Arestin
1. NAME OF THE MEDICINAL PRODUCT
Arestin 1 mg periodontal powder
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 single-dose container contains:
1 mg minocycline as minocycline hydrochloride.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL form
Periodontal powder.
Yellow powder in single-dose containers.
4. Clinical particulars
4.1 Therapeutic indications
Arestin periodontal powder is indicated for the local treatment of chronic periodontitis in adults when pocket depths are 5mm. Arestin should always be used as an adjunctive to conventional non-surgical treatment.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
Only professional health care personnel who are experienced in the management of periodontal disease should administer Arestin.
Posology
Adults
The first treatment with Arestin should be administered as soon as possible after conventional non-surgical treatment (scaling and root planing). Only one single-dose container of 1 mg of Arestin periodontal powder should be administered to each pocket identified for treatment. The total dose varies with the total number of pockets, maximal dose administration being 140 mg.
Up to two further treatments may be given with an interval of three months between applications.
The product may be less effective in smokers.
Paediatric population
The safety and efficacy of Arestin in children less than 18 years of age has not been established. Arestin is contraindicated in children less than 12 years of age (see section 4.3).
Method of administration
Subgingival use only.
Subgingival application of Arestinis done by placing the top of the container, which contains the 1-mg unit dose, at the bottom of the periodontal pocket and then pressing the thumb ring in the dispenser to push out the powder, while the top of the container slowly is pulled out of the pocket.
For further information regarding administration of the medicinal product, see section 6.6.
After treatment patients should postpone brushing for a 12 hour period and should be advised to avoid eating hard, crunchy, sticky foods for one week as well as avoid touching treated areas. Patients should also postpone the use of interproximal cleaning devices in areas treated with Arestin for 10 days after administration of Arestin.
Arestin does not have to be removed after treatment, as it is bioresorbable. It is not necessary to apply adhesive or a dressing to keep the product in the pocket.
4.3 Contraindications
- Hypersensitivity to the active substance, other tetracyclines, or to any of the excipients listed in section 6.1.
- Children less than 12 years of age.
- Pregnant and lactating women.
- Patients who have severely impaired liver function.
- Acute or chronic end stage renal failure.
4.4 Special warnings and precautions for use
Mild to moderate sensitivity to the teeth is normal during the first week after scaling and root planing and administration of Arestin. However, patients should be advised that they should notify the dentist promptly if pain, swelling or other problems occur.
In addition, there is a potential for local manifestation of hypersensitivity reactions to occur. Patients should be notified to inform the dentist urgently if itching, swelling, papules, reddening or other signs and symptoms of possible hypersensitivity occur.
As no dose response curve has been evaluated only one dose per pocket can be administered.
Warnings:
Antibiotics of the tetracycline class are known to cause photosensitivity reactions to the sun.
The possibility of photosensitivity reactions cannot be ruled out during the short period after administration when detectable blood levels of minocycline can occur.
The treatment should be discontinued immediately at the first cutaneous erythema.
Special precautions:
The insertion of Arestin in periodontal pockets affected by acute abscess formation has not been studied and therefore is not recommended.
Although systemic exposure to minocycline is low after administration of Arestininto periodontal pockets, patients with severe hepatic impairment or renal failure should not be treated (see section 4.3). Arestinshould be used with caution in patients treated with drugs that are toxic to the liver.
As for other tetracylines, there is demonstrable antagonism in vitro between minocycline and either beta-.lactam or aminoglycoside antibacterial agents. However the clinical relevance of these findings, especially when minocycline is inserted directly into periodontal pockets, is unclear. Nevertheless, the possibility of such an interaction should be taken into account if Arestinis to be administered to patients who require prophylaxis against endocarditis before dental treatments.
In patients with earlier occurrence of candidainfections minocycline may increase the risk of oral candidainfection.
As with other antibiotics the use of this drug may result in superinfection of resistant microorganisms, including candida.
Because tetracyclines may decrease the plasma prothrombin activity patients treated with anticoagulants may need adjustment to a lower dose of anticoagulant drugs. Even if this effect is unlikely with the use of Arestin because of the low plasma concentration of minocycline, caution is advised.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
Considering the very low blood levels of minocycline observed after Arestinadministration, well-known interactions occurring through systemic administration are unlikely to occur with this local use.
However, although plasma levels of minocycline or low and detectable levels persist for only a few days after treatment with Arestin, there is a risk that plasma prothrombin activity may decrease so that patients treated with anticoagulants may need a temporary reduction in dose.
4.6 Fertility, pregnancy and lactation
Minocycline is suspected to cause severe congenital malformations when administered during pregnancy (see section 5.3). Arestin is contraindicated during pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception during and up to three weeks following administration of Arestin.
Arestin is excreted in human milk, and so administration is contraindicated during breast-feeding (see section 4.3).
4.7 Effects on ability to drive and use machines
It is not expected that Arestin would interfere with the ability to drive or operate machinery.
Undesirable effects
Adverse reactions that are associated with systemic administration of minocycline are thought to be less likely to occur following subgingival applications due to the low and short- lived plasma levels. However, the possibility of such reactions occurring should be borne in mind. The following reactions were observed in clinical trial in which all treatments were administered at months 0, 3 and 6 to 923 adults. Adverse drug reactions from spontaneous reports during the worldwide post marketing experience with Arestinthat meet threshold criteria are also included (as frequency unknown) below.
The adverse drug reactions are ranked by frequency, using the following convention.
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)
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Common (≥1/100 to 1/10) |
Not known (cannot be estimated from the available data) |
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Infections and infestations |
Infection |
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Immune system disorders |
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Hypersensitivity reactions |
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Nervous system disorders |
Headache |
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Gastrointestinal disorders |
Dyspepsia, gingivitis, stomatitis, pharyngitis, periodontitis ulcers in the mouth, toothache, transient shooting pain in the oral cavity |
Gingival swelling |
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Skin and subcutaneous tissue disorders |
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Angioneurotic oedema (e.g. swelling face), urticaria, rash |
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General disorders and administration site conditions |
Flu-like symptoms, pain |
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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 national reporting system.
4.9 Overdose
Due to the mode of application of Arestin, overdose is not likely to occur.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Minocycline.
ATC code:A01AB23.
Mechanism of action
Minocycline is an antibacterial agent of the tetracycline class that inhibits bacterial protein synthesis by binding to bacterial ribosomes and preventing the access of aminoacyl tRNA to the receptor site on the mRNA ribosome complex.
It is possible that minocycline also exerts an anti-collagenase effect when applied to periodontal pockets.
Susceptibility
The following species are often implicated in the causation and exacerbation of periodontal disease and are susceptible to minocycline in the absence of acquired mechanisms of drug resistance:
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P. gingivalis |
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P. intermedius |
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Capnocytophaga sp. |
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E. corrodens |
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F. nucleatum |
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A.actinomycetemcomitans |
Resistance
Resistance to minocycline is most commonly mediated by efflux mechanisms or by ribosomal changes (target modification), included those encoded by the genes TetA-D and TetK (the commonest acquired genes encoding drug efflux mechanisms) and TetM (ribosomal modification). More recently tetracycline inactivation has been described by Bacteroides spp., encoded by TetX.
5.2 Pharmacokinetic properties
Following subgingival application of Arestin after scaling and root planing, minocycline is released into the gingival crevicular fluid where detectable drug concentrations persist for at least 14 days. Peak concentrations of minocycline in saliva after application of Arestinare approximately 1000-fold those in the blood.
The mean maximal serum and saliva concentrations after subgingival administration are 0.00488 and 5.55 µg/mL per 1mg unit dose respectively. Tmaxis 4.83 and 0.748 h respectively. The half-lives are 23.8 and 44.7 h in serum and saliva respectively.
After 14 days the serum values are not detectable.
Minocycline is metabolised in the liver. Both unchanged minocycline and three microbiologically inactive metabolites have been found in urine and faeces after oral administration.
5.3 Preclinical safety data
In repeated dose toxicology studies minocycline caused miscoloration of bones, teeth and thyroid gland as well as hyperplasia and tumors in thyroid glands. At repeated dosing in monkeys nystagmus and changes in the hair cells of the ear were observed. These findings are not considered to be of relevance for humans at single administrations, based on systemic exposure, however the clinical relevance during long-time treatment is unknown.
In reproduction toxicological studies minocycline treatment administered by the oral route resulted (at 100 mg/kg resulted in embryonal death and skeletal defects in foetuses mostly related to retarded ossification.
Conventional genotoxicity studies showed no mutagenic or clastogenic effects.
Fertility studies have provided evidence that minocycline impairs fertility in rats.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Poly (D,L-lactide-co-glycolide)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
Shelf life after first opening of the pouch: 1month after opening and resealing the pouch after use.
6.4 Special precautions for storage
Do not store above 25C.
Nature and contents of container
4, 12 and 24 single dose polypropylene containers, with polycarbonate stopper and polypropylene tip cap.
The packages consists of 1 blister card including 4 or 12 single-dose containers, or 2 blister cards each including 12 single-dose containers.
The blister cards are included in a re-sealable aluminium foil pouch and a desiccant.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Put one single dose container containing powder into the dispenser (provided separately) and twist the single-dose container until it engages (clicks). Remove the protective tip cap.
Subgingival administration: Place the tip of the single-dose container into the base of the periodontal pocket. Press the dispenser thumb ring to push the powder out while, simultaneously, withdrawing the single-dose container tip from the pocket.
When finished, pull back the thumb ring to separate the single-dose container from the dispenser.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
[To be completed nationally]
10. DATE OF REVISION OF THE TEXT
2015-11-19