Atridox (doxycycline hyclate) periodontal label

ATRIDOX

(doxycycline hyclate) 10%

in the ATRIGEL

Delivery System

for controlled release in

subgingival application

DESCRIPTION

The ATRIDOX

product* is a subgingival controlled-release product composed of a two

syringe mixing system. Syringe A contains 450 mg of the ATRIGEL

Delivery System,

which is a bioabsorbable, flowable polymeric formulation composed of 36.7% poly(DL-

lactide) (PLA) dissolved in 63.3% N-methyl-2-pyrrolidone (NMP). Syringe B contains 50

mg of doxycycline hyclate which is equivalent to 42.5 mg doxycycline. The constituted

product is a pale yellow to yellow viscous liquid with a concentration of 10% of

doxycycline hyclate. Upon contact with the crevicular fluid, the liquid product solidifies

and then allows for controlled release of drug for a period of 7 days.

*ATRIDOX

is a registered trademark of TOLMAR Inc. ATRIGEL

is a registered

trademark of TOLMAR Therapeutics, Inc.

Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline.

The structural formula of doxycycline hyclate is:

Empirical Formula: (C

•HCI)

•C

O•H

CLINICAL PHARMACOLOGY

Microbiology

Doxycycline is a broad-spectrum semisynthetic tetracycline.

Doxycycline is

bacteriostatic, inhibiting bacterial protein synthesis due to disruption of transfer RNA and

messenger RNA at ribosomal sites.

In vitro testing has shown that Porphyromonas

gingivalis, Prevotella intermedia, Campylobacter rectus, and Fusobacterium nucleatum,

which are associated with periodontal disease, are susceptible to doxycycline at

concentrations ≤ 6.0 µg/mL.

A single-center, single-blind, randomized, clinical study in

45 subjects with periodontal disease demonstrated that a single treatment with

ATRIDOX

resulted in the reduction in the numbers of P. gingivalis, P. intermedia, C.

rectus, F. nucleatum, Bacteroides forsythus, and E. corrodens in subgingival plaque

samples. Levels of aerobic and anaerobic bacteria were also reduced after treatment with

ATRIDOX

. The clinical significance of these findings, however, is not known. During

these studies, no overgrowth of opportunistic organisms such as Gram-negative bacilli

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and yeast were observed. However, as with other antibiotic preparations, ATRIDOX

therapy may result in the overgrowth of nonsusceptible organisms including fungi. (See

PRECAUTIONS)

Pharmacokinetics

In a clinical pharmacokinetic study, subjects were randomized to receive either

ATRIDOX

covered with Coe-Pak™ periodontal dressing (n=13), ATRIDOX

covered

with Octyldent™ periodontal adhesive (n=13), or oral doxycycline (n=5) (according to

package dosing instructions). The doxycycline release characteristics in gingival

crevicular fluid (GCF), saliva, and serum were evaluated.

Doxycycline levels in GCF peaked (~1,500 µg/mL and ~2000 µg/mL for Coe-Pak™ and

Octyldent™ groups, respectively) 2 hours following treatment with ATRIDOX

. These

levels remained above 1000 µg/mL through 18 hours, at which time the levels began to

decline gradually. However, local levels of doxycycline remained well above the

minimum inhibitory concentration (MIC

) for periodontal pathogens (≤ 6.0 µg/mL)

through Day 7. In contrast, subjects receiving oral doxycycline had peak GCF levels of

~2.5 µg/mL at 12 hours following the initial oral dosing with levels declining to ~0.2

µg/mL by Day 7. High variability was observed for doxycycline levels in GCF for both

oral and ATRIDOX

treatment groups.

The ATRIDOX

doxycycline release profile in GCF is illustrated in the figure below.

The maximum concentration of doxycycline in saliva was achieved at 2 hours after both

treatments with ATRIDOX

, with means of 4.05 µg/mL and 8.78 µg/mL and decreased

to 0.36 µg/mL and 0.23 µg/mL at Day 7 for the Coe-Pak™ group and the Octyldent™

group, respectively.

The concentration of doxycycline in serum following treatment of ATRIDOX

never

exceeded 0.1 µg/mL.

CLINICAL STUDIES

In two well-controlled, multicenter, parallel-design, nine-month clinical trials, 831

patients (Study 1=411; Study 2=420) with chronic adult periodontitis characterized by a

mean probing depth of 5.9 to 6.0 mm were enrolled. Subjects received one of four

treatments: 1) ATRIDOX

, 2) Scaling and Root Planing, 3) Vehicle Control, or 4) Oral

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Hygiene. Treatment was administered to sites with probing depths 5 mm or greater that

bled on probing. Subjects with detectable subgingival calculus on greater than 80% of all

tooth surfaces were excluded from enrollment. All subjects received a second

administration of the initially randomized treatment four months after their Baseline

treatment. Changes in the efficacy parameters, attachment level, pocket depth, and

bleeding on probing, between Baseline and Month 9 showed that: 1) ATRIDOX

was

superior to Vehicle Control and Oral Hygiene, and 2) ATRIDOX

met the decision rule

of being at least 75% as good as Scaling and Root Planing (SRP) (the standard of at least

75% as good as SRP is required for any product approved as a stand alone therapy for

periodontitis). Clinicians should note that the studies were of nine months duration.

Additional research would be necessary to establish long term comparability to SRP. The

results of Studies #1 and 2 for efficacy parameters of attachment level gain and probing

depth reduction are included in the following graphs.

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A third clinical trial was conducted to determine whether the product can be left in the

pocket to bioabsorb or be expelled naturally and achieve comparable clinical results. In

this study the product was retained with Octyldent™ dental adhesive rather than Coe-

Pak™ periodontal dressing as in the previously mentioned studies. This was a 3-arm,

randomized, controlled, parallel group, single blind trial that enrolled 605 subjects. The

patient population studied and study design were comparable to that in Studies 1 and 2.

Subjects received one of three treatments: 1) ATRIDOX

with Coe-Pak™ removed after

7 days as in the pivotal trials, 2) ATRIDOX

retained with Octyldent™ and left to

bioabsorb or be expelled naturally or 3) Vehicle Control with Octyldent™ left to

bioabsorb or be expelled naturally. Changes in the efficacy parameters, attachment level,

pocket depth and bleeding on probing were equivalent to those observed in Studies 1 and

2. The results of the third study support the use of ATRIDOX

retained with Octyldent™

and left to bioabsorb or be expelled naturally.

INDICATIONS AND USAGE

ATRIDOX

is indicated for use in the treatment of chronic adult periodontitis for a gain

in clinical attachment, reduction in probing depth, and reduction in bleeding on probing.

CONTRAINDICATIONS

ATRIDOX

should not be used in patients who are hypersensitive to doxycycline or any

other drug in the tetracycline class.

WARNINGS

THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH

DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY, AND CHILDHOOD

TO THE AGE OF EIGHT YEARS) MAY CAUSE PERMANENT DISCOLORATION

OF THE TEETH. This adverse reaction is more common during long-term use of the

drugs, but has been observed following repeated short-term courses. Enamel hypoplasia

has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE

USED IN THIS AGE GROUP, OR IN PREGNANT WOMEN, UNLESS OTHER

DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal

tissues, and can have toxic effects on the developing fetus (often related to skeletal

development). Evidence of embryotoxicity has also been noted in animals treated early in

pregnancy. If any tetracycline is used during pregnancy, 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 doxycycline or other tetracyclines. Patients apt to be exposed to

direct sunlight or ultraviolet light should be advised that this reaction can occur with

tetracycline drugs.

PRECAUTIONS

General

ATRIDOX

has not been clinically tested in pregnant women.

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ATRIDOX

has not been clinically evaluated in patients with conditions involving

extremely severe periodontal defects with very little remaining periodontium.

ATRIDOX

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.

ATRIDOX

has not been clinically tested in immunocompromised patients (such as

patients immunocompromised by diabetes, chemotherapy, radiation therapy, or infection

with HIV).

As with other antibiotic preparations, ATRIDOX

therapy may result in overgrowth of

nonsusceptible organisms, including fungi.

The effects of prolonged treatment, greater

than six months, have not been studied.

ATRIDOX

should be used with caution in patients with a history of or predisposition to

oral candidiasis. The safety and effectiveness of ATRIDOX

have not been established

for the treatment of periodontitis in patients with coexistent oral candidiasis.

Information for Patients

Mechanical oral hygiene procedures (i.e., tooth brushing, flossing) should be avoided on

any treated areas for 7 days.

Avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline.

Doxycycline may decrease the effectiveness of birth control pills.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not

been conducted. However, there has been evidence of oncogenic activity in rats in studies

with the related antibiotics, oxytetracycline (adrenal and pituitary tumors), and

minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline

have not been conducted, positive results in in vitro mammalian cell assays have been

reported for related antibiotics (tetracycline, oxytetracycline). Doxycycline administered

orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of

female rats. Effect on male fertility has not been studied.

Pregnancy Category D. See “WARNINGS” section

Nursing Mothers

Tetracyclines appear in breast milk following oral administration. It is not known

whether doxycycline is excreted in human milk following use of ATRIDOX

. Because of

the potential for serious adverse reactions in nursing infants from doxycycline, a decision

should be made whether to discontinue nursing or to discontinue the drug, taking into

account the importance of the drug to the mother. (See WARNINGS)

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Pediatrics

The safety and effectiveness of ATRIDOX

in pediatric patients have not been

established. Oral doses of doxycycline in children up to 8 years of age have caused

permanent discoloration of teeth.

ADVERSE REACTIONS

In clinical trials involving a total of 1436 patients, adverse experiences from all

causalities were monitored across treatment groups.

In the Circulatory System category, 10 subjects (1.6%) in the ATRIDOX

group were

reported as having "unspecified essential hypertension." Only 1 subject (0.2%) in the

Vehicle group, and none in the Scaling and Root Planing or Oral Hygiene groups were

reported to have "unspecified essential hypertension." In all cases, the event occurred

anywhere from 13 to 134 days post treatment. There is no known association of oral

administration of doxycycline with essential hypertension.

Two patients in the polymer vehicle group and none in the ATRIDOX

group (0.2% for

both groups combined) reported adverse events consistent with a localized allergic

response.

Sex, age, race and smoking status did not appear to be correlated with adverse events.

The following table lists the incidence of treatment-emergent adverse events from all

causalities, across all treatment groups, occurring in ≥1% of the entire study population.

Body System

Verbatim Terms

Doxycycline

n=609

Vehicle

n=413

n=204

SRP

n=210

Circulatory

High blood pressure

Digestive

Gum discomfort, pain or soreness;

loss of attachment; increased

pocket depth

Toothache, pressure sensitivity

Periodontal abscess, exudate,

infection, drainage, extreme

mobility, suppuration

Thermal tooth sensitivity

Gum inflammation, swelling,

sensitivity

Soft tissue erythema, sore mouth,

unspecified pain

Indigestion, upset stomach,

1.6%

18.1%

14.3%

9.9%

7.7%

4.1%

4.3%

3.6%

0.2%

23.0%

14.3%

10.9%

8.5%

5.8%

5.3%

4.1%

0.0%

20.1%

10.3%

4.4%

5.4%

2.7%

2.9%

0.0%

21.0%

18.1%

8.6%

6.7%

5.7%

6.2%

3.8%

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stomachache

Diarrhea 3.3% 2.4% 1.0% 1.0%

Tooth mobility, bone loss 2.0% 0.7% 0.5% 2.4%

Periapical abscess, lesion 1.5% 1.9% 1.0% 0.5%

Aphthous ulcer, canker sores 0.7% 1.7% 1.0% 1.4%

Fistula 0.8% 1.5% 1.5% 1.0%

Endodontic abscess, pulpitis 1.5% 1.5% 0.0% 0.5%

Jaw pain 1.1% 0.5% 1.0% 1.9%

Tooth loss 0.8% 1.5% 1.5% 0.0%

Bleeding gums 1.0% 0.7% 0.0% 2.4%

Genitourinary

Premenstrual tension syndrome 4.4% 3.1% 2.5% 3.3%

Ill-Defined Conditions

Headache 27.3% 28.1% 23.5% 23.8%

Cough 3.6% 6.1% 2.9% 2.4%

Sleeplessness 3.4% 1.5% 2.0% 2.9%

Body aches, soreness 1.6% 1.2% 1.5% 1.4%

Nausea and vomiting 1.8% 0.7% 2.5% 0.5%

Fever 1.0% 1.9% 1.0% 1.9%

Injury & Poisoning

Broken tooth 5.1% 4.1% 4.9% 5.7%

Mental

Tension headache 1.8% 0.7% 0.0% 1.0%

Musculoskeletal

Muscle aches 6.4% 4.6% 4.9% 3.3%

Backache 3.6% 5.3% 2.5% 6.2%

Pain in arms or legs 1.5% 2.2% 2.0% 2.4%

Lower back pain 1.6% 1.7% 0.5% 2.9%

Neck pain 1.3% 1.7% 1.0% 1.9%

Shoulder pain 1.0% 1.0% 1.5% 1.0%

Nervous System

Ear infection 1.6% 1.9% 2.0% 0.0%

Respiratory

Common cold

25.5% 25.2% 18.1% 16.7%

Flu, respiratory 6.1% 9.0% 3.9% 6.7%

Stuffy head, post nasal drip, 5.6% 7.7% 2.9% 4.8%

congestion

Sore throat 5.7% 6.5% 2.0% 3.3%

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Sinus infection 5.3% 2.7% 1.0% 1.9%

Flu 2.8% 2.9% 2.9% 3.3%

Bronchitis 2.3% 1.9% 1.5% 1.0%

Allergies 1.0% 1.0% 1.0% 1.9%

Skin & Subcutaneous Tissue

Skin infection or inflammation 1.3% 1.0% 1.0% 1.0%

DOSAGE AND ADMINISTRATION

ATRIDOX

is a variable dose product dependent on the size, shape, and number of

pockets being treated.

Preparation for Use

1. If refrigerated, remove the product from refrigeration at least 15 minutes prior to

mixing.

2. Couple Syringe A (liquid delivery system) and Syringe B (drug powder).

3. Inject the liquid contents of Syringe A (indicated by red stripe) into Syringe B

(doxycycline powder) and then push the contents back into Syringe A. This entire

operation is one mixing cycle.

4. Complete 100 mixing cycles at a pace of one cycle per second using brisk strokes.

If immediate use is desired, skip to step 7.

5. If necessary, the coupled syringes can be stored at room temperature for a

maximum of three days. Some of the Atridox systems are packaged in resealable

pouches that can be used for this purpose. If the Atridox system is packaged in a

try, use an airtight container.

6. After storage, perform an additional ten mixing cycles just prior to use.

Continue with immediate use instructions.

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7. The contents will be in Syringe A (indicated by red stripe). Hold the coupled syringes

vertically with Syringe A at the bottom. Pull back on the Syringe A plunger and

allow the contents to flow down the barrel for several seconds.

8. Uncouple the two syringes and attach one of the provided cannulae to Syringe A.

Product is now ready for application.

Product Administration

ATRIDOX® does not require local anesthesia for placement. Bend the cannula to

resemble a periodontal probe and explore the periodontal pocket in a manner similar to

periodontal probing. Keeping the cannula tip near the base of the pocket, express the

product into the pocket until the formulation reaches the top of the gingival margin.

Withdraw the cannula tip from the pocket. In order to separate the tip from the

formulation, turn the tip of the cannula towards the tooth, press the tip against the tooth

surface, and pinch the string of formulation from the tip of the cannula. Variations on this

technique may be needed to achieve separation between ATRIDOX

and cannula.

If desired, using an appropriate dental instrument, ATRIDOX

may be packed into the

pocket. Dipping the edge of the instrument in water before packing will help keep

ATRIDOX

from sticking to the instrument, and will help speed coagulation of

ATRIDOX

. A few drops of water dripped onto the surface of ATRIDOX

once in the

pocket will also aid in coagulation. If necessary, add more ATRIDOX

as described

above and pack it into the pocket until the pocket is full.

Cover the pockets containing ATRIDOX

with either Coe-Pak™ periodontal dressing or

a cyanoacrylate dental adhesive.

Application of ATRIDOX

may be repeated four months after initial treatment.

HOW SUPPLIED

The final blended product is 500 mg of formulation containing 50 mg of doxycycline

hyclate (doxycycline hyclate, 10%).

ATRIDOX

is available as a tray or pouch containing a doxycycline hyclate syringe (50

mg), an ATRIGEL

Delivery System syringe (450 mg), and a blunt cannula. The

pouched product is available in a box of six (NDC 63646-191-00) a box of two (NDC-

63646-191-02), or a professional sample pouch (NDC 63646-191-01). The trayed product

is available in a box of six (NDC 63646-191-05), a box of four (NDC 63646-191-04), or

a professional sample box of two (NDC 63646-191-03).

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Each ATRIDOX

syringe system is intended for use in only one patient. Do not use if

packaging has been previously opened or damaged.

Storage Conditions

Store at 2° - 30°C (36° - 86°F).

Rx Only

REFERENCES

1. Stratton CW, Lorian V. Mechanisms of action for antimicrobial agents: general

principles and mechanisms for selected classes of antibiotics. Antibiotics in

Laboratory Medicine, 4th edition, Williams and Wilkins, Baltimore, MD, 1996.

2. Slots J, Rams TE. Antibiotics in periodontal therapy: advantages and disadvantages.

J Clin Periodontol 1990; 17:479-493.

ATRIDOX

products are produced under one or more of these patents: U.S. 5,324,519;

U.S. BI 4,938,763; U.S. 5,278,201; U.S. 5,077,049; U.S. 5,739,176; U.S. 5,733,950

Manufactured by TOLMAR Inc.

Fort Collins, CO 80526

Distributed by Zila Therapeutics, Inc.

Part Number: 44406 Rev. 02/11

ATRIDOX

(doxycycline hyclate) 10%

in the ATRIGEL

Delivery System

for controlled release in

subgingival application

To Order Call: 1-800-228-5595

www.atridox.com

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