SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Eposin, concentrate for solution for infusion 20 mg/ml

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 vial with 5 ml concentrate for solution for infusion contains 100 mg etoposide, Ph.Eur.

1 vial with 25 ml concentrate for solution for infusion contains 500 mg etoposide, Ph.Eur.

1 ml concentrate for solution for infusion contains 20 mg etoposide.

Excipients:

1 ml concentrate for solution for infusion contains 30 mg benzyl alcohol.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion (to dilute).

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Etoposide is indicated for the management of:

-    testicular tumours in combination with other chemotherapeutic agents

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

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

4.2 Posology and method of administration

The usual dose of etoposide, in combination with other approved chemotherapeutic agents, ranges from 100-120 mg/m²/day via continuous infusion over 30 minutes for 3-5 days, followed by a resting period of 10-20 days.

Generally 3 to 4 chemotherapy cycles are administered. Dose and amount of cycles should be adjusted to the level of bone marrow suppression and the reaction of the tumour.

Etoposide is administered by slow intravenous infusion. ETOPOSIDE SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION.

Dose adjustments

Dosage of etoposide should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior X-ray therapy or chemotherapy which may have compromised bone marrow reserve.

Patients should not begin a new cycle of treatment with etoposide 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 subsequent to the 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 other grade 3 or 4 toxicity develops or if renal clearance is less than 50 ml/min.

Patients with renal impairment: 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

Subsequent dosing should be based on patient tolerance and clinical effect. Data are not available in patients with creatinine clearance <15 ml/min and further dose reductions should be considered in these patients. Subsequent etoposide dosing should be based on patient tolerance and clinical effect.

Administration Precautions

Hypotension following rapid intravenous administration has been reported. Hence it is recommended that the etoposide solution be administered over a 30- to 60-minute period. Longer infusion times may be required based on patient tolerance. As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of etoposide. Skin reactions associated with accidental exposure to etoposide may occur. The use of gloves is recommended. If etoposide solution contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Eposin, concentrate for solution for infusion 20 mg/ml must be diluted immediately prior to use with either 5 % dextrose in water, or 0.9 % sodium chloride solution to give a final concentration of 0.2 to 0.4 mg/ml. At higher concentrations precipitation of etoposide may occur.

4.3 Contraindications

•    Severe myelosuppression, unless when this is caused by the underlying disease.

•    Severe hepatic impairment.

•    Hypersensitivity to etoposide or to any of the excipients.

•    Breast-feeding (see section 4.6).

•    Concomitant use of yellow fever vaccine or other live vaccines is contraindicated in immunosuppressed patients (see section "Interaction with other medicinal products and other forms of interaction")

This product contains benzyl alcohol. It must not be given to premature babies or neonates.

4.4 Special warnings and precautions for use

Etoposide should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Injection site reactions may occur during the administration of etoposide. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.

Severe myelosuppression with resulting infection or bleeding may occur.

Fatal myelosuppression has been reported following etoposide administration. Patients being treated with etoposide must be observed for myelosuppression carefully and frequently both during and after therapy. Dose limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. The following studies should be obtained at the start of therapy and prior to each subsequent dose of etoposide: platelet count, hemoglobin, 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 the 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 other grade 3 or 4 oxicity develops or if renal clearance is less than 50 ml/min. Dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior radiation therapy or chemotherapy which may have compromised bone marrow reserve.

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 etoposide, manifested by chills, fever, tachycardia, bronchospasm, dyspnea and hypotension, which can be fatal. Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.

Etoposide 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. It should not be injected intraarterially, intrapleurally, or intraperitoneally.

In all instances where the use of etoposide 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 etoposide 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.

Patients with low serum albumin may be at increased risk for etoposide-associated toxicities. Patients with impaired hepatic and renal function should regularly have their renal and hepatic function monitored due to the risk of accumulation.

Bacterial infections should be brought under control before treatment with etoposide. Great care should be taken on giving etoposide to patients who have, or have been exposed to infection with herpes zoster.

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 "Pregnancy and lactation").

Paediatric population

Safety and effectiveness of etoposide in pediatric patients have not been systematically studied.

Etoposide injections contain polysorbate 80. In premature infants a life threatening syndrome of liver and renal failure, pulmonary deterioration, thrombocytopenia and ascites has been associated with an injectable vitamin E product containing polysorbate 80.This product contains 24 % m/v of ethanol. Each 5 ml vial contains up to 1,2 g of alcohol, each 25 ml vial contains up to 6 g of alcohol. This can be harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or disease as well as for children and pregnant women. Alcohol also may modify or increase the effect of other medicines.

This product contains benzyl alcohol. It may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

4.5 Interaction with other medicinal products and other forms of interaction

High dose cyclosporine, resulting in 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.

Concomitant warfarin therapy may result in elevated international normalized ratio (INR). Close monitoring of INR is recommended.

There is an increased risk of fatal systemic vaccinal disease with the use of yellow fever vaccine. Live vaccines are contraindicated in immunosuppressed patients. (See section "Contraindications".)

Prior or concurrent use of other drugs with similar myelosuppressant action as etoposide/etoposide phosphate may be expected to have additive or synergetic effects (see section "Special warnings and precautions for use").

In vitro plasma protein binding is 97 %. Phenylbutazone, sodium salicylate, and aspirin may displace etoposide from plasma protein binding.

Cross resistance between anthracyclines and etoposide has been reported in preclinical experiments.

The occurrence of acute leukaemia, which can occur with or without preleukemic phase has been reported in patients treated with etoposide in association with other anti-neoplastic drugs, e.g. bleomycin, cisplatin, ifosfamide, methotrexate.

4.6 Fertility, pregnancy and lactation

Pregnancy and women of child-bearing potential

Etoposide can cause fetal harm when administered to pregnant women. Etoposide have been shown to be teratogenic in mice and rats (see section “preclinical safety data”). There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant. If these drugs are used during pregnancy, or if the patient becomes pregnant while receiving these drugs, the patient should be apprised of the potential hazard to the fetus.

Contraception in males and females

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.

Breast-feeding

It is not known whether these drugs are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from etoposide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed with etoposide. If the patient experiences side effects such as fatigue and somnolence they should avoid driving or operating machines.

4.8 Undesirable effects

The following frequencies have been used:

•    Very common (>1/10)

•    Common (>1/100, <1/10)

•    Uncommon (>1/1,000, <1/100)

•    Rare (>1/10,000, <1/1,000)

•    Very rare (<1/10,000)

•    Not known (cannot be estimated from the available data)

System Organ Class	Very common (>1/10)	Common (>1/100, <1/10)	Uncommon (>1/1,000, <1/100)	Rare (>1/10,00 0, <1/1,000)	Very rare (<1/10,00 0)	Not known
Neoplasms benign and malignant (including cysts and polyps)		Acute leukaemia *				Acute promyelo cytic leukaemia* *
Blood and lymphatic systems disorders*	Myelo- suppressio n*** 11 5 leucopenia , thrombocytopenia, anaemia
Immune system disorders		Ana phylactic- type reactions* ***
Nervous system disorders	Neurotoxicities (e.g. somnolence, fatigue)	Dizzines	Neuropathy peripheral	Seizure** *** optic neuritis, transient cortical blindness
Cardiac disorders		Myocardia l	Cyanosis

		infarction, arrythmia
System Organ Class	Very common (>1/10)	Common (>1/100, <1/10)	Uncommon (>1/1,000, <1/100)	Rare (>1/10,00 0, <1/1,000)	Very rare (<1/10,00 0)	Not known
Vascular disorders		Heam- orrhage, Transient systolic hypo tension following rapid intravenous administration, hypertension
Respiratory , thoracic and mediastinal disorders			Broncho- spasm, coughing, laryngo- spasm	Pulmonary fibrosis, interstitial pneumo nitis, apnoea
Gastro intestinal disorders	Abdomina l pain, constipation, nausea and vomiting, anorexia	Mucositis (including stomatitis and esophagitis), diarrhea		Dysphagia 5 dysgeusia
Hepato biliary disorders	Hepato- toxicity
Skin and subcutaneous tissue disorders	Alopecia, pigmen tation	Rash, urticaria, pruritus		Stevens- Johnson syndrome, toxic epidermal necrolysis, radiation recall dermatitis, hand foot syndrome
General disorders and administration site	Asthenia, malaise	Extra vasation 5 phlebitis, fatigue

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 etoposide therapy.

Hematological 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 - 14 days after administration of etoposide or etoposide phosphate depending on the way of administration and treatment scheme. Nadirs tend to occur earlier with intravenous administration compared to oral administration.

Leukopenia and severe leukopenia (less than 1,000 cells/mm³) were observed in 60 -91 % and 7 - 17 %, respectively, for etoposide/etoposide phosphate. Thrombocytopenia and severe thrombocytopenia (less than 50,000 platelets/mm3) were seen in 28 - 41 % and 4 - 20 %, respectively, for etoposide/etoposide phosphate. Reports of fever and infection were also very common in patients with neutropenia treated with etoposide/etoposide phosphate.

Gastrointestinal Toxicity:

Nausea and vomiting are the major gastrointestinal toxicities of etoposide. The nausea and vomiting can usually be controlled by antiemetic therapy. They have been noted in 31 - 43 % of patients given intravenous etoposide. Anorexia was seen in 10 - 13 % of patients and stomatitis in 1 - 6 % of those patients given intravenous etoposide. Diarrhea was noted in 1 - 13 % of these patients.

Alopecia:

Reversible alopecia, sometimes progressing to total baldness, has been observed in up to 66 % of patients treated with etoposide and 44 % of patients treated with etoposide phosphate.

Blood Pressure Changes

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.

Allergic Reactions:

Anaphylactic-type 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-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 etoposide.

Acute fatal reactions associated with bronchospasm have been reported with etoposide. Facial flushing was reported in 2 % of patients and skin rashes in 3 % treated with etoposide phosphate.

Metabolic Complications:

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

4.9 Overdose

Acute overdosage results in severe forms of normally occurring adverse reactions, in particular leucopenia and thrombopenia.

Severe mucositis and elevated values of serum bilirubin, SGOT and alkaline phosphatase have been reported after administration of high doses of etoposide (total doses of 2.4 g/m² to 3.5 g/m² administered intravenously over three days). Metabolic acidosis and severe hepatic toxicity have been reported after administration of dosages higher than recommended.

The management of bone marrow depression is symptomatic, including antibiotics and transfusions.

If hypersensitivity to etoposide occurs, antihistamines and intravenously administered corticosteroids are appropriate.

A specific antidote is not available. Treatment should therefore be symptomatic and supportive, and patients should be closely monitored.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic classification: podophyllotoxine derivatives (ATC: L01CB01)

Etoposide is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases. Podophyllotoxins inhibit mitosis by blocking microtubular assembly. Etoposide inhibits cell cycle progression at a premitotic phase (late S and G2).

It does not interfere with the synthesis of nucleinic acids.

5.2 Pharmacokinetic properties

The concentration of etoposide in blood and organs is low with maximum values in the liver and the kidneys. Protein binding could be as high as 98 %.

On intravenous administration, the disposition of etoposide is best described as a biphasic process with an initial half-life of about 1.5 hours. After distribution, halflife is about 40 hours. The terminal half-life is 6 - 8 hours.

Following a single intravenous dose etoposide is excreted in the urine for about 63 % and in the faeces for about 31 % after 80 hours.

Etoposide is cleared by both renal and nonrenal processes i.e. metabolism and biliary excretion. In patients with renal dysfunction plasma etoposide clearance is decreased.

In adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentration and nonrenal clearance. In children, elevated serum ALT levels are associated with reduced drug total body clearance. Prior use of cisplatin may result in a decrease of etoposide total body clearance.

5.3 Preclinical safety data

Etoposide has been shown to be embryotoxic and teratogenic in animal experiments with rats and mice.

There are positive results from in vitro and in vivo test with regard to gene and chromosome mutations induced by etoposide. The results justify the suspicion of a mutagenic effect in humans.

No animal tests with regard to carcinogenicity were performed. Based on the DNA-damaging effect and the mutagenic properties, etoposide is potentially carcinogenic.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Macrogol 300, polysorbate 80, benzyl alcohol, ethanol, citric acid, anhydrous.

6.2 Incompatibilities

Plastic devices made of acrylic or ABS polymers have been reported to crack when used with undiluted Eposin, concentrate for solution for infusion 20 mg/ml. This effect has not been reported with etoposide after dilution of the concentrate for solution for infusion according to instructions.

6.3 Shelf life

Vial before opening: 3 years.

After dilution:

Chemical and physical in-use stability of the solution diluted to a concentration of 0.2 mg/ml or 0.4 mg/ml has been demonstrated for 24 hours at 15 - 25 °C. From a microbiological point of view, the diluted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 12 hours at 15 -25 °C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store below 25 °C, protected from light (keep vials in the outer carton). Do not freeze.

Diluted solutions: see section 6.3

Do not store the diluted product in a refrigerator (2 - 8 °C) as this might cause precipitation.

Solutions showing any sign of precipitation should not be used.

6.5 Nature and contents of container

Each injection vial contains 100 mg (5 ml) of etoposide.

Each injection vial contains 500 mg (25 ml) of etoposide. One package contains 1 vial or 10 vials of Eposin.

6.6 Special precautions for disposal

Eposin should not be used without diluting! Dilute with 0.9 % sodium chloride or 5 % dextrose. Solutions showing any signs of precipitation should not be used.

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.

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

7 MARKETING AUTHORISATION HOLDER

Pharmachemie B.V.

P.O. Box 552 2003 RN Haarlem The Netherlands

8    MARKETING AUTHORISATION NUMBER(S)

PL 04946/0033

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/03/2015 12/03/2015