SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Adjusan 140 mg/g Periodontal gel

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 g of periodontal gel contains 140 mg of doxycycline equivalent to 161.5 mg doxycycline hyclate.

1 pre-filled cylinder cartridge with 260 mg periodontal gel contains 36.40 mg doxycycline.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Periodontal gel in a pre-filled cylinder cartridge.

Non-transparent yellow gel.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of chronic and aggressive periodontitis with a pocket depth of >5mm in adults as an adjunct to conventional non-surgical treatment of periodontitis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

The dosage of Adjusan varies depending on the size, shape and depth of the periodontal pockets.

Paediatric population

Adjusan is contraindicated in children and adolescents below 18 years of age (see section 4.3).

Method of administration For periodontal use.

Adjusan should only be administered by dental care professionals into periodontal pockets using a designated device (periodontal use).

The administration should be continued until excess gel appears at the gingival line, which shows the entire pocket is completely filled with the gel. Any excess gel can be removed using a paper tip or wetted cotton pellet.

Any mechanical tooth cleaning other than brushing the occlusal area of the teeth and the tongue should be avoided on any area treated with Adjusan for the following 7 days after treatment.

For detailed information on the handling of application of Adjusan, please refer to section 6.6.

4.3 Contraindications

Adjusan is contra-indicated:

-    hypersensitivity to the active substance doxycycline, to other tetracycline antibiotics or to any of the excipients listed in section 6.1.

-    in patients treated with systemic antibiotics before or during the treatment of periodontitis.

-    during pregnancy.

-    in children and adolescents by disorders of odontogenesis.

-    in patients at higher risk for development of acute porphyria.

-    in patients with severe hepatic impairment.

4.4 Special warnings and precautions for use

Treatment with tetracycline antibiotics is known to be potentially associated with light sensitivity and can result in hypersensitivity reactions following sun exposure of patients. The treatment should be discontinued in case of any apparent skin reactions, e.g. reddening of skin.

Precautions

Tetracycline antibiotics such as doxycycline should be used with caution in patients with hepatic impairment and in patients treated with hepatotoxic drugs.

In patients with renal impairment, accumulation of tetracycline antibiotics can occur, which may lead to hepatic toxicity. It appears unlikely that these effects occur following treatment with Adjusan, since the doxycycline plasma concentration was found to be very low following treatment with Adjusan.

In patients with a previous history of candida infection, treatment with doxycycline might increase the risk of oral candida infections. As with other antibiotics, the use of Adjusan may result in an increase of resistance of microorganisms (including fungi) to tetracyclines.

Tetracycline antibiotics can cause to a decreased prothrombin activity in plasma. Therefore, if patients are simultaneously treated with anticoagulants, a dose reduction of the anticoagulant may be necessary. Although this effect is unlikely to occur during the treatment with Adjusan due to the low plasma concentration of doxycycline, these patients need to be treated with special caution.

4.5 Interaction with other medicinal products and other forms of interaction

Since bacteriostatic drugs can interact with the bactericidal effect of beta-lactam antibiotics, simultaneous administration of doxycycline to patients receiving beta-lactam antibiotics is not recommended.

Simultaneous administration of tetracyclines and an anaesthesia with methoxyflurane can cause fatal kidney failure.

Doxycycline can increase the toxic effect of cyclosporine A.

The systemic exposure with doxycycline after treatment with Adjusan is very low. It appears unlikely that the above-mentioned systemic interactions occur, taken into consideration the low plasma concentration of doxycycline after administration of Adjusan.

4.6    Fertility, pregnancy and lactation

Pregnancy

There are no or limited data (less than 300 pregnancy outcomes) from the use of Adjusan in pregnant women.

Animal studies have shown that tetracyclines cross the placental barrier being detectable in the foetal tissue which might result in developmental toxicity which is often manifested as delayed osteogenesis.

Signs of embryotoxicity have been observed on animals treated with tetracyclines during early pregnancy.

The use of tetracyclines during odontogenesis can cause permanent discoloration of the teeth and defects of the dental enamel (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Adjusan during pregnancy.

Breastfeeding

Doxycycline is excreted in human milk. Adjusan should not be used during breast-feeding, as a risk to the suckling child cannot be excluded.

Fertility

There are no data on the possible effects of doxycycline on male or female fertility.

4.7    Effects on ability to drive and use machines

Adjusan has no influence on the ability to drive and use machines.

4.8    Undesirable effects

Frequencies of undesirable effects are defined as:

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)

Side effects reported in the clinical study:

Uncommon: Swelling of the gingiva and a chewing-gum like taste.

General disorders and administration site conditions - Hypersensitivity reactions

Unknown frequency: Urticaria, angioneurotic oedema, anaphylaxis, allergic purpura.

A complete cross-allergy exists within the group of tetracyclines.

Undesirable effects reported for orally taken doxycycline are not listed here.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Acute overdosing is not expected. If Adjusan has been overdosed, it should be removed from the periodontal pocket.

Acute toxicity of doxycycline is low, even after oral intake of multiples of the conventional dose for systemic treatment. In cases of accidental overdose, gastrointestinal absorption can be prevented by administration of antacids or magnesium or calcium containing salts which results in formation of nonabsorbable chelate complexes. If necessary, other general supportive measures should be undertaken. Doxycycline is not dialyzable.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antiinfectives and antiseptics for local oral treatment, doxycycline ATC code: A01AB22

Doxycycline is a semi-synthetic broad-spectrum tetracycline antibiotic. The bacteriostatic action of doxycycline is based on the inhibition of the ribosomal protein synthesis.

In a double blind randomised multicentre study employing a split-mouth design adult patients with untreated and recurrent moderate to severe periodontal disease were evaluated 3 and 6 months following a single treatment with scaling/root planing (SRP) with doxycycline gel (doxycycline group), SRP with placebo gel (placebo gel group) or with scaling/root planing alone (control or reference group). Three different treatment modalities were assigned randomly to 3 test teeth. The main parameter of the therapeutic effect was the change of relative vertical probing attachment level (RAL-V) between the control group and the doxycycline group. A difference of 0.5mm in RAL-V gain between the doxycycline and the control was considered as being clinically relevant. Probing pocket depths and microbiological parameters were considered as secondary endpoints.

Treatment results (ITT population)

	relative vertical probing attachment level in mm		pocket depth reduction in mm
Treatment groups	3 months (n=110)	6 months (n=108)	3 months (n=110)	6 months (n=108)
SRP+doxycycline gel	2.0 ± 1.6	2.0 ± 1.7	-2.9 ± 1.3	-3.1 ± 1.2
SRP+placebo gel	1.7 ± 1.9	1.6 ± 2.2	-2.6 ± 1.5	-2.7 ± 1.6
SRP control	1.8 ± 1.7	1.6 ± 1.9	-2.5 ± 1.6	-2.4 ± 1.4
	Statistical evaluation (ANOVA for repeat analysis		according to Huynh & Feldt)
SRP vs. SRP+doxycycline gel	p = 0.21	p = 0.027	p = 0.006	p = 0.0001
Placebo vs. SRP+doxycycline gel	p = 0.15	p = 0.038	p = 0.085	p = 0.0066

n = number of subjects SRP = scaling/root planing

The pivotal study has shown that a single treatment of patients with periodontal diseases with Adjusan lowered the levels of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola in subgingival plaque. The levels were lowered in all test groups from baseline to month 3, only minor changes were observed thereafter.

Resistance mechanisms

A resistance against doxycycline can be based on the following mechanisms:

-    In most cases the resistance is based on the existence of efflux pumps, which actively transport tetracyclines from the cell.

-    As further mechanism ribosomal protective proteins are described, which inhibit the connection of doxycycline and the ribosome.

-    A rare mechanism is the enzymatic inactivation of doxycycline.

A cross-resistance between doxycycline and other tetracyclines exists. Tetracycline-intermediate/resistant strains can be sensitive to doxycycline.

For suspected periodontal pathogens the reported in vitro MIC₉₀-levels for doxycycline vary between 1 - 6pg/ml. The highest in vitro MIC₉₀-levels are 32pg/ml. In vivo the doxycycline levels are initially about 60 times higher than the highest reported levels, and 8 days post treatment they are still about 4 times higher than these levels.

MIC90-levels for periodontically pathogene germs:
Aggregatibacter actinomycetemcomitans Tannerella forsythia	MIC90 6pg/ml MIC90 <6pg/ml

Campylobacter rectus	MIC90 1pg/ml
Eikenella corrodens	MIC90 6pg/ml
Fusobacterium nucleatum	MIC90 2pg/ml
Porphryomonas gingivalis	MIC90 1pg/ml
Prevotella intermedia	MIC90 3pg/ml

The major therapeutic effect of the treatment of periodontal disease with doxycycline is based on the antibacterial effect. However, doxycycline is thought to also exert additional effects which might contribute to the clinical improvement. Amongst these effects the collagenase inhibiting effects, which appears most pronounced on the collagenase of granulocytes, the antiinflammatory effect and the inhibition of bone resorption are thought to be of relevance. These effects are considered to improve the course of periodontal disease.

5.2 Pharmacokinetic properties

Concentration levels of doxycycline in gingival crevicular fluid (GCF), saliva and serum have been determined after administration of Adjusan to 20 patients.

The results of these studies can be summarised as follows: Within the first 5 hours after administration, the concentrations of doxycycline in GCF (maximum after 15 min: 19.97 ± 5.85mg/ml) and saliva (maximum after 15 min: 17.83 ± 2.84mg/ml) were similar. The concentration of doxycycline in saliva subsequently decreased (28.90 ± 19.44pg/ml after 3 days) compared to the concentrations in GCF (577.41 ± 127.34pg/ml after 3 days).

After subgingival administration of Adjusan, mean doxycycline levels in GCF exceeded 16pg/ml these levels being maintained for at least 12 days.

Doxycycline levels in serum were below the quantitation limit (50ng/ml).

5.3 Preclinical safety data

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use, especially taking into account the route of administration and the administered dose of Adjusan.

An 18-month study conducted in rats did not reveal evidence for a tumorigenic potential of doxycycline.

Teratogenicity studies performed in different species (rats, mice, monkeys, rabbits) did not demonstrate any congenital malformations. In foetuses, discoloration of teeth, defects on dental enamel and retardation of osteogenesis have been observed from the 4^th month on.

Doxycycline and partially the excipient polyethyleneglycol-DL-lactide/glycolide copolymer are gradually eluted from the gel. The other excipients degrade by glycolysis thus forming end products of established safety such as ethylene glycol, Glycolic acid and Lactic acid.

6.1    List of excipients

Polyglycolide

Macrogol -DL-lactide/glycolide copolymer (high viscosity)

Macrogol DL-lactide/glycolide copolymer (low viscosity)

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years

After first opening of the laminated bag: Use immediately.

6.4    Special precautions for storage

Store the cylinder cartridge in a refrigerator (2 - 8°C) in the original unopened laminated bag.

6.5    Nature and contents of container

Pre-filled cylinder cartridge consisting of a polyamide cylinder, LDPE plunger and Ethylene-vinylacetate-copolymer cap. The cartridge is packed in a heat sealed aluminium foil including a small bag with silica gel as desiccant.

Pack sizes: 2, 4, 8, 10 or 16 pre-filled cartridges each with 260mg periodontal gel.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Adjusan is to be administered exclusively using the prefilled cylinder cartridge with Adjusan in connection with the cartridge gun. A pre-filled cylinder cartridge is only for single use.

a.    Remove the laminated bag from the refrigerator 20 minutes prior to the start of treatment. Let the laminated bag closed for proper adaption to room temperature and to avoid moisture by condensation of water.

Open the sealed laminated bag directly before use and remove the cylinder cartridge which contains the Adjusan.

Do not use Adjusan if the laminated bag is damaged.

b.    Insert the cylinder cartridge into the cartridge gun and remove the closure from the tip of the cartridge nozzle.

c.    Operate the handle of the cartridge gun until Adjusan is extruded from the tip of the cartridge nozzle.

d.    The product is now ready for administration.

e.    Clean and dry the periodontal pocket as usual.

f.    Gently insert the tip of the cartridge nozzle into the periodontal pocket. Place the tip of the cartridge nozzle at the basis of the pocket and operate the handle of the cartridge gun to extrude the gel. Slowly remove the tip of the cartridge nozzle from the periodontal pocket whilst continuously extruding the gel.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Heraeus Kulzer GmbH Gruner Weg 11 63450 Hanau Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL 39635/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/07/2013

10    DATE OF REVISION OF THE TEXT

03/07/2013