INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
VEPESID Capsules 50 mg
VEPESID Capsules 100 mg
VEPESID Injection 100 mg

SCHEDULING STATUS
S4

PROPRIETARY NAMES
(and dosage form)

VEPESID Capsules 50 mg
VEPESID Capsules 100 mg
VEPESID Injection 100 mg

COMPOSITION
Capsules containing 50 mg and 100 mg Etoposide respectively.
Each 5 mL vial contains;

Etoposide	100 mg
Citric acid	10 mg
Benzyl alcohol	150 mg
Polysorbate 80 (Tween 80)	400 mg
Polyethylene glycol 300 (Macrogol 300)	3 250 mg
Absolute ethanol qs to	5 mL (30,5%)

PHARMACOLOGICAL CLASSIFICATION
A26 Cytostatic agents.

PHARMACOLOGICAL ACTION
VEPESID (Etoposide; commonly known as VP-16-213 or VP-16) is a semi-synthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases. It is 4'-Demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-beta-D-glucopyranoside]. It is very soluble in methanol and chloroform, slightly soluble in ethanol and sparingly soluble in water and ether. It is made more miscible with water by means of organic solvents. It has a molecular mass of 588,58 and a molecular formula of C29H32O13.
Clinical Pharmacology
VEPESID has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however, appears to be at the G₂ portion of the cell cycle in mammalian cells. Two different dose-dependent responses are seen. At high concentrations (10 micrograms/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0,3 to 10 micrograms/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of VEPESID appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals.
Pharmacokinetics
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 - 600 mg/mL. 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. Etoposide does not accumulate in the plasma following daily administration of 100 mg/m² for 4 to 6 days.
The mean volumes of distribution at steady state fall in the range of 18 to 29 litres or 7 to17 L/m². Etoposide enters the CSF poorly. Although it is detectable in CSF and intracerebral tumours, the concentrations are lower than in extracerebral tumours and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumours and normal tissues of the myometrium. In vitro, Etoposide is highly protein bound (97%) to human plasma proteins. An inverse relationship between plasma albumin levels and Etoposide renal clearance is found in children.
Phenylbutazone, sodium salicylate and aspirin at concentrations achieved in vivo displace protein-bound etoposide.
Etoposide binding ratio correlates directly with serum albumin in cancer patients and normal volunteers. Unbound fraction of etoposide correlates significantly with bilirubin in some cancer patients. There appears to be a significant inverse correlation between serum albumin concentrations and free etoposide fraction (see Precautions).
After intravenous administration of 3H-Etoposide (70 - 290 mg/m²) mean recoveries of radioactivity in the urine range from 42 to 67% and faecal recoveries range from 0 to 16% of the dose. Less than 50% of an intravenous dose is excreted in the urine as Etoposide with mean recoveries of 8 to 35%, within 24 hours.
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, i.e., metabolism and biliary excretion. The effect of renal disease on plasma Etoposide clearance is not known in children.
Biliary excretion of the unchanged medicine appears to be a minor route of Etoposide elimination.Only 6% or less of an intravenous dose is recovered in the bile as Etoposide.
Metabolism accounts for most of the non-renal clearance of Etoposide. The major urinary metabolite of Etoposide in adults and children is the hydroxy acid metabolite [4'-demethyl epipodophyllic acid-9-(4,6-0-ethylidene-beta-D-glucopyranoside)], formed by opening of the lactone ring.
It is also present in human plasma, presumably as the trans isomer. Glucuronide and/or sulphate conjugates of Etoposide are also excreted in human urine.
In adults, the total body clearance of Etoposide is correlated with creatinine clearance, serum albumin concentrations, and non-renal clearance.
The total body clearance of Etoposide is reduced and the AUC is increased in patient’s with impaired renal function (see dosage and directions for use).
In children, elevated serum 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.
After either intravenous infusion or oral capsule administration, the Cmax and AUC values exhibit marked intra- and inter-subject variability. This results in variability in the estimates of the absolute oral bioavailability of Etoposide oral capsules.
Cmax and AUC values for orally administered Etoposide capsules consistently fall in the same range as the Cmax and AUC values for an intravenous dose of one-half the size of the oral dose. The overall mean value of oral capsule bioavailability is approximately 50% (range 25 - 75%). Dose proportionality in absorption following oral capsule administration has not been established. (Refer to dosage and directions for use)
There is no evidence of a first-pass effect for Etoposide. For example, 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.

INDICATIONS
VEPESID has been shown to be useful in the management of the following neoplasms:
Testicular tumour - first line
In combination therapy with other approved chemotherapeutic agents.
NOTE: The intravenous formulation should be used in first-line combination chemotherapeutic regimens.
Refractory Testicular Tumours
In combination therapy with other approved chemotherapeutic agents in patients with refractory testicular tumours who have already received appropriate surgical, chemotherapeutic and radiotherapeutic therapy.
Small Cell Anaplastic Lung Tumours
In combination therapy with other approved chemotherapeutic agents in patients with small cell anaplastic lung tumours.
Malignant (non-Hodgkin's) Lymphomas, especially of the histiocytic (large cell diffuse) variety
In combination with other approved chemotherapeutic agents.

CONTRA-INDICATIONS
Hypersensitivity to etoposide or any component of the formulation.
Severe hepatic dysfunction.
Severely impaired medullary haemopoiesis (especially after extensive radio and/or chemotherapy or as a result of neoplastic infiltration). This condition may be evidenced by mild to marked leucopenia and/or thrombocytopenia.

WARNINGS
VEPESID (ETOPOSIDE) SHOULD BE ADMINISTERED UNDER THE SUPERVISION OF A QUALIFIED PHYSICIAN EXPERIENCED IN THE USE OF CANCER CHEMOTHERAPEUTIC AGENTS. SEVERE MYELOSUPPRESSION WITH RESULTING INFECTION OR BLEEDING MAY OCCUR WHICH MAY BE FATAL.
Patients being treated with VEPESID 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 VEPESID therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of VEPESID; platelet count, haemoglobin, white blood cell count and differential. The occurrence of a platelet count below 50 000/mm³ or an absolute neutrophil count below 500/mm³ is an indication to withhold further therapy until the blood counts have sufficiently recovered.
Physicians should be aware of the possible occurence of an anaphylactic reaction manifested by chills, fever, tachycardia, brochospasm, dyspnoea and hypotension. Treatment is symptomatic. Administration of VEPESID should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.
VEPESID 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.

Pregnancy
VEPESID can cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

DOSAGE AND DIRECTIONS FOR USE
Oral
The effective oral dose is approximately twice the effective intravenous dose, rounded to the nearest 50 mg. The dose of VEPESID capsules is based on the recommended IV dose with consideration given to the bioavailability of VEPESID capsules appearing to be dependent upon the dose administered. The bioavailability also varies from patient to patient following any oral dose. This should be taken into consideration when prescribing this medication. In view of significant intra-patient variability, dose adjustment may be required to achieve the desired therapeutic effect. In view of the wide variability in absorption in any given dose, patients who receive oral etoposide must be carefully monitored for myleosuppression. The usual dose for VEPESID administered orally is 100-200 mg/m²/day, days 1 to 5 or 200 mg/m²/day, 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 X-ray therapy or chemotherapy which may have compromised bone marrow reserve. Capsules should be taken on an empty stomach.
Intravenous
The usual dose for VEPESID is 50 to 100 mg/m²/day, days 1 to 5 or 100 mg/m², 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 X-ray therapy or chemotherapy which may have compromised bone marrow reserve.
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
>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 reduction should be considered in those patients.
Administration Precautions
As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of VEPESID. Skin reactions associated with accidental exposure to VEPESID may occur. The use of gloves is recommended. If VEPESID solution contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.
GREAT CARE SHOULD BE TAKEN TO ENSURE THAT THE CATHETER (INFUSION) REMAINS IN THE VEIN DURING VEPESID ADMINISTRATION BECAUSE OF POSSIBLE TISSUE IRRITATION. VEPESID MUST NOT BE ADMINISTERED INTRA-ARTERIALLY, INTRA-PLEURALLY OR INTRA-PERITONEALLY
Hypotension following rapid intravenous administration has been reported, hence, it is recommended that the VEPESID solution be administered over a 30 to 60 minute period. Longer infusion times may be required based on patient tolerance.
VEPESID SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS PUSH.

Preparation for Intravenous Administration
NOTE: Hard plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) have been reported to crack and leak when used with UNDILUTED VEPESID injection. This effect has not been reported with diluted VEPESID.
VEPESID injection may be diluted with either 5% Dextrose Injection or 0,9% Sodium Chloride Injection to give a final concentration of 0,2 or 0,4 mg/mL.
More concentrated solutions show crystal formation upon stirring or seeding within 5 minutes and should not be given intravenously. VEPESID diluted to 0,4 mg/mL and administered through tubing connected to a pump with a peristaltic mechanism may precipitate out of solution in the tubing.
Parenteral drug products should be inspected visually for particulate matter and discolouration (see IDENTIFICATION section) prior to administration whenever solution and container permit.
NOTE
For more details regarding the stability of the diluted VEPESID refer to the section under "Storage instructions".

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-Effects
Haematological Toxicity:
Myelosuppression with fatal outcome has been reported following etoposide administration (See warnings). Myelosuppression is most often dose-limiting, with granulocyte nadirs occurring 7 to 14 days, and platelet nadirs occurring 9 to 16 days, after drug administration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Leukopenia and severe leukopenia (less than 1 000 cells/mm³) were observed in patients treated with a single agent VEPESID. Thrombocytopenia and severe thrombocytopenia (less than 50 000 platelets/mm³) were seen in this same group of patients. The occurrence of acute leukaemia with or without a preleukaemic phase has been reported in patients treated with VEPESID in association with other anti-neoplastic agents.
Gastrointestinal Toxicity
Nausea and vomiting are the major gastrointestinal toxicities. The nausea and vomiting can usually be controlled by anti-emetic therapy. Mild to severe mucositis/esophagitis may occur. Anorexia, stomatitis and diarrhoea were noted.
Alopecia
Reversible alopecia, sometimes progressing to total baldness, has been observed.
Hypotension
Transient hypotension following rapid intravenous administration has been reported. The incidence has not been associated with cardiac toxicity or electrocardiographic changes. No delayed hypotension has been noted. To prevent this rare occurrence, it is recommended that VEPESID be administered by slow intravenous infusion over a 30 to 60 minute period. 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.       
Allergic Reactions
Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnoea and hypotension have also been reported to occur in patients, occurring during or immediately after VEPESID administration. Higher rates of anaphylactic-like reactions have been reported in children receiving VEPESID infusion at concentrations higher than those recommended. The role that concentration of infusion (or rate of infusion) plays in the development of anaphylactic reactions is uncertain. Anaphylactic-like reactions have occurred very rarely in patients treated with oral capsules. These reactions have usually responded promptly to the cessation of administration of VEPESID and subsequent administration of pressor agents, corticosteroids, antihistamines or volume expanders as appropriate. Acute fatal reactions associated with bronchospasm have been reported. Hypertension and flushing and/or seizures have also been reported. Blood pressure usually normalizes within a few hours after cessation of the infusion.
Anaphylactic-like reactions can occur with the initial dose of VEPESID. Apnea has occurred in patients receiving etoposide infusion.
Neuropathy
The use of VEPESID has been reported to cause peripheral neuropathy. The associated use of vincristine sulphate can possibly enhance this neuropathy.
Other Toxicities
The following reactions have been rarely reported:
Interstitial pneumonitis/pulmonary fibrosis , seizures, central nervous system toxicity (somnolence and fatigue), liver toxicity, (see KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT) aftertaste, fever, Stevens-Johnson syndrome , toxic epidermal necrolysis (one fatal case has been reported), rash, pigmentation, pruritus, urticaria, abdominal pain, constipation, dysphagia, asthenia, malaise, transient cortical blindness ,optic neuritis and a single report of radiation recall dermatitis.
Occasionally following extravasation, soft tissue irritation and inflammation has occurred; ulceration is generally not seen.

PRECAUTIONS
General
In all instances where the use of VEPESID 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. Re-institution of VEPESID 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. Patients with low serum albumin may be at increased risk for etoposide- associated toxicities.
Laboratory Tests
Periodic complete blood counts should be done during the course of VEPESID treatment. They should be performed prior to therapy and at appropriate periods during therapy. At least one determination should be done prior to each dose of VEPESID.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity tests with VEPESID have not been conducted in laboratory animals. Given its mechanism of action, it should be considered a possible carcinogen in humans. (See also hematological toxicity)
Acute leukemia , with or without a preleukemic phase has been reported in patients treated with etoposide in association with other antineoplastic drugs.
Nursing Mothers
It is not known whether this drug is excreted in human milk
Paediatric Use
Safety and effectiveness in paediatric patientshave not been established.
VEPESID injection contains polysorbate 80. In premature infants a life threatening syndrome consisting of liver and renal failure, pulmonary deterioration, thrombocytopenia and ascites has been associated with an injectable Vitamin E product containing polysorbate 80.
Drug interactions
High dose cyclosporine co-administered with etoposide led to a increase in etoposide exposure (AUC) with a decrease in total body clearance of etoposide compared to etoposide alone.
Concomitant cisplatin therapy is associated with reduced total body clearance of etoposide.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Overdosage of Etoposide is accompanied by severe myelosuppression and severe nausea and vomiting.
No proven antidotes have been established for VEPESID overdosage.
Total dose of 2,4 g/m² to 3,5 g/m²administered IV over 3 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 doses of etoposide.

IDENTIFICATION

100 mg injection	A clear yellow liquid in a clear glass vial.
50 mg capsules	Opaque, pink, oblong, soft gelatin capsule with a diameter of approx. 8,1 mm and an approx. length of 19,8 mm.
100 mg capsules	Opaque, pink, oblong, soft gelatin capsule with a diameter of approx. 10 mm and an approx. length of 24 mm.

PRESENTATION

100 mg injection	One vial per carton.
50 mg capsules	Twenty capsules in blister packs.
100 mg capsules:	Ten capsules in blister packs.

STORAGE INSTRUCTIONS
When stored at temperatures not exceeding 25°C and protected from light the vials are stable until expiration date indicated on package. Etoposide when diluted as recommended to a concentration of 0,2 or 0,4 mg/mL, is stable for 96 and 24 hours respectively, at room temperature (25°C) under normal room fluorescent light in both glass and plastic containers. (Please note that for solution held at room temperature, one should take into consideration not only physical stability but also sterility. Solutions should be prepared in an aseptic manner).
The capsules should be stored at temperatures not lower than 10°C, nor higher than 25°C. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS

Vial:	N/26/127
Capsules:	N/26/125 & 126.

NAME AND BUSINESS ADDRESS OF APPLICANT
Bristol-Myers Squibb (Pty) Ltd *
47 Van Buuren Road
BEDFORDVIEW
2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT
July 1999

*        Authorised user of the TM VEPESID

Updated on this site: November 2005
Source: Pharmaceutical Industry
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