ETOPOPHOS Etoposide phosphate 113.6mg; 500mg Vials Powder for Injection
Each single use vial contains 113.6mg of etoposide phosphate (equivalent to 100mg etoposide) as a lyophilised powder for injection. In addition each single dose vial contains 32.7mg sodium citrate and 300mg of Dextran 40. ETOPOPHOS injection is also available in a pharmacy bulk vial containing 568mg of etoposide phosphate (equivalent to 500mg etoposide). This vial also contains 163.5mg of sodium citrate and 1.5g of Dextran 40.
ETOPOPHOS, a lyophilised powder form of etoposide (VP-16-213), a semi-synthetic derivative of podophyllotoxin, is an anti-neoplastic drug for intravenous use, which can be used alone or in combination with other oncolytic drugs.
Etoposide phosphate is converted in vivo to the active moiety, etoposide, by dephosphorylation. The mechanism of action of etoposide phosphate is believed to be the same as that of etoposide. Etoposide 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 ug/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 ug/mL), cells are inhibited from entering prophase. It does not interfere with micro tubular assembly. The predominant macromolecular effect of etoposide appears to be DNA synthesis inhibition.
Following intravenous administration of ETOPOPHOS, etoposide phosphate is rapidly and completely converted to etoposide in plasma. A direct comparison of the pharmacokinetic parameters (AUC and CMAX) of etoposide following intravenous administration of molar Etopophos V5.0 equivalent doses of ETOPOPHOS and etoposide was made in two randomized cross-over studies in patients with a variety of malignancies. Results from both studies demonstrated no statistically significant differences in the AUC and CMAX for etoposide when administered as ETOPOPHOS or etoposide. In addition, there were no statistically significant differences in the pharmacodynamic parameters (haematologic toxicity) after administration of ETOPOPHOS or etoposide. Because of the pharmacokinetic and pharmacodynamic bioequivalence of ETOPOPHOS to etoposide, the following information on etoposide should be considered. 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 48mL/min or 16 to 36mL/min/m2 and, like the terminal elimination half-life, are independent of dose over a range 100-600mg/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 100mg/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 to 17/m2. Etoposide enters the CSF poorly. Although it is detectable in CSF and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumors 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. Phenyl butazone, sodium salicylate and aspirin at concentrations achieved in vivo displace protein-bound etoposide. After intravenous administration of 14C-etoposide (100-124mg/m2), mean recovery of radioactivity in the urine range was 56% of the dose at 120 hours, 45% of which was excreted as etoposide; faecal recovery of radioactivity was 44% of the dose at 120 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 10mL/min/m2 or about 35% of the total body clearance over a dose range of 80 to 600mg/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 unchanged drug and/or metabolites is an important route of etoposide elimination as faecal recovery of radioactivity is 44% of the intravenous dose. The hydroxy acid metabolite [4'-demethylepipodophyllic acid-9-(4,6-0-(R)-ethylidene-b -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. Only 8% or less of an intravenous dose is excreted in the urine as radiolabeled metabolites of 14C-etoposide. In addition, 0- demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol. Etopophos V5.0 In adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentration, and non-renal clearance. In adult cancer patients with liver dysfunction, total body clearance of etoposide is not reduced. Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and higher steady state volume of distribution (see DOSAGE AND ADMINISTRATION). 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.
ETOPOPHOS is indicated in the treatment of:
Small Cell Lung Cancer
- ETOPOPHOS Injection in combination with other approved chemotherapeutic agents as first-line treatment in patients with small cell lung cancer.
Hodgkin's Disease
Malignant (non-Hodgkin's) lymphomas,
especially of the histiocytic variety.
Acute non-lymphocytic leukaemia
Testicular tumors
both as first-line combination regimens and for the treatment of refractory testicular tumours.
ETOPOPHOS is administered by slow intravenous infusion. ETOPOPHOS SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION. The usual dose for etoposide is 50 to 100 mg/m2 /day, days 1 to 5 or 100 mg/m2/day, days 1, 3 and 5 every 3 to 4 weeks in combination with other agents approved for use in the disease to be treated. Dosage should be modified to take into account the myelosuppressive effects of other medications in the combination or the effects of prior X-ray therapy or chemotherapy which may have compromised bone marrow reserve. ETOPOPHOS may be infused over 5-210 minutes. Prior to use, the contents of each vial must be reconstituted with Sterile Water for Injection, 5% Dextrose Injection, 0.9% Sodium Chloride Injection, Bacteriostatic Water for Injection with Benzyl Alcohol, or Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol to a concentration equivalent to 20mg/mL or 10mg/mL etoposide (22.7mg/mL or 11.4mg/mL etoposide phosphate), respectively. Use the following quantity of diluent: Etopophos V5.0
| Volume of Diluent | Final Concentration (Etoposide Equivalent) | |
| Vial Strength | ||
| 113.6mg | 5 mL 10 mL | 22.7 mg/mL (20 mg/mL) 11.4 mg/mL (10 mg/mL) |
| 568 mg | 25 mL 50 mL | 22.7 mg/mL (20 mg/mL) 11.4 mg/mL (10 mg/mL) |
Following reconstitution the solution may be administered without further dilution or it can be further diluted to concentrations as low as 0.1mg/mL etoposide (0.11mg/mL etoposide phosphate) with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection. The 500mg pharmacy bulk vial is intended for use in a pharmacy admixture service only under a laminar flow hood. The closure should be penetrated only once with a sterile transfer set or other sterile dispensing device, which allows measured distribution of the contents, and the contents dispensed in aliquots using aseptic technique. Following closure puncture, container should be maintained at controlled room temperature, 20o - 25oC (68o - 77oF), under a laminar flow hood until contents are dispensed. Contents should be used as soon as possible following initial closure puncture. Unused portion should be discarded within 24 hours of closure puncture.
In patients with impaired renal function, the following initial dose modifications should be considered based on measured creatinine clearance:
| Measured Creatinine Clearance | >50mL/min | 15-50mL/min |
| Etoposide | 100% of dose | 75% of dose |
Subsequent etoposide dosing should be based on patient tolerance and clinical effect. Equivalent dose adjustments of ETOPOPHOS should be used. Data are not available in patients with creatinine clearances <15 mL/min and further dose reduction should be considered in these patients.
There are indications that patients with severely impaired liver function (as expressed by an elevation of serum bilirubin above 85 micromoles/L and clinical jaundice) may develop more Etopophos V5.0 profound myelotoxicity during etoposide treatment. Its use is contraindicated in patients with severe hepatic dysfunction, and it should be used with caution in patients with mild to moderate hepatic impairment.
ETOPOPHOS is contraindicated in patients with severe hepatic dysfunction or in those patients who have demonstrated a previous hypersensitivity to etoposide, etoposide phosphate or any component of the formulation. ETOPOPHOS must not be given by intra-cavity injection.
ETOPOPHOS 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.
Fatal myelosuppression has been reported following etoposide administration. Patients being treated with ETOPOPHOS 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 ETOPOPHOS therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent dose of ETOPOPHOS: 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. 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 reserves. Infections must be brought under control before using etoposide due to bone marrow suppression following use of the drug and the risk of septicaemia. Combined chemotherapy may cause increased bone marrow suppression and should be used with caution.
Etopophos V5.0 Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnoea and hypotension. Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician; however, the reactions can be fatal. Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain, and/or loss of consciousness have sometimes occurred in association with anaphylactic- type reactions. Injection site reactions may occur during the administration of ETOPOPHOS (see ADVERSE EFFECTS). Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.
ETOPOPHOS should be given cautiously in individuals with a degree of hepatic and renal dysfunction (see DOSAGE AND ADMINISTRATION).
In all instances where the use of ETOPOPHOS is considered for chemotherapy, the physician must evaluate the need and usefulness of the medicine against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the medicine should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of ETOPOPHOS therapy should be carried out with caution, and with adequate consideration of the further need for the medicine and alertness as to possible recurrence of toxicity. Patients with low serum albumin may be at increased risk for etoposide-associated toxicities.
The carcinogenic potential of ETOPOPHOS has not been studied. However, based upon its pharmacodynamic mechanism of action, ETOPOPHOS is a potential carcinogenic and genotoxic agent. Etoposide has been shown to be mutagenic in mammalian cells and ETOPOPHOS is expected to have similar mutagenic effects. The occurrence of acute leukaemia, which can occur with or without a preleukaemic phase, has been reported rarely in patients treated with etoposide in association with other antineoplastic drugs.
ETOPOPHOS can cause foetal harm when administered to pregnant women. Etoposide has been shown to be teratogenic in mice and rats, and it is therefore assumed the ETOPOPHOS is also teratogenic. There are no adequate and well-controlled studies in pregnant women. If this medicine is used during pregnancy, or if the patient becomes pregnant while receiving this medicine, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant. Etopophos V5.0
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ETOPOPHOS, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in children have not been systematically studied.
ETOPOPHOS has been found to be well tolerated as a single agent in clinical studies involving 206 patients with a wide variety of malignancies, and in combination with cisplatin in 60 patients with small cell lung cancer. The most frequent clinically significant adverse experiences were leukopenia and neutropenia. Unless otherwise stated, the following safety data relate to 98 patients administered single agent ETOPOPHOS therapy at or above 450mg/m2 on a 5 consecutive day or day 1, 3 and 5 schedule. Adverse events reported were those occurring during or following the first course of therapy. Acute fatal reactions associated with bronchospasm have been reported. The most frequent undesirable effect of ETOPOPHOS was leukopenia, occurring in 91% of patients (<4000 cells/mm3). Severe leukopenia (<1000 cells/mm3) in 17% of patients. Neutropenia (<2000 cells/mm3) occurred in 88% of patients and was severe (<500 cells/mm3) in 37% of patients. Fever and infection have also been reported in patients wth neutropenia. Thrombocytopenia (<100,000 thrombocytes/mm3) was reported in 23% of patients. Nine percent of patients had a platelet count nadir 50,000 thrombocytes/mm3. Anaemia (Hb<11g/dL) was observed in 72% of patients and was severe (Hb8g/dL) in 19% of patients. Gastrointestinal adverse events were usually mild to moderate: Nausea and/or vomiting (37% of patients), anorexia (16%), mucositis (11%), constipation (8%), abdominal pain (7%), diarrhoea (6%) and taste alteration (6%) were reported. Treatment discontinuation was required in 1% of patients. Asthenia or malaise affected 39% of patients and was severe in 3% of patients. Alopecia was observed in 23% of patients. In clinical studies involving ETOPOPHOS, 151 patients were treated with infusion times ranging from 30 minutes to 3.5 hours, and 63 patients received a 5 minute bolus injection. Four patients experienced one or more episodes of hypertension and 8 patients one or more episodes Etopophos V5.0 of hypotension, which may or may not be drug related. Only one of the episodes of hypotension was reported among the patients receiving the 5 minute bolus injection. If clinically significant hyper or hypotension occurs in patients receiving ETOPOPHOS, appropriate supportive therapy should be initiated. Other events reported were: chills and/or fever (24% of patients), dizziness (5%) and extravasation/phlebitis (5%). Since etoposide phosphate is converted to etoposide, the adverse experiences reported below that are associated with etoposide can be expected to occur with ETOPOPHOS. The following data on adverse reactions are based on both oral and intravenous administration of etoposide as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.
Haematological Toxicity
Myelosuppression with fatal outcome has been reported following etoposide administration (see WARNINGS AND PRECAUTIONS). Myelosuppression is most often dose-limiting, with leukocyte nadirs occurring 15 to 22 days, granulocyte nadirs occurring 12 to 19 days, and platelet nadirs occurring 10 to 15 days, after administration. Bone marrow recovery is usually complete by day 21, and no cumulative toxicity has been reported. Fever and infection have also been reported in patients with neutropenia. Leukopenia and severe leukopenia (less than 1,000 cells/mm3) were observed from 60 to 91% and 7 to 17%, respectively, in patients treated with single agent etoposide. Thrombocytopenia and severe thrombocytopenia (less than 50,000 platelets/mm3) were seen in 28 to 41% and 4 to 20%, respectively, with this same group of patients. The occurrence of acute leukaemia with or without a preleukaemic phase has been reported in patients treated with etoposide in association with other antineoplastic agents.
Gastrointestinal Toxicity
Nausea and vomiting are the major gastrointestinal toxicities. They have been noted in 31-43% of patients given intravenous etoposide. The nausea and vomiting can usually be controlled by antiemetic therapy. Anorexia was seen in 10 to 13% of patients and stomatitis in 1-6% of those patients given intravenous etoposide. Mild to severe mucositis/esophagitis may occur. Diarrhoea was noted in 1 to 13% of these patients.
Alopecia
Reversible alopecia, sometimes progressing to total baldness, has been observed in up to 44% of patients.
Hypotension
Temporary hypotension following rapid intravenous administration has been reported. The incidence has been reported between 1 and 2% of patients and has not been associated with cardiac toxicity or electrocardiographic changes. No delayed hypotension has been noted. If hypotension occurred with etoposide, it usually responded to stopping the infusion and administering fluid or other supportive therapy as appropriate. Etopophos V5.0
Allergic Reactions
Anaphylactic-like reactions characterized by chills, rigors, fever, tachycardia, bronchospasm, dyspnoea, diaphoresis, fever, pruritis, hypertension or hypotension, loss of consciousness, nausea, and vomiting have also been reported to occur in 3% of patients. These have occurred during or immediately after etoposide administration. Higher rates of anaphylactic-like reactions have been reported in children who received infusions at concentrations higher than those recommended. The role that concentration of infusion (or rate of infusion plays in the development of anaphylactic-like reactions) is uncertain. Anaphylactic-like reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines or volume expanders as appropriate. However, the reactions can be fatal. Hypertension and/or flushing 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 etoposide. Apnea with spontaneous resumption of breathing following discontinuation of the infusion has been described. Rash, urticaria, and/or pruritis have infrequently been reported at recommended doses. At investigational doses, a generalized pruritic erythematous maculopapular rash, consistent with perivasculitis, has been reported.
Neuropathy
The use of etoposide has been reported to cause peripheral neuropathy in 0.7% of patients. 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 (occasionally associated with allergic reactions), central nervous system toxicity (somnolence and fatigue), liver toxicity, aftertaste, fever, oesophagitis, Stevens Johnson syndrome, toxic epidermal necrolysis (one fatal case has been reported), rash, pigmentation, pruritis, urticaria, abdominal pain, constipation, dysphagia, asthenia, malaise, transient cortical blindness, a single report of radiation recall dermatitis, and optic neuritis. Rarely, hepatic toxicity may be seen. Hepatic toxicity, generally in patients receiving higher doses of etoposide than those recommended, has been reported. Metabolic acidosis has also been reported in patients receiving higher doses. Local soft tissue toxicity has been reported following extravasation of ETOPOPHOS. Infiltration of ETOPOPHOS may result in swelling, pain, cellulitis and necrosis including skin necrosis.
Etopophos V5.0 ETOPOPHOS should not be physically mixed with any other drug. Caution should be exercised when administering ETOPOPHOS with drugs that are known to inhibit of phosphatase activities (eg, levamisole hydrochloride). High dose cyclosporin, (concentrations >2000 ng/mL), administered with oral etoposide has led to an 80% increase in etoposide exposure (AUC) with a 38% decrease in total body clearance of etoposide, compared to etoposide alone. Concomitant cisplatin therapy is associated with reduced total body clearance of etoposide.
No proven antidotes have been established for ETOPOPHOS overdosage. Metabolic acidosis and cases of serious hepatic toxicity have been reported in patients receiving higher than recommended intravenous doses of etoposide. Total etoposide doses doses of 2.4g/m2 to 3.5g/ m2 administered intravenously over three days have resulted in severe mucositis and myelotoxicity.
As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of ETOPOPHOS. Skin reactions associated with accidental exposure to etoposide may occur. The use of gloves is recommended. If ETOPOPHOS solution contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. Procedures for proper handling and disposal of anti-cancer agents should be considered. Several guidelines on this subject have been published. ETOPOPHOS powder for injection should be stored at 2-8degC (refrigerate). The injection should be protected from light. At these temperatures, ETOPOPHOS will remain stable until expiration date indicated on package.
Solutions of ETOPOPHOS should be prepared in an aseptic manner. Prior to use, the contents of each vial must be reconstituted with Sterile Water for Injection, 5% Dextrose Injection, 0.9% Sodium Chloride Injection, Bacteriostatic Water for Injection with Benzyl Alcohol, or Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol to a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide (22.7 mg/mL or 11.4 mg/mL etoposide phosphate), respectively. Following reconstitution the solution may be administered without further dilution or it can be further diluted to concentrations as low as 0.1 mg/mL etoposide (0.14 mg/mL etoposide phosphate) with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection. When reconstituted as directed, ETOPOPHOS solutions can be stored in glass or plastic containers under refrigeration 2o-8 oC (36 o-46 oF) for 7 days; at controlled room temperature Etopophos V5.0 20o-25 oC (68o-77 oF) for 24 hours following reconstitution with Sterile Water for Injection, USP, 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP; or at controlled room temperature 20o-25 oC (68o-77 oF) for 48 hours following reconstitution with Bacteriostatic Water for Injection with Benzyl Alcohol or Bacteriostatic Sodium chloride for Injection with Benzyl Alcohol. ETOPOPHOS solutions further diluted as directed can be stored under refrigeration 2o-8 oC (36 o-46 oF) or at controlled room temperature 20o-25 oC (68o-77 oF) for 24 hours. Solutions of ETOPOPHOS should be prepared in an aseptic manner. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. The intravenous solution is suitable for infusion in glass or PVC containers.
ETOPOPHOS Injection: 36 months when stored at 2-8oC.
Prescription Medicine.
ETOPOPHOS injection is packed in cartons of single vials each vial containing 113.6mg or 568mg etoposide phosphate (equivalent to 100mg or 500mg etoposide respectively).
BRISTOL-MYERS SQUIBB (NZ) LIMITED Private Bag 92518 AUCKLAND 1141 Date of Preparation - 15 February 2013 Etopophos V5.0