Vepesid

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. Similar toxicities can be expected with oral formulation. A specific antidote is not available. Treatment should therefore be symptomatic and supportive, and patients should be closely monitored. Etoposide and its metabolites are not dialyzable.

Shelf life

3 years

Incompatibilities

Not applicable

List of excipients

Capsule content

Citric acid, anhydrous (E330)

Macrogol 400 (E1521)

Glycerol (85 per cent) (E422)

Water, purified

Capsule shell

Glycerol (85 per cent) (E422)

Gelatin (E441)

Sodium ethyl parahydroxybenzoate (E215)

Sodium propyl parahydroxybenzoate (E217)

Titanium dioxide (E171)

Red iron oxide (E172)

Undesirable effects

Summary of the safety profile

Dose limiting bone marrow suppression is the most significant toxicity associated with VEPESID therapy. In clinical studies in which VEPESID was administered as a single agent either orally or by injection the most frequent adverse reactions of any severity were leucopenia (60 to 91%), thrombocytopenia (22 to 41%), nausea and/or vomiting (31 to 43%), and alopecia (8 to 66%).

Tabulated summary of adverse reactions

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

Description of selected adverse reactions

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

Haematological Toxicity

Myelosuppression with fatal outcome has been reported following administration of etoposide. Myelosuppression is most often dose-limiting. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Granulocyte and platelet nadirs tend to occur about 10 to 14 days after administration of etoposide depending on the way of administration and treatment scheme. Nadirs tend to occur earlier with intravenous administration compared to oral administration. Leucopenia and severe leucopenia (less than 1,000 cells/mm3) were observed in 60 to 91% and 3 to 17%, respectively, for etoposide. Thrombocytopenia and severe thrombocytopenia (less than 50,000 platelets/mm3) were seen in 22 to 41% and 1 to 20%, respectively, for etoposide. Reports of fever and infection were also very common in patients with neutropenia treated with etoposide.

Gastrointestinal Toxicity

Nausea and vomiting are the major gastrointestinal toxicities of etoposide. The nausea and vomiting can usually be controlled by antiemetic therapy.

Alopecia

Reversible alopecia, sometimes progressing to total baldness, was observed in up to 66% of patients treated with etoposide.

Hypertension

In clinical studies involving etoposide, episodes of hypertension have been reported. If clinically significant hypertension occurs in patients receiving etoposide, appropriate supportive therapy should be initiated.

Hypersensitivity

Anaphylactic reactions manifested by chills, fever, tachycardia, bronchospasm, dyspnoea, and hypotension which can be fatal can occur with the initial dose of etoposide. Acute fatal reactions associated with bronchospasm have been reported with etoposide. Syncope, face oedema, swelling face, tongue oedema and swelling tongue can also occur with etoposide.

Metabolic Complications

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

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Preclinical safety data

Chronic toxicity

Anaemia, leucopenia, and thrombocytopenia were observed in rats and mice, while dogs had mild reversible deterioration of liver and kidney functions. The dose multiple (based on mg/m2 doses) for these findings at the no-observed adverse-effect-level in the preclinical studies were > approximately 0.05 times compared to the highest clinical dose. Historically, preclinical species have been more sensitive compared to humans towards cytotoxic agents. Testicular atrophy, spermatogenesis arrest, and growth retardation were reported in rats and mice.

Mutagenicity

Etoposide is mutagenic in mammalian cells.

Reproductive toxicity

In animal studies etoposide was associated with dose-related embryotoxicity and teratogenicity.

Carcinogenic potential

Given its mechanism of action, etoposide should be considered a possible carcinogen in humans.

Pharmacotherapeutic group

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.

Pharmacokinetic properties

Absorption

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

Distribution

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

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

Biotransformation

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

Elimination

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

Linearity/non-linearity

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

Hepatic impairment

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

Elderly population

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

Paediatric population

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

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

Gender

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

Drug interactions

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

Date of revision of the text

November 2017

Marketing authorisation holder

Bristol-Myers Squibb Pharmaceuticals Limited

Uxbridge Business Park

Sanderson Road

Uxbridge

Middlesex

UB8 1DH

Special precautions for storage

Do not store above 25°C.

Store in the original package.

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

Nature and contents of container

50 mg:

Pack of 20, 50 Capsules, softgels

100 mg:

Pack of 10, 60 Capsules, softgels

Not all pack sizes may be marketed.

Marketing authorisation number(s)

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. Given the mutagenic potential of etoposide, an effective contraceptive 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 treatment.

Pregnancy

There are no or limited amount of data from the use of etoposide in pregnant women. Studies in animals have shown reproductive toxicity. In general etoposide can cause fetal harm when administered to pregnant women. VEPESID 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.

Breastfeeding

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

Fertility

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

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 and use machines such as fatigue, somnolence, nausea, vomiting, cortical blindness, hypersensitivity reactions with hypotension. Patients who experience such adverse reactions should be advised to avoid driving or using machines.

Special precautions for disposal and other handling

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

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

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

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

Date of first authorisation/renewal of the authorisation