ARESTIN MICROSPHERES

2 Recommended Dose and Dosage Adjustment The recommended dose is one cartridge of ARESTIN MICROSPHERES, containing 1 mg minocycline and 3 mg of polymer carrier, administered sub-gingivally, per periodontal pocket greater than or equal to 5 mm as soon as possible after SRP.

The total dose per patient varies with the number of pockets treated. The maximum number of pockets treated in one visit during the clinical trials was 122 (122 ARESTIN MICROSPHERES cartridges, 122 mg minocycline). The mean dose administered, per visit, was 31 mg.

In the two pivotal trials, probing depths were maintained for up to 9 months during which ARESTIN MICROSPHERES alone was reapplied twice; however, the trials did not provide evidence that reapplication of ARESTIN MICROSPHERES alone provided additional or incremental clinical benefit.

4 Administration ARESTIN MICROSPHERES is provided as a dry powder, packaged in a unit dose cartridge, which is inserted into a cartridge handle to administer the product. The oral healthcare professional removes the disposable dispenser from its pouch, removes a cartridge and connects it to the handle mechanism as shown in Figure 1 below.

Figure 1:

Removal of Cartridge from Package and Insertion onto Handle The administration of ARESTIN MICROSPHERES does not require local anaesthesia. Professional subgingival administration is accomplished by inserting the tip of the unit dose cartridge to the base of the periodontal pocket and then pressing the thumb ring in the handle mechanism to expel the powder while gradually withdrawing the tip from the base of the pocket.

The handle mechanism should be sterilized between patients. ARESTIN MICROSPHERES does not have to be removed, as it is bioresorbable, nor is an adhesive or dressing required. Patients should be cautioned about foods touching the site of ARESTIN MICROSPHERES insertion and the need to delay tooth brushing and cleaning following treatment (see 7 1a 1b 1c PrARESTIN® MICROSPHERES Minocycline Hydrochloride Microspheres Page 6 of 34 WARNINGS AND PRECAUTIONS).

1 Adverse Reaction Overview The most frequently reported non-dental treatment emergent adverse events irrespective of causation in pivotal clinical trials with ARESTIN MICROSPHERES, were headache, infection, flu syndrome and pain. The most frequently reported dental treatment-emergent adverse events which were reported in pivotal trials, irrespective of causation, were dental pain (toothache, pain associated with teeth and discomfort after dental procedures, periodontitis and gingivitis, tooth disorders (tooth fractures, problems with fillings and hot/cold sensitivity), tooth caries (root surface decay, recurrent decay, and dental caries), stomatitis, dental infections.

2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. Three major studies were conducted in 922 subjects to evaluate the safety and efficacy of ARESTIN MICROSPHERES.

At baseline all subjects received SRP and ARESTIN MICROSPHERES, vehicle, or nothing. ARESTIN MICROSPHERES or vehicle alone was re- administered twice during the 9-month observation period. Adverse events reported, irrespective of causation are presented in Table 2.

Table 2:

Incidence of Adverse Events Reported by ≥ 1% of ARESTIN MICROSPHERES Subjects. 4 Abnormal laboratory findings: Hematologic, clinical chemistry and other quantitative data No clinical laboratory safety evaluations were performed in the three Phase 3 studies.

5 Post-Market Adverse Reactions The following adverse reactions have been identified during post-approval use of ARESTIN MICROSPHERES. Because these events were reported voluntarily from a population of PrARESTIN® MICROSPHERES Minocycline Hydrochloride Microspheres Page 12 of 34 unknown size, frequencies cannot be estimated accurately.

). 5 OVERDOSAGE There have been no reports of overdosage with the use of ARESTIN MICROSPHERES and such risks are limited due primarily to the method and route of its administration. Overdose symptoms reported with oral use of minocycline hydrochloride include dizziness, nausea, vomiting, abdominal pain, intestinal haemorrhage, hypotension, lethargy, coma, acidosis, and azotemia without a concomitant rise in creatinine.

Treatment Dilute well with water or milk due to the possibility of esophageal ulceration. , calcium carbonate or lactate, milk of magnesia, aluminum hydroxide). Measures to reduce absorption such as induction of emesis or use of cathartic may be beneficial in certain cases.

For management of a suspected drug overdose, contact your regional poison control centre. 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING Table 1: Dosage Forms, Strengths, Composition and Packaging Description ARESTIN MICROSPHERES (minocycline hydrochloride) is a subgingival controlled-release product, containing the antibiotic minocycline hydrochloride incorporated into a bioresorbable polymer, poly (glycolide-co-dl-lactide) or PGLA, and it is intended for professional subgingival administration into periodontal pockets.

Each unit dose cartridge delivers microspheres in powder form and contains minocycline hydrochloride equivalent to 1 mg minocycline free base in 3 mg of polymer. ARESTIN MICROSPHERES is supplied in single dose cartridges equivalent to 1 mg (as minocycline base).

12 cartridges are packaged in one tray with desiccant in a heat-sealed foil laminate resealable pouch. Each cartridge contains 4 mg of powder made up of minocycline hydrochloride and poly (glycolide-co-DL-lactide), PGLA. There is one pouch (total of 12 units) or two pouches (total of 24 units) in each box.

Each unit dose cartridge contains the product Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients Subgingival Controlled-release microspheres, minocycline 1 mg as base Poly (glycolide-co-dl-lactide) PrARESTIN® MICROSPHERES Minocycline Hydrochloride Microspheres Page 7 of 34 identifier "OP-1".

• Patients who are hypersensitive to minocycline or tetracyclines or to any ingredient in the formulation or component of the container. For a complete listing, see the 6 DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.