LEDERMIX PASTE 1. NAME OF THE MEDICINAL PRODUCT Ledermix paste. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 g paste contains: 30.

21 mg demeclocycline calcium (equivalent to 30 mg demeclocycline hydrochloride) 10 mg triamcinolone acetonide. Excipients: 3 mg sodium sulphite anhydrous. For a complete list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Paste for use in tooth cavities Ledermix Paste is a greyish-yellow soft paste 4. CLINICAL PARTICULARS

4.1 Therapeutic indications Compound for dental use, prophylaxis or treatment of acute pulpitis and periodontitis. 4.2 Posology and method of administration A: Cases of pulpitis with exposure of the pulp Use of Ledermix paste. Practical procedure: 1st session: If after preparing a cavity and creating the extension and retention element the removal of the carious dentine close to the pulp has resulted in exposure of the pulp, carefully clean the cavity and pulp wound (3% hydrogen peroxide or physiological saline solution). Press out a small amount of Ledermix onto a small pellet of cotton wool or felt and apply to the exposed pulp. Close the cavity with zinc-oxide eugenol or another tightly sealing temporary cavity filling material. 2nd session: (two to three days later): Vitality test. Remove the temporary filling and pellet. Clean the cavity and pulp wound (3% hydrogen peroxide or physiological saline solution). Inspect the pulp wound. Local anaesthesia if required. Cap the exposed pulp. Then perform underfilling and final cavity filling in the same session. B: Cases of pulpitis with closed pulp cavity. Since exposure of the inflamed pulp will endanger its vitality, it should be avoided if possible by applying the principles of indirect capping. Then place the final filling. The same approach as for pulpitis prophylaxis is recommended for iatrogenic pulpitis. Important note Suppression of the inflammatory mechanism by the corticoid is associated with a temporary reduction in the connective tissue activity of the pulp. It should therefore be ensured in case of exposed pulp that the water-soluble preparation Ledermix paste does not remain in contact with the dental pulp for too long (see under A above). If the watersoluble preparation is left in place uncontrolled or the temporary filling is not leak-tight, there is a risk of pulp death.

C: Cases of periodontitis Both for primary acute periodontitis developing from total purulent pulpitis and for acute episodes of chronic periodontitis, prepare the canal as far as the apex in the first session (mechanical and chemical preparation: sodium hypochlorite, hydrogen peroxide), dry and fill with Ledermix paste using a spiral plugger (lentulo). In the second session (about 1 week later), rinse the Ledermix paste out of the canal (hydrogen peroxide) and complete the gangrene treatment using one of the recognised methods. For periodontitic irritations (especially following root canal widening) during the course of root treatment, introduce Ledermix paste into the cleaned root canal with rotating motion and leave in place for about 1 week. In the next session, remove Ledermix paste from the canal and after an inert temporary filling complete the root treatment. Dosage: The dosage depends on the type and scope of use. Use in children (from 3 years old) has not been sufficiently studied. For safety reasons the use of this product in this age group should only be considered after a very rigorous risk-benefit assessment since the known systemic actions of glucocorticoids and tetracyclines cannot be reliably ruled out. 4.3 Contraindications Known hypersensitivity to demeclocycline, triamcinolone acetonide, other corticoids or tetracyclines, sodium sulphite or one of the other ingredients, purulent pulpitis, root canal treatment of milk teeth. 4.4 Special warnings and precautions for use In rare cases sodium sulphite may induce severe allergies and bronchial cramps (bronchial spasms). Important note: The corticoid contained in the water-soluble Ledermix paste is released during the entire period of application. Due to the antiproliferative effect of all corticoids Ledermix paste may not be left on the open pulpa for a longer period (e.g. 2 - 3 days) to avoid possible pulpa necrosis; potential development of a chronic pulpitis must also be taken into account (the suppression of the inflammatory process by the use of a corticosteroid
may result in a temporary reduction of the resistance of the pulp to infection and a reducing healing capacity).

4.5

Interaction with other medicinal products and other forms of interaction Not known when applied correctly.

4.6

Pregnancy and lactation: Ledermix paste should not be used during pregnancy or lactation. Use of Triamcinolone is inadvisable in the first five months of pregnancy is particular, since animal experiments have revealed evidence of teratogenic effects, and no data have been collected on the safety of use in humans during this period. The possibility of intrauterine growth disorders cannot be excluded in long-term applications. Treatment at the end of pregnancy involves the risk of atrophy of the foetal adrenal cortex. Glucocorticoids pass into breast milk. Breast-feeding should be stopped if treatment with higher doses or a long-term therapy is required. Demeclocycline penetrates the placenta membrane and is excreted into breast milk. Due to the antianabolic effect and teratogenic effects including deposits in bones and teeth demeclocycline should, if possible, not be used during pregnancy and lactation.

4.7

Effects on ability to drive and use machines Not applicable.

4.8

Undesirable effects The following terminology is used in assessment of the frequency of adverse drug reactions (ADRs): very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to 1</100); rare (>1/10,000 to 1</1,000); very rare (<1/10,000); not known (cannot be estimated from the available data) Immune system disorders: Very rare cases of allergic reactions up to an anaphylactic shock may occur. Crossallergies with other tetracyclines are possible. Sodium sulphite may, in rare cases, induce severe allergies and bronchial cramps (bronchial spasms).

4.9

Overdose There were no reports of overdose. Overdoses are not to be expected because of the method of application and the very low absorption rate.

5. 5.1

PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Pharmacotherapeutic group: Fixed combination of antibiotic and corticoid for local oral use ATC code : A01AB13 and A01AC01 "Stomatological preparations / antiinfectives and antiseptics for local oral use / tetracylines (A01AB13)" and "Stomatological preparations / corticosteroids for local oral use / triamcinolone (A01AC01)". The active ingredients contained in Ledermix Paste are the potent anti-inflammatory corticoid triamcinolone acetonide in combination with the broad-spectrum antibiotic demeclocycline. Clinical effect: rapid relief of pain associated with acute inflammatory conditions of the pulp and periodontium. Demeclocycline is a broad-spectrum antibiotic of the tetracycline series and is effective against tetracycline-sensitive gram-positive and gram-negative pathogens as well as against clamydias, mycoplasma, spirochaetes and rickettsia. It is effective against both extracellular and intracellular pathogens. The mechanisms of action of this substance e is based on inhibition of the ribosomal protein synthesis in the bacteria. Triamcinolone acetonide is a fluorinated glucocorticoid with strong antiallergic, antiphlogistic and membrane stabilizing properties. In comparison with cortisol triamcinolone acetonide shows a 160-fold increase in glucocorticoid efficacy with a practically non-existent mineralocorticoid effect. Following local application on the skin, the following effects of glucocorticoids on dermal cell systems have been described: Inhibition of the proliferation of epidermis cells, reduced collagen synthesis, inhibited migration and proliferation of lymphocytes and granulocytes, stabilisation of mast cell membranes, vasoconstriction of cutaneous vessels, inhibited pigmentary development in melanocytes, Inhibition of proliferation of fat cells.

5.2

Pharmacokinetic properties In in-vitro studies on extracted teeth with radioactively marked tetracyclines resp. triamcinolone acetonide, both substances diffused in small quantities through root and crown dentine, depending on the number of dentine canals. Both substances were released in minimum concentrations (in the nMol range) over a period of days to weeks.

5.3

Preclinical safety data Toxicological properties Demeclocycline: Long-term studies with demeclocycline in animals revealed low-level toxic effect on haematology, blood chemistry and organ histopathology. Teratogenic effect have been found in both animal experiments and in humans. There is no evidence of mutagenic or carcinogenic effects. Triamcinolone acetonide: Studies of chronic toxicity were carried out on rats, dogs and monkeys. Depending on the dose, duration of the treatment and type of administration, and aside from some lethal outcomes, haemogram changes, disturbances of electrolyte balance, infections and liver changes were observed. The observed diminishment of the adrenal cortex and lymphatic tissue is directly associated with the glucocorticoid effect. In rats and dogs the above-mentioned phenomena were observed in addition to an influence on coagulation factors and a reduction of the amount of glycogen in the liver, heart and skeletal muscle. No studies were done on the mutagenic potential and no long-term animal studies of potential tumour induction are available. Existing study results for glucocorticoids do not indicate any clinically relevant genotoxic properties. The embryotoxic properties of triamcinolone acetonide have been studied in three rodent species (rat, mouse, hamster), in rabbits and in three non-human primate species (rhesus, baboon, capuchin). In the rodents and the rabbits, cleft palates and intrauterine growth disorders occurred, whereby teratogenic effects, e.g. in the rat, were triggered by doses in the human therapy range. A cartilage formation disorder in the chondrocranium was observed in the monkeys, leading to skull abnormalities (encephalocele) and facial dysmorphia. Deformities of the thymus and intrauterine growth disorders also occured. No experience is available on the safety of application in humans.

6. 6.1

PHARMACEUTICAL PARTICULARS List of excipients Triethanolamine, calcium chloride x 2 H2O, sodium sulphite anhydrous, Macrogol 400, Macrogol 3000, zinc oxide, sodium calcium edetate, colloidal silicon anhydrous; purified water.

6.2

Incompatibilities Not applicable

6.3

Shelf-life 2 years In-use shelf life after first opening of the tube is 2 months

6.4

Special precautions for storage Do not store above 25C!

6.5

Nature and contents of container Aluminium-tube containing 5g paste

6.6

Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product To prevent Ledermix paste from hardening at the tube opening, always keep the tip of the tube clean and close the tube carefully after each use. Variations in the colour of Ledermix paste have no influence on the efficacy of the product. If your patient experienced any of the side effects listed above, or any other side effect please report us: Neopharm LTD. email: drugsafety@neopharmisrael.com

7.

MANUFACTURER
RIEMSER Arzneimittel AG An der Wiek 7 D-17493 Greifswald - Insel Riems Federal Republic of Germany

8.

REGISTRATION HOLDER NEOPHARM LTD P.O. Box 7063 Petach Tiqva, 49170 Israel

The format of this leaflet has been defined by the MOH and its content has been checked and approved on March 2011.