Temozolomide

Temozolomide is a small, lipophilic alkylating agent of the triazene (imidazotetrazine) class, with a molecular mass of 194. It is a prodrug. It is stable in acid, which allows oral dosing, and at the near-neutral pH of the body it converts spontaneously, without liver enzymes, to the active compound monomethyl triazenoimidazole carboxamide (MTIC). It crosses the blood-brain barrier and reaches the cerebrospinal fluid, which makes it suitable for brain tumours.

Mechanism of Action

• Activation: MTIC forms by spontaneous hydrolysis at physiological pH and is itself hydrolysed to 5-aminoimidazole-4-carboxamide (AIC), a natural intermediate in purine synthesis, and a reactive methylating species.
• DNA methylation: the methylating species adds methyl groups to DNA, mainly at the O6 and N7 positions of guanine. The cytotoxicity is thought to come mainly from methylation at O6 of guanine and from the cell’s faulty attempts to repair it.
• Futile repair: unrepaired O6-methylguanine mispairs with thymine. The mismatch repair system keeps removing the thymine but not the methylguanine, so repair cycles repeat, DNA strands break and the cell dies.
• Resistance: the enzyme MGMT removes the methyl group from O6-guanine. Tumours with high MGMT activity, or with reduced mismatch repair, are less sensitive; tumours with little MGMT and intact mismatch repair are the most sensitive.
• Effect on the bone marrow: dividing blood cells are also affected, so myelosuppression is the dose-limiting toxicity.

Pharmacokinetics

• Absorption: rapid. After an oral dose, peak concentrations are reached as early as 20 minutes (mean time 0.5–1.5 hours), and only 0.8% of a radiolabelled dose appears in the faeces, indicating complete absorption. Food lowers the peak concentration by 33% and the exposure (AUC) by 9%. Exposure after a 90-minute infusion is similar to that after the same oral dose.
• Distribution: plasma protein binding is low (10–20%). Temozolomide crosses the blood-brain barrier rapidly; in one patient the exposure in cerebrospinal fluid was about 30% of that in plasma.
• Metabolism: spontaneous chemical hydrolysis rather than liver metabolism. Exposure to MTIC and AIC is about 2.4% and 23% of the temozolomide exposure, and MTIC has a half-life similar to that of temozolomide.
• Elimination: the plasma half-life is about 1.8 hours. The main route is renal: 5–10% of the dose is recovered unchanged in urine over 24 hours, and the rest as temozolomide acid, AIC or unidentified polar metabolites. Plasma levels rise in proportion to dose, and clearance, volume of distribution and half-life do not depend on dose.
• Special populations: clearance does not depend on age, renal function or smoking. Patients with mild or moderate hepatic impairment have a profile similar to those with normal liver function. Children have a higher AUC than adults, but the maximum tolerated dose per cycle (1,000 mg/m²) is the same.

Temodal hard capsules and powder for solution for infusion share the same indications:

• Newly diagnosed glioblastoma multiforme: adults, together with radiotherapy and then as monotherapy.
• Recurrent or progressive malignant glioma: children from 3 years of age, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, whose disease has recurred or progressed after standard therapy.

• Hypersensitivity to temozolomide or to any of the excipients.
• Hypersensitivity to dacarbazine (DTIC).
• Severe myelosuppression.

In clinical trials the most common reactions were nausea, vomiting, constipation, anorexia, headache, fatigue, convulsions and rash. Most blood-count changes were reported as common rather than very common. In patients with recurrent or progressive glioma, nausea (43%) and vomiting (36%) were mostly grade 1 or 2 and either settled by themselves or were controlled with standard anti-emetics; severe nausea and vomiting occurred in 4%. The frequencies below come from clinical studies and reports after marketing.

Very common (≥1/10): anorexia, convulsions, hemiparesis, aphasia or dysphasia, headache, diarrhoea, constipation, nausea, vomiting, rash, alopecia, fatigue.

Common (≥1/100 to <1/10): infections, herpes zoster, pharyngitis, oral candidiasis; febrile neutropenia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, anaemia; allergic reaction; cushingoid features; hyperglycaemia; agitation, amnesia, depression, anxiety, confusion, insomnia; ataxia, impaired balance, cognition and concentration, decreased consciousness, dizziness, hypoaesthesia, impaired memory, neurological disorder, neuropathy, paraesthesia, somnolence, speech disorder, taste perversion, tremor; hemianopia, blurred vision, visual disorder, visual field defect, diplopia, eye pain; deafness, vertigo, tinnitus, earache; haemorrhage, pulmonary embolism, deep vein thrombosis, hypertension; pneumonia, dyspnoea, sinusitis, bronchitis, cough, upper respiratory infection; stomatitis, abdominal pain, dyspepsia, dysphagia; erythema, dry skin, pruritus; myopathy, muscle weakness, arthralgia, back pain, musculoskeletal pain, myalgia; urinary frequency, urinary incontinence; fever, influenza-like symptoms, asthenia, malaise, pain, oedema (including peripheral oedema); raised liver enzymes, decreased or increased weight; radiation injury.

Uncommon (≥1/1,000 to <1/100): opportunistic infection (including Pneumocystis pneumonia), sepsis, herpetic meningoencephalitis, cytomegalovirus infection and reactivation, hepatitis B virus infection, herpes simplex, reactivation of infection, wound infection, gastroenteritis; myelodysplastic syndrome and secondary malignancies including myeloid leukaemia; prolonged pancytopenia, aplastic anaemia, pancytopenia, petechiae; anaphylaxis; diabetes insipidus; hypokalaemia, raised alkaline phosphatase; behaviour disorder, emotional lability, hallucination, apathy; status epilepticus, hemiplegia, extrapyramidal disorder, parosmia, abnormal gait, hyperaesthesia, sensory disturbance, abnormal coordination; reduced visual acuity, dry eyes; hearing impairment, hyperacusis, otitis media; palpitation; cerebral haemorrhage, flushing, hot flushes; respiratory failure, interstitial pneumonitis or pneumonitis, pulmonary fibrosis, nasal congestion; abdominal distension, faecal incontinence, gastrointestinal disorder, haemorrhoids, dry mouth; hepatic failure, liver injury, hepatitis, cholestasis, hyperbilirubinaemia; toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, erythroderma, skin exfoliation, photosensitivity reaction, urticaria, exanthema, dermatitis, increased sweating, abnormal pigmentation; dysuria; vaginal haemorrhage, menorrhagia, amenorrhoea, vaginitis, breast pain, impotence; worsening of the condition, rigors, face oedema, tongue discolouration, thirst, tooth disorder; raised gamma-glutamyltransferase.

Not known: drug reaction with eosinophilia and systemic symptoms (DRESS).

Serious reactions of note: cases with a fatal outcome have been reported for sepsis, herpetic meningoencephalitis, hepatitis B reactivation, aplastic anaemia, respiratory failure and hepatic failure. In newly diagnosed glioblastoma, grade 3 or 4 neutrophil abnormalities (including neutropenic events) occurred in 8% of patients and grade 3 or 4 platelet abnormalities (including thrombocytopenic events) in 14%. In recurrent or progressive glioma, grade 3 or 4 thrombocytopenia and neutropenia occurred in 19% and 17%, leading to hospitalisation or discontinuation in 8% and 4%. The lowest counts usually come between day 21 and day 28 of a cycle and recover within 1–2 weeks, with no cumulative effect seen. In a pooled analysis women had more grade 4 neutropenia (12% against 5%) and thrombocytopenia (9% against 3%) than men in the first cycle.

• Food: taking temozolomide with food lowered the peak concentration by 33% and the AUC by 9%. As the fall in peak concentration may matter clinically, capsules are taken without food (fasting).
• Ranitidine: in a phase I study it did not change the absorption of temozolomide or the exposure to MTIC.
• Dexamethasone, anti-emetics (prochlorperazine, ondansetron), antiepileptics (phenytoin, carbamazepine, phenobarbital) and H2 receptor antagonists: no effect on temozolomide clearance in a population pharmacokinetic analysis.
• Valproic acid: associated with a small but statistically significant fall in temozolomide clearance.
• Other myelosuppressive medicines: using temozolomide with them may increase the likelihood of myelosuppression.
• Effect of temozolomide on other medicines: not studied. Because temozolomide is not metabolised by the liver and binds little to proteins, it is unlikely to change the pharmacokinetics of other medicines.
• Children: interaction studies have been done only in adults.

Temodal should only be prescribed by physicians experienced in the oncological treatment of brain tumours. Doses are calculated from body surface area (mg/m²) and are the same for the capsules and the infusion. Anti-emetic therapy may be given (see Special Instructions).

Newly Diagnosed Glioblastoma: Concomitant Phase

Temozolomide is given with focal radiotherapy (60 Gy in 30 fractions), followed by up to 6 cycles of temozolomide alone.

• Dose: 75 mg/m² daily for 42 days alongside the radiotherapy. Dose reductions are not recommended; delay or discontinuation is decided weekly from blood counts and non-haematological toxicity.
• Continuation: treatment can continue throughout the 42 days (up to 49 days) if neutrophils are at least 1.5 × 10⁹/L, platelets at least 100 × 10⁹/L and non-haematological toxicity is grade 1 or less (alopecia, nausea and vomiting excepted).
• Monitoring: a complete blood count is taken weekly.

Newly Diagnosed Glioblastoma: Monotherapy Phase

• Start: four weeks after the end of the concomitant phase, for up to 6 cycles of 28 days.
• Cycle 1: 150 mg/m² once daily for 5 days, then 23 days without treatment.
• Cycle 2 onwards: 200 mg/m² once daily for the first 5 days of each cycle, if in cycle 1 non-haematological toxicity was grade 2 or less (alopecia, nausea and vomiting excepted), neutrophils were at least 1.5 × 10⁹/L and platelets at least 100 × 10⁹/L. If the dose is not raised at cycle 2 it is not raised later. Once raised, it stays at 200 mg/m² unless toxicity occurs.
• Monitoring: a complete blood count is taken on day 22 (21 days after the first dose of the cycle).

Recurrent or Progressive Malignant Glioma

Adults and children from 3 years of age are treated in 28-day cycles.

• No previous chemotherapy: 200 mg/m² once daily for the first 5 days, then 23 days without treatment.
• Previous chemotherapy: 150 mg/m² once daily for 5 days in the first cycle, raised to 200 mg/m² once daily for 5 days in the second cycle if there is no haematological toxicity.

Dose Adjustments for Side Effects

• Concomitant phase: interrupt temozolomide if neutrophils are 0.5 to below 1.5 × 10⁹/L, platelets 10 to below 100 × 10⁹/L, or non-haematological toxicity is grade 2 (alopecia, nausea and vomiting excepted). Discontinue it if neutrophils are below 0.5 × 10⁹/L, platelets below 10 × 10⁹/L, or toxicity is grade 3 or 4. Treatment may resume when the conditions listed under Continuation are met again.
• Monotherapy phase: the dose levels are −1 (100 mg/m²), 0 (150 mg/m²) and 1 (200 mg/m²). Reduce by one level if neutrophils fall below 1.0 × 10⁹/L, platelets below 50 × 10⁹/L, or grade 3 non-haematological toxicity occurs (alopecia, nausea and vomiting excepted). Discontinue for grade 4 non-haematological toxicity, if the 100 mg/m² level still causes unacceptable toxicity, or if the same grade 3 toxicity returns after a reduction.

Capsules and Infusion

• Hard capsules: taken in the fasting state, swallowed whole with a glass of water, and never opened or chewed.
• Powder for solution for infusion: given only as an intravenous infusion, never by the intrathecal, intramuscular or subcutaneous route. The dose is infused with a pump over 90 minutes. It may run through the same line as 0.9% sodium chloride injection but is incompatible with dextrose solutions. Care is needed to avoid extravasation.

Special Populations

• Children: from 3 years of age, temozolomide is used only for recurrent or progressive malignant glioma, with very limited experience. Safety and efficacy under 3 years have not been established.
• Hepatic or renal impairment: pharmacokinetics were similar in mild or moderate hepatic impairment. There are no data in severe hepatic impairment (Child-Pugh class C) or in renal impairment. Dose reductions are unlikely to be needed, but caution is advised.
• Elderly: clearance is not affected by age, but patients over 70 appear to be at greater risk of neutropenia and thrombocytopenia.

Vomiting After a Dose

If vomiting occurs after a capsule dose, a second dose is not given that day.

Pneumocystis Pneumonia and Other Infections

• Prophylaxis: against Pneumocystis jirovecii pneumonia (PCP) is required in all patients given temozolomide with radiotherapy on the 42-day (up to 49-day) schedule, whatever their lymphocyte count. If lymphopenia occurs, prophylaxis continues until it recovers to grade 1 or less.
• Vigilance: all patients, particularly those on steroids, should be watched for PCP. Fatal respiratory failure has been reported, especially with dexamethasone or other steroids.
• Other infections: opportunistic infections and reactivation of infections (such as hepatitis B virus and cytomegalovirus) have occurred. After marketing, herpetic meningoencephalitis, including fatal cases, was seen in patients given temozolomide with radiotherapy, including those on steroids.

Hepatitis B and Liver Toxicity

• Hepatitis B: reactivation has caused hepatitis, in some cases fatal. A liver specialist should be consulted before treatment in patients with positive hepatitis B serology, and they are monitored during treatment.
• Liver injury: hepatic injury, including fatal hepatic failure, has been reported. Liver function tests are done before treatment and, if abnormal, the benefit and risk are weighed. On the 42-day schedule they are repeated midway through the cycle, and in all patients after each treatment cycle. Liver toxicity may appear several weeks or more after the last treatment.

Bone-Marrow Suppression

Myelosuppression, including prolonged pancytopenia that may lead to aplastic anaemia (occasionally fatal), can occur. Complete blood counts are taken weekly during the concomitant phase and on day 22 of each monotherapy cycle (see Administration and Dosage). Thrombocytopenia may raise the risk of bleeding, and neutropenia or leukopenia the risk of infection. Women and patients over 70 are at higher risk of severe neutropenia and thrombocytopenia.

Nausea and Vomiting

Nausea and vomiting are very common. In newly diagnosed glioblastoma, anti-emetic prophylaxis is recommended before the first dose of the concomitant phase and strongly recommended during the monotherapy phase. Patients with recurrent glioma who had severe (grade 3 or 4) vomiting in earlier cycles may need anti-emetic therapy.

Secondary Cancers

Myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have been reported.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women, and rat and rabbit studies showed teratogenicity or foetal toxicity. Temodal should not be given to pregnant women; if use in pregnancy must be considered, the patient is told of the potential risk to the foetus.
• Contraception in women: women of child-bearing potential must use effective contraception during treatment and for at least 6 months after it ends.
• Men: temozolomide can have genotoxic effects. Men should use effective contraception, should not father a child for at least 3 months after the last dose, and should seek advice on sperm cryopreservation before treatment because of possible irreversible infertility.
• Breastfeeding: it is not known whether temozolomide passes into human milk, so breastfeeding should be stopped during treatment.

Excipients

• Lactose: the capsules contain anhydrous lactose, from 132.8 mg (5 mg capsule) to 316.3 mg (180 mg capsule). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.
• Powder for infusion: each vial contains 55.2 mg of sodium, which patients on a controlled sodium diet should take into account, and 120 mg of polysorbate 80.

Effect on Driving

Temozolomide has a minor influence on the ability to drive and use machines because of fatigue and somnolence.

• Hard capsules: do not store above 30 °C. They are supplied in sachets of one capsule each, in cartons of 5 or 20; not all pack sizes may be marketed.
• Powder for solution for infusion: store in a refrigerator at 2–8 °C. Keep the cold chain unbroken from dispatch to the hospital pharmacy. For storage of the reconstituted solution see Shelf Life.

• Hard capsules: 3 years.
• Powder for infusion, unopened vial: 4 years.
• Reconstituted solution: chemical and physical in-use stability has been shown for 14 hours at 25 °C, including the infusion time. From a microbiological point of view it should be used immediately. If not, in-use times and conditions are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C, unless reconstitution took place under controlled and validated aseptic conditions.

Prescription only (Rx), under restricted medical prescription (Annex II B), on the prescription of a physician experienced in the oncological treatment of brain tumours. The hard capsules are taken at home in short courses, so they are supplied to the patient or to the treating clinic on prescription. The powder for infusion is given in a hospital or clinic, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.