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%).
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).
Infections and infestations: Common: Infection.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Common: Acute leukaemia.
Blood and the lymphatic system disorders: Very common: Anaemia, leucopenia, myelosuppression*, neutropenia, thrombocytopenia.
Immune system disorders: Common: Anaphylactic reactions**.
Not known: Angioedema, bronchospasm.
Metabolism and nutrition disorders: Not known: Tumour lysis syndrome.
Nervous system disorders: Common: Dizziness.
Uncommon: Neuropathy peripheral.
Rare: Cortical blindness transient, neurotoxicities (e.g., somnolence and fatigue), optic neuritis, seizure***.
Cardiac disorders: Common: Arrhythmia, myocardial infarction.
Vascular disorders: Common: Hypertension, transient systolic hypotension following rapid intravenous administration.
Respiratory, thoracic and mediastinal disorders: Rare: Interstitial pneumonitis, pulmonary fibrosis.
Not known: Bronchospasm.
Gastrointestinal disorders: Very common: Abdominal pain, anorexia, constipation, nausea and vomiting.
Common: Diarrhoea, mucositis (including stomatitis and oesophagitis).
Rare: Dysgeusia, dysphagia.
Hepatobiliary disorders: Very common: Alanine aminotransferase increased, alkaline phosphatase increased, aspartate amino transferase increased, bilirubin increased, hepatotoxicity.
Skin and subcutaneous tissue disorders: Very common: Alopecia, pigmentation.
Common: Pruritus, rash, urticaria.
Rare: Radiation recall dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Reproductive system and breast disorders: Not known: Infertility.
General disorders and administration site conditions: Very common: Asthenia, malaise.
Common: Extravasation****, phlebitis.
* Myelosuppression with fatal outcome has been reported.
** Anaphylactic reactions can be fatal.
*** Seizure is occasionally associated with allergic reactions.
**** Postmarketing 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 as follows the incidences of adverse events, given as the mean percent, are derived from studies that utilised single agent etoposide therapy.
Haematological toxicity: Myelosuppression (see Precautions) 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 to 14 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/mm3) 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, was observed in up to 44% of patients treated with etoposide phosphate.
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 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 reactions can occur with the initial dose of etoposide.
Anaphylactic reactions (see Precautions), 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 also 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 medicinal products (see Precautions).
Paediatric population: The safety profile between paediatric patients and adults is expected to be similar.