Etoposido Microsules

Etoposido Microsules Injection is indicated in adults for the management of:

- resistant non-seminomatous testicular tumours in combination with other chemotherapeutic agents

- small cell lung cancer, in combination with other chemotherapeutic agents

- acute monoblastic leukaemia (AML M5) and acute myelomonoblastic leukaemia (AML M4) when standard induction therapy has failed (in combination with other chemotherapeutic agents).

Recurrent or refractory testicular cancer

Etoposido Microsules is indicated in combination with other approved chemotherapeutic agents for the treatment of recurrent or refractory testicular cancer in adults.

Small cell lung cancer

Etoposido Microsules is indicated in combination with other approved chemotherapeutic agents for the treatment of small-cell lung cancer in adults.

Hodgkin's lymphoma

Etoposido Microsules is indicated in combination with other approved chemotherapeutic agents for the second line treatment of Hodgkin's lymphoma in adults.

Non-Hodgkin's lymphoma

Etoposido Microsules is indicated in combination with other approved chemotherapeutic agents for the treatment of relapsed or refractory non-Hodgkin's lymphoma in adults.

Acute myeloid leukaemia

Etoposido Microsules is indicated in combination with other approved chemotherapeutic agents for the treatment of relapsed or refractory acute myeloid leukaemia in adults.

Ovarian cancer

Etoposido Microsules is indicated in combination with other approved chemotherapeutic agents for the treatment of non-epithelial ovarian cancer in adults.

Etoposido Microsules is indicated for the treatment of platinum-resistant/refractory epithelial ovarian cancer in adults.

Treatment with Etoposido Microsules should be initiated by or in consultation with a qualified physician experienced in cancer chemotherapy.

Etoposido Microsules Injection is intended for slow intravenous infusion. Etoposido Microsules should not be administered as a rapid intravenous injection.

Posology:

Adults

The recommended dose of Etoposido Microsules is 60-120 mg/m² i.v. per day for 5 subsequent days. As Etoposido Microsules causes myelosuppression, the course of treatment must not be repeated more often than in intervals of 10 to 20 days. For non-haematological indications courses may not be repeated more frequently than at 21 days intervals. Repeated courses of treatment with Etoposido Microsules infusion must not be given before the blood picture has been controlled for signs of myelosuppression and found satisfactory.

Overall, a dosage schedule of 100 mg/m² for 5 days or 120 mg/m² every other day on days 1, 3, and 5 is used frequently.

The necessary dose of Etoposido Microsules must be diluted either with a 5% glucose solution or a 0.9% sodium chloride solution, in order to achieve a final concentration of 0.2 - 0.4 mg/ml of Etoposido Microsules (i.e 1 ml or 2 ml concentrate in 100 ml of diluent to achieve concentration of 0.2 mg/ml and 0.4 mg/ml respectively). This solution is administered as an intravenous solution over a period of no less than 30 minutes and no more than 2 hours.

Administration precautions:

Hypotension after rapid intravenous administration has been reported. Therefore, it is recommended that Etoposido Microsules be administered over a 30 to 60 minute period. Longer infusion times may be required depending on the patient's tolerance. As with other potentially toxic compounds, caution should be exercised in the handling and preparation of Etoposido Microsules. Skin reactions associated with unintentional exposure to Etoposido Microsules may occur. The use of gloves is recommended. If Etoposido Microsules Injection comes into contact with skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Dosage adjustment:

The dosage of Etoposido Microsules should be adjusted taking into account the myelosuppressive effects of other drugs in combination, or the effects of prior radiation or chemotherapy which may have compromised bone marrow reserve. Etoposido Microsules cycles should not be begin if the neutrophil count is less than 1,500 cells/mm³ or the platelet count is less than 100,000 cells/mm³, unless caused by malignant disease.

Doses following the first dose should be adjusted if the neutrophil count is less than 500 cells/mm³ for more than 5 days or if this is associated with fever or infection, if the platelet count is less than 25,000 cells/mm³, if any other grade 3 or 4 toxicity develops or if the clearance is less than 50 ml / min.

In the case of combination therapy, the dosage of Etoposido Microsules should be set in accordance with the relevant treatment plan.

The duration of therapy is set by the doctor, taking into account the underlying disease, the combination therapy being administered (if relevant), and the individual therapeutic circumstances. Etoposido Microsules should be discontinued if the tumour does not respond to treatment and/or progresses or if intolerable undesirable effects occur.

Paravenous injection must be carefully avoided. Etoposido Microsules may not be administered as an intra-arterial and intracavitary injection.

Paediatric population:

Safety and effectiveness in children and adolescents have not been established.

Elderly patients

The dosage does not need to be adjusted.

Patients with impaired renal function

In patients with renal impairment the following initial dose adjustment should be considered based on measured creatinine clearance.

Subsequent dosing should be based on patient tolerance and clinical efficacy.

Etoposido Microsules capsules should only be administered and monitored under the supervision of a qualified physician experienced in the use of anti-neoplastic medicinal products.

Posology

The dose of Etoposido Microsules capsules is based on the recommended intravenous dose taking into account the dose-dependent bioavailability of Etoposido Microsules capsules. A 100 mg oral dose would be comparable to a 75 mg intravenous dose; a 400 mg oral dose would be comparable to a 200 mg intravenous dose. Within-patient variability in exposure (i.e. between cycles) is larger with oral administration than after intravenous administration.

Monotherapy

The usual dose of Etoposido Microsules administered orally is 100 to 200 mg/m²/day on days 1 to 5 or 200 mg/m²/day on days 1, 3 and 5 every 3 to 4 weeks. Daily doses greater than 200 mg should be divided and given twice per day.

Combination therapy

The usual dose of Etoposido Microsules administered orally is 100 to 200 mg/m²/day on days 1 to 5 or 200 mg/m²/day on days 1, 3 and 5 every 3 to 4 weeks in combination with other drugs approved for use in the disease to be treated.

Dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior radiotherapy or chemotherapy , which may have compromised bone marrow reserve. The doses after the initial dose should be adjusted if neutrophil count is below 500 cells/mm³ for more than 5 days. In addition the dose should be adjusted in case of occurrence of fever, infections, or at a thrombocyte count below 25,000 cells/mm³, which is not caused by the disease. Follow up doses should be adjusted in case of occurrence of grade 3 or 4 toxicities or if renal creatinine clearance is below 50 ml/min. At decreased creatinine clearance of 15 to 50 mL/min a dose reduction by 25% is recommended.

Alternative dosage schedule

An alternative dosage schedule for Etoposido Microsules capsules is 50 mg/m²/day for 2 to 3 weeks, with courses repeated after a one week rest period or upon recovery from myelosuppression.

Neutropenia and thrombocytopenia

Patients should not begin a new cycle of treatment with Etoposido Microsules if the neutrophil count is less than 1,500 cells/mm³ or the platelet count is less than 100,000 cells/mm³, unless caused by malignant disease.

Elderly population

No dosage adjustment is necessary in elderly patients (age > 65 years old), other than based on renal function.

Paediatric population

The safety and efficacy of Etoposido Microsules in children below 18 years of age have not been established.

Renal impairment

In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance.

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.

Method of administration

Capsules should be taken on an empty stomach.

- Severe liver impairment

- Severe myelosuppression

- Breastfeeding

- Concomitant use of yellow fever vaccine or other live vaccines is contraindicated in immunosuppressed patients (see 4.5 interaction with other medicinal products and other forms of interaction).

Concomitant use of yellow fever vaccine or other live vaccines is contraindicated in immunosuppressed patients.

Lactation

Etoposido Microsules should be administered under the supervision of qualified physician experienced in the use of cancer chemotherapeutic agents. Physicians should be aware that the treatment with Etoposido Microsules may be an anaphylactic reaction manifested as chills, fever, flushing, tachycardia, bronchospasm, dyspnea and hypotension, which may be fatal. Treatment is symptomatic. The infusion must be stopped and followed by administration of pressor agents, corticosteroids, antihistamines or volume expanding resources by physician. There may be reactions at injection site during administration.

If Etoposido Microsules is to be administered intravenously, paravenous injection must be carefully avoided. It is recommended to monitor the infusion site closely for possible infiltration during drug administration. There is no known specific treatment for extravasation at this time.

There may be severe myelosuppression with resultant infection or bleeding.

There have been reports of fatal myelosuppression after administration of Etoposido Microsules. Patients treated with Etoposido Microsules should be monitored closely and frequently for myelosuppression both during and after treatment. Dose limiting bone marrow suppression is the most significant toxicity associated with Etoposido Microsules treatment. The following observations should be made at the start of treatment and before each subsequent dose Etoposido Microsules: platelet count, hemoglobin and total and differential count of leukocytes. If radiotherapy or chemotherapy was carried out before the start of Etoposido Microsules treatment, a suitable interval must elapse for the bone marrow to recover.

After the initial dose, subsequent doses adjusted if the neutrophil count below 500 cells/mm³ occurring in more than 5 days or associated with fever or infection, if there is platelet counts below 25,000 cells/mm³ if they develop any other toxicity of grade 3 or 4, or if the renal clearance is below 50 ml / min. The dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of previous radiation therapy or chemotherapy which may have compromised bone marrow reserve.

Occurrence of acute leukemia, which can occur with or without a pre-leukaemic phase, has been reported rarely in patients treated with Etoposido Microsules in combination with other antineoplastic drugs.

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 Etoposido Microsules 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.

Before Etoposido Microsules treatment is started, bacterial infections should be brought under control.

The infusion should be given slowly, during 30 to 60 minutes, to avoid hypotension or bronchospasm.

In all instances where the use of Etoposido Microsules 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 judgement of the physician. Reinstitution of Etoposido Microsules therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity

In patients with a lower serum albumin level, the risk of toxicity caused by Etoposido Microsules can be elevated. Before the start of therapy, during the therapy, and before each course of treatment, a peripheral blood panel (white blood cells, platelets, haemoglobin), renal function, and hepatic function should be checked, and neurological functions should be investigated. Courses of therapy with Etoposido Microsules should in generally be carried out only if the patient's liver and kidneys are functioning normally. If the patient is suffering from hepatic or renal dysfunction, renal and hepatic function should regularly monitored due to the risk of accumulation. Furthermore, courses of therapy with Etoposido Microsules should be carried out only if the peripheral nervous system is functioning normally.

Etoposido Microsules is mutagenic and carcinogenic. This should be taken into account when a long-term treatment is performed.

In view of Etoposido Microsules mutagenic potential, both male and female patients use effective contraception during treatment and up to 6 months after treatment.

It is recommended to seek genetic counseling if the patient wants to have children after treatment. Since Etoposido Microsules may reduce fertility in men, may be considered to allow sperm storage for subsequent paternity.

Paediatric population

Safety and efficacy in children has not been systematically studied.

Anaphylactic reactions have been reported in paediatric patients who received Etoposido Microsules Injection

Excipient (s ) that the clinician should be aware of :

Ethanol

Etoposido Microsules Injection contains 30.5% alcohol (ethanol), which corresponds to 240.64 mg of ethanol per ml of concentrate i.e up to 1.2 gm of ethanol per 5 ml vial, equivalent to 30 ml of beer or 12.55 ml of wine and up to 3 gm of ethanol per 12.5 ml vial, equivalent to 75 ml of bear or 31.4 ml of wine.

There is a health risk to hepatic patients, alcoholics, epileptics, patients with organic brain diseases, pregnant women, breastfeeding women, and children, amongst others. The effect of other drugs may be reduced or increased.

Benzyl alcohol

Because of the presence of benzyl alcohol, Etoposido Microsules Injection must not be given to premature babies or neonates. It may cause toxic and allergic reactions in infants and children upto 3 years old.

Polysorbate 80

Etoposido Microsules Injection contains polysorbate 80. In newborn infants a life threatening syndrome of liver, cholestasis and renal failure, pulmonary deterioration, thrombocytopenia and ascites has been associated with an injectable vitamin E product containing polysorbate 80.

Etoposido Microsules 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 Etoposido Microsules 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 Etoposido Microsules 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.

Within-patient variability

The available efficacy data for etoposide in the different indications are generally based on studies in which etoposide was used intravenously. Within-patient variability in exposure (i.e. between cycles) is larger with oral administration than after intravenous administration. The coefficient of variation is around 30% after oral administration versus 10% after intravenous administration (between-patient variability is similar after intravenous or oral administration, i.e. 30 to 40%). Increased within-patient variability in exposure may lead to greater variability in the dose-response relationship, i.e., leading to greater variability in patients' sensitivity to experience treatment-related toxicity from cycle to cycle, and potentially affecting overall efficacy of treatment in some patients. For this reason, it is critical that the advantages of the oral administration route are carefully weighed against the disadvantages of larger within-patient variability in exposure after oral administration. In case of curative intent the intravenous formulation should be used.

Myelosuppression

Dose limiting bone marrow suppression is the most significant toxicity associated with Etoposido Microsules therapy. Fatal myelosuppression has been reported following etoposide administration. Patients being treated with Etoposido Microsules 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 Etoposido Microsules: 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. Etoposido Microsules should not be administered to patients with neutrophil counts less than 1,500 cell/mm³ or platelet counts less than 100,000cells/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 Etoposido Microsules.

Secondary leukaemia

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.

Hypersensitivity

Physicians should be aware of the possible occurrence of an anaphylactic reaction with Etoposido Microsules, manifested by chills, pyrexia, tachycardia, bronchospasm, dyspnoea and hypotension, which can be fatal. Treatment is symptomatic. Etoposido Microsules should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.

Low serum albumin

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.

Impaired renal function

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. 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.

Impaired hepatic function

Patients with impaired hepatic function should regularly have their hepatic function monitored due to the risk of accumulation.

Tumour lysis syndrome

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.

Mutagenic potential

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.

Etoposido Microsules contains sodium ethyl parahydroxybenzoate and sodium propyl parahydroxybenzoate

Etoposido Microsules capsules contain sodium propyl parahydroxybenzoate and sodium ethyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

Paediatric population

Safety and effectiveness of Etoposido Microsules in paediatric patients has not been systematically studied.

No studies on the effects on the ability and use machines have been performed with Etoposido Microsules. Fatigue, somnolence, nausea, vomiting and acute hypersensitivity reactions may occur due to a drop in blood pressure, and this may impair the ability to drive and use machines.

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.

The following adverse events have been reported in association with Etoposido Microsules therapy:

Frequencies are defined using 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)

Hematological Toxicity:

The dose-limiting effect of Etoposido Microsules is myelosuppression. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported.

Granulocyte and platelet nadirs tend to occur about 10-14 days after administration of Etoposido Microsules depending on the way of administration and treatment scheme. Nadirs tend to occur earlier with intravenous administration compared to oral administration.

Leucopenia in 60-91%, severe leucopenia (< 1,000/µl) in 7-17% of patients, thrombocytopenia in 28-41%, severe thrombocytopenia (< 50,000/µl) in 4-20% of patients. The reports of fever and infection were also very common in patient with neutropenia treated with Etoposido Microsules.

Gastrointestinal Toxicity

Nausea and vomiting are the main gastrointestinal undesirable effects and occur in 31-43% of patients given intravenous. Loss of appetite was observed with a frequency of 10-13% of patients.

Stomatitis has been observed in approximately 1-6% of patients. Diarrhea is noted in 1-13% of these patients.

Alopecia:

Reversible alopecia, sometimes progressing to toal baldness has been observed in upto 66% of patients.

Blood pressure changes

Hypotension:

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

Hypertension:

In clinical studies involving Etoposido Microsules injection, hypertension has been reported. If clinically significant hypertension occurs in patients receiving Etoposido Microsules injection, appropriate supportive therapy should be initiated.

Allergic reactions:

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

Actual fatal reactions associated with bronchospasm have been reported with Etoposido Microsules. Facial flushing was reported in 2% and skin rashes in 3% patients.

Metabolic complications:

Tumour lysis syndroms (sometime fatal) has been reported following the use of Etoposido Microsules in association with other chemotherapeutic drugs.

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard..

Summary of the safety profile

Dose limiting bone marrow suppression is the most significant toxicity associated with Etoposido Microsules therapy. In clinical studies in which Etoposido Microsules 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%).

Tabulated summary of adverse reactions

The following adverse reactions were reported from Etoposido Microsules 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).

Description of selected adverse reactions

In the paragraphs below the incidences of adverse events, given as the mean percent, are derived from studies that utilized single agent Etoposido Microsules therapy.

Haematological Toxicity

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.

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 66% of patients treated with etoposide.

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 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.

Metabolic Complications

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

Paediatric population

Safety and effectiveness of Etoposido Microsules in paediatric patients has not been systematically studied.

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Overdose can lead within one-two weeks to severe myelosuppression. Total doses of 2.4-3.5 g/m² of Etoposido Microsules administered intravenously over 3 days have caused mucositis and myelotoxicity. Metabolic acidosis and severe hepatic toxicity have been reported after the administration of doses that were higher than recommended. There is no specific antidote available. Treatment should therefore be symptomatic and supportive, and patients should be closely monitored.

Total doses of 2.4 g/m² to 3.5 g/m² administered intravenously over three days have resulted in severe mucositis and myelotoxicity. Metabolic acidosis and cases of serious hepatic toxicity have been reported in patients receiving higher than recommended intravenous doses of etoposide. Similar toxicities can be expected with oral formulation. A specific antidote is not available. Treatment should therefore be symptomatic and supportive, and patients should be closely monitored. Etoposide and its metabolites are not dialyzable.

Pharmacotherapeutic group: antineoplastic agent—podophyllotoxin derivatives

ATC code: L01CB01

Etoposido Microsules is a semi-synthetic podophyllotoxin derivative. Its main effect seems to occur during the G₂ phase of the cell cycle. Two dose-dependent reactions occur: at high concentrations (> 10 µg/ml), lysis can be observed of the cells entering mitosis; at low concentrations (0.3-10 µg/ml), the cells are prevented from entering the prophase. The main macromolecular effect appears to be inhibition of DNA synthesis.

Pharmacotherapeutic group: Cytostatics, plant alkaloids and other natural products, podophyllotoxin derivatives, ATC code: L01CB01

Mechanism of action

The main effect of etoposide appears to be at the late S and early G₂ portion of the cell cycle in mammalian cells. Two dose-dependent responses are seen: At high concentrations (10 mcg/mL or more), cells entering mitosis are lysed; at low concentrations (0.3 to 10 mcg/mL), cells are inhibited from entering prophase. Microtubule assembly is not affected. The predominant macromolecular effect of etoposide seems to be the rupture of the double strand by an interaction with DNA-topoisomerase II or by the formation of free radicals. Etoposide has been shown to cause metaphase arrest in chick fibroblasts.

Following intravenous infusion plasma levels of Etoposido Microsules declines bi-exponentially with a distribution half-life of approximately 1.5 hours followed by a terminal elimination half-life of 4-11 hours. The total body clearance is 16-36 ml/minute/m² and is dose-independent within the dose interval 100-600 mg/m². The terminal half-life is also dose-independent in this dose interval. Etoposido Microsules does not accumulate in plasma when given as a daily intravenous administration of 100 mg/m² over 4-6 days. The steady state distribution volume is 7-17 l/m². The distribution to CSF is low and variable. In vitro studies shows that Etoposido Microsules is extensively bound to human plasma proteins (97%).

The elimination of Etoposido Microsules is both renal and non-renal. Following intravenous administration of ³H-Etoposido Microsules (70-290 mg/m²) 42-67% of the dose was recovered in urine and 0-16% in faeces. 8-35% of the dose was excreted in the urine as unchanged drug within 24 hours. The main non-renal elimination route of Etoposido Microsules is metabolism. Less than 6% of the given dose is excreted in the bile. In adults the total body clearance Etoposido Microsules correlated with creatinine clearance, low serum albumin concentration and non-renal clearance. In children, elevated serum GPT has been associated with decreased Etoposido Microsules clearance. Impaired hepatic or renal function may increase Etoposido Microsules concentration in tissues due to metabolic and excretion routes.

Absorption

After either intravenous infusion or oral capsule administration, the C_max and AUC values exhibit marked intra- and inter-subject variability. The oral bioavailability is variable but averages 76% at the 100 mg oral dose and 48% at the 400 mg oral dose.

Distribution

The mean volumes of distribution at steady state fall in the range of 18 to 29 liters or 7 to 17 L/m². Etoposide shows low penetration into the CSF. In vitro, etoposide is highly protein bound (97%) to human plasma proteins.

Etoposide binding ratio correlates directly with serum albumin in cancer patients and normal volunteers. Unbound fraction of etoposide correlates significantly with bilirubin in cancer patients.

Biotransformation

The hydroxyacid metabolite [4' dimethyl-epipodophyllic acid-9-(4,6 0-ethylidene-β-D-glucopyranoside)], formed by opening of the lactone ring, is found in the urine of adults and children. It is also present in human plasma, presumably as the trans isomer. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. In addition, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol. There is no evidence of a hepatic first-pass effect for etoposide. No correlation exists between the absolute oral bioavailability of etoposide capsules and non-renal clearance. No evidence exists for any other differences in etoposide metabolism and excretion after administration of oral capsules as compared to intravenous infusion.

Elimination

On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min or 16 to 36 mL/min/m² and, like the terminal elimination half-life, are independent of dose over a range 100 to 600 mg/m². After intravenous administration of ¹⁴C etoposide (100 to 124 mg/m²), mean recovery of radioactivity in the urine was 56% (45% of the dose was excreted as etoposide) and faecal recovery of radioactivity was 44% of the administered dose at 120 hours.

Linearity/non-linearity

Total body clearance and the terminal elimination half-life are independent of dose over a range 100 to 600 mg/m². Over the same dose range, the areas under the plasma concentration vs. time curves (AUC) and the maximum plasma concentration (C_max) values increase linearly with dose.

Renal impairment

Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and higher steady state volume of distribution.

Hepatic impairment

In adult cancer patients with liver dysfunction, total body clearance of etoposide is not reduced.

Elderly population

Although minor differences in pharmacokinetic parameters between patients ≤65 years and >65 years of age have been observed, these are not considered clinically significant.

Paediatric population

In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m² or about 35% of the total body clearance over a dose range of 80 to 600 mg/m². Etoposide, therefore, is cleared by both renal and nonrenal processes, ie, metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known in children. In children, elevated SGPT levels are associated with reduced drug total body clearance. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children.

An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children.

Gender

Although minor differences in pharmacokinetic parameters between genders have been observed, these are not considered clinically significant.

Drug interactions

In a study of the effects of other therapeutic agents on in vitro binding of ¹⁴C etoposide to human serum proteins, only phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations generally achieved in vivo.

Not applicable

Etoposido Microsules Injection should be handled in accordance with instruction for cytotoxic agents.

If solution showing sign of precipitation or contains visible particles, it should be discarded.

Etoposido Microsules Injection must be diluted prior to use with Sodium chloride injection (0.9 % w/v) or glucose injection (5% w/v) to concentration of 0.2 mg/mL (i.e 1 ml of concentrate in 100 ml of diluent) to 0.4 mg/mL (i.e 2 ml of concentrate in 100 ml of diluent). The concentration of diluted solution should not exceed 0.4 mg/mL because of risk of precipitation.

For waste-disposal and safety information guidelines on safe-handling of antineoplastic drugs should be followed.

Any contact with the fluid should be avoided. During preparation and reconstitution a strictly aseptic working technique should be used; protective measures should include the use of gloves, mask, safety goggles and protective clothing. Use of a vertical laminar airflow (LAF) hood is recommended.

Gloves should be worn during administration. Waste-disposal procedures should take into account the cytotoxic nature of this substance.

Pregnant personnel are advised not to handle chemotherapeutic agents.

If Etoposido Microsules contacts skin, mucosae or eyes, immediately wash thoroughly with water. Soap may be used for skin cleansing.

Any unused product or waste material should be disposed of in accordance with local requirements.

Procedures for proper handling and disposal of anti-cancer drugs should be followed.

Care must be taken whenever handling cytostatic products. Always take steps to prevent exposure. This includes appropriate equipment, such as wearing gloves and washing hands with soap and water after handling such products. If etoposide should contact the skin, mucosa or eyes, immediately wash the skin with soap and water and flush the mucosa or eyes with water.

Do not open any blister in which there is evidence of capsule leakage.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.