Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections (such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8).
In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids administration.
Patients who received concomitant TMZ 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 TMZ 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 TMZ is administered during a longer dosing regimen. However, all patients receiving TMZ, 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 TMZ, in particular in combination with dexamethasone or other steroids.
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.
Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see section 4.8). 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.
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have also been reported very rarely (see section 4.8).
Nausea and vomiting are very commonly associated with TMZ. Anti-emetic therapy may be administered prior to or following administration of TMZ.
Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is strongly recommended during the monotherapy phase.
Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may require anti-emetic therapy.
Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anaemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, the following laboratory parameters must be met: ANC ≥1.5 × 109/l and platelet count ≥100 × 109/l. 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 ANC >1.5 × 109/l and platelet count >100 × 109/l. If ANC falls to <1.0 × 109/l or the platelet count is <50 × 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m², 150 mg/m², and 200 mg/m². The lowest recommended dose is 100 mg/m².
There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children and adolescents is very limited (see sections 4.2 and 5.1).
Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when TMZ is administered in elderly patients.
Men being treated with TMZ 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 (see section 4.6).
This medicinal product contains 2.4 mmol sodium per vial. This should be taken into consideration by patients on a controlled sodium diet.
In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the extent of absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC).
Administration of TMZ with food resulted in a 33% decrease in Cmax and a 9% decrease in area under the curve (AUC). As it cannot be excluded that the change in Cmax is clinically significant, Temodal should be administered without food.
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated with a small but statistically significant decrease in clearance of TMZ.
No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products (see section 5.2).
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.
Interaction studies have only been performed in adults.
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m² TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal 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 TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with TMZ.
Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.
TMZ 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 TMZ.
TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see section 4.8).
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 Table 4. 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%.
Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed in Table 4. 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.
Table 4. Adverse reactions in patients treated with temozolomide:
Common: Infections, herpes zoster, pharyngitisa, candidiasis oral
Uncommon: Opportunistic infection (including PCP), sepsis†, meningoencephalitis herpetic†, CMV infection, CMV reactivation, hepatitis B virus†, herpes simplex, infection reactivation, wound infection, gastroenteritisb
Uncommon: Myelodysplastic syndrome (MDS), secondary malignancies, including myeloid leukaemia
Common: Febrile neutropenia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, anaemia
Uncommon: Prolonged pancytopenia, aplastic anaemia†, pancytopenia, petechiae
Common: Allergic reaction
Uncommon: Anaphylaxis
Common: Cushingoidc
Uncommon: Diabetes insipidus
Very common: Anorexia
Common: Hyperglycaemia
Uncommon: Hypokalaemia, alkaline phosphatase increased
Common: Agitation, amnesia, depression, anxiety, confusion, insomnia
Uncommon: Behaviour disorder, emotional lability, hallucination, apathy
Very common: Convulsions, hemiparesis, aphasia/dysphasia, headache
Common: Ataxia, balance impaired, cognition impaired, concentration impaired, consciousness decreased, dizziness, hypoesthesia, memory impaired, neurologic disorder, neuropathyd, paraesthesia, somnolence, speech disorder, taste perversion, tremor
Uncommon: Status epilepticus, hemiplegia, extrapyramidal disorder, parosmia, gait abnormality, hyperaesthesia, sensory disturbance, coordination abnormal
Common: Hemianopia, vision blurred, vision disordere , visual field defect, diplopia, eye pain
Uncommon: Visual acuity reduced, eyes dry
Common: Deafnessf, vertigo, tinnitus, earacheg
Uncommon: Hearing impairment, hyperacusis, otitis media
Uncommon: Palpitation
Common: Haemorrhage, embolism pulmonary, deep vein thrombosis, hypertension
Uncommon: Cerebral haemorrhage, flushing, hot flushes
Common: Pneumonia, dyspnoea, sinusitis, bronchitis, coughing, upper respiratory infection
Uncommon: Respiratory failure†, interstitial pneumonitis/pneumonitis, pulmonary fibrosis, nasal congestion
Very common: Diarrhoea, constipation, nausea, vomiting
Common: Stomatitis, abdominal painh, dyspepsia, dysphagia
Uncommon: Abdominal distension, faecal incontinence, gastrointestinal disorder, haemorrhoids, mouth dry
Uncommon: Hepatic failure†, hepatic injury, hepatitis, cholestasis, hyperbilirubinemia
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)
Common: Myopathy, muscle weakness, arthralgia, back pain, musculoskeletal pain, myalgia
Common: Micturition frequency, urinary incontinence
Uncommon: Dysuria
Uncommon: Vaginal haemorrhage, menorrhagia, amenorrhoea, vaginitis, breast pain, impotence
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
Common: Liver enzymes elevationj, weight decreased, weight increased
Uncommon: Gamma-glutamyltransferase increased
Common: Radiation injuryk
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
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.
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.
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.
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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