Temozolomide

L01A - Alkylating agents ATC L01AX03 Small molecule approved 1999 Oral Parenteral Prodrug Natural product Black-box warning

Active form: Mtic.

JFDA label: TEMODAL Capsules

⚠ Black-Box Warning

Mechanism of Action

Inhibitor of DNA — DNA inhibitor

Target	Action	Gene / class
DNA efficacy	INHIBITOR

Indications

Approved

Anaplastic astrocytoma
Glioblastoma multiforme

Off-label

Anaplastic oligodendroglioma
Cutaneous T-cell lymphomas, advanced (mycosis fungoides [MF] and Sézary syndrome [SS]
Ewing’s sarcoma (recurrent or progressive)
Glioblastoma multiforme, recurrent
Low-grade astrocytoma
Low-grade oligodendroglioma
Melanoma, advanced or metastatic
Metastatic CNS lesions
Neuroblastoma (pediatric)
Neuroendocrine tumors, advanced (carcinoid or islet cell)
Primary CNS lymphoma, refractory
Soft tissue sarcomas, extremity/retroperitoneal/intra-abdominal
Soft tissue sarcomas, hemangiopericytoma/solitary fibrous tumor

Contraindications

Source: Lexicomp

Additional contraindications (not in U.S. labeling): Not recommended in patients with severe myelosuppression Absolute
Hypersensitivity (eg, allergic reaction, anaphylaxis, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis) to temozolomide or any component of the formulation Absolute
hypersensitivity to dacarbazine (both drugs are metabolized to MTIC) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Very Common Peripheral edema

Nervous system disorders (16)

Very Common ataxia · dizziness · Fatigue · headache · hemiparesis · seizure

Common abnormal gait · Amnesia · anxiety · confusion · depression · drowsiness · insomnia · memory impairment · paresis · paresthesia

Renal and urinary disorders (4)

Common mastalgia · urinary frequency · Urinary incontinence · urinary tract infection

Blood and lymphatic system disorders (5)

Very Common leukopenia · Lymphocytopenia · neutropenia · thrombocytopenia

Common Anemia

Immune system disorders (1)

Common Hypersensitivity reaction

Metabolism and nutrition disorders (2)

Common Hypercorticoidism · weight gain

Gastrointestinal disorders (9)

Very Common anorexia · constipation · diarrhea · Nausea · vomiting

Common abdominal pain · dysgeusia · dysphagia · Stomatitis

Skin and subcutaneous tissue disorders (5)

Very Common Alopecia · skin rash

Common erythema · Pruritus · xeroderma

Musculoskeletal and connective tissue disorders (4)

Very Common Weakness

Common arthralgia · Back pain · myalgia

Eye disorders (3)

Common Blurred vision · diplopia · visual disturbance

Infections and infestations (1)

Very Common Viral infection

General disorders and administration site conditions (2)

Very Common Fever

Common Radiation injury

Respiratory, thoracic and mediastinal disorders (5)

Common cough · dyspnea · Pharyngitis · sinusitis · upper respiratory tract infection

Dosing

Source: Lexicomp

Note: Temozolomide is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting. Prior to dosing, ANC should be ≥1,500/mm3 and platelets ≥100,000/mm3. Anaplastic astrocytoma (refractory): Oral, IV: Initial dose: 150 mg/m2 once daily for 5 consecutive days of a 28-day treatment cycle. If ANC ≥1,500/mm3 and platelets ≥100,000/mm3, on day 1 of subsequent cycles, may increase to 200 mg/m2 once daily for 5 consecutive days of a 28-day treatment cycle. May continue until disease progression. Dosage modification for toxicity: ANC 3 or platelets 3 on day 22 or day 29 (day 1 of next cycle): Postpone therapy until ANC >1,500/mm3 and platelets >100,000/mm3; reduce dose by 50 mg/m2/day (but not below 100 mg/m2) for subsequent cycle ANC 1,000 to 1,500/mm3 or platelets 50,000-100,000/mm3 on day 22 or day 29 (day 1 of next cycle): Postpone therapy until ANC >1,500/mm3 and platelets >100,000/mm3; maintain initial dose Glioblastoma multiforme (newly diagnosed, high-grade glioma): Oral, IV: Concomitant phase: 75 mg/m2 once daily for 42 days with focal radiotherapy (60 Gy administered in 30 fractions). Note: PCP prophylaxis is required during concomitant phase and should continue in patients who develop lymphocytopenia until lymphocyte recovery to ≤grade 1. Obtain weekly CBC. Continue at 75 mg/m2 once daily throughout the 42-day concomitant phase (up to 49 days) as long as ANC ≥1,500/mm3, platelet count ≥100,000/mm3, and nonhematologic toxicity ≤grade 1 (excludes alopecia, nausea/vomiting) Dosage modification for toxicity: ANC ≥500/mm3 but 3 or platelet count ≥10,000/mm3 but 3 or grade 2 nonhematologic toxicity (excludes alopecia, nausea/vomiting): Interrupt therapy ANC 3 or platelet count 3 or grade 3/4 nonhematologic toxicity (excludes alopecia, nausea/vomiting): Discontinue therapy Maintenance phase (consists of 6 treatment cycles): Begin 4 weeks after concomitant phase completion. Note: Each subsequent cycle is 28 days (consisting of 5 days of drug treatment followed by 23 days without treatment). Draw CBC on day 22 (or within 48 hours of day 22); hold next cycle and do weekly CBC until ANC >1,500/mm3 and platelet count >100,000/mm3; dosing modification should be based on lowest blood counts and worst nonhematologic toxicity during the previous cycle. Cycle 1: 150 mg/m2 once daily for 5 days of a 28-day treatment cycle Cycles 2 to 6: May increase to 200 mg/m2 once daily for 5 days; repeat every 28 days (if ANC ≥1,500/mm3, platelets ≥100,000/mm3 and nonhematologic toxicities for cycle 1 are ≤grade 2 [excludes alopecia, nausea/vomiting]); Note: If dose was not escalated at the onset of cycle 2, do not increase for cycles 3 to 6) Dosage modification (during maintenance phase) for toxicity: ANC 3, platelet count 3, or grade 3 nonhematologic toxicity (excludes alopecia, nausea/vomiting) during previous cycle: Decrease dose by 1 dose level (by 50 mg/m2/day for 5 days), unless dose has already be

(For additional information see "Temozolomide: Pediatric drug information") Note: Temozolomide is associated with a moderate emetic potential (Dupuis 2011); antiemetics are recommended to prevent nausea and vomiting. Ewing’s sarcoma, recurrent or progressive (off-label use): Children and Adolescents: Oral: Refer to adult dosing. Neuroblastoma, relapsed or refractory (off-label use): Children and Adolescents: Oral: 100 mg/m2/dose days 1 to 5 every 21 days (in combination with irinotecan) for up to 6 cycles (Bagatell 2011) Children ≥6 months and Adolescents: Oral: 150 mg/m2/dose days 1 to 5 every 28 days (in combination with topotecan) until disease progression or unacceptable toxicity (Di Giannatale 2014)

Refer to adult dosing. Note: Patients ≥70 years of age in the anaplastic astrocytoma study had a higher incidence of grade 4 neutropenia and thrombocytopenia in the first cycle of therapy than patients

Oral: CrCl ≥36 mL/minute/m2: There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage adjustment is not likely needed as no effect on temozolomide clearance was demonstrated. Severe renal impairment (CrCl 2): There are no dosage adjustments provided in the manufacturer’s labeling; use with caution (has not been studied). Dialysis patients: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetics are similar to patients with normal hepatic function. Severe hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution (has not been studied).

Warnings & Precautions

Source: Lexicomp

Bone marrow suppression

Myelosuppression may occur; may require treatment interruption, dose reduction and/or discontinuation; monitor blood counts. An increased incidence has been reported in geriatric and female patients. Prolonged pancytopenia resulting in aplastic anemia has been reported (may be fatal); concurrent use of temozolomide with medications associated with aplastic anemia (eg, carbamazepine, co-trimoxazole, phenytoin) may obscure assessment for development of aplastic anemia. ANC should be ≥1,500/mm3 and platelets ≥100,000/mm3 prior to treatment.

Gastrointestinal toxicity

Temozolomide is associated with a moderate emetic potential (Dupuis 2011; Hesketh 2017; Roila 2016); antiemetics are recommended to prevent nausea and vomiting.

Hepatotoxicity

Hepatotoxicity has been reported; may be severe or fatal. Monitor liver function tests at baseline, halfway through the first cycle, prior to each subsequent cycle, and at ~2 to 4 weeks after the last dose. Postmarketing reports of hepatotoxicity have included liver function abnormalities, hepatitis, hepatic failure, cholestasis, hepatitis cholestasis, jaundice, cholelithiasis, hepatic steatosis, hepatic necrosis, hepatic lesion, and hepatic encephalopathy (Sarganas 2012).

Pneumonia

Pneumocystis jirovecii pneumonia (PCP) may occur; risk is increased in those receiving steroids or longer dosing regimens. Monitor all patients for development of PCP (particularly if also receiving corticosteroids). PCP prophylaxis is required in patients receiving radiotherapy in combination with the 42-day temozolomide regimen.

Secondary malignancies

Rare cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been reported. Disease-related concerns:

Hepatic impairment

Use with caution in patients with severe hepatic impairment.

Renal impairment

Use with caution in patients with severe renal impairment; has not been studied in dialysis patients. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Polysorbate 80

Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling. Other warnings/precautions:

Infusion time

Bioequivalence has only been established when IV temozolomide is administered over 90 minutes; shorter or longer infusion times may result in suboptimal dosing.

Temozolomide resistance

Increased MGMT (O-6-methylguanine-DNA methyltransferase) activity/levels within tumor tissue is associated with temozolomide resistance. Glioblastoma patients with decreased levels (due to methylated MGMT promoter) may be more likely to benefit from the combination of radiation therapy and temozolomide (Hegi 2008; Stupp 2009). Determination of MGMT status may be predictive for response to alkylating agents.

Pregnancy & Lactation

Pregnancy

FDA category D

Adverse events were observed in animal reproduction studies. May cause fetal harm when administered to pregnant women. Male and female patients should avoid pregnancy while receiving temozolomide.

Lactation

It is not known if temozolomide is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.

Monitoring

Clinical pearl	CBC with differential and platelets (prior to each cycle; weekly during glioma concomitant phase treatment; at or within 48 hours of day 22 and weekly until ANC >1,500/mm3 and platelets >100,000/mm3 for glioma maintenance and astrocytoma treatment). Monitor liver function tests at baseline, halfway through the first cycle, prior to each subsequent cycle, and at ~2 to 4 weeks after the last dose. Monitor adherence.

Clinical pearl

CBC with differential and platelets (prior to each cycle; weekly during glioma concomitant phase treatment; at or within 48 hours of day 22 and weekly until ANC >1,500/mm3 and platelets >100,000/mm3 for glioma maintenance and astrocytoma treatment). Monitor liver function tests at baseline, halfway through the first cycle, prior to each subsequent cycle, and at ~2 to 4 weeks after the last dose. Monitor adherence.

Chemistry & Properties

Formula	C6H6N6O2
Molecular weight	194.15 g/mol
IUPAC name	3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide
CAS	85622-93-1
PubChem CID	5394
InChIKey	`BPEGJWRSRHCHSN-UHFFFAOYSA-N`
logP	-2.08 (XLogP -1.1)
Polar surface area	108.17 Å²
H-bond acceptors / donors	7 / 1
Drug-likeness (QED)	0.56
Lipinski violations	0

SMILES

Cn1nnc2c(C(N)=O)ncn2c1=O

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB -0.47)

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Certolizumab pegol	major
Cladribine	major
Clozapine	major
Deferiprone	major
Etanercept	major
Fingolimod	major
Golimumab	major
Infliximab	major
Leflunomide	major
Lomitapide	major
Measles virus vaccine live attenuated	major
Mipomersen	major
Mumps virus strain B level jeryl lynn live antigen	major
Natalizumab	major
Ozanimod	major
Pexidartinib	major
Rotavirus vaccine	major
Rubella virus vaccine	major
Samarium (153Sm) lexidronam	major
Siponimod	major
Smallpox (Vaccinia) Vaccine, Live	major
Talimogene laherparepvec	major
Teriflunomide	major
Thalidomide	major
Tofacitinib	major
Typhoid vaccine (live)	major
Upadacitinib	major
Varicella Zoster Vaccine (Recombinant)	major
Yellow Fever Vaccine	major
Aldesleukin	moderate
Alefacept	moderate
Alemtuzumab	moderate
Anakinra	moderate
Anthrax vaccine	moderate
Asparaginase Erwinia chrysanthemi	moderate
Asparaginase Escherichia coli	moderate
Azathioprine	moderate

Showing 40 of 100+.

Registered Products (16)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Tegozol	Capsule 5 mg	5 cap	Hikma Pharmaceuticals Co.Ltd/Jordan	10.220
Gliotem	Capsule 20 mg	5 cap	Reda Jardaneh Drug Store	22.260
Tolid	Capsule 20 mg	5 cap	MS PHARMA/JORDAN	22.260
Tegozol	Capsule 20 mg	5 cap	Hikma Pharmaceuticals Co.Ltd/Jordan	28.620
TEMODAL Capsules	Capsule 20 mg	5 cap	Adatco Drug Store	31.800
TEMAZ 100	Capsule 100.000 mg	5 cap	Omicron Pharma	46.970
Gliotem	Capsule 100 mg	5 cap	Reda Jardaneh Drug Store	54.800
Zema	Capsule 100 mg	5 cap	ORIENT DRUG STORE CO	54.800
Tegozol	Capsule 100 mg	5 cap	Hikma Pharmaceuticals Co.Ltd/Jordan	70.450
TEMODAL Capsules	Capsule 100 mg	5 cap	Adatco Drug Store	78.280
Gliotem	Capsule 250 mg	5 cap	Reda Jardaneh Drug Store	—
TEMODAL Capsules	Capsule 250 mg	5 cap	Adatco Drug Store	—
Tegozol	Tablet 250 mg	5 tab	Hikma Pharmaceuticals Co.Ltd/Jordan	—
Tolid	Capsule 250 mg	5 cap	MS PHARMA/JORDAN	—
Tolid	Capsule 100 mg	5 cap	MS PHARMA/JORDAN	—
Zema	Capsule 250 mg	5 cap	ORIENT DRUG STORE CO	—