ETOPUL

Indications

• Small cell lung cancer
• Testicular cancer
• Lymphomas
• Neuroblastoma
• Rhabdomyosarcoma
• Acute lymphoblastic leukemia
• Acute myeloid leukemia

Dosage

Adults: Typically, etoposide is administered at a dose of 20-240 mg/m² daily for 5 days, but specific dosing should be guided by

Mechanism of action

Etoposide inhibits DNA topoisomerase II, preventing the re-ligation of DNA strands after they have been cleaved. This inhibition leads to the accumulation of DNA breaks, disrupting DNA synthesis and function. Etoposide is cell cycle-dependent, predominantly affecting the S and G2 phases of cell division, which is crucial for its anti-tumor activity. The drug also induces single-stranded and double-stranded DNA breaks, promoting apoptosis in cancer cells.

Pharmacodynamics

As an antineoplastic agent, etoposide's pharmacodynamic effects are linked to its ability to cause DNA damage that is lethal to cancer cells. It shows dose-dependent responses, with lower concentrations inhibiting cell cycle progression and higher concentrations leading to cell lysis. The predominant mechanism of action involves DNA strand breaks mediated through interactions with DNA-topoisomerase II, resulting in impaired DNA synthesis and function.

Pharmacokinetics

Etoposide is absorbed variably when administered orally, with peak plasma concentrations typically reached within 1 to 2 hours. The drug exhibits a volume of distribution of about 20-30 L/m² and is primarily metabolized in the liver. Its elimination half-life ranges from 4 to 11 hours, with renal clearance being significant; dose adjustments may be necessary in cases of renal impairment. Etoposide is mainly excreted in the urine as inactive metabolites.

Contra-indications

• Peripheral neuropathy with functional impairment

Adverse effects

• Alopecia
• Anaemia
• Appetite decrease
• Arthralgia
• Asthenia
• Chills
• Conjunctivitis
• Constipation
• Cough
• Decreased leukocytes
• Dehydration
• Depression
• Diarrhoea
• Dizziness
• Dyspnoea
• Electrolyte imbalance
• Embolism and thrombosis
• Fever
• Flushing
• Gastrointestinal discomfort
• Gastrointestinal disorders
• Haemorrhage
• Headache
• Hiccups
• Hyperglycaemia
• Hyperhidrosis
• Hypersensitivity
• Hypertension
• Increased risk of infection
• Insomnia
• Meningism
• Mucositis
• Nail disorders
• Neuropathy
• Pneumonitis
• Sepsis
• Taste altered
• Thrombocytopenia
• Urinary disorders
• Vision disorders
• Vomiting
• Weight changes

Interactions

• Ciclosporin: Moderate (increases exposure)
• Antiepileptics (carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone): Unknown (decreases efficacy)
• Live vaccines: Unknown (increases risk of generalized infection, possibly life-threatening)
• Netupitant: Unknown (increases exposure)

Precautions

• Use with caution in patients with renal impairment
• Monitor for signs of infection due to decreased leukocyte counts
• Assess for potential hypersensitivity reactions

Pregnancy

Manufacturer advises to avoid due to toxicity observed in animal studies.

Breast-feeding

Discontinue breast-feeding.

Storage

Store in a cool, dry place away from light, and keep out of reach of children.

Formulations

• Etoposide 20 mg per 1 ml solution for infusion

Mechanism of action

Etoposide inhibits DNA topoisomerase II, thereby inhibiting DNA re-ligation. This causes critical errors in DNA synthesis at the premitotic stage of cell division and can lead to apoptosis of the cancer cell. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases of cell division. Inhibition of the topoisomerase II alpha isoform results in the anti-tumour activity of etoposide. The drug is also capable of inhibiting the beta isoform but inhibition of this target is not associated with the anti-tumour activity. It is instead associated with the carcinogenic effect. The drug appears to produce its cytotoxic effects by damaging DNA and thereby inhibiting or altering DNA synthesis. ... Etoposide appears to be cell-cycle dependent and cycle-phase specific, inducing G2 phase arrest and preferentially filling cells in the G2 and late S phases. Etoposide has been shown to arrest metaphase in chick fibroblasts, but its principal effect in mammalian cells appears to be in the G2 phase. At etoposide concentrations of 0.3-10 ug/ml in vitro, cells are inhibited from entering prophase; at concentrations of 10 ug/ml or higher, lysis of cells entering mitosis occurs. ... Etoposide does not inhibit microtubule assembly. Etoposide has been shown to induce single-stranded DNA breaks in HeLa cells and in murine leukemia L1210 cells in vitro; the drug also induces double-stranded DNA breaks and DNA-protein crosslinks in L1210 cells. Etoposide induced DNA damage appears to correlate well with the cytotoxicity of the drug. ... Etoposide appears to induce single-stranded DNA breaks indirectly, possibly through endonuclease activation, inhibition of intranuclear type II topoisomerase, or formation of a free-radical metabolite via an enzymatic reaction involving the hydroxyl group at the C-4' position of the E ring. Etoposide also reversibly inhibits the facilitated diffusion of nucleosides into HeLa cells in a concentration dependent manner in vitro. Etoposide may stabilize type II topoisomerase DNA complexes, preventing rejoining of single and double strand DNA breaks. Etoposide may also require cellular activation into intermediates, which then bind to DNA and disrupt cellular function.

Pharmacodynamics

Etoposide is an antineoplastic agent and an epipodophyllotoxin (a semisynthetic derivative of the podophyllotoxins). It inhibits DNA topoisomerase II, thereby ultimately inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases. Two different dose-dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 µg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals.