Chemical formula: C₂₉H₃₂O₁₃ Molecular mass: 588.557 g/mol PubChem compound: 36462
Etoposide interacts in the following cases:
In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance.
| Measured Creatinine Clearance | Dose of Etoposide Phosphate |
|---|---|
| >50 mL/min | 100% of dose |
| 15-50 mL/min | 75% of dose |
In patients with creatinine clearance less than 15 mL/min and on dialysis further dose reduction is likely to be required as etoposide clearance is further reduced in these patients. Subsequent dosing in moderate and severe renal impairment should be based on patient tolerance and clinical effect. Since etoposide and its metabolites are not dialyzable, it can be administered pre- and post-haemodialysis.
Cross resistance between anthracyclines and etoposide has been reported in preclinical experiments.
Co-administration of antiepileptic drugs and etoposide can lead to decreased seizure control due to pharmacokinetic interactions between the drugs.
As etoposide may decrease male fertility, preservation of sperm may be considered for the purpose of later fatherhood.
High dose ciclosporin, resulting in plasma concentrations above 2000 ng/mL, administered with oral etoposide has led to an 80% increase in etoposide exposure (AUC) with a 38% decrease in total body clearance of etoposide compared to etoposide alone.
Concomitant cisplatin therapy is associated with reduced total body clearance of etoposide.
In vitro plasma protein binding of etoposide is 97%. Phenylbutazone, sodium salicylate, and aspirin may displace etoposide from plasma protein binding.
Concomitant phenytoin therapy is associated with increased etoposide clearance and reduced efficacy, and other enzyme-inducing antiepileptic therapy may be associated with increased etoposide clearance and reduced efficacy.
Co-administration of warfarin and etoposide may result in elevated international normalized ratio (INR). Close monitoring of INR is recommended.
Tumour lysis syndrome (sometimes fatal) has been reported following the use of etoposide in association with other chemotherapeutic drugs. Close monitoring of patients is needed to detect early signs of tumour lysis syndrome, especially in patients with risk factors such as bulky treatment-sensitive tumours, and renal insufficiency. Appropriate preventive measures should also be considered in patients at risk of this complication of therapy.
Dose limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. Fatal myelosuppression has been reported following etoposide phosphate administration. Patients being treated with etoposide must be observed for myelosuppression carefully and frequently both during and after therapy. The following haematological parameters should be measured at the start of therapy and prior to each subsequent dose of etoposide: platelet count, haemoglobin, white blood cell count and differential. If radiotherapy or chemotherapy has been given prior to starting etoposide treatment, an adequate interval should be allowed to enable the bone marrow to recover. Etoposide should not be administered to patients with neutrophil counts less than 1,500 cells/mm³ or platelet counts less than 100,000 cells/mm³, unless caused by malignant disease. Doses subsequent to initial dose should be adjusted if neutrophil count less than 500 cells/mm³ occurs for more than 5 days or is associated with fever or infection, if platelet count less than 25,000 cells/mm³ occurs, if any grade 3 or 4 toxicity develops or if renal clearance is less than 50 ml/min.
Severe myelosuppression with resulting infection or haemorrhage may occur. Bacterial infections should be brought under control before treatment with etoposide.
There are no or limited amount of data from the use of etoposide in pregnant women. Studies in animals have shown reproductive toxicity. In general etoposide can cause fetal harm when administered to pregnant women. Etoposide should not be used during pregnancy unless the clinical condition of the woman requires treatment with etoposide. Women of childbearing potential should be advised to avoid becoming pregnant. Women of childbearing potential have to use effective contraception during and up to 6 months after treatment. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be informed of the potential hazard to the fetus.
Etoposide is excreted in human milk. There is the potential for serious adverse reactions in nursing infants from etoposide. A decision must be made whether to discontinue breast-feeding or to discontinue etoposide, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during etoposide therapy. Etoposide has been shown to be teratogenic in mice and rats. Given the mutagenic potential of etoposide, an effective contraceptive is required for both male and female patients during treatment and up to 6 months after ending treatment. Genetic consultation is recommended if the patient wishes to have children after ending treatment.
As etoposide may decrease male fertility, preservation of sperm may be considered for the purpose of later fatherhood.
No studies on the effects on the ability to drive and use machines have been performed. Etoposide may cause adverse reactions that affect the ability to drive and use machines such as fatigue, somnolence, nausea, vomiting, cortical blindness, hypersensitivity reactions with hypotension. Patients who experience such adverse reactions should be advised to avoid driving or using machines.
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 either orally or by injection the most frequent adverse reactions of any severity were leucopenia (60 to 91%), thrombocytopenia (22 to 41%), nausea and/or vomiting (31 to 43%), and alopecia (8 to 66%).
The following adverse reactions were reported from etoposide clinical studies and post-marketing experience. These adverse reactions 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).
not known: infection
common: acute leukaemia
very common: anaemia, leucopenia, myelosuppression*, neutropenia, thrombocytopenia
rare: anaphylactic reactions
not known: angioedema, bronchospasm
not known: tumour lysis syndrome
common: dizziness
uncommon: neuropathy peripheral
rare: cortical blindness transient, neurotoxicities (e.g., somnolence and fatigue), optic neuritis, seizure**
common: arrythmia, myocardial infarction
common: hypertension
not known: haemorrhage
rare: interstitial pneumonitis, pulmonary fibrosis
very common: abdominal pain, anorexia, constipation, nausea and vomiting
common: diarrhoea, mucositis (including stomatitis and esophagitis)
rare: dysgeusia, dysphagia
very common: hepatotoxicity
not known: alanine aminotransferase increased, alkaline phosphatase increased, aspartate amino transferase increased, bilirubin increased
very common: alopecia, pigmentation
common: pruritus, rash, urticaria
rare: radiation recall dermatitis, Stevens-Johnsons syndrome, toxic epidermal necrolysis
not known: infertility
very common: asthenia, malaise
rare: pyrexia
* Myelosuppression with fatal outcome has been reported
** Seizure is occasionally associated with allergic reactions.
In the paragraphs below the incidences of adverse events, given as the mean percent, are derived from studies that utilized single agent etoposide therapy.
Myelosuppression 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 60 to 91% and 3 to 17%, respectively, for etoposide. Thrombocytopenia and severe thrombocytopenia (less than 50,000 platelets/mm³) were seen in 22 to 41% and 1 to 20%, respectively, for etoposide. Reports of fever and infection were also very common in patients with neutropenia treated with etoposide.
Nausea and vomiting are the major gastrointestinal toxicities of etoposide. The nausea and vomiting can usually be controlled by antiemetic therapy.
Reversible alopecia, sometimes progressing to total baldness, was observed in up to 66% of patients treated with etoposide.
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.
Anaphylactic reactions manifested by chills, fever, tachycardia, bronchospasm, dyspnoea, and hypotension which can be fatal can occur with the initial dose of etoposide. Acute fatal reactions associated with bronchospasm have been reported with etoposide. Syncope, face oedema, swelling face, tongue oedema and swelling tongue can also occur with etoposide.
Tumour lysis syndrome (sometimes fatal) has been reported following the use of etoposide in association with other chemotherapeutic drugs.
Safety and effectiveness of etoposide in paediatric patients has not been systematically studied.
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%).
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).
common: infection
common: acute leukaemia
very common: anaemia, leucopenia, myelosuppression*, neutropenia, thrombocytopenia
common: anaphylactic reactions**
not known: angioedema, bronchospasm
not known: tumour lysis syndrome
common: dizziness
uncommon: neuropathy peripheral
rare: cortical blindness transient, neurotoxicities (e.g. somnolence and fatigue), optic neuritis, seizure***
common: arrythmia, myocardial infarction
common: hypertension, transient systolic hypotension following rapid intravenous administration
uncommon: haemorrhage
rare: interstitial pneumonitis, pulmonary fibrosis
not known: bronchospasm
very common: abdominal pain, anorexia, constipation, nausea and vomiting
common: diarrhoea, mucositis (including stomatitis and esophagitis)
rare: dysgeusia, dysphagia
very common: alanine aminotransferase increased, alkaline phosphatase increased, aspartate amino transferase increased, bilirubin increased, hepatotoxicity
very common: alopecia, pigmentation
common: pruritus, rash, urticaria
rare: radiation recall dermatitis, Stevens-Johnsons syndrome, toxic epidermal necrolysis
not known: acute renal failure
not known: infertility
very common: asthenia, malaise
common: extravasation****, phlebitis
rare: pyrexia
* 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.
In the paragraphs below the incidences of adverse events, given as the mean percent, are derived from studies that utilized single agent etoposide therapy.
Myelosuppression with fatal outcome has been reported following administration of etoposide phosphate. 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 phosphate 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 phosphate. Thrombocytopenia and severe thrombocytopenia (less than 50,000 platelets/mm³) were seen in 23% and 9% respectively, for etoposide phosphate. Reports of fever and infection were also very common in patients with neutropenia treated with etoposide phosphate. Bleeding has been reported.
Nausea and vomiting are the major gastrointestinal toxicities of etoposide phosphate. The nausea and vomiting can usually be controlled by antiemetic therapy.
Reversible alopecia, sometimes progressing to total baldness, was observed in up to 44% of patients treated with etoposide phosphate.
Transient hypotension following rapid intravenous administration has been reported in patients treated with etoposide phosphate and has not been associated with cardiac toxicity or electrocardiographic changes. Hypotension usually responds to cessation of infusion of etoposide phosphate and/or other supportive therapy as appropriate. When restarting the infusion, a slower administration rate should be used. No delayed hypotension has been noted.
In clinical studies involving etoposide phosphate, episodes of hypertension have been reported. If clinically significant hypertension occurs in patients receiving etoposide phosphate, appropriate supportive therapy should be initiated.
Anaphylactic reactions have been reported to occur during or immediately after intravenous administration of etoposide phosphate. The role that concentration or rate of infusion plays in the development of anaphylactic reactions is uncertain. Blood pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic reactions can occur with the initial dose of etoposide phosphate.
Anaphylactic reactions, 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 phosphate. Apnoea with spontaneous resumption of breathing following cessation of infusion have also been reported.
Tumour lysis syndrome (sometimes fatal) has been reported following the use of etoposide phosphate in association with other chemotherapeutic drugs.
Reversible acute renal failure has been reported in postmarketing experience.
The safety profile between paediatric patients and adults is expected to be similar.
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