Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Summary of the safety profile
Dose-limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. In clinical studies in which etoposide was administered as a single agent at a total dose of ≥450 mg/m2, the most frequent adverse reactions of any severity were leucopenia (91%), neutropenia (88 %), anaemia (72 %), thrombocytopenia (23 %), asthenia (39 %), nausea and/or vomiting (37 %), alopecia (33 %) and chills and/or fever (24 %).

Tabulated summary of adverse reactions
The following adverse reactions were reported from etoposide clinical studies and post-marketing experience.
These adverse reactions are presented by system organ class and frequency, which is defined by the following categories: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), not known (cannot be estimated from the available data).

System Organ Class                      Frequency             Adverse Reaction (MedDRA Terms) Infections and infestations             Common               Infection* Neoplasms benign, malignant             Common               Acute leukaemia and unspecified (including cysts and polyps)
Blood and lymphatic system              Very common          Myelosuppression**, leucopenia, disorders                                                    thrombocytopenia, neutropenia, anaemia Immune system disorders                 Common               Anaphylactic reactions*** Not known            Angioedema, bronchospasm
Metabolism and nutrition                Not known            Tumour lysis syndrome disorders
Nervous system disorders                Common               Dizziness Uncommon             Neuropathy peripheral
Rare                 Seizure**** optic neuritis, cortical blindness transient, neurotoxicities (e.g.,
somnolence, fatigue)
Cardiac disorders                       Common               Myocardial infarction, arrhythmia Vascular disorders                      Common               Transient systolic hypotension following rapid intravenous administration,
hypertension
Uncommon             Haemorrhage
Respiratory, thoracic and               Rare                 Pulmonary fibrosis, interstitial pneumonitis mediastinal disorders                   Not known            Bronchospasm Gastrointestinal disorders              Very common          Abdominal pain, constipation, nausea and vomiting, anorexia
Common               Mucositis (including stomatitis and esophagitis), diarrhea
Rare                 Dysphagia, dysgeusia
Hepatobiliary disorders                 Very common          Alanine aminotransferase increased, alkaline phosphatase increased, aspartate amino transferase increased, bilirubin increased,
hepatotoxicity
Skin and subcutaneous tissue            Very common          Alopecia, pigmentation disorders                               Common               Rash, urticaria, pruritus Rare                 Stevens-Johnson syndrome, toxic epidermal necrolysis, radiation recall dermatitis
Renal and urinary disorders             Not known            Acute renal failure 
Reproductive system and breast          Not known            Infertility disorders
General disorders and                   Very common          Asthenia, malaise administration site conditions          Common               Extravasation*****, phlebitis Rare                 Pyrexia
* Including opportunistic infections like pneumocystis jirovecii pneumonia ** Myelosuppression with fatal outcome has been reported.
*** Anaphylactic reactions can be fatal.
****Seizure is occasionally associated with allergic reactions.
*****Post-marketing complications reported for extravasation included local soft tissue toxicity, swelling, pain, cellulitis, and necrosis including skin necrosis.


Description of selected adverse reactions
In the paragraphs below the incidences of adverse events, given as the mean percent, are derived from studies that utilised single agent etoposide therapy.

Haematological toxicity
Myelosuppression (see section 4.4) with fatal outcome has been reported following administration of etoposide.
Myelosuppression is most often dose-limiting. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported.
Granulocyte and platelet nadirs tend to occur about 10 to14 days after administration of etoposide, depending on the way of administration and treatment scheme. Nadirs tend to occur earlier with intravenous administration compared to oral administration.
Leucopenia and severe leucopenia (less than 1,000 cells/mm3) were observed in 91% and 17%, respectively, for etoposide. Thrombocytopenia and severe thrombocytopenia (less than 50,000 platelets/mm 3) were seen in 23% and 9%, respectively, for etoposide. Reports of fever and infection were also very common in patients with neutropenia treated with etoposide. Bleeding has been reported.

Gastrointestinal toxicity
Nausea and vomiting are the major gastrointestinal toxicities of etoposide. The nausea and vomiting can usually be controlled by antiemetic therapy.

Alopecia
Reversible alopecia, sometimes progressing to total baldness, has been observed in up to 44% of patients treated with etoposide.

Hypotension
Transient hypotension following rapid intravenous administration has been reported in patients treated with etoposide and has not been associated with cardiac toxicity or electrocardiographic changes. Hypotension usually responds to cessation of infusion of etoposide and/or other supportive therapy as appropriate. When restarting the infusion, a slower administration rate should be used. No delayed hypotension has been noted.

Hypertension
In clinical studies involving etoposide, episodes of hypertension have been reported. If clinically significant hypertension occurs in patients receiving etoposide, appropriate supportive therapy should be initiated.

Hypersensitivity
Anaphylactic reactions have also been reported to occur during or immediately after intravenous administration of etoposide. The role that concentration or rate of infusion plays in the development of anaphylactic reactions is uncertain. Blood pressure usually normalises within a few hours after cessation of the infusion. Anaphylactic-type reactions can occur with the initial dose of etoposide.

Anaphylactic reactions (see section 4.4), manifested by chills, tachycardia, bronchospasm, dyspnoea, diaphoresis, pyrexia, pruritus, hypertension or hypotension, syncope, nausea, and vomiting have been reported to occur in 3 % (7 of 245 patients treated with etoposide in 7 clinical studies) of patients treated with etoposide. Facial flushing was reported in 2% of patients and skin rashes in 3%. These reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders as appropriate.


Acute fatal reactions associated with bronchospasm have been reported with etoposide. Apnoea with spontaneous resumption of breathing following cessation of infusion have also been reported.

Metabolic complications
Tumour lysis syndrome (sometimes fatal) has been reported following the use of etoposide in association with other chemotherapeutic drugs (see section 4.4).

Acute renal failure
Reversible acute renal failure has been reported in post-marketing experience (see section 4.4).

Paediatric population
The safety profile between paediatric patients and adults is expected to be similar.
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.