Temozolomide

Co-administration of temozolomide with valproic acid was associated with a small but statistically significant decrease in clearance of temozolomide.

Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with temozolomide.

Pneumocystis jirovecii pneumonia

Patients who received concomitant temozolomide and RT in a pilot trial for the prolonged 42-day schedule were shown to be at particular risk for developing Pneumocystis jirovecii pneumonia (PCP). Thus, prophylaxis against PCP is required for all patients receiving concomitant temozolomide and RT for the 42-day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they are to continue the prophylaxis until recovery of lymphopenia to grade ≤1.

There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have been reported in patients using temozolomide, in particular in combination with dexamethasone or other steroids.

HBV

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Experts in liver disease should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease). During treatment patients should be monitored and managed appropriately.

Nausea and vomiting are very commonly associated with temozolomide. Anti-emetic therapy may be administered prior to or following administration of temozolomide.

Hepatic injury, including fatal hepatic failure, has been reported in patients treated with temozolomide. Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving temozolomide in combination with radiotherapy, including cases of concomitant steroids administration.

Temozolomide can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with temozolomide.

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m² temozolomide, teratogenicity and/or foetal toxicity were demonstrated. Temozolomide should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.

It is not known whether temozolomide is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with temozolomide.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving temozolomide.

Male fertility

Temozolomide can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with temozolomide.

Temozolomide has minor influence on the ability to drive and use machines due to fatigue and somnolence.

Summary of the safety profile

Clinical trial experience

In patients treated with TMZ in clinical trials, the most common adverse reactions were nausea, vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematologic adverse reactions were reported commonly; the frequency of Grade 3-4 laboratory findings is presented after the list below. For patients with recurrent or progressive glioma, nausea (43%) and vomiting (36%) were usually Grade 1 or 2 (0–5 episodes of vomiting in 24 hours) and were either self-limiting or readily controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4%.

List of adverse reactions

Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed below. These reactions are classified according to System Organ Class and frequency. Frequency groupings are defined according to the following convention: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions in patients treated with temozolomide:

Infections and infestations

Common: Infections, herpes zoster, pharyngitis^a, candidiasis oral

Uncommon: Opportunistic infection (including PCP), sepsis^†, meningoencephalitis herpetic^†, CMV infection, CMV reactivation, hepatitis B virus^†, herpes simplex, infection reactivation, wound infection, gastroenteritis^b

Neoplasm benign, malignant, and unspecified

Uncommon: Myelodysplastic syndrome (MDS), secondary malignancies, including myeloid leukaemia

Blood and lymphatic system disorders

Common: Febrile neutropenia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, anaemia

Uncommon: Prolonged pancytopenia, aplastic anaemia^†, pancytopenia, petechiae

Immune system disorders

Common: Allergic reaction

Uncommon: Anaphylaxis

Endocrine disorders

Common: Cushingoid^c

Uncommon: Diabetes insipidus

Metabolism and nutrition disorders

Very common: Anorexia

Common: Hyperglycaemia

Uncommon: Hypokalaemia, alkaline phosphatase increased

Psychiatric disorders

Common: Agitation, amnesia, depression, anxiety, confusion, insomnia

Uncommon: Behaviour disorder, emotional lability, hallucination, apathy

Nervous system disorders

Very common: Convulsions, hemiparesis, aphasia/dysphasia, headache

Common: Ataxia, balance impaired, cognition impaired, concentration impaired, consciousness decreased, dizziness, hypoesthesia, memory impaired, neurologic disorder, neuropathy^d, paraesthesia, somnolence, speech disorder, taste perversion, tremor

Uncommon: Status epilepticus, hemiplegia, extrapyramidal disorder, parosmia, gait abnormality, hyperaesthesia, sensory disturbance, coordination abnormal

Eye disorders

Common: Hemianopia, vision blurred, vision disordere , visual field defect, diplopia, eye pain

Uncommon: Visual acuity reduced, eyes dry

Ear and labyrinth disorders

Common: Deafness^f, vertigo, tinnitus, earacheg

Uncommon: Hearing impairment, hyperacusis, otitis media

Cardiac disorders

Uncommon: Palpitation

Vascular disorders

Common: Haemorrhage, embolism pulmonary, deep vein thrombosis, hypertension

Uncommon: Cerebral haemorrhage, flushing, hot flushes

Respiratory, thoracic and mediastinal disorders

Common: Pneumonia, dyspnoea, sinusitis, bronchitis, coughing, upper respiratory infection

Uncommon: Respiratory failure^†, interstitial pneumonitis/pneumonitis, pulmonary fibrosis, nasal congestion

Gastrointestinal disorders

Very common: Diarrhoea, constipation, nausea, vomiting

Common: Stomatitis, abdominal pain^h, dyspepsia, dysphagia

Uncommon: Abdominal distension, faecal incontinence, gastrointestinal disorder, haemorrhoids, mouth dry

Hepatobiliary disorders

Uncommon: Hepatic failure^†, hepatic injury, hepatitis, cholestasis, hyperbilirubinemia

Skin and subcutaneous tissue disorders

Very Common: Rash, alopecia

Common: Erythema, dry skin, pruritus

Uncommon: Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, erythroderma, skin exfoliation, photosensitivity reaction, urticaria, exanthema, dermatitis, sweating increased, pigmentation abnormal

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

Musculoskeletal and connective tissue disorders

Common: Myopathy, muscle weakness, arthralgia, back pain, musculoskeletal pain, myalgia

Renal and urinary disorders

Common: Micturition frequency, urinary incontinence

Uncommon: Dysuria

Reproductive system and breast disorders

Uncommon: Vaginal haemorrhage, menorrhagia, amenorrhoea, vaginitis, breast pain, impotence

General disorders and administration site conditions

Very common: Fatigue

Common: Fever, influenza-like symptoms, asthenia, malaise, pain, oedema, oedema peripheralⁱ

Uncommon: Condition aggravated, rigors, face oedema, tongue discolouration, thirst, tooth disorder

Investigations

Common: Liver enzymes elevation^j, weight decreased, weight increased

Uncommon: Gamma-glutamyltransferase increased

Injury, poisoning and procedural complications

Common: Radiation injury^k

^a Includes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal
^b Includes gastroenteritis, gastroenteritis viral
^c Includes cushingoid, Cushing syndrome
^d Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy, peripheral motor neuropathy
^e Includes visual impairment, eye disorder
^f Includes deafness, deafness bilateral, deafness neurosensory, deafness unilateral
^g Includes earache, ear discomfort
^h Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort
ⁱ Includes oedema peripheral, peripheral swelling
^j Includes liver function test increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzymes increased
^k Includes radiation injury, radiation skin injury
^† Including cases with fatal outcome

Newly-diagnosed glioblastoma multiforme

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events were observed in 8% of the patients. Grade 3 or Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14% of the patients who received TMZ.

Recurrent or progressive malignant glioma

Laboratory results

Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19% and 17% respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8% and 4%, respectively. Myelosuppression was predictable (usually within the first few cycles, with the nadir between Day 21 and Day 28), and recovery was rapid, usually within 1-2 weeks. No evidence of cumulative myelosuppression was observed. The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia or leukopenia may increase the risk of infection.

Gender

In a population pharmacokinetics analysis of clinical trial experience there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of Grade 4 neutropenia (ANC <0.5 × 10⁹/l), 12% vs 5%, and thrombocytopenia (<20 × 10⁹/l), 9% vs 3%, in women vs men in the first cycle of therapy. In a 400 subject recurrent glioma data set, Grade 4 neutropenia occurred in 8% of female vs 4% of male subjects and Grade 4 thrombocytopenia in 8% of female vs 3% of male subjects in the first cycle of therapy. In a study of 288 subjects with newly-diagnosed glioblastoma multiforme, Grade 4 neutropenia occurred in 3% of female vs 0% of male subjects and Grade 4 thrombocytopenia in 1% of female vs 0% of male subjects in the first cycle of therapy.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in children under the age of 3 years has not been established.