Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
Etoposide Teva 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 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.

Myelosuppression
Dose-limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. 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. The following haematological parameters should be measured at the start of therapy and prior to each subsequent dose of etoposide: platelet count, haemoglobin, white blood cell count and differential. If radiotherapy or chemotherapy has been given prior to starting etoposide treatment, an adequate interval should be allowed to enable the bone marrow to recover.


Etoposide should not be administered to patients with neutrophil counts less than 1,500 cells/mm3 or platelet counts less than 100,000 cells/mm3, unless caused by malignant disease.

Doses subsequent to initial dose should be adjusted if neutrophil count less than 500 cells/mm3 occurs for more than 5 days or is associated with fever or infection, if platelet count less than 25,000 cells/mm3 occurs, if any grade 3 or 4 toxicity develops or if renal clearance is less than 50 ml/min.

Severe myelosuppression with resulting infection or haemorrhage may occur. Bacterial infections should be brought under control before treatment with etoposide.

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 etoposide, manifested by chills, pyrexia, tachycardia, bronchospasm, dyspnoea and hypotension, which can be fatal. Treatment is symptomatic.
Etoposide should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician. An increased risk for infusion-related hypersensitivity reactions was observed when in-line filters were used during etoposide administration. In-line filters should not be used.

Hypotension
Etoposide Teva 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 reaction
Injection site reactions may occur during administration of etoposide. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration.

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.

Acute renal failure
Mostly in children, reversible acute renal failure has been reported when a high dose (2,220 mg/m2 or 60 mg/kg) of this medicinal product and total body irradiation were used for haematopoietic stem cell transplantation. Renal function should be evaluated prior to and after etoposide administration until complete renal function recovery (see section 4.8).

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 (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.

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 6 months after ending treatment for females and 3 months after ending treatment for males. 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).

Excipients
Ethanol
This product contains 30 vol % ethanol (alcohol).
Adults
A dose of 120 mg/m2 of this medicine administered to an adult weighing 70 kg would result in exposure to 37.2 mg/kg of ethanol, which may cause a rise in blood alcohol concentration (BAC) of about 6.2 mg/100 ml. For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC is likely to be about 50 mg/100 ml.
The amount of alcohol in this medicine is not likely to have an effect in adults.
The amount of alcohol in this medicine may alter the effects of other medicines (see section 4.5).
To be taken into account in pregnant women. To be taken into account in patients who are addicted to alcohol.
Paediatric population
A dose of 150 mg/m2 of this medicine administered to a child weighing 17 kg would result in exposure to 75.5 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 12.6 mg/100 ml.
The amount of alcohol in this medicine may alter the effects of other medicines (see section 4.5).
The alcohol in this preparation is likely to affect children weighing <17 kg. These effects may include feeling sleepy and changes in behaviour. It may also affect their ability to concentrate and take part in physical activities.
To be taken into account in children with epilepsy or liver disease.
Because this medicine is usually given slowly over 30-60 minutes, the effects of alcohol may be reduced.


..

Polysorbate 80
Etoposide Teva contains 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.


4.5   Interaction with other medicinal products and other forms of interactions
Effects of other drugs on the pharmacokinetics of etoposide
High-dose ciclosporin, resulting in plasma concentrations above 2,000 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 etoposide clearance and reduced efficacy.

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

Effect of etoposide on the pharmacokinetics of other drugs
Co-administration of antiepileptic drugs and etoposide 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.

Pharmacodynamic interactions
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.

Paediatric population
Interaction studies have only been performed in adults.
Because this medicinal product contains ethanol, interactions might occur with other medicinal products.
Therefore, if other medicinal products are co-administered, it should be checked whether there are interactions with ethanol for these.
Co-administration with medicines containing, e.g., propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects, in particular in young children with low or immature metabolic capacity.

4.6 Fertility, pregnancy and lactation
Women of childbearing potential/ Contraception in males and females
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 contraception is required for both male and female patients during treatment and 6 months after ending treatment for females and 3 months after ending treatment for males (see section 4.4). Genetic consultation is recommended if the patient wishes to have children after ending treatment.

Pregnancy
There are no or only limited amount of data from the use of etoposide 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. Etoposide should not be used during pregnancy unless the clinical condition of the woman requires treatment with etoposide. Women of childbearing potential should be advised to avoid becoming pregnant. Women of childbearing potential have to use effective contraception during and up to 6 months after treatment. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be informed of the potential hazard to the fetus.

Breast-feeding
Etoposide is excreted in human milk. There is a potential for serious adverse reactions from etoposide in nursing infants. A decision must be made whether to discontinue breast-feeding or to discontinue etoposide, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman (see section 4.3).

Fertility
As etoposide may decrease male fertility, preservation of sperm may be considered for the purpose of later fatherhood.

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. Etoposide 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.

4.8 Undesirable effects
Summary of the safety profile
Dose-limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. In clinical studies in which etoposide was administered as a single agent at a total dose of ≥450 mg/m2, the most frequent adverse reactions of any severity were leucopenia (91%), neutropenia (88 %), anaemia (72 %), thrombocytopenia (23 %), asthenia (39 %), nausea and/or vomiting (37 %), alopecia (33 %) and chills and/or fever (24 %).

Tabulated summary of adverse reactions
The following adverse reactions were reported from etoposide clinical studies and post-marketing experience.
These adverse reactions are presented by system organ class and frequency, which is defined by the following categories: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), not known (cannot be estimated from the available data).

System Organ Class                      Frequency             Adverse Reaction (MedDRA Terms) Infections and infestations             Common               Infection* Neoplasms benign, malignant             Common               Acute leukaemia and unspecified (including cysts and polyps)
Blood and lymphatic system              Very common          Myelosuppression**, leucopenia, disorders                                                    thrombocytopenia, neutropenia, anaemia Immune system disorders                 Common               Anaphylactic reactions*** Not known            Angioedema, bronchospasm
Metabolism and nutrition                Not known            Tumour lysis syndrome disorders
Nervous system disorders                Common               Dizziness Uncommon             Neuropathy peripheral
Rare                 Seizure**** optic neuritis, cortical blindness transient, neurotoxicities (e.g.,
somnolence, fatigue)
Cardiac disorders                       Common               Myocardial infarction, arrhythmia Vascular disorders                      Common               Transient systolic hypotension following rapid intravenous administration,
hypertension
Uncommon             Haemorrhage
Respiratory, thoracic and               Rare                 Pulmonary fibrosis, interstitial pneumonitis mediastinal disorders                   Not known            Bronchospasm 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          Alanine aminotransferase increased, alkaline phosphatase increased, aspartate amino transferase increased, bilirubin increased,
hepatotoxicity
Skin and subcutaneous tissue            Very common          Alopecia, pigmentation disorders                               Common               Rash, urticaria, pruritus Rare                 Stevens-Johnson syndrome, toxic epidermal necrolysis, radiation recall dermatitis
Renal and urinary disorders             Not known            Acute renal failure 
Reproductive system and breast          Not known            Infertility disorders
General disorders and                   Very common          Asthenia, malaise administration site conditions          Common               Extravasation*****, phlebitis Rare                 Pyrexia
* Including opportunistic infections like pneumocystis jirovecii pneumonia ** Myelosuppression with fatal outcome has been reported.
*** Anaphylactic reactions can be fatal.
****Seizure is occasionally associated with allergic reactions.
*****Post-marketing complications reported for extravasation included local soft tissue toxicity, swelling, pain, cellulitis, and necrosis including skin necrosis.


Description of selected adverse reactions
In the paragraphs below the incidences of adverse events, given as the mean percent, are derived from studies that utilised single agent etoposide therapy.

Haematological toxicity
Myelosuppression (see section 4.4) 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 to14 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 91% and 17%, respectively, for etoposide. Thrombocytopenia and severe thrombocytopenia (less than 50,000 platelets/mm 3) were seen in 23% and 9%, respectively, for etoposide. Reports of fever and infection were also very common in patients with neutropenia treated with etoposide. Bleeding has been reported.

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, has been observed in up to 44% of patients treated with etoposide.

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.

Hypersensitivity
Anaphylactic 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 reactions is uncertain. Blood pressure usually normalises within a few hours after cessation of the infusion. Anaphylactic-type reactions can occur with the initial dose of etoposide.

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 etoposide in 7 clinical studies) of patients treated with etoposide. Facial flushing was reported in 2% of patients and skin rashes in 3%. These reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders as appropriate.


Acute fatal reactions associated with bronchospasm have been reported with etoposide. Apnoea with spontaneous resumption of breathing following cessation of infusion have also been reported.

Metabolic complications
Tumour lysis syndrome (sometimes fatal) has been reported following the use of etoposide in association with other chemotherapeutic drugs (see section 4.4).

Acute renal failure
Reversible acute renal failure has been reported in post-marketing experience (see section 4.4).

Paediatric population
The safety profile between paediatric patients and adults is expected to be similar.
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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il.

4.9 Overdose
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.
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 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.

5.2   Pharmacokinetic properties
Absorption
After either intravenous infusion or oral capsule administration, the C max and AUC values exhibit marked intra- and inter-subject variability.

Distribution
The mean volumes of distribution at steady state range from 18 to 29 liters. 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 (see section 4.4). 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.

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 (Cmax) 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 (see section 4.2).

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/m 2 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, i.e., 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.

Effects on Driving

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. Etoposide 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.