Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Neon Healthcare Limited, Mill Studio Business Centre, Crane Mead, Ware, Hertfordshire, SG12 9PY, United Kingdom
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concomitant use of yellow fever vaccine or other live vaccines is contraindicated in immunosuppressed patients (see section 4.5).
Lactation (see section 4.6).
ETOPOPHOS should only be administered and monitored under the supervision of a qualified physician experienced in the use of anti-neoplastic medicinal products. In all instances where the use of ETOPOPHOS is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of ETOPOPHOS therapy should be carried out with caution, and with adequate consideration of the further need for the drug and close attention to possible recurrence of toxicity.
Dose limiting bone marrow suppression is the most significant toxicity associated with ETOPOPHOS therapy. Fatal myelosuppression has been reported following etoposide phosphate administration. Patients being treated with ETOPOPHOS 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 ETOPOPHOS: 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. ETOPOPHOS 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 ETOPOPHOS.
The occurrence of acute leukaemia, which can occur with or without myelodysplastic syndrome, has been described in patients that were treated with etoposide containing chemotherapeutic regimens. Neither the cumulative risk, nor the predisposing factors related to the development of secondary leukaemia are known. The roles of both administration schedules and cumulative doses of etoposide have been suggested, but have not been clearly defined.
An 11q23 chromosome abnormality has been observed in some cases of secondary leukaemia in patients who have received epipodophyllotoxins. This abnormality has also been seen in patients developing secondary leukaemia after being treated with chemotherapy regimens not containing epipodophyllotoxins and in leukaemia occurring de novo. Another characteristic that has been associated with secondary leukaemia in patients who have received epipodophyllotoxins appears to be a short latency period, with average median time to development of leukaemia being approximately 32 months.
Physicians should be aware of the possible occurrence of an anaphylactic reaction with ETOPOPHOS, manifested by chills, pyrexia, tachycardia, bronchospasm, dyspnoea and hypotension, which can be fatal. Treatment is symptomatic.
ETOPOPHOS should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.
ETOPOPHOS should be given only by slow intravenous infusion (usually over a 30 to 60 minute period) since hypotension has been reported as a possible side effect of rapid intravenous injection.
Injection site reactions may occur during administration of ETOPOPHOS. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration.
Low serum albumin is associated with increased exposure to etoposide. Therefore patients with low serum albumin may be at increased risk for etoposide-associated toxicities.
In patients with moderate (CrCl =15 to 50 mL/min), or severe (CrCl <15ml/min) renal impairment undergoing haemodialysis, etoposide should be administered at a reduced dose (see section 4.2). Haematological parameters should be measured and dose adjustments in subsequent cycles considered based on haematological toxicity and clinical effect in moderate and severe renal impaired patients.
Mostly in children, reversible acute renal failure has been reported when high dose (2220 mg/m² or 60 mg/kg) ETOPOPHOS and total body irradiation were used for haematopoietic stem cell transplantation. Renal function should be evaluated prior to and after ETOPOPHOS administration until complete renal function recovery (See section 4.8).
Patients with impaired hepatic function should regularly have their hepatic function monitored due to the risk of accumulation.
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.
Given the mutagenic potential of etoposide, an effective contraception 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 the treatment. As etoposide may decrease male fertility, preservation of sperm may be considered for the purpose of later fatherhood (see section 4.6).
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.
Concomitant phenytoin therapy is associated with increased etoposide clearance and reduced efficacy, and other enzyme-inducing antiepileptic therapy may be associated with increased ETOPOPHOS clearance and reduced efficacy.
As etoposide phosphate is converted in vivo to etoposide by phosphorylation, caution should be exercised when administering etoposide phosphate with drugs that are known to inhibit phosphatase activity as such combination may reduce efficacy of etoposide phosphate.
In vitro plasma protein binding is 97%. Phenylbutazone, sodium salicylate, and aspirin may displace etoposide from plasma protein binding.
Co-administration of antiepileptic drugs and ETOPOPHOS can lead to decreased seizure control due to pharmacokinetic interactions between the drugs.
Co-administration of warfarin and etoposide may result in elevated international normalized ratio (INR). Close monitoring of INR is recommended.
There is increased risk of fatal systemic vaccinal disease with the use of yellow fever vaccine. Live vaccines are contraindicated in immunosuppressed patients (see section 4.3).
Prior or concurrent use of other drugs with similar myelosuppressant action as etoposide may be expected to have additive or synergetic effects (see section 4.4).
Cross resistance between anthracyclines and etoposide has been reported in preclinical experiments.
Interaction studies have only been performed in adults.
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 (see section 5.3). 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 (see section 4.4). Genetic consultation is recommended if the patient wishes to have children after ending treatment.
There are no or limited amount of data from the use of etoposide phosphate in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). In general etoposide can cause fetal harm when administered to pregnant women. ETOPOPHOS 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 ETOPOPHOS. A decision must be made whether to discontinue breast-feeding or to discontinue ETOPOPHOS, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman (see section 4.3).
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 phosphate may cause adverse reactions that affect the ability to drive or 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 ETOPOPHOS therapy. In clinical studies in which ETOPOPHOS 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 ETOPOPHOS 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 ETOPOPHOS therapy.
Myelosuppression (see section 4.4) 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 (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 ETOPOPHOS in 7 clinical studies) of patients treated with ETOPOPHOS. 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 (see section 4.4).
Reversible acute renal failure has been reported in postmarketing experience (see section 4.4).
The safety profile between paediatric patients and adults is expected to be similar.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
ETOPOPHOS should not be physically mixed with any other drug.
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