SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Etoposide Concentrate for Solution for Infusion, 20 mg/ml

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Etoposide Concentrate for solution for Infusion contains Etoposide 20mg/ml. For excipients, see section 6.1.

3    PHARMACEUTICAL FORM

- Concentrate for solution for infusion

Etoposide concentrate for solution for infusion 20 mg/ml is a clear yellowish, slightly viscous solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Etoposide is an antineoplastic drug which can be used alone or in combination with other oncolytic drugs.

Present data indicate that etoposide is applicable in the therapy of small cell lung cancer and resistant non-seminomatous testicular carcinoma.

Use in children: safety and effectiveness in children have not been established.

4.2    Posology and method of administration

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

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.

Dosage: For all the indications the recommended course of Etoposide Concentrate for Infusion is 60-120 mg/m², I.V., daily for five consecutive days. Maximum dose per cycle: 650 mg/m . As etoposide produces myelosuppression, courses may not be repeated more frequently than at 21-day intervals. In any case, repeated courses of etoposide should not be given until the blood picture has been checked for evidence of myelosuppression and found to be satisfactory.

The required dose of etoposide concentrate must be diluted with either 5% dextrose solution for injection or 0.9% saline solution for injection to give a final concentration of 0.2 mg/ml of etoposide; it should then be given by intravenous infusion over a period of not less than 30 minutes and not more than 2 hours.

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/mm 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.

In combination therapy the dosage of etoposide should be adjusted according to the corresponding plan.

The duration of therapy is determined by the physician, taking into account the underlying disease, the combined regimen administered (if applicable) and the individual therapeutic situation. Etoposide should be discontinued when the tumour does not respond or when progressive disease or intolerable toxicity occurs.

Care should be taken to avoid extravasation.

Use in the elderly: no dosage adjustment is necessary.

In patients with renal function impairment the dose should be adjusted. In patients with a measured creatinine clearance of greater than 50 mL/minute, no initial dose modification is required. In patients with a measured creatinine clearance of 15-50

mL/minute, 75% of the initial recommended etoposide dose should be administered. In patients with a measured creatinine clearance less than 15 mL/minute, no data are available and further dose reductions should be considered in these patients.

Since etoposide-induced hematologic toxicity appeared to be more severe in patients with elevated serum bilirubin concentrations in one study and there is some evidence that total plasma clearance and elimination of the drug may be reduced in patients with impaired hepatic function, etoposide should probably be used with caution and the need for dosage reduction considered in patients with hepatic impairment.

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

•    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")

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

3    3

1,500 cell/mm or platelet counts less than 100,000 cells/mm , unless caused by malignant disease.

Doses subsequent to the initial dose should be adjusted if neutrophil count less than 500 cells/mm 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. 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, orintraperitoneally.

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.

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 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 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 a preleukaemic phase has been reported rarely 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. 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.

Breastfeeding

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)

Neoplasms Benign and Malignant (including cysts and polyps)	Common	Acute leukaemia*
	Not known	Acute promyelocytic leukemia**
Blood and the Lymphatic System Disorders*	Very common	Myelosuppression*, leukopenia, thrombocytopenia, neutropenia, anemia
Cardiac Disorders	Common	Myocardial infarction, arrythmia
Immune System Disorders	Common	Anaphylactic-type reactions**
Nervous System Disorders	Very common	neurotoxicities (e.g., somnolence, fatigue)
	Common	Dizzines
	Uncommon	Neuropathy peripheral
	Rare	Seizure*** optic neuritis, transient cortical blindness
Vascular Disorders	Common	Heamorrhage ,Transient systolic hypotension following rapid intravenous administration, hypertension
Respiratory, Thoracic and Mediastinal Disorders	Uncommon	Bronchospasm, coughing, laryngospasm
	Rare	Pulmonary fibrosis, interstitial pneumonitis, apnoea
Gastrointestinal Disorders	Very common	Abdominal pain, constipation, nausea and vomiting, anorexia
	Common	Mucositis (including stomatitis and esophagitis), diarrhea
	Rare	Dysphagia, dysgeusia
Hepatobiliary Disorders	Very common	Hepatotoxicity
Skin and Subcutaneous Tissue Disorders	Very common	Alopecia, pigmentation
	Common	Rash, urticaria, pruritus
	Rare	Stevens-Johnson syndrome, toxic epidermal necrolysis, radiation recall

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 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 dosages of 2.4 to

3.5 g/m etoposide, 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

L01CB01: Cytostatics - Podophyllotoxin - derivative Etoposide is a semisynthetic derivative of podophyllotoxin.

Its main effect appears to be at the G2 portion of the cell cycle. Two dose-dependent responses occur: at high concentrations (equal or more than 10 pg/ml), lysis of cells entering mitosis is seen; at low concentrations (0.3-10 pg/ml), cells are inhibited from entering prophase. The predominant macromolecular effect appears to be DNA synthesis inhibition.

5.2 Pharmacokinetic properties

Absorption/Distribution

On IV administration, the disposition of etoposide is a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4-11 hours. Total body clearance values range from 33-48 ml/min and, like the terminal elimination half-life, are independent of dose. The area under the plasma concentration-time curves (AUC) and maximum plasma concentration (Cmax) values increase linearly with dose. Etoposide does not accumulate in the plasma following daily I.V. administration of 100 mg/m² for 4-5 days. After I.V. infusion, C_max and AUC values exhibit marked intrasubject and intersubject variability.

The mean volumes of distribution at steady state range from 18-29L. Although detectable in CSF and intracerebral tumors, the concentrations are lower than in extracerebral tumors and plasma. Concentrations are higher in normal lung than in lung metastases and are similar in primary tumors and normal tissues of the myometrium. In vitro, etoposide is highly bonded (97%) to human plasma proteins. An inverse relationship between plasma albumin levels and renal clearance is found in children.

Metabolism/Excretion

Less than 50% of an I.V. dose is excreted in the urine as etoposide, with mean recoveries of 8-35% within 24 hours (approximately 55% in children). The mean renal clearance is 7-10 ml/min/m2, or about 35% of the total body clearance over a dose range of 80-600 mg/m2. 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.

Only 6% or less of an IV dose is recovered in the bile as etoposide. Metabolism accounts for most of the nonrenal clearance. The major urinary metabolite is the hydroxy acid. Glucuronide or sulphate conjugates of etoposide are excreted in human urine and represent 5-22% of the dose.

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 rats and mice.

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

Carcinogenicity tests with etoposide have not been conducted in laboratory animals. Etoposide should be considered a potential carcinogen in humans based on the DNA-damaging effect and the mutagenic potential.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

-    Citric acid

-    Polysorbate 80

-    Ethanol

-    Macrogol 300

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

Shelf - life of the medicinal product as packaged for sale: 3 years Shelf - life after dilution: 8 hours

The infusion has been shown to be physically and chemically stable for up to 120 hours at 25°C. However, in light of microbiological considerations, it is recommended that the infusion be prepared centrally in a hospital pharmacy department and should be discarded within 8 hours.

Etoposide concentrate for infusion is stable for up to 72 hours (3 days) at 25°C following piercing of the rubber stopper. It is therefore suitable for multidose use.

6.4 Special precautions for storage

Special precautions for storage of the medicinal product as packaged for sale: Do not store above 25°C Store in the original package

Special precautions for storage of the medicinal product after dilution:

Do not store above 25°C

Special precautions for storage after first opening the concentrate for solution: Do not store above 25°C

Multi-dose use

Etoposide Concentrate for Infusion is stable for up to 72 hours (3 days) at 25°C following piercing of the rubber stopper.

After dilution

The infusion has been shown to be physically and chemically stable for up to 120 hours at 25°C. However, in light of microbiological considerations, it is recommended that the infusion be prepared centrally in a hospital pharmacy department and should be discarded within 8 hours.

6.5 Nature and contents of container

Clear, colourless glass vial, closed with chlorobutyl grey siliconised stopper (20 mm, coated with black teflon) held by an aluminium crimped cap with flip-top plastic disc.

Vials containing 20 mg/ml of etoposide as follows:

100 mg of etoposide/5 ml,

200 mg of etoposide/10 ml,

400 mg of etoposide/20 ml,

500 mg of etoposide/25 ml 1000 mg of etoposide/50 ml.

Pack sizes:

All presentations are packaged as individual vials.

6.6 Special precautions for disposal

Do not autoclave.

Etoposide should not be used without diluting. 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 solution should be avoided. During preparation and dilution a strictly aseptic working technique should be used. Protective measures should include the use of gloves, mask, safety goggles and protective clothing. Use of vertical laminar air flow hood is recommended. Gloves should be worn during administration. If etoposide contacts skin, mucosae or eyes, immediately wash thoroughly with water. Soap may be used for skin cleaning. Any unused product or waste materials should be disposed of in accordance with the local requirements.

7    MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne BN22 9AG United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0473

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/04/2010

10 DATE OF REVISION OF THE TEXT

10/12/2014