Etoposide Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Etoposide Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Ovarian Cancer, Small Cell Lung Cancer
Class: Antineoplastics, Mitotic inhibitors
Form: Liquid solution, Intravenous (IV)
Ingredients: Etoposide, dehydrated alcohol, polyethylene glycol 300, polysorbate 80

Pharmaceutical Information

Drug Substance

Proper name: Etoposide
Chemical name: (1) Furo[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one-, 9-[(4,6-O-ethylidene-β-D-glucopyranoxy]5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl), [5R-[5α,5aβ,-8aα,9β(R*)]]-

(2) 4'-Demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside]

Molecular formula: C29H32O13
Molecular weight: 588.57 g/mol
Molecular structure:

Physiochemical Properties: Etoposide is a fine, white to off-white, crystalline powder, very slightly soluble in water, slightly soluble in alcohol, chloroform, ethyl acetate, methylhloride, and sparingly soluble in methanol. It is made water soluble by means of organic solvents. The melting range of etoposide is 236 °C ‒ 251 °C. The pKa is 9.8. Etoposide is a semi-synthetic derivative of podophyllotoxin.

Preparation for Intravenous Administration

Etoposide Injection MUST BE DILUTED PRIOR TO USE with either 5% Dextrose Injection USP or 0.9% Sodium Chloride Injection USP to give a final concentration of 0.2 or 0.4 mg/mL. It is recommended that the product be used immediately after reconstitution.

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leackage should not be used.

Storage and Stability

Etoposide Injection should be stored at room temperature (15 °C ‒ 30 °C) protected from light.

Etoposide Injection diluted with 0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP to a concentration of 0.2 or 0.4 mg/mL should be stored no longer than 24 hours at room temperature due to the possibility of microbial contamination during preparation. Discard unused portion after this time.

Special Instructions for Handling Cytotoxic Drugs

Handling and Disposal

  1. Preparation of Etoposide Injection should be done in a vertical laminar flow hood (Biological Safety Cabinet - Class II).
  2. Personnel preparing Etoposide Injection should wear PVC gloves, safety glasses, disposable gowns and masks.
  3. All needles, syringes, vials and other materials which have come in contact with etoposide should be segregated and incinerated at 1,000 °C or more. Sealed containers may explode. Intact vials should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport.
  4. Personnel regularly involved in the preparation and handling of etoposide should have bi-annual blood examinations.

Dosage Forms, Composition and Packaging

Each mL contains 20 mg etoposide, 30.5% (v/v) dehydrated alcohol, 650 mg polyethylene glycol 300, 80 mg polysorbate 80, citric acid for pH adjustment with 30 mg benzyl alcohol as preservative.

Etoposide Injection is available as follows:

    5 mL (100 mg etoposide) multiple-dose vial packaged in 10's

    25 mL (500 mg etoposide) multiple-dose vial packaged individually

    50 mL (1 g etoposide) multiple-dose vial packaged individually

Human Pharmacology

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/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. Etoposide does not accumulate in the plasma following daily administration of 100 mg/m2 for 4 to 5 days.

The mean volumes of distribution at steady state fall in the range of 18 to 29 litres or 7 to 17 L/m2. Etoposide enters the CSF poorly. Although it is detectable in CSF and intracerebral tumours, the concentrations are lower than in extra cerebral 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. Phenylbutazone, sodium salicylate, and aspirin at concentrations achieved in vivo displace protein-bound etoposide.

After intravenous administration of 3H-etoposide (70 ‒ 290 mg/m2), mean recoveries of radioactivity in the urine range from 42 to 67%, and fecal 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. An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children.

Etoposide, therefore, is cleared by both renal and non-renal processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known.

Biliary excretion 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 [(4'-demethyl epipodophyllic acid-9-(4, 6-O-(R)-ethylidene-β-D-glucopyranoside)], formed by opening of the lactone ring. It is also present in human plasma, presumable as the trans isomer. Glucuronide and/or sulfate conjugates of etoposide are excreted in human urine and represent 5 to 22% of the dose.

After intravenous infusion, the Cmax and AUC values exhibit marked intra- and inter-subject variability.

In adults, the total body clearance of etoposide is correlated with creatinine clearance, low serum albumin concentration, and non-renal clearance. In adult cancer patients with liver dysfunction, total body clearance of etoposide is not reduced. 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. Further study is required to determine if dosage modification is required in patients with decreased body clearance.

Animal Pharmacology

In vitro

Etoposide interferes with the synthesis of DNA. In vitro experiments with radiolabelled thymidine have demonstrated that etoposide has a concentration dependent inhibition of thymidine uptake.

It has been shown that etoposide, in vitro tests on chick connective tissue (fibroblasts) arrested mitosis at metaphase. These effects appeared to be concentration dependent.

Etoposide will inhibit tissue culture in vitro as shown in studies with cell line of P-815, HeLa and L types.

Human hemopoietic cell lines treated with etoposide showed a high incidence of multiple chromosomal abnormalities.

The drug has shown activity in rodent transplantable tumors of the sarcomas 37 and 180 and the Walker carcinosarcoma, as well as leukemias P-1534 and L-1210.

Etoposide has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however, appears to be at the late S or early G2 portion of the cell cycle in mammalian cells. Two different dose-dependent responses are seen. At high concentrations (10 mcg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 mcg/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.

Pharmacokinetics

In rats, etoposide was distributed in highest concentrations in liver, kidney and small intestine thirty minutes after intravenous injection of radio-labelled etoposide. Etoposide accumulated to a significant degree after 24 hours in liver, kidney, bile and thyroid, and its major route of excretion was shown to be the bile.

In monkeys, following oral administration, a maximum blood level of etoposide was achieved after 45 minutes and following an intravenous bolus administration, a maximum level was seen after 15 minutes.

In monkeys, the oral half life was 1.7 hours, and the intravenous half life was 1.3 hours. Nineteen percent of the etoposide oral dose was excreted in the urine after 80 hours, and 63% of etoposide oral dose was found in the feces.

Toxicology

Acute Toxicity

The LD50 was determined in mice, rats and rabbits (see following Table 1).

Table 1: LD50 of Etoposide Intravenous
  Etoposide solution Ampoule solvent
mg/kg mL/kg mL/kg
Mouse 118 ± 9.5 5.9 6.6 ± 0.3
Rat 68 ± 3.5 3.4 4.2 ± 0.4
Rabbit 80 4.0 ca 4.0

The exact estimate of the toxicity of etoposide is limited by the toxicity of the solvent, so acute intravenous toxicity of etoposide cannot be given with certainty.

Subacute Toxicity

Etoposide was administered intraperitoneally at doses of 0.6, 1.8 and 6.0 mg/kg/day to three groups of 20 rats (10 males and 10 females) for four weeks.

A 0.6 mg/kg

Produced no significant effects. No deaths occurred.

At 1.8 mg/kg/day

Produced anemia and transient lymphopenia with significant thymus involution and reduced splenic lymphoid tissue in some animals. No deaths occurred.

At 6.0 mg/kg/day

Significant effects on the hemopoietic and lymphopoietic systems, characterized by fairly severe anemia and marked leucopenia with agranulocytosis in one case. Spermiogenesis in the males was diminished or absent. Non-specific effects (weight loss, diarrhea, pulmonary lesions, hepatocyte degeneration) were reported. Mortality was 2/20 in this group.

At 0.6 mg/kg/day at necropsy showed slight evidence of thymus involution in 11/20 rats. There were marked areas of retroperitoneal hemorrhage and small petechial hemorrhages in the pleura and renal capsule.

At 1.8 mg/kg/day at necropsy showed moderate thymus involution in 18/20 rats. There was a small quantity of serosanguinous ascitic fluid in 7/20 rats. Also seen were small petechial hemorrhages in pleura and renal capsule as in other dosage groups.

At 6.0 mg/kg/day at necropsy resulted in two spontaneous deaths, one with no postmortem changes, the other with hemorrhagic peritonitis due to perforation. At necropsy significant thymus involution was seen in three, with obvious involution in the remainder. The liver appeared swollen and edematous in 10/18 rats.

Petechial hemorrhages in lungs and renal capsule were observed.

Etoposide was administered intravenously at dosage levels of 0.4, 1.2 and 3.6 mg/kg/day to three groups of four rhesus monkeys (two males and two females) for four weeks.

At 0.4 mg/kg/day

Was without any significant effect.

At 1.2 mg/kg/day

Produced non-significant anemia and leucopenia and diminished lymphoid tissue.

At 3.6 mg/kg/day

Produced progressive anemia and severe leucopenia and agranulocytosis and impaired platelet function (plasma clot retraction). There was diminished lymphoid tissue and reaction centres in the spleen and lymph nodes in all four monkeys and evidence of focal hepatocyte degeneration. Non-specific effects at this dosage included weight loss, reduced serum albumin, mild enteritis and increased hemosiderin deposition in one or two animals. Mortality was zero in all groups.

At 0.4 mg/kg/day at necropsy showed small grey/yellow nodules in the lungs of two monkeys.

At 1.2 mg/kg/day showed small grey/yellow nodules in the lungs of one monkey, and in another the liver was congested with small surface scars.

At 3.6 mg/kg/day at necropsy showed findings of enlarged submandibular glands, small lung abscesses, grey nodules, small hemorrhagic foci, enlarged mesenteric lymph nodes and fatty bone marrow.

The veins showed no evidence of poor local tolerance.

Chronic Toxicity

Three groups of 80 rats (40 males and 40 females) were given etoposide ampoule solution orally for 26 weeks at 3, 10 and 30 mg/kg daily. Following the completion of the 26 week study,

40 rats at the mid and high dose level received no drug orally for an additional eight weeks to detect possible reversibility of effects.

At 3 mg/kg

Females had a decrease in leukocytes. Both females and males had decreases in RBC, erythropoiesis, leukopoiesis and increased serum cholesterol.

At 10 mg/kg

Decreased total leukocytes, lymphocytes and monocytes, plasma cell increase, bone marrow changes showing moderate disturbance of erythropoiesis and leukopoiesis.

At 30 mg/kg

Females had increased platelet counts. Males had diarrhea. Both females and males had impaired food intake and weight gain, decreased leukocytes, lymphocytes, monocytes, neutrophils and anemia due to changes in the bone marrow. Serum cholesterol was increased. Urine volume was increased with enhanced electrolyte excretion.

At necropsy, the following changes were noted ‒ reduced weight of testes, ovaries and spleen; increased liver weights; thymus involution; a mammary adenocarcinoma and nephroblastoma; degenerative changes in seminal epithelium. These immunosuppressive effects on the hemopoietic and lymphatic system were reversible following treatment, however, histological lung changes were more pronounced after the recovery phase. The tumor findings can be related to the cytostatic mechanism.

Three groups of six beagle dogs (three males and three females) were given etoposide ampoule solution for 26 weeks orally at 0.5, 1.5 and 5 ‒ 6 mg/kg once daily. Following the completion of the 26 week study, two dogs each of the mid and high dose level were kept for a further five weeks without drug administration to demonstrate reversibility of effects. The following toxicity was reported:

At 0.5 mg/kg

Changes in bone marrow, slight disturbances of erythropoiesis, sporadic occurrence of micronuclei in normoblasts and leukocytes, increased urinary excretion of potassium.

At 1.5 mg/kg

Increased platelet counts, disturbed erythropoiesis and leukopoiesis, ECG change.

Three males showed decreased testicular weights and reduced spermiogenesis.

At 5.6 mg/kg

Reduction in body weight gain, food intake impaired, loss of weight, black pigmentation of ear skin due to melanin deposition in basal cells of epidermis. Hematological findings showed a decrease in total leukocyte counts, neutrophils, lymphocytes and monocytes and a slight decrease in erythrocytes, hematocrit and hemoglobin. Also macrocytosis, hypochromic anemia and micronuclei in the erythrocytes and leukocytes, bone marrow changes, and increased platelet count were noted. Also a marked transient increase of SGPT values and a slight trend to increased BUN and creatinine values together with a decrease in blood protein were observed.

The immunosuppressive effects on the hematopoietic and lymphatic system were reversible following withdrawal of treatment.

In summary, the results of the two oral 26-week toxicity studies revealed clear-cut toxic effects after oral administration of high doses of the ampoule solution of etoposide in rats and dogs. The main evidence of toxicity was seen in the erythro and leukopoietic organs, thymus and testes.

Hemolysis Studies

Etoposide given in a four-week intravenous study in monkeys produced no evidence of intravascular hemolysis. Plasma protein precipitation studies in vivo and in vitro indicate that intravenous administration of etoposide ampoule solution should have no untoward effects on human blood and plasma at the doses likely to be used.

Teratology

Etoposide was subjected to a teratology study in SPF rats at doses of 0.13, 0.4, 1.2 and 3.6 mg/kg/day administered intravenously on days 6 to 15 of gestation.

Etoposide caused dose-related maternal toxicity, embryotoxicity and teratogenicity at dose levels of 0.4 mg/kg/day and higher. Embryonic resorptions were 90 and 100 percent at the two highest dosages. At 0.4 and 1.2 mg/kg, fetal weights were decreased and fetal abnormalities occurred including major skeletal abnormalities, exencephaly, encephalocele and anophthalmia. At the dose of 1.2 mg/kg, a prenatal mortality of 92 percent was observed with 50 percent of the implanting fetuses abnormal. Even at the lowest dose tested, 0.13 mg/kg, a significant increase in retarded ossification was observed.

A study of Swiss-Albino mice given a single intraperitoneal injection of etoposide at dosages of 1.0, 1.5 and 2 mg/kg on days 6, 7 and 8 of gestation disclosed dose-related embryotoxicity, various cranial abnormalities, major skeletal malformations, an increased incidence of intrauterine death and significantly decreased average fetal body weights. Maternal weight gain was not affected.

Etoposide induced aberrations in chromosome number and structure in embryonic murine cells.