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.
Other Uses:
- Neuroendocrine tumours
- Ewing's sarcoma
- Melanoma
Emetogenic Potential:
Low – No routine prophylaxis; PRN recommended (≤ 75 mg/m2/day)
Extravasation Potential: Irritant
The following table contains adverse effects reported mainly in maintenance treatment for newly diagnosed glioma.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Auditory | Hearing impaired (4%) | E | |||
| Cardiovascular | Arterial thromboembolism (rare) | E | |||
| Venous thromboembolism (2%) | E | ||||
| Dermatological | Alopecia (55%) | E | |||
| Rash (13%) (may be severe) | E | ||||
| Gastrointestinal | Abdominal pain (5%) | E | |||
| Anorexia, weight loss (27%) | E | ||||
| Constipation (22%) | E | ||||
| Diarrhea (10%) | E | ||||
| Dyspepsia (2%) | E | ||||
| Mucositis (9%) | E | ||||
| Nausea, vomiting (49%) | I | ||||
| General | Delayed wound healing (1%) | E | |||
| Edema (2%) | E | ||||
| Fatigue (61%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (14%) (severe, include opportunistic infections) | E | |||
| Hepatobiliary | ↑ LFTs (2%) (may be severe) | E D | |||
| Hypersensitivity | Hypersensitivity (3%) | I | |||
| Immune | Other - other viral reactivation (hepatitis B, CMV; rare) | E D | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (1%) (↓ K) | E | |||
| Hyperglycemia (1%) | E | ||||
| Other - diabetes insipidus (rare) | E | ||||
| Musculoskeletal | Musculoskeletal pain (6%) | E | |||
| Neoplastic | Secondary malignancy | D | |||
| Nervous System | Anxiety (4%) | E | |||
| Confusion (5%) | E | ||||
| Dizziness (5%) | E | ||||
| Dysgeusia (5%) | I | ||||
| Headache (23%) | E | ||||
| Insomnia (4%) | E | ||||
| Memory impairment (7%) | E | ||||
| Paresthesia (2%) | E | ||||
| Seizure (11%) | E | ||||
| Somnolence (2%) | E | ||||
| Ophthalmic | Blurred vision (8%) (plus other eye changes) | E | |||
| Reproductive and breast disorders | Irregular menstruation (1%) | E | |||
| Respiratory | Cough, dyspnea (8%) | E | |||
| Pneumonitis (also fibrosis, rare) | E D | ||||
| Urinary | Other (2%) (urinary symptoms) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
Myelosuppression is the major dose-limiting toxicity and is generally not cumulative. There have been reports of prolonged pancytopenia, which may result in aplastic anemia (fatal in some cases).
The most common non-hematologic adverse effects associated with temozolomide were nausea and vomiting and were either self-limiting or readily controlled with standard antiemetic therapy. These effects were generally mild to moderate (grade 1, 2).
All patients on temozolomide should be monitored closely for Pneumocystis carinii pneumonia (PCP). There may be a higher incidence of PCP in patients receiving a longer dosing temozolomide regimen, or in patients receiving corticosteroids. PCP prophylaxis is required for patients receiving temozolomide concurrently with radiotherapy for the 42-day regimen. Screen patients for HBV infection before starting temozolomide treatment. Patients with active hepatitis B should not be treated; those with inactive disease should be closely monitored (see Monitoring).
Herpes simplex encephalitis (HSE), including fatal cases, have been reported, mainly with concomitant radiotherapy.
Potentially fatal cases of interstitial pneumonitis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported during post-marketing.
Hepatic dysfunction may be severe and may occur several weeks after starting temozolomide or after treatment discontinuation. Fatal cases have been reported. Hepatitis B reactivation has been observed rarely and resulted in death in some cases.
Refer to the protocol being used. Antiemetic therapy is recommended prior to or following administration of temozolomide, especially for patients with emesis.
In general, doses of less than 100mg/m2 should not be given except in combination with radiation treatment (RT).
PCP prophylaxis is required when used in combination with radiation.
Newly diagnosed
Concurrent with RT (for 42-49 days):
- 75 mg/m2 daily for 42 days (up to 49 days maximum).
- Check CBC weekly and modify according to Table 1.
THEN
Maintenance (post-RT; q 28 days x 6 cycles starting 4 weeks after completion of RT):
- Cycle 1: 150 mg/m2 daily for 5 days.
- Cycle 2: In absence of hematologic toxicity and ≥ grade 3 of other toxicities in cycle 1, increase to 200mg/m2 x 5 d starting from cycle 2. Otherwise, continue with 150mg/m2 and do not escalate dose in subsequent cycles.
- CBC on day 22 and day 29 (day 1 of next cycle); modify doses as indicated in Table 2.
Recurrent/Progressive
Chemotherapy-naive:
- 200 mg/m2 once daily for 5 days, q28d
- Modify doses as indicated in Table 2.
Previously treated:
- Cycle 1: 150 mg/m2 daily for 5 days.
- Cycle 2: In absence of hematologic toxicity and ≥ grade 3 of other toxicities in cycle 1, increase to 200mg/m2 x 5 d starting from cycle 2. Otherwise, continue with 150mg/m2 and do not escalate dose in subsequent cycles.
- CBC on day 22 and day 29 (day 1 of next cycle); modify doses as indicated in Table 2.
Dose Modification for Newly Diagnosed-Concurrent RT:
- No specific dose reductions are recommended for concurrent RT phase. (Continued on next page)
|
Table 1: Modifications during concurrent treatment |
|||||
|
ANC (109/L) |
|
Platelets (109/L) |
|
Non-hematologic toxicity# |
Action during RT |
|
≥0.5 to <1.5 |
OR |
≥10 to <100 |
OR |
Grade 2 |
Hold until recovery and then restart |
|
< 0.5 |
OR |
<10 |
OR |
≥ Grade 3, including pneumonitis or severe rash |
Discontinue during RT |
| Hepatotoxicity | Assess risk/benefit before continuing treatment | ||||
| Hepatitis B or HSE | Discontinue if active disease or reactivation | ||||
|
# except for alopecia, nausea, vomiting |
|||||
(Continued on next page)
Dose Modifications for Adjuvant-Maintenance and Recurrent/Progressive disease:
- Dose levels are 200, 150 and 100 mg/m2
|
Table 2: Modifications for worst toxicity in previous cycle |
|||||
|
ANC (109/L) |
|
Platelets (109/L) |
|
Non-hematologic toxicity# |
Dose for Next Cycle ** |
|
<1
|
OR
|
< 50 |
OR
|
Grade 3 |
Reduce by 1 dose level* |
|
-
|
OR
|
-
|
OR
|
Grade 4 or Recurrent Grade 3 or pneumonitis or severe rash |
Discontinue
|
| Hepatotoxicity | Assess risk/benefit before continuing treatment | ||||
| Hepatitis B or HSE | Discontinue if active disease or reactivation | ||||
|
# except for alopecia, nausea, vomiting
* Discontinue if < 100mg/m2 ** New cycles of temozolomide should not be started until ANC is ≥ 1.5 x 109/L and platelets ≥ 100 x 109/L and patient has recovered from ≥ grade 3 organ toxicity.
|
|||||
No formal studies have been performed. Population pharmacokinetics appear unchanged in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment should be monitored closely and consideration given to dose modification.
No formal studies have been performed. Population pharmacokinetics appear unchanged in patients with mild-moderate renal impairment. Patients with severe renal impairment should be monitored closely and consideration given to dose modification.
Patients > 70 years of age appear to be at an increased risk of myelosuppression and should be monitored closely.
Lower clearance of temozolomide and higher incidence of grade 4 thrombocytopenia or neutropenia in females, especially in the first cycle. Monitor for toxicity.
Use of temozolomide in children has not been approved in North America. Doses used in children are similar to doses used in adults, although the AUC appears to be higher compared to adults. Pediatric patients appeared to tolerate higher plasma concentrations of temozolomide before reaching dose-limiting toxicity, which may likely be due to increased bone marrow reserves.
- It is preferable to give temozolomide on an empty stomach, at least one hour before or at least 2 hours after a meal, as this may help reduce nausea and vomiting. Alternatively, it may be given with food; however, administration timing relative to meals should be consistent.
- Capsules must not be opened or chewed, but are to be swallowed whole with a glass of water.
- If vomiting occurs after the dose is administered, do not administer a second dose.
- Store capsules at room temperature (15 to 30°C).
- Patients with hypersensitivity to its components or to dacarbazine
- Patients with severe myelosuppression
- Patients with active hepatitis B infection
- Patients with hepatic impairment, poor performance status, severe debilitating diseases or infection
Other Drug Properties:
-
Carcinogenicity:
Yes
-
Fetotoxicity:
Yes
Temozolomide is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
Impaired fertility in males was observed in animals; advice on cryoconservation of sperm should be sought.
-
Breastfeeding:
Not recommended
Coadministration of the following drugs did not alter the clearance of temozolomide: dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor antagonists, or phenobarbital.
Temozolomide does not appear to affect the metabolism of drugs by CYP450, although concomitant administration with other drugs has not been fully studied. Increased myelosuppression is expected when combined with other alkylating agents.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Valproic acid | ↑ toxicity | ↓ clearance of temozolomide by 5%; clinically insignificant | Use with Caution |
| Drugs associated with aplastic anemia (e.g. cotrimoxazole, carbamazepine, phenytoin) | ↑ risk of aplastic anemia and complicates assessment | Possibly additive | Monitor patient carefully |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline then weekly for concurrent RT; Baseline then on day 1 and 22 (for q28d cycles) |
Liver function tests |
Baseline then each cycle (28-day cycles); Baseline then at mid-cycle (42-day cycle) |
Hepatitis B screening |
Baseline. If active, do not treat with temozolomide. If not active, monitor every 1-2 cycles for reactivation & continue for 6 months after treatment discontinuation. |
Signs & symptoms of HSE, especially in patients with previous herpes simplex viral infections |
At each visit |
Clinical toxicity assessment including fatigue, constipation, infections (including opportunistic such as PCP and Hepatitis B), bleeding, nausea and vomiting, pneumonitis, hypersensitivity, thromboembolism, skin and respiratory toxicity |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Brada M, Judson I, Beale P, et al. Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. Br J Cancer 1999 Nov;81(6):1022-30.
Hvizdos KM, Goa KL. Temozolomide. CNS Drugs 1999;12(3):237-43.
Product Monograph: Temozolomide (Temodal®). Merck Canada Inc., June 2017.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
June 2021 temozolomide is ODB general benefit
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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