INFORMATION FOR HEALTH PROFESSIONALS
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ORASCREEN™ Oral Cancer Diagnostic System is a screening test, comprising of a three component diagnostic kit presented in the form of oromucosal rinses:
Pre-rinse Solution: Acetic acid 1%w/w
Active Dye Rinse Solution: Toluidine Blue O 1%w/w
Post-rinse Solution: Acetic acid 1%w/w
All three solutions are contained in amber polyethylene terephthalate (PET) single use vials of nominal capacity 30 ml single use aluminium tamper evident pull-off metal caps incorporating a pulp and vinyl liner. The Pre-rinse and Post-rinse solutions are presented in 30ml quantities, and the Toluidine Blue O active dye rinse solution in a 10ml quantity.
The product, a screening test, is a diagnostic kit, indicated as an adjunct to complete clinical examination, and biopsy in the diagnosis and monitoring of malignant lesions of the oral mucosa. In New Zealand, the product is limited to use by Dental Practitioners and Ear, Nose & Throat Surgeons.
The product is a stain, used as follows:
Pre-rinse - with a portion of OraScreen Pre-Rinse solution (Bottle 1) for 20 seconds and expectorate. This step can be repeated if required. Then rinse with water for 20 seconds, and expectorate.
Staining - rinse and gargle with entire contents (10ml) OraScreen Toluidine Blue O solution (Bottle 2) for 20 seconds, then expectorate.
Post-rinse - with a portion of OraScreen Post-Rinse solution (Bottle 3) for 20 seconds, expectorate, repeat with remaining Post-Rinse solution, followed by a final rinse with water.
Staining should only be carried out following a complete head and neck examination and a visual inspection of the oral cavity, and prior to any instrumentation of soft tissues.
The procedure must be repeated after 10-14 days in the case of an initial positively staining lesion. This period allows time for healing of any ulcerative or traumatic lesions, thus reducing the likelihood of false positives. A second positive stain mandates a biopsy.
The administration of OraScreen is contraindicated in the case of any patient with a known history of hypersensitivity to any of the ingredients. There is little justification for the use of the product in infants and children. Clinical judgement might contraindicate its use in the case of severe physical or mental handicap.
OraScreen is not intended to be used for screening in the general population. It is an adjunct to clinical examination in a group of patients at high risk of having malignant lesions or conditions of the oral mucosa. For example, those who are long term consumers of alcohol and/or tobacco.
The clinical studies have shown an overall false negative rate of about 6%, resulting in a sensitivity for the test method of about 94%.
During the early evaluation of the technique it was observed that a major potential source of false positives were benign lesions with areas of ulceration or inflammation. The level of false positives is minimised by repeating the test in 10-14 days in which time the inflammatory lesions should have healed. When following the treatment regimen currently recommended for OraScreen the false positive rate has been shown overall to be in the order of approximately 8%.
Removable prostheses must be removed prior to use of the product and any associated trauma or inflammation be given time to heal.
The product does not stain composite or resin restorations, porcelain crowns or dentures. Interactions with other medicaments is extremely unlikely.
The safety of OraScreen for use during pregnancy or lactation has not been established. Experimental animal studies are insufficient to assess the safety with respect to the development of the foetus, the course of gestation and peri and post-natal development. Thus the use of OraScreen during pregnancy and breast-feeding is not recommended.
The product is not likely to affect ability to drive or to use machinery.
There is no known allergy or any other reaction to the materials in the dye rinse solution. There is a possibility that local irritation of the mucosa may occur as a result of application of the dye solution and the tongue may be temporarily stained by the Toluidine Blue O. Toluidine Blue O has been reported to cause degranulaton of rat mast cells in vitro at a minimum concentration of 5µg/ml. The significance of these in vitro results is not clear, but it is unlikely that this blood level would be reached in man after use of the dye rinse solution by the recommended rinsing method. However, the potential risk for locally released histamine resulting in oedema in the oral cavity can not be excluded in patients with inflammatory lesions (lichen planus, gingivitis, pulpitis and periapical inflammation).
The pre- and post-rinse solutions contain sodium benzoate which may cause hypersensitivity reactions including respiratory reactions especially in those patients susceptible to aspirin-induced asthma, urticarial reactions (both immunological and non-immunological), erythema multiforme and anaphylaxis.
If OraScreen is accidentally swallowed, the urine and/or stools may be coloured temporarily blue-green or blue colour respectively.
The product contains a dye. The patient should be draped prior to staining to protect clothing and environmental surfaces that cannot easily be cleaned should be covered or removed. Stain removal is facilitated by using a dilute solution of acetic acid (1%) or the pre or post-rinse solution.
There have been no reported incidences of overdosage.
A dose of 100mg/kg has been administered in a single dose animal toxicity study with a 14 day observation period. No pharmacotoxicological signs were observed.
Information on repeated oral ingestion of up to 5mg/kg/day in animals has produced minimal side effects. Accidental ingestion of the entire contents of the pack would result in a single oral dose of 1.4mg/kg in a 70kg adult. On the basis of this, only usual medical surveillance is necessary following such an incident.
Toluidine Blue is a cationic metachromic dye which selectively binds to the free anionic groups such as sulphate, phosphate and carboxylate radicals of large molecules. It is used as an in vitro nuclear stain, binding the phosphate groups of nucleic acids.
In vivo, malignant lesions stain a brilliant deep dark blue. The precise mechanism of action of the stain has not been fully elucidated, however an accumulation of the dye between tumour cells has been reported, thus the stain penetrates the enlarged intercellular spaces which are a feature of carcinomatous epithelium. The stain is of limited duration (2-4 hours) indicating that there is no permanent binding to any cellular component.
The pre-stain rinse acts as an astringent and the post-stain rinse acts as a decolouriser to enhance the visual differentiation of normal and malignant epithelium.
The pharmacokinetics of the stain following application are not known. It is assumed that the dye desorbs and diffuses out of the interstices with time and is then swallowed. The amount involved, however, is extremely small, of the order of 6mg per test, based on dye retention studies.
Animal data supports the view that Toluidine Blue O, used at a concentration of 1%, in OraScreen is most unlikely to have significant local or systemic pharmacotoxicological activity in man. In the event of the accidental ingestion of a full container of OraScreen staining solution, by a patient, significant toxicity is unlikely to result.
Formal animal pharmacokinetic studies have not been performed using OraScreen and no literature reports have been located on the fate of Toluidine Blue O following oral administration in either animals or man. However, some experiments have been reported with Toluidine Blue O given intravenously in rats and rabbits. When given to rats, Toluidine Blue O concentrates to the highest degree in the parathyroid followed by the heart, pancreas, kidney, stomach, lungs, thyroid, muscle, liver and blood. In rabbits 80% of radio-labelled dye was metabolised within 5 minutes after intravenous injection and appeared in the plasma and urine in a colourless form. 74% of the radio label dye had been excreted in the urine and faeces within 24 hours, and 99% within 3 days. Approximately two-thirds of the dose was excreted in the urine and one-third in the faeces.
The Toluidine Blue O dye solution contains the following excipients: glacial acetic acid, sodium acetate (trihydrate or anhydrous form), ethyl alcohol, hydrogen peroxide solution, raspberry flavouring and purified water.
The 1% w/w acetic acid pre and post-rinse solutions contain glacial acetic acid, sodium benzoate, raspberry flavouring and purified water.
Not applicable.
The proposed shelf life in the packaging as proposed for marketing is 27 months. The product is not reconstituted prior to use and is intended for immediate single use only.
Store below 25°C, do not refrigerate.
All three solutions are contained in amber polyethylene terephthalate bottles of nominal capacity 30ml with single use aluminium peel-off metal caps. The caps have a pulp and vinyl liner. The pre- and post-rinse solutions are presented in 30ml quantities and the Toluidine Blue O dye rinse solution in 10ml quantities.
The patient should be instructed to avoid swallowing the material. Care should be taken to avoid splashing the material into the eyes. The patient should be draped to protect clothing, and positioned near a sink, as expectoration is required. Since the product is a stain, it is preferable to expectorate into a large cup, which can be disposed of in an infectious waste container after use, or pour the contents down the centre of the drain. Environmental surfaces that cannot be easily cleaned should be removed or covered. Should accidental spilling occur, or staining of the outer lip surface, a 1% acetic acid solution (bottles 1 and 3) may be used to help reduce the stain.
The bottles are opened using a tab and are to be used in numerical order. Four cups are included in the kit to be used separately for the pre-rinse solution, the Toluidine Blue O dye rinse solution, the post-rinse solution and the water.
The pre-rinse solution is astringent and will have the effect of removing excess saliva and producing a consistent oral environment. It is not necessary to rinse the mouth with water before use of the pre-rinse solution.
Prescription Medicine.
ORASCREEN™ Oral Cancer Diagnostic System:
Single unit diagnostic kit pack, containing three vials
Vial #1, Pre-rinse Solution: Acetic acid 1%w/w, 30ml
Vial #2, Active dye rinse solution: Toluidine Blue O 1%w/w, 10ml
Vial #3 Post-rinse Solution: Acetic acid 1%w/w, 30ml,
and three plastic cups, with instruction leaflet.
Stafford-Miller (NZ) Ltd
Unit F, Level 2, 9 Apollo Drive
Mairangi Bay
P O Box 100-490, North Shore Mailing Centre
AUCKLAND
Telephone: 0800 5000 90
March, 1999