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VUMON

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

VUMON
For I.V. infusion.

COMPOSITION:
Each ampoule contains 50 mg teniposide, benzyl alcohol 150 mg as preservative and dehydrated ethanol 42,7% (v/v) per 5 mL.

PHARMACOLOGICAL CLASSIFICATION:
A26 Cytostatic agents.

PHARMACOLOGICAL ACTION:
VUMON (also known as VM-26) is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases. It is 4'-0-demethyl-1-0 (4,6-0-2 thenylidene-beta-D-glucopyranosyl) epipodophyllotoxin.
VUMON is a phase-specific cytotoxic drug, acting in the late S2 or G2 phase of the cell cycle by preventing cells from entering mitosis. VUMON also produces single-strand breaks in DNA. The mechanism of action appears to be due to inhibition of type II topoisomerases.
Cells resistant to etoposide were fully cross resistant to teniposide and vice versa in both in vivo and in vitro studies, although there have been occasional clinical reports suggesting a lack of complete cross-resistance.
Pharmacokinetics
The pharmacokinetics of teniposide appear to be linear over a range of doses. Accumulation does not occur after daily administration for 3 days. No major differences in the disposition of the agent in adults and children have been identified.
Following intravenous infusion, initial clearance from the central compartment is rapid with a distribution half-life of approximately 1 hour. Teniposide is highly protein bound, >99%, which may limit its distribution within the body. Levels of teniposide in CSF are low relative to simultaneously measured plasma levels. Mean terminal half-life has ranged from approximately 6 to 20 hours with renal clearance accounting for only about 10% of total clearance. While metabolic pathways for teniposide have not been characterised, agents such as phenobarbital and phenytoin that induce hepatic metabolism have been shown to increase the clearance of teniposide.

INDICATIONS:
VUMON is indicated in the following:
Malignant lymphomas
Hodgkin's disease
Relapsed and resistant acute lymphocytic leukaemia, as combination therapy in children and adults.
Intracranial malignant tumours; i.e. glioblastoma, ependymoma, astrocytoma.
Urinary bladder carcinoma.
Refractory neuroblastoma as single or combination therapy.

CONTRA-INDICATIONS:
VUMON should not be given to individuals who have demonstrated a previous hypersensitivity to teniposide or to any component of the formulation.
VUMON is contra-indicated in patients who have severe leukopenia or thrombocytopenia.
Pregnancy:
VUMON may cause foetal harm when administered to a pregnant women. Embryotoxic and teratogenic effects have been seen in pregnant rats given teniposide. No studies in pregnant women have been conducted.
Contra-indicated in lactation.

WARNINGS:
VUMON is a potent medicine and should be used only by physicians experienced with cancer chemotherapeutic medicines. Blood counts as well as renal and hepatic function tests must be done regularly. Discontinue the medicine if abnormal depression of bone marrow or abnormal renal or hepatic function is seen.
Life threatening anaphylactic reactions have occurred following teniposide administration.

DOSAGE AND DIRECTIONS FOR USE:
Monotherapy:
The following dosage schedules are recommended:
Malignant lymphomas and urinary bladder carcinoma:
Initial treatment:

a.	Cyclic regime consisting of 30 mg/m²/day for five consecutive days, and followed by a rest period of ten days (this constitutes one treatment cycle). Six to ten such treatment cycles are necessary. This dosage schedule was successful in cases of malignant lymphoma and urinary bladder carcinoma.
b.	Twice weekly administration at a dose of 40-50 mg/m² over a period of at least six to nine weeks. In patients with good bone marrow reserve this dose may be given carefully three times a week. This dosage schedule was successful in cases of malignant lymphomas.

Maintenance treatment:
A single dose of 150 mg of VUMON given every ten to fourteen days for a prolonged period of several months is indicated in order to maintain the remission, as shown in cases of malignant lymphomas.
Cerebral malignancy:
The following dosage schedule was successful in brain tumours:
A high single dose of 100-130 mg/m² is given once weekly.
One treatment course consists of six to eight such doses followed by a rest period of 14 days. Depending on the evolution, a total of six to nine treatment courses are recommended.
Hodgkin's disease:
A dose of 40 mg/m² of VUMON on the 1^st, 4^th, 8^th, 11^th and 14^th day of treatment, and then followed by a rest period of 14 days, has been shown to be safe and efficacious in combination with procarbazine and prednisone.
Relapsed and resistant acute lymphocytic leukaemia. The following dosage regimen has been used: Vumon 165 mg/m² in combination with cytarabine 300 mg/m² twice weekly for 8 doses.
Neuroblastoma in children:
130-180 mg/m² weekly.
Dosage should be adjusted according to individual patient variability and toxicity, when employed as a single agent or in combination with other antineoplastic agents.
Combination Therapy:
VUMON has been used in combination with several other approved chemotherapeutic agents. When it is used in combination with other myelosuppressive drugs, the dose should be appropriately reduced. Peripheral blood counts should be monitored and, if necessary, marrow evaluations performed regularly.

NOTE:
Patients with Down's Syndrome may be especially sensitive to myelosuppressive chemotherapy, therefore, dose modification may need to be considered in these patients.

METHOD OF ADMINISTRATION
Hard plastic devices made of ABS (a polymer composed of acronitrile, butadine and styrene) have been reported to decompose when exposed to N,N-dimethylacetamide, one of the solvents present in the VUMON formulation. This effect has not been reported for VUMON itself, or for diluted solutions of VUMON.
In order to prevent extraction of the plasticizer DEHP (di(2-ethylhexyl)phthalate) from polyvinyl chloride (PVC) containers, solutions of VUMON should be prepared in non-DEHP containing large volume parenteral containers such as glass or polyolefin containers. VUMON solutions should be administered with non-DEHP containing administration sets.
Immediately before administration, each 5 mL ampule of VUMON containing 50 mg of teniposide must be diluted with 50, 125, 250 or 500 mL of either 5 percent Dextrose Injection or 0.9 percent Sodium Chloride Injection. Such dilution provides final teniposide concentrations of 1, 0,4, 0,2 and 0,1 mg/mL, respectively. The diluted solution should then be administered by intravenous infusion over a minimum of thirty minutes. To reduce the possibility of hypotensive reactions, VUMON should not be administered by bolus injection or rapid infusion. Greatest care should be taken to ensure that the catheter tip remains in the vein during administration, to avoid extravasation and possible tissue irritation.
When diluted as recommended above, solutions that contain teniposide 0,1 mg, 0,2 mg or 0.4 mg/mL, are stable under normal fluorescent lighting for 24 hours in the recommended large volume glass or polyolefin parenteral containers. Refrigeration is not recommended. VUMON solutions prepared at a final teniposide concentration of 1 mg/mL, and stored at room temperature under normal fluorescent lighting are less stable, and should be administered within 4 hours of preparation to reduce the potential or precipitation.
NOTE:
This product may precipitate when diluted in any manner, with any diluent or to any concentration other than those described above. If evidence of precipitation does appear, the solution should not be administered. Likewise, precipitation has occurred when prolonged infusions of teniposide (24 hour) were administered through a variety of infusion devices. These infusions, and their delivery systems, should be inspected frequently during administration. Heparin solution can cause precipitation of teniposide, therefore, administration sets/tubing, etc., should be flushed thoroughly with 5% Dextrose Injection or 0.9% Sodium Chloride Injection, before and after administration of VUMON. Diluted VUMON solutions should be subjected to as little agitation as is necessary to prepare the solution, since excessive agitation can result in precipitation. No other drugs should be mixed with VUMON infusion.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Haematological Toxicity:
Myelosuppression is often dose-limiting, with leukopenia and thrombocytopenia occurring 7-14 days after VUMON (teniposide) treatment. Bone marrow recovery is usually complete within 2-3 weeks. Leukopenia is more frequent and more severe than thrombocytopenia.
Anemia also occurs and immune haemolytic anemia has been reported.
The occurrence of acute nonlymphocytic leukaemia has been reported in patients treated with VUMON in association with other antineoplastic agents.
Gastrointestinal Toxicity:
Nausea and vomiting are the major gastrointestinal toxicities. The nausea and vomiting can usually be controlled by antiemetic therapy. Stomatitis/mucositis, hepatic dysfunction, anorexia, diarrhoea and abdominal pain may occur.
Alopecia:
A high incidence of alopecia has been reported, especially in patients receiving multiple courses of therapy.
Hypersensitivity:
Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnoea and hypotension have been reported to occur during or immediately after VUMON (teniposide) administration. They may be due to the Cremophor EL component of the vehicle or to teniposide itself. These reactions may occur on the first dose and may occur more commonly in patients with brain tumors or in patients with neuroblastoma. The risk of having a reaction may be related to repeated exposure and cumulative dose. These reactions have usually responded promptly to cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines or volume expanders as appropriate. Flushing, sweating, hypertension and oedema have also been reported.
Dermatologic
Urticaria, with or without pruritus have been reported.
Neurotoxicity:
Neurotoxicity has been reported including severe cases of neuropathy in patients due to an interaction of vincristine sulphate and VUMON (teniposide). Central nervous system depression has been observed in patients receiving higher than recommended doses.
Hypotension:
Transient hypotension may occur following rapid intravenous administration of VUMON (see Preparation and Administration). Sudden death due to probable arrhythmia and hypotension has been reported.
Other toxicities:
The following reactions have been rarely reported:
Headache and confusion, infection, renal dysfunction, hypertension, asthenia.
Urinary bladder irritation has occasionally been observed, but only in patients with an infiltrative form of bladder carcinoma where the drug was administered intravesically.

PRECAUTIONS:
VUMON (teniposide) should be administered with care to patients with marrow involvement by tumour and to patients with impaired renal or hepatic function.
Regular monitoring of white blood cell and platelet counts should be performed during treatment with VUMON (teniposide). If white blood cell count is below 2000 cell/mm³ or platelets below 75,000 cell/mm³, unless caused by malignant disease, treatment should be postponed until bone marrow recovery is complete.
Care should be taken to ensure that VUMON (teniposide) infusions are given intravenously with indwelling catheter in proper position prior to infusion as extravasation, necrosis and/or thrombophlebitis may result with improper administration.
Instances of hypotension have been reported during VUMON (teniposide) infusion. Therefore, vital signs should be monitored during the first 30 minutes.
Paediatrics:
Benzyl alcohol has been associated with toxicity in newborns. A syndrome characterized by gasping respirations, kernicterus, metabolic acidosis, neurologic deterioration, hematologic abnormalities and death have been reported to occur following administration of benzyl alcohol containing flush solutions to low birth weight, preterm infants.
Acute central nervous system depression and hypotension have been observed in patients who were receiving higher than recommended doses of VUMON, and who were also pre-treated with antiemetic medicines.
VUMON should not be given intra-arterially, intrapleural or intraperitonially.
Interactions:
Anticonvulsants such as phenobarbital and phenytoin increase the clearance rate of teniposide resulting in lower systemic exposure for a given teniposide dose. Increased doses may be required in patients receiving anticonvulsant therapy.
Tolbutamide, sodium salicylate and sulfamethiazole have been shown in vitro to displace teniposide from plasma proteins. Because of extremely high binding of teniposide to proteins, small decreases in binding could result in substantial increases in free drug with associated increased drug effect and toxicity.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Overdosage:
No proven antidotes have been established for VUMON (teniposide) overdosage.

IDENTIFICATION:
Clear glass ampoule with a clear, slightly yellow to yellow liquid.

PRESENTATION:
Ampoules: 50 mg/5 mL in single packs.

STORAGE INSTRUCTIONS:
When stored at temperature not exceeding (25°C), VUMON packaged in flint glass ampoules will remain stable until expiration date indicated on package.
Keep out of reach of children.
See "Method of administration" for stability of diluted product.

REGISTRATION NUMBER:
H/26/141

APPLICANT:
BRISTOL-MYERS SQUIBB (PTY) LTD*
47 Van Buuren Road
BEDFORDVIEW
2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
June 1994

* Authorised user of the ^®VUMON

New addition to this site: June 2005
Source: Pharmaceutical Industry
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