Label: ARESTIN- minocycline hydrochloride powder

Mechanism of Action

The mechanism of action of ARESTIN as an adjunct to scaling and root planing procedures for reduction of pocket depth in patients with adult periodontitis is unknown.

Microbiology

Minocycline, a member of the tetracycline class of antibiotics, has a broad spectrum of activity. It is bacteriostatic and exerts its antimicrobial activity by inhibiting protein synthesis. In vitro susceptibility testing has shown that the organisms Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, Eikenella corrodens, and Actinobacillus actinomycetemcomitans, which are associated with periodontal disease, are susceptible to minocycline at concentrations of ≤8 mcg/mL; qualitative and quantitative changes in plaque microorganisms have not been demonstrated in subjects with periodontitis, using this product.

The emergence of minocycline-resistant bacteria in single-site plaque samples was studied in subjects before and after treatment with ARESTIN at 2 centers. There was a slight increase in the numbers of minocycline-resistant bacteria at the end of the 9-month study period; however, the number of subjects studied was small and the clinical significance of these findings is unknown.

The emergence of minocycline-resistant bacteria and changes in the presence of Candida albicans and Staphylococcus aureus in the gastrointestinal tract were studied in subjects treated with ARESTIN in one phase 3 study. No changes in the presence of minocycline-resistant bacteria or Candida albicans or Staphylococcus aureus were seen at the end of the 56-day study period.

Pharmacokinetics

In a pharmacokinetic study, 18 subjects (10 men and 8 women) with moderate to advanced chronic periodontitis were treated with a mean dose of 46.2 mg (25 to 112 unit doses) of ARESTIN. After fasting for at least 10 hours, subjects received subgingival application of ARESTIN (1 mg per treatment site) following scaling and root planing at a minimum of 30 sites on at least 8 teeth. Investigational drug was administered to all eligible sites ≥5 mm in probing depth. Mean dose normalized saliva AUC and Cmax were found to be approximately 125 and 1000 times higher than those of serum parameters, respectively.

Clinical Studies

In 2 well-controlled, multicenter, investigator-blind, vehicle-controlled, parallel-design studies (3 arms), 748 subjects (study OPI-103A=368, study OPI-103B=380) with generalized moderate to advanced adult periodontitis characterized by a mean probing depth of 5.90 and 5.81 mm, respectively, were enrolled. Subjects received 1 of 3 treatments: (1) scaling and root planing (SRP), (2) SRP + vehicle (bioresorbable polymer, PGLA), and (3) SRP + ARESTIN. To qualify for the study, subjects were required to have 4 teeth with periodontal pockets of 6 to 9 mm that bled on probing. However, treatment was administered to all sites with mean probing depths of 5 mm or greater. Subjects studied were in good general health. Subjects with poor glycemic control or active infectious diseases were excluded from the studies. Retreatment occurred at 3 and 6 months after initial treatment, and any new site with pocket depth ≥5 mm also received treatment. Subjects treated with ARESTIN were found to have statistically significantly reduced probing pocket depth compared with those treated with SRP alone or SRP + vehicle at 9 months after initial treatment, as shown in Table 1.

In these 2 studies, an average of 29.5 (5-114), 31.7 (4-137), and 31 (5-108) sites were treated at baseline in the SRP alone, SRP + vehicle, and SRP + ARESTIN groups, respectively. When these studies are combined, the mean pocket depth change at 9 months was -1.18 mm, -1.10 mm, and -1.42 mm for SRP alone, SRP + vehicle, and SRP + ARESTIN, respectively.

Table 2: Numbers (Percentage) of Pockets Showing a Change of Pocket Depth ≥2 mm at

SRP + ARESTIN resulted in a greater percentage of pockets showing a change of PD ≥2 mm and ≥3 mm compared to SRP alone at 9 months, as shown in Table 2.

*SRP vs SRP + ARESTIN P ≤0.05; **SRP vs SRP + ARESTIN P ≤ 0.001

In both studies, the following patient subgroups were prospectively analyzed: smokers, subjects over and under 50 years of age, and subjects with a previous history of cardiovascular disease. The results of the combined studies are presented in Table 3.

In smokers, the mean reduction in pocket depth at 9 months was less in all treatment groups than in nonsmokers, but the reduction in mean pocket depth at 9 months with SRP + ARESTIN was significantly greater than with SRP + vehicle or SRP alone.

Table 4: Mean Pocket Depth Change in Subjects with Mean Baseline

*Statistically significant comparison between SRP + ARESTIN and SRP alone

The combined data from these 2 studies also show that for pockets 5 mm to 7 mm at baseline, greater reductions in pocket depth occurred in pockets that were deeper at baseline.

Hypersensitivity Reactions and Hypersensitivity Syndrome

 

The following adverse events have been reported with minocycline products when taken orally. Hypersensitivity reactions and hypersensitivity syndrome that included, but were not limited to anaphylaxis, anaphylactoid reaction, angioneurotic edema, urticaria, rash, eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, and pericarditis may be present. Swelling of the face, pruritus, fever and lymphadenopathy have been reported with the use of ARESTIN. Some of these reactions were serious. Post-marketing cases of anaphylaxis and serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme have been reported with oral minocycline.

Autoimmune Syndromes

 

Tetracyclines, including oral minocycline, have been associated with the development of autoimmune syndromes including a lupus-like syndrome manifested by arthralgia, myalgia, rash, and swelling. Sporadic cases of serum sickness-like reaction have presented shortly after oral minocycline use, manifested by fever, rash, arthralgia, lymphadenopathy and malaise. In symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. No further treatment with ARESTIN should be administered to the patient.

The use of ARESTIN in an acutely abscessed periodontal pocket has not been studied and is not recommended.

While no overgrowth by opportunistic microorganisms, such as yeast, was noted during clinical studies, as with other antimicrobials, the use of ARESTIN may result in overgrowth of non-susceptible microorganisms including fungi. The effects of treatment for greater than 6 months have not been studied.

ARESTIN should be used with caution in patients having a history of predisposition to oral candidiasis. The safety and effectiveness of ARESTIN have not been established for the treatment of periodontitis in patients with coexistent oral candidiasis.

ARESTIN has not been clinically tested in immunocompromised patients (such as those immunocompromised by diabetes, chemotherapy, radiation therapy, or infection with HIV).

If superinfection is suspected, appropriate measures should be taken.

ARESTIN has not been clinically tested in pregnant women.

ARESTIN has not been clinically tested for use in the regeneration of alveolar bone, either in preparation for or in conjunction with the placement of endosseous (dental) implants or in the treatment of failing implants.

Information for Patients

After treatment, patients should avoid chewing hard, crunchy, or sticky foods (i.e., carrots, taffy, and gum) with the treated teeth for 1 week, as well as avoid touching treated areas. Patients should also postpone the use of interproximal cleaning devices around the treated sites for 10 days after administration of ARESTIN. Patients should be advised that although some mild to moderate sensitivity is expected during the first week after SRP and administration of ARESTIN, they should notify the dentist promptly if pain, swelling, or other problems occur. Patients should be notified to inform the dentist if itching, swelling, rash, papules, reddening, difficulty breathing, or other signs and symptoms of possible hypersensitivity occur.

Carcinogenicity, Mutagenicity, Impairment of Fertility

Dietary administration of minocycline in long-term tumorigenicity studies in rats resulted in evidence of thyroid tumor production. Minocycline has also been found to produce thyroid hyperplasia in rats and dogs. In addition, there has been evidence of oncogenic activity in rats in studies with a related antibiotic, oxytetracycline (i.e., adrenal and pituitary tumors). Minocycline demonstrated no potential to cause genetic toxicity in a battery of assays which included a bacterial reverse mutation assay (Ames test), an in vitro mammalian cell gene mutation test (L5178Y/TK+/- mouse lymphoma assay), an in vitro mammalian chromosome aberration test, and an in vivo micronucleus assay conducted in ICR mice.

Fertility and general reproduction studies have provided evidence that minocycline impairs fertility in male rats.

Pregnancy

Teratogenic Effects: (see WARNINGS).

Labor and Delivery

The effects of tetracyclines on labor and delivery are unknown.

Nursing Mothers

Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from the tetracyclines, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother (see WARNINGS).

Pediatric Use

Since adult periodontitis does not affect children, the safety and effectiveness of ARESTIN in pediatric patients cannot be established.

Postmarketing Experience

The following adverse reaction has been identified during postapproval use of minocycline products when taken orally. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: Acute febrile neutrophilic dermatosis (Sweet’s syndrome).

To report SUSPECTED ADVERSE REACTIONS, contact OraPharma at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Storage Conditions

Store at 20° to 25°C (68° to 77°F)/60% RH: excursions permitted to 15° to 30°C (59° to 86°F). Avoid exposure to excessive heat.