ETOPOPHOS Injection

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ETOPOPHOS Injection
Powder for infusion

COMPOSITION
Each vial contains etoposide phosphate equivalent to 100mg etoposide.

PHARMACOLOGICAL CLASSIFICATION
A26 Cytostatic agents.

PHARMACOLOGICAL ACTION
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 (10micrograms/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10micrograms/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-topoisomeraseII or the formation of free radicals.
Pharmacokinetics
Following intravenous administration of ETOPOPHOS, etoposide phosphate is rapidly and completely converted to etoposide in plasma. The disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1,5hours and terminal elimination half-life ranging from 4 to 11hours. After intravenous infusion, the Cmax and AUC values exhibit marked intra- and inter-subject variability. 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 6days.
The mean volumes of distribution at steady state fall in the range of 18 to 29litres or 7 to 17L/m². Etoposide enters the cerebrospinal fluid (CSF) poorly. Although it is detectable in CSF and intracerebral tumours, the concentrations are lower than in extracerebral 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. An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children. Phenylbutazone, sodium salicylate and aspirin at concentrations achieved in vivo displace protein-bound etoposide.
Etoposide binding ratio correlates directly with serum albumin in cancer patients and normal volunteers. Unbound fraction of etoposide correlates significantly with bilirubin in some cancer patients. There appears to be a significant inverse correlation between serum albumin concentrations and free etoposide fraction (See PRECAUTIONS).
After intravenous administration of 3H-etoposide (70 - 290mg/m²), mean recoveries of radioactivity in the urine range from 42 to 67%, and faecal 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 24hours.
In children, approximately 55% of the dose is excreted in the urine as etoposide in 24hours. 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 in children is not known.
Biliary excretion of the unchanged medicine appears to be a minor route . 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-(4,6-0-ethylidene-beta-D-glucopyranoside)], formed by opening of the lactone ring. It is also present in human plasma, presumably as the trans isomer. Glucuronide and/or sulphate conjugates of etoposide are excreted in human urine and represent 5 to 22% of the dose.
In adults, the total body clearance of etoposide is correlated with creatinine clearance, serum albumin concentrations, and non-renal clearance. The total body clearance of etoposide is reduced and the AUC is increased in patients with impaired renal function (See dosage and directions for use)
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.

INDICATIONS
ETOPOPHOS has been shown to be useful in the management of the following neoplasms:
Testicular tumour - first line
In combination therapy with other approved chemotherapeutic agents.
Refractory Testicular Tumours
In combination therapy with other approved chemotherapeutic agents in patients with refractory testicular tumours who have already received appropriate surgical, chemotherapeutic and radiotherapeutic therapy.
Small Cell Anaplastic Lung Tumours
In combination therapy with other approved chemotherapeutic agents in patients with small cell anaplastic lung tumours.
Malignant (non-Hodgkin's) Lymphomas, especially of the histiocytic (large cell diffuse) variety
In combination with other approved chemotherapeutic agents.

CONTRA-INDICATIONS
Hypersensitivity to etoposide or etoposide phosphate or any other component of the ETOPOPHOS formulation.
Severe hepatic dysfunction.
Severely impaired medullary haemopoiesis (especially after extensive radio- and/or chemotherapy or as a result of neoplastic infiltration). This condition may be evidenced by mild to marked leucopenia and/or thrombocytopenia.
Breastfeeding mothers, as safety has not been demonstrated.
Paediatric Use
Safety and effectiveness in children have not been established.

WARNINGS
ETOPOPHOS (ETOPOSIDE PHOSPHATE) 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, WHICH MAY BE FATAL
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. 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 50000/mm³ or an absolute neutrophil count below 500/mm³ is an indication to withhold further therapy until the blood counts have sufficiently recovered.
Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnoea and hypotension which may be fatal.
Treatment is symptomatic. Administration of ETOPOPHOS should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.
Pregnancy
ETOPOPHOS can cause foetal harm when administered to pregnant women. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant.

DOSAGE AND DIRECTIONS FOR USE
ETOPOPHOS should be administered intravenously. The usual dose for ETOPOPHOS is 50 to 100mg/m²/day days 1 to 5, or 100mg/m² days 1, 3 and 5, every 3 to 4weeks in combination with other drugs approved for use in the disease to be treated. 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 reserve. ETOPOPHOS solutions may be infused over 30minutes to 3.5hours. (Maximum dose/course 450mg/m²)
Renal impairment: In patients with impaired renal function the following initial dose modification should be considered based on measured creatinine clearance.
Measured Creatinine clearance Dose of Etoposide Phosphate
> 50mL/min 100% of dose
15-50mL/min 75% of dose
Subsequent dosing should be based on patient tolerance and clinical effect. Data are not available in patients with creatinine clearance <15mL/min and further dose reductions should be considered in these patients.
Administration Precautions
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 ETOPOPHOS may occur. The use of gloves is recommended. If ETOPOPHOS solution contacts the skin or mucosa, immediately wash the skin with soap and water and flush the mucosa with water.
Preparation for Intravenous Administration
Prior to use, the content of each vial must be reconstituted with either 5-mL or 10-mL Sterile Water for Injection, 5% Dextrose Injection or, 0.9% Sodium Chloride Injection, to a concentration equivalent to 20mg/mL or 10mg/mL etoposide (22.7mg/mL or 11.4mg/mL etoposide phosphate), respectively.
Following reconstitution the solution may be administered without further dilution or it can be further diluted to concentration as low as 0.1mg/mL etoposide (0.14mg/mL etoposide phosphate) with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
When reconstituted and/or diluted as directed, ETOPOPHOS solutions are chemically and physically stable for 24hours at 25°C and 7days under refrigeration (2-8°C) under normal room fluorescent light in both glass and plastic containers. Note that for solutions held at room temperature, one should take into consideration not only physical and chemical stability but also sterility. Solutions of ETOPOPHOS should be prepared in an aseptic manner.
Parenteral drug products should be inspected visually for particulate matter and discolouration (see IDENTIFICATION section) prior to administration whenever solution and container permit.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-Effects
Since etoposide phosphate is converted to etoposide, those adverse experiences reported below that are associated with etoposide can be expected to occur with ETOPOPHOS.
Haematological Toxicity
Myelosuppression with fatal outcome has been reported following etoposide administration (see WARNING) 
Myelosuppression is most often dose-limiting, with leukocyte mean nadir counts usually occurring from day 15 to day22, granulocyte mean nadirs usually occurring 12 to 22days, and platelet mean nadirs usually occurring 10 to 15days, after drug administration. Bone marrow recovery is usually complete by day 21, and no cumulative toxicity has been reported. Fever and infection may occur in patients with neutropenia after Etopophos. Leucopenia and severe leucopenia (less than 1000cells/mm³) were observed in patients treated with a single agent ETOPOPHOS. Thrombocytopenia and severe thrombocytopenia (less than 50000platelets/mm³) were seen in this same group of patients. The occurrence of acute leukaemia with or without a preleukemic phase has been reported in patients treated with ETOPOPHOS in association with other anti-neoplastic agents.
Gastrointestinal Toxicity
Nausea and vomiting are the major gastrointestinal toxicities. The nausea and vomiting can usually be controlled by anti-emetic therapy. Mild to severe mucositis / esophagitis may occur. Anorexia, stomatitis and diarrhoea were noted.
Alopecia
Reversible alopecia, sometimes progressing to total baldness, has been observed.
Blood Pressure Changes
In clinical studies, one hundred fifty-one patients were treated with ETOPOPHOS with infusion times ranging from thirty minutes to three and one-half hours. Sixty-three patients received ETOPOPHOS as a five minute bolus infusion. Four patients experienced one or more episodes of hypertension and eight patients experienced one or more episodes of hypotension, which may or may not be drug related. One episode of hypotension was reported among those patients who received a five minute bolus infusion. If clinically significant hypotension or hypertension occurs with ETOPOPHOS, appropriate supportive therapy should be initiated. If hypotension occurs, it usually responds to stopping the infusion and administering fluids or other supportive therapy as appropriate. When restarting the infusion, a slower administration rate should be used.
Allergic Reactions
Anaphylactic type reactions characterised by chills, rigors, fever, tachycardia, bronchospasm, dyspnea, sweating, pruritus, hypertension or hypotension, loss of consciousness, nausea, and vomiting have been reported to occur in patients treated with ETOPOPHOS. Facial flushing and skin rashes were reported in patients receiving ETOPOPHOS. These reactions have usually responded promptly to 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 been reported. Blood pressure usually normalises within a few hours after cessation of the initial infusion.
Anaphylactic-like reactions have occurred during the initial infusion of ETOPOPHOS, (see WARNING section). Facial/tongue swelling, coughing, sweating, cyanosis, tightness in throat, laryngospasm, back pain, and/or loss of consciousness have sometimes occurred in association with the above reactions. In addition, an apparent hypersensitivity-associated apnoea has been reported rarely. 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 reactions is uncertain.
Rash, urticaria, and/or pruritus have infrequently been reported at recommended doses. At investigational doses, a generalised pruritic erythematous maculopapular rash, consistent with perivasculitis, has been reported.
Neuropathy
The use of etoposide has been associated with peripheral neuropathy. The associated use of vincristine sulphate can enhance this neuropathy.
Other Toxicities
Other side-effects are:
Interstitial pneumonitis/pulmonary fibrosis, seizures, central nervous system toxicity (somnolence and fatigue), liver toxicity (See known symptoms of overdosage and particulars of its treatment) aftertaste, fever, Stevens-Johnson syndrome, toxic epidermal necrolysis (one fatal case has been reported), rash, pigmentation, pruritus, urticaria, abdominal pain, chills and/or fever, dizziness, constipation, dysphagia, asthenia, malaise, transient cortical blindness, optic neuritis and a single report of radiation recall dermatitis.
Occasionally following extravasation, soft tissue irritation and inflammation has occurred; ulceration is generally not seen. Metabolic acidosis and cases of serious hepatic toxicity have been reported in patients receiving higher than recommended intravenous doses of etoposide.

PRECAUTIONS
General
In all instances where the use of ETOPOPHOS is considered for chemotherapy, the physician must eva luate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Re-institution of ETOPOPHOS therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity. Patients with low serum albumin may be at increased risk for etoposide-associated toxicities.
Laboratory Tests
Periodic complete blood counts should be done during the course of ETOPOPHOS treatment. They should be performed prior to therapy and at appropriate periods during therapy. At least one determination should be done prior to each dose of ETOPOPHOS.
Interactions with other medicaments and other forms of interaction
Caution should be exercised when administering ETOPOPHOS with drugs that are known to inhibit phosphatase activities (e.g. levamisole hydrochloride). High dose cyclosporin, co-administered with oral etoposide led to a increase in etoposide exposure (AUC) with a decrease in total body clearance of etoposide, compared to etoposide alone.
Concomitant cisplatin therapy is associated with reduced total body clearance of etoposide.
Phenylbutazone, sodium salicylate and aspirin at concentrations achieved in vivo displace protein-bound etoposide.
Acute leukaemia, which can occur with or without a preleukaemic phase, has been reported in patients treated with ETOPOPHOS in association with other antineoplastic agents.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Overdosage of etoposide is accompanied by severe myelosuppression and severe nausea and vomiting.
No proven antidotes have been established for ETOPOPHOS overdosage.
Total dose of 2,4g/m² to 3,5g/m² administered intravenously over 3days have resulted in severe mucositis and myelotoxicity. Metabolic acidosis and cases of serious hepatic toxicity have been reported in patients receiving higher than recommended doses of etoposide.

IDENTIFICATION
Injection Sterile Powder: White to off-white lyophilised solid in a clear glass vial.
Reconstituted product: Clear and colourless, free from visible evidence of contamination.

PRESENTATION
Injection: Single dose glass vials packed in cartons.

STORAGE INSTRUCTIONS
Powder for injection:
Store under refrigeration (2-8°C). Protect from light.
Reconstituted Solution:
When reconstituted and/or diluted as directed ETOPOPHOS solutions are chemically and physically stable for 24hours at 25°C and 7days under refrigeration (2-8°C) under normal fluorescent light in both glass and plastic containers.
Any unused portion must be discarded.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
100mg Vials: 31/26/158

NAME AND BUSINESS ADDRESS OF APPLICANT
Bristol-Myers Squibb (Pty) Ltd *
47 Van Buuren Road
BEDFORDVIEW
2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
May 2002

Updated on this site: June 2005
Source: Pharmaceutical Industry