ARESTIN® Table 3: Mean Pocket Depth Changes (SE) in Subpopulations, Studies 103A and 103B
sites for 10 days after administration of ARESTIN®. Patients should be advised that
(minocycline hydrochloride) Microspheres, 1 mg
although some mild to moderate sensitivity is expected during the first week after SRP and
DESCRIPTION
administration of ARESTIN®, they should notify the dentist promptly if pain, swel ing, or
ARESTIN® (minocycline hydrochloride) Microspheres is a subgingival sustained-
other problems occur. Patients should be notified to inform the dentist if itching, swelling,
release product containing the antibiotic minocycline hydrochloride incorporated into a
rash, papules, reddening, difficulty breathing, or other signs and symptoms of possible
bioresorbable polymer, Poly (glycolide-co-dl-lactide) or PGLA, for professional
subgingival administration into periodontal pockets. Each unit-dose cartridge
Carcinogenicity, Mutagenicity, Impairment of Fertility
delivers minocycline hydrochloride equivalent to 1 mg of minocycline free base.
Dietary administration of minocycline in long-term tumorigenicity studies in rats
The molecular formula of minocycline hydrochloride is C
resulted in evidence of thyroid tumor production. Minocycline has also been
molecular weight is 493.94. The structural formula of minocycline hydrochloride is:
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
Teratogenic Effects: Pregnancy Category D. (See WARNINGS.) Labor and Delivery
The effects of tetracyclines on labor and delivery are unknown. CLINICAL PHARMACOLOGY Nursing Mothers Microbiology
SRP = scaling and root planing; YOA = years of age; CV = cardiovascular.
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
Minocycline, a member of the tetracycline class of antibiotics, has a broad
*SRP vs SRP + ARESTIN® P ≤0.05; **SRP vs SRP + ARESTIN® P ≤0.001.
whether to discontinue nursing or discontinue the drug, taking into account the
spectrum of activity.1 It is bacteriostatic and exerts its antimicrobial activity by
In both studies, the following patient subgroups were prospectively analyzed:
importance of the drug to the mother. (See WARNINGS.)
inhibiting protein synthesis.1 In vitro susceptibility testing has shown that the
smokers, patients over and under 50 years of age, and patients with a previous history
organisms Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium
of cardiovascular disease. The results of the combined studies are presented in Table
Pediatric Use nucleatum, Eikenella corrodens, and Actinobacillus actinomycetemcomitans,
3. In smokers, the mean reduction in pocket depth at 9 months was less
Since adult periodontitis does not affect children, the safety and effectiveness of
which are associated with periodontal disease, are susceptible to minocycline
in all treatment groups than in nonsmokers, but the reduction in mean pocket depth at
ARESTIN® in pediatric patients cannot be established.
at concentrations of ≤8 µg/mL2; qualitative and quantitative changes in plaque
9 months with SRP + ARESTIN® was significantly greater than with
ADVERSE REACTIONS
microorganisms have not been demonstrated in patients with periodontitis,
The most frequently reported nondental treatment-emergent adverse events in the
Table 4: Mean Pocket Depth Change in Patients With Mean Baseline
3 multicenter US trials were headache, infection, flu syndrome, and pain.
The emergence of minocycline-resistant bacteria in single-site plaque samples was
PD ≥5 mm, ≥6 mm, and ≥7 mm at 9 Months From 2 Multicenter
Table 5: Adverse Events (AEs) Reported in ≥3% of the Combined Clinical
studied in subjects before and after treatment with ARESTIN® at 2 centers. There was
Trial Population of 3 Multicenter US Trials by Treatment Group
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 C albicans or S aureus were seen at the
Pharmacokinetics
In a pharmacokinetic study, 18 patients (10 men and 8 women) with moderate to
advanced chronic periodontitis were treated with a mean dose of 46.2 mg (25 to
*Statistically significant comparison between SRP + ARESTIN® and SRP alone.
112 unit doses) of ARESTIN®. After fasting for at least 10 hours, patients received
The combined data from these 2 studies also show that for pockets 5 mm to 7 mm at
® (1 mg per treatment site) following scaling and
root planing at a minimum of 30 sites on at least 8 teeth. Investigational drug was
baseline, greater reductions in pocket depth occurred in pockets that were deeper at
administered to all eligible sites ≥5 mm in probing depth. Mean dose normalized saliva
INDICATIONS AND USE
max were found to be approximately 125 and 1000 times higher
than those of serum parameters, respectively.
ARESTIN® is indicated as an adjunct to scaling and root planing procedures for
Clinical Studies
reduction of pocket depth in patients with adult periodontitis. ARESTIN® may be
In 2 wel -control ed, multicenter, investigator-blind, vehicle-control ed, paral el-design
used as part of a periodontal maintenance program which includes good oral
studies (3 arms), 748 patients (study OPI-103A = 368, study OPI-103B = 380)
hygiene, and scaling and root planing.
with generalized moderate to advanced adult periodontitis characterized by a mean
CONTRAINDICATIONS
probing depth of 5.90 and 5.81 mm, respectively, were enrolled. Subjects received 1
ARESTIN® should not be used in any patient who has a known sensitivity
of 3 treatments: (1) scaling and root planing, (2) scaling and root planing + vehicle
(bioresorbable polymer, PGLA), and (3) scaling and root planing + ARESTIN®. To
WARNINGS
qualify for the study, patients were required to have 4 teeth with periodontal pockets of
THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH
The change in clinical attachment levels was similar across all study arms,
6 to 9 mm that bled on probing. However, treatment was administered to al sites with
DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY, AND CHILDHOOD TO THE AGE
suggesting that neither the vehicle nor ARESTIN® compromise clinical attachment.
mean probing depths of 5 mm or greater. Patients studied were in good
OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH
DOSAGE AND ADMINISTRATION
general health. Patients with poor glycemic control or active infectious diseases were
(YELLOW-GRAY BROWN). This adverse reaction is more common during long-term use
ARESTIN® is provided as a dry powder, packaged in a unit-dose cartridge, which is
excluded from the studies. Retreatment occurred at 3 and 6 months after initial
of the drugs, but has been observed following repeated short-term courses. Enamel
inserted into a cartridge handle to administer the product. The oral health care
treatment, and any new site with pocket depth ≥5 mm also received treatment.
hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT
professional removes the disposable cartridge from its pouch and connects the
Patients treated with ARESTIN® were found to have statistically significantly reduced
BE USED IN THIS AGE GROUP, OR IN PREGNANT OR NURSING WOMEN, UNLESS THE
cartridge to the handle mechanism (see Figures 1-3). ARESTIN® is a variable dose
probing pocket depth compared with those treated with SRP alone or SRP + vehicle at
POTENTIAL BENEFITS ARE CONSIDERED TO OUTWEIGH THE POTENTIAL RISKS.
product, dependent on the size, shape, and number of pockets being treated. In US
9 months after initial treatment, as shown in Table 1.
Results of animal studies indicate that tetracyclines cross the placenta, are found in
clinical trials, up to 122 unit-dose cartridges were used in a single visit and up to 3
Table 1: Probing Pocket Depth at Baseline and Change in Pocket Depth
fetal tissues, and can have toxic effects on the developing fetus (often related to
treatments, at 3-month intervals, were administered in pockets with pocket depth of
at 9 Months From 2 Multicenter US Clinical Trials
retardation of skeletal development). Evidence of embryotoxicity has also been noted in
animals treated early in pregnancy. If any tetracyclines are used during pregnancy, or if
the patient becomes pregnant while taking this drug, the patient should be apprised of
the potential hazard to the fetus. Photosensitivity manifested by an exaggerated
sunburn reaction has been observed in some individuals taking tetracyclines. Patients
apt to be exposed to direct sunlight or ultraviolet light should be advised that this
reaction can occur with tetracycline drugs, and treatment should be discontinued at the
PRECAUTIONS Hypersensitivity Reactions
The administration of ARESTIN® does not require local anesthesia. Professional
Hypersensitivity reactions that included, but were not limited to anaphylaxis,
subgingival administration is accomplished by inserting the unit-dose cartridge to the
angioneurotic edema, urticaria, rash, swelling of the face and pruritus have been
base of the periodontal pocket and then pressing the thumb ring in the handle
±0.07 ±0.54 ±0.07 ±0.07 ±0.07 ±0.07
reported with the use of ARESTIN®. Some of these reactions were serious.
mechanism to expel the powder while gradually withdrawing the tip from the base
Post-marketing cases of anaphylaxis and serious skin reactions such as Stevens-
of the pocket. The handle mechanism should be sterilized between patients.
SE = standard error; SRP = scaling and root planing; PD = pocket depth.
Johnson syndrome and erythema multiforme have been reported with oral minocycline.
ARESTIN® does not have to be removed, as it is bioresorbable, nor is an
Significantly different from SRP *(P ≤0.05); **(P ≤0.001).
Significantly different from SRP + vehicle
Autoimmune Syndromes
†(P ≤0.05); ††(P ≤0.001).
Tetracyclines, including oral minocycline, have been associated with the development
HOW SUPPLIED
In these 2 studies, an average of 29.5 (5-114), 31.7 (4-137), and 31 (5-108) sites
of autoimmune syndromes including a Lupus-like syndrome manifested by arthralgia,
ARESTIN® (minocycline hydrochloride) Microspheres, 1 mg is supplied as follows:
were treated at baseline in the SRP alone, SRP + vehicle, and SRP + ARESTIN®
myalgia, rash, and swelling. Sporadic cases of serum sickness have presented shortly
• 1 unit-dose cartridge with desiccant in a heat-sealed, foil-laminated pouch
groups, respectively. When these studies are combined, the mean pocket depth
after oral minocycline use, manifested by fever, rash, arthralgia, and malaise. In
change at 9 months was -1.18 mm, -1.10 mm, and -1.42 mm for SRP alone, SRP
symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests
• 12 unit-dose cartridges in 1 tray with desiccant in a heat-sealed, foil-laminated,
+ vehicle, and SRP + ARESTIN®, respectively.
should be performed to evaluate the patients. No further treatment with ARESTIN®
resealable pouch (NDC 65976-100-12). There is 1 pouch in each box.
Table 2: Numbers (percentage) of Pockets Showing a Change of Pocket
should be administered to the patient.
• 12 unit-dose cartridges in 1 tray with desiccant in a heat-sealed, foil-laminated,
Depth ≥2 mm at 9 Months From 2 Multicenter US Clinical Trials
The use of ARESTIN® in an acutely abscessed periodontal pocket has not been studied
resealable pouch (NDC 65976-100-24). There are 2 pouches in each box.
Each unit-dose cartridge contains the product identifier “OP-1.”
While no overgrowth by opportunistic microorganisms, such as yeast, were noted during
Storage Conditions
clinical studies, as with other antimicrobials, the use of ARESTIN® may result in
Store at 20° to 25°C (68° to 77°F)/60% RH: excursions permitted to 15° to 30°C
overgrowth of nonsusceptible microorganisms including fungi. The effects of treatment
(59° to 86°F). Avoid exposure to excessive heat.
for greater than 6 months has 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® has not been established for the
treatment of periodontitis in patients with coexistent oral candidiasis.
ARESTIN® has not been clinical y tested in immunocompromised patients (such as those
immunocompromised by diabetes, chemotherapy, radiation therapy, or infection with HIV).
® resulted in a greater percentage of pockets showing a change of
If superinfection is suspected, appropriate measures should be taken.
ARESTIN® has not been clinically tested in pregnant women.
PD ≥2 mm and ≥3 mm compared to SRP alone at 9 months, as shown in Table 2.
ARESTIN® has not been clinically tested for use in the regeneration of alveolar bone,
REFERENCES: 1. Stratton CW, Lorian V. Mechanisms of action of antimicrobial agents:
either in preparation for or in conjunction with the placement of endosseous (dental)
general principles and mechanisms for selected classes of antibiotics.
implants or in the treatment of failing implants.
In: Antibiotics in Laboratory Medicine. 4th ed. Baltimore, Md: Williams and
Information for Patients
Wilkins; 1996. 2. Slots J, Rams TE. Antibiotics in periodontal therapy: advantages and
After treatment, patients should avoid chewing hard, crunchy, or sticky foods (i.e., carrots,
disadvantages. J Clin Periodontol. 1990;17:479-493.
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
Patents: Protecting Inventors and the Public Good “In a world in which science is a rich-country prerogative while the poor continue to die, the niceties of intellectual property rights are likely to prove less compelling than social realities.” —Jeffrey Sachs, economist and director of the Earth Institute at Columbia University1Every year U.S. companies charge thousands of dollars
Chronic fatigue syndrome Signs and symptoms Chronic fatigue syndrome is a flu-like condition that can drain your energy and, sometimes, last for years. People previously healthy and full of energy may experience a variety of signs and symptoms. People with chronic fatigue syndrome exhibit signs and symptoms similar to those of most common viral infections. Unlike flu (influenza) symptom
ARESTIN®