Etoposide

Etoposide is a semisynthetic derivative of podophyllotoxin (an epipodophyllotoxin) with antineoplastic activity. It acts mainly in the late S and early G2 phases of the cell cycle by inhibiting DNA topoisomerase II, and it does not interfere with microtubule assembly.

Mechanism of Action

• Topoisomerase II inhibition: etoposide stops DNA topoisomerase II from re-joining DNA strands. The resulting strand breaks (possibly also through free radical formation) cause critical errors in DNA synthesis before mitosis and can lead to apoptosis. Inhibition of the topoisomerase II alpha isoform underlies the antitumour effect.
• Dose-dependent effects: at high concentrations (10 µg/mL or more) cells entering mitosis are lysed; at low concentrations (0.3 to 10 µg/mL) cells are blocked from entering prophase. Microtubule formation is not affected.

Pharmacokinetics

• Absorption (capsules): oral bioavailability is variable, averaging about 76% at a 100 mg dose and 48% at 400 mg; peak concentrations are reached after about 1–1.5 hours. There is no evidence of a hepatic first-pass effect. An oral dose of 100 mg is comparable to an intravenous dose of 75 mg, and 400 mg orally to 200 mg intravenously. Cmax and AUC vary considerably within and between patients.
• Distribution: mean steady-state volume of distribution 18–29 L (7–17 L/m²); low penetration into cerebrospinal fluid; about 97% bound to plasma proteins. Binding correlates with serum albumin, and the unbound fraction with bilirubin, in patients with cancer.
• Metabolism: CYP3A4-mediated O-demethylation of the dimethoxyphenol ring forms the corresponding catechol. A hydroxy-acid metabolite (from opening of the lactone ring) is found in urine and plasma, and glucuronide and/or sulfate conjugates are excreted in urine.
• Elimination: after intravenous use, disposition is biphasic, with a distribution half-life of about 1.5 hours and a terminal half-life of 4–11 hours. Total body clearance is 33–48 mL/min (16–36 mL/min/m²) and independent of dose between 100 and 600 mg/m². After an intravenous dose about 44% was recovered in faeces and 56% in urine, 45% of that urinary fraction as unchanged etoposide.
• Special populations: clearance is lower in renal impairment, which is why the dose is reduced when creatinine clearance is below 50 mL/min (see Administration and Dosage).

Etoposide is always used in combination with other approved chemotherapy agents, except where noted. The two national SmPCs word their indications differently, so the SmPC of the product in use applies.

Vepesid soft capsules (adults)

• Testicular cancer: relapsed or refractory disease.
• Small-cell lung cancer.
• Hodgkin lymphoma: second-line treatment of relapsed or refractory disease.
• Non-Hodgkin lymphoma: relapsed or refractory disease.
• Acute myeloid leukaemia: relapsed or refractory disease.
• Ovarian cancer: non-epithelial ovarian cancer in combination; platinum-resistant or refractory epithelial ovarian cancer.

Etoposide 20 mg/mL concentrate for infusion

• Testicular cancer (adults): the SmPC wording refers to first-line treatment and to recurrent or refractory disease.
• Small-cell lung cancer (adults).
• Hodgkin lymphoma, non-Hodgkin lymphoma and acute myeloid leukaemia: adult and paediatric patients.
• High-risk gestational trophoblastic neoplasia (adults): first- and second-line treatment.
• Ovarian cancer (adults): non-epithelial ovarian cancer in combination; platinum-resistant or refractory epithelial ovarian cancer.

• Hypersensitivity to etoposide or to any of the excipients (for the capsules this includes sodium ethyl parahydroxybenzoate E215 and sodium propyl parahydroxybenzoate E217).
• Concomitant use of the yellow fever vaccine or other live virus vaccines in immunocompromised patients.
• Breastfeeding.

Bone-marrow suppression is the dose-limiting and most significant toxicity. With the capsules or injection used as a single agent, the most frequent reactions of any severity were leukopenia (60–91%), thrombocytopenia (22–41%), nausea and/or vomiting (31–43%) and alopecia (8–66%). With the infusion used alone at total doses of 450 mg/m² or more, the most frequent were leukopenia (91%), neutropenia (88%), anaemia (72%), asthenia (39%), nausea and/or vomiting (37%), alopecia (33%), chills and/or fever (24%) and thrombocytopenia (23%).

The frequencies below are from the capsule SmPC.

Very common (≥1/10): anaemia, leukopenia, myelosuppression, neutropenia, thrombocytopenia; abdominal pain, anorexia, constipation, nausea and vomiting; hepatotoxicity; alopecia, pigmentation; asthenia, malaise.

Common (≥1/100 to <1/10): acute leukaemia; dizziness; arrhythmia, myocardial infarction; hypertension; diarrhoea, mucositis (including stomatitis and oesophagitis); pruritus, rash, urticaria.

Uncommon (≥1/1,000 to <1/100): peripheral neuropathy.

Rare (≥1/10,000 to <1/1,000): anaphylactic reactions; transient cortical blindness, neurotoxicity (for example somnolence and fatigue), optic neuritis, convulsions (occasionally linked to allergic reactions); interstitial pneumonitis, pulmonary fibrosis; dysgeusia, dysphagia; radiation recall dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis; pyrexia.

Not known: infection (including opportunistic infections such as Pneumocystis jirovecii pneumonia); angioedema, bronchospasm; tumour lysis syndrome; haemorrhage; raised alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase and bilirubin; infertility.

Differences listed in the infusion SmPC: infection, anaphylactic reactions and transient systolic hypotension after rapid intravenous injection are common; haemorrhage is uncommon; acute renal failure and bronchospasm are of unknown frequency; hand-foot syndrome is rare; extravasation and phlebitis are common; raised liver enzymes and bilirubin are listed as very common.

Granulocytes and platelets reach their lowest level about 10–14 days after a dose, earlier with intravenous than with oral use, and marrow recovery is usually complete by day 20 without cumulative toxicity. Alopecia is reversible, sometimes progressing to total baldness. Anaphylactic reactions (chills, fever, tachycardia, bronchospasm, hypotension) can be fatal and may occur with the first dose; fatal myelosuppression, tumour lysis syndrome and secondary acute leukaemia have also been reported.

• Ciclosporin (high dose): concentrations above 2,000 ng/mL with oral etoposide raised etoposide exposure (AUC) by 80% and lowered its total body clearance by 38%.
• Cisplatin: associated with reduced total body clearance of etoposide.
• Phenytoin and other enzyme-inducing antiepileptics: increase etoposide clearance and reduce its efficacy. Conversely, combining antiepileptics with the capsules may reduce seizure control through pharmacokinetic interactions.
• Protein-binding displacement: phenylbutazone, sodium salicylate and acetylsalicylic acid may displace etoposide from plasma proteins (binding is about 97%).
• Warfarin (capsule SmPC): may raise the INR; close INR monitoring is recommended.
• Live vaccines: yellow fever vaccine and other live virus vaccines are contraindicated in immunocompromised patients because of the risk of fatal systemic vaccine disease.
• Other myelosuppressive medicines or radiotherapy: additive or synergistic effects are expected, before or during treatment.
• Anthracyclines: cross-resistance with etoposide was seen in preclinical experiments.
• Ethanol in the concentrate: the alcohol it contains may alter the effects of other medicines.
• Food and herbal products: grapefruit inhibits CYP3A4 and may raise etoposide levels; St John’s wort induces CYP3A4 and may lower them.

Interaction studies have been done in adults only.

Etoposide must be given and monitored only under the supervision of a qualified physician experienced in the use of antineoplastic medicines. The regimen depends on the disease and the combination used.

Soft Capsules (Vepesid)

• Method: taken on an empty stomach.
• Usual dose, alone or in combination: 100–200 mg/m² per day on days 1–5, or 200 mg/m² on days 1, 3 and 5, every 3–4 weeks. Daily doses above 200 mg are divided and taken twice a day.
• Alternative schedule: 50 mg/m² per day for 2–3 weeks, repeated after a week’s rest or on recovery from myelosuppression.
• Dose adjustment: the dose takes into account the marrow-suppressing effects of the other medicines in the combination and of previous radiotherapy or chemotherapy. Later doses are adjusted if neutrophils are below 500 cells/mm³ for more than 5 days, if fever, infection or platelets below 25,000 cells/mm³ occur that are not caused by the disease, with grade 3 or 4 toxicity, or if creatinine clearance is below 50 mL/min (a 25% reduction is recommended for 15–50 mL/min).
• New cycles: not started if neutrophils are below 1,500 cells/mm³ or platelets below 100,000 cells/mm³, unless caused by the cancer.

Concentrate for Infusion (20 mg/mL)

• Method: slow intravenous infusion, generally over 30–60 minutes, after dilution as described in section 6.6 of the SmPC. In-line filters must not be used.
• Adults: 50–100 mg/m² per day on days 1–5 of the cycle, or 100–120 mg/m² on days 1, 3 and 5 of the cycle, every 3–4 weeks, with the other medicines indicated for the disease. Dose adjustments follow the same criteria as for the capsules.
• Children (Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukaemia): 75–150 mg/m² per day for 2–5 days with other antineoplastic agents, with the regimen chosen according to local standard of care. For the other indications, safety and efficacy below 18 years have not been established and no dose can be recommended.
• Handling: caution is needed when handling and preparing the solution; skin reactions may follow accidental exposure, gloves are recommended, and skin or mucosal contact is treated by washing the skin immediately with soap and water and rinsing mucous membranes with water.

Special Populations

• Renal impairment: the starting dose is based on measured creatinine clearance: above 50 mL/min, 100% of the dose; 15–50 mL/min, 75% of the dose. Below 15 mL/min and on dialysis a further reduction is probably needed. Later dosing follows tolerance and clinical effect. Etoposide and its metabolites are not dialysable, so it can be given before and after haemodialysis.
• Elderly (over 65 years): no adjustment other than for renal function.
• Hepatic impairment: liver function should be checked regularly because of the risk of accumulation.
• Children: safety and efficacy of the capsules below 18 years have not been established, and no dose can be recommended.

Myelosuppression

Platelet count, haemoglobin and white-cell count with differential are measured before treatment and before every dose, and patients are monitored closely during and after treatment. Time is left for marrow recovery after earlier radiotherapy or chemotherapy. Etoposide should not be given when neutrophils are below 1,500 cells/mm³ or platelets below 100,000 cells/mm³ unless the cancer explains this. Severe myelosuppression can lead to infection or bleeding, and bacterial infections should be controlled before treatment.

Oral Versus Intravenous Treatment

Most evidence in the indications comes from studies of the intravenous form. With the capsules, exposure varies more from one cycle to the next (coefficient of variation about 30% versus about 10% intravenously; between-patient variability is 30–40% for both), which can make toxicity and efficacy less predictable. The benefit of oral dosing must be weighed against this, and the intravenous form is used when treatment is given with curative intent.

Secondary Leukaemia

Acute leukaemia, with or without a myelodysplastic syndrome, has occurred in patients given etoposide-containing regimens. The cumulative risk and predisposing factors are unknown, and a link with cumulative dose has been suggested but is not clearly defined. A chromosome 11q23 abnormality has been seen in some cases, and a short latency (mean about 32 months) appears typical after epipodophyllotoxins.

Hypersensitivity, Hypotension and Infusion-Site Reactions

Anaphylactic reactions can be fatal and are treated symptomatically: the infusion is stopped at once, and pressor agents, corticosteroids, antihistamines and/or plasma volume expanders are given as judged by the physician. Hypersensitivity reactions were more frequent when in-line filters were used, so they must not be used. Hypotension has been reported with rapid intravenous injection, which is why etoposide is infused slowly. Injection-site reactions can occur, and because of possible extravasation the infusion site is watched closely for infiltration.

Tumour Lysis Syndrome

Tumour lysis syndrome, sometimes fatal, has followed the use of etoposide with other chemotherapy. Patients are monitored closely for early signs, especially with bulky treatment-sensitive tumours or renal impairment, and preventive measures are considered in those at risk.

Renal Function, Hepatic Function and Albumin

Reversible acute renal failure has been reported, mainly in children, with high doses (2,220 mg/m² or 60 mg/kg) plus total body irradiation before stem cell transplantation; renal function is assessed before and after etoposide until it has fully recovered. Low serum albumin is associated with higher etoposide exposure and may increase the risk of toxicity. In moderate or severe renal impairment the dose is reduced and blood counts guide later cycles.

Pregnancy, Breastfeeding, Contraception and Fertility

• Contraception: because of etoposide’s mutagenic potential, patients of both sexes must use effective contraception during treatment and for up to 6 months afterwards. Genetic counselling is recommended for those who wish to have children after treatment.
• Pregnancy: data are absent or limited, and etoposide was teratogenic in mice and rats. It can cause foetal harm, so it is not used in pregnancy unless the woman’s clinical condition requires it, and women of childbearing potential are advised to avoid pregnancy.
• Breastfeeding: etoposide passes into breast milk and serious reactions in nursing infants are possible, so it is contraindicated.
• Fertility: infertility is listed as an adverse reaction of unknown frequency. Etoposide may reduce male fertility, and sperm preservation can be considered.

Excipients

• Capsules: they contain sodium ethyl parahydroxybenzoate (E215) and sodium propyl parahydroxybenzoate (E217), which may cause allergic reactions, possibly delayed (per 100 mg capsule 1.22 mg and 0.61 mg respectively; per 50 mg capsule 0.93 mg and 0.47 mg).
• Concentrate: it contains ethanol (30% vol.; 1.2 g in the 5 mL vial up to 12 g in the 50 mL vial, equivalent to 241 mg/mL). A 120 mg/m² dose in a 70 kg adult gives about 37.2 mg/kg ethanol and a blood alcohol rise of about 6.2 mg/100 mL, unlikely to have an effect in adults, but this should be considered in pregnant women and alcohol-dependent patients. In children weighing 17 kg or less, effects such as drowsiness and behaviour changes are likely, and caution applies in children with epilepsy or liver disease.
• Polysorbate 80 (concentrate): in premature infants, an injectable vitamin E product containing polysorbate 80 has been linked to a life-threatening syndrome of liver and kidney failure, lung deterioration, low platelets and ascites.

Effect on Driving

Etoposide may cause fatigue, somnolence, nausea, vomiting, cortical blindness and hypersensitivity reactions with hypotension. Patients who experience these should avoid driving and using machines.

Vepesid soft capsules and the concentrate for infusion are not stored above 25 °C and are kept in the original package. The capsules come in PVC/Aclar blisters (50 mg: packs of 20 capsules; 100 mg: packs of 10 capsules). No refrigeration is needed, so no cold-chain handling applies.

• Capsules: 3 years.
• Concentrate: 3 years in the package as sold. After dilution the infusion is physically and chemically stable for up to 120 hours at 25 °C, but for microbiological reasons it should be prepared in the hospital pharmacy and discarded after 8 hours. After the rubber stopper is first pierced, the concentrate remains stable for up to 72 hours (3 days) at 25 °C, so multi-dose use is possible.

Prescription only (Rx), for use under the supervision of a physician experienced in antineoplastic medicines. The soft capsules are taken at home on an empty stomach, so they are supplied to the patient or to the treating clinic on prescription. The concentrate for infusion is prepared and given in hospital, so it is supplied to the hospital or clinic that administers it.