Adverse reactions : תופעות לוואי

4.8   Undesirable effects

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 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 %.

Tabulated list of adverse reactions
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
Infections and infestations
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
Neoplasm benign, malignant, and unspecified

Table 4. Adverse reactions in patients treated with temozolomide
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:                                     Cushingoidc
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, neuropathyd, 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:                                     Deafnessf, 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 
Table 4. Adverse reactions in patients treated with temozolomide
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 painh, 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 elevationj, weight decreased, weight increased
Uncommon:                                   Gamma-glutamyltransferase increased Injury, poisoning and procedural complications
Common:                                    Radiation injuryk


Table 4. Adverse reactions in patients treated with temozolomide 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 (anaplastic astrocytoma, glioblastoma multiforme) or malignant melanoma


Laboratory results
In adult patients, myelosuppression was common with grade 3 or 4 thrombocytopenia and neutropenia observed in 19% and 17% of patients respectively treated for glioma and 20% and 22% respectively of patients with metastatic melanoma. This led to hospitalisation and/or discontinuation of TEMODAL in 8% and 4% respectively of patients with glioma and 3% and 1.3% respectively of those with melanoma.
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. Pancytopenia, leukopenia, and anaemia have also been reported. Lymphopenia has also been reported.
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 x 109/l), 12% vs 5%, and thrombocytopenia (< 20 x 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.


Reporting of suspected adverse reactions
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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il