The ATRIDOX® product* is a subgingival controlled-release product composed of a 2 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- ethyl-2-pyrrolidone (NMP). Syringe B contains 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.

Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. The structural formula of doxycycline hyclate is:

Empirical Formula: (C₂₂H₂₄N₂O₈•HCI)₂•C₂H₆O•H₂O

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.

Preparation for Use

1. If refrigerated, remove the pouched 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 purple stripe) into Syringe B (doxycycline powder) and then push the contents back into Syringe A. This entire operation is 1 mixing cycle.
4. Complete 100 mixing cycles at a pace of 1 cycle per second using brisk strokes.
   
   If immediate use is desired, skip to step 7.
5. If necessary, the coupled syringes can be stored in the resealable pouch at room temperature for a maximum of 3 days.
6. After storage, perform an additional 10 mixing cycles just prior to use.
   
   Continue with immediate use instructions.
7. The contents will be in Syringe A (indicated by purple 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 2 syringes and attach the blunt cannula 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 4 months after initial treatment.

ATRIDOX® is available in a pouch containing a doxycycline hyclate syringe (50 mg), an ATRIGEL® Delivery System syringe (450 mg), and a blunt cannula.

Each ATRIDOX® syringe system is intended for use in only 1 patient. Do not use if pouch has been previously opened or damaged.

Dosage Information

The final blended product is 500 mg of formulation containing 50.0 mg of doxycycline hyclate (doxycycline hyclate, 10%).

ATRIDOX® is a variable dose product dependent on the size, shape, and number of pockets being treated.

NDC 63646-191-00

Storage Conditions

Store at 2°- 30°C (36°-86°F).

Manufactured by Atrix Laboratories, Inc. exclusively for: CollaGenex Pharmaceuticals, Inc., Newtown, PA 18940. Rev. 7 7/03. FDA revision date: 6/20/2003

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.

No information provided.

THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY, AND CHILDHOOD TO THE AGE OF 8 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.

General

ATRIDOX® has not been clinically tested in pregnant women.

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.¹ The effects of prolonged treatment, greater than 6 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.

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 section)

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.

No information provided.

ATRIDOX® should not be used in patients who are hypersensitive to doxycycline or any other drug in the tetracycline class.

Microbiology

Doxycycline is a broad-spectrum semisynthetic tetracycline.¹ Doxycycline is bacteriostatic, inhibiting bacterial protein synthesis due to disruption of transfer RNA and messenger RNA at ribosomal sites.¹ 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.² 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 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 (MIC90) for periodontal pathogens ( 6.0 μg/mL)² 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 2 well-controlled, multicenter, parallel-design, 9-month clinical trials, 831 patients 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 1 of 4 treatments: 1) ATRIDOX® , 2) Scaling and Root Planing, 3) Vehicle Control, or 4) Oral 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 4 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 9 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.

* denotes statistically significant superiority of ATRIDOX® and Sc/RP vs. Vehicle and Oral Hygiene
† denotes statistically significant superiority of ATRIDOX® vs. Vehicle and Oral Hygiene
Data were not collected at months 3 and 7

* denotes statistically significant superiority of ATRIDOX® and Sc/RP vs. Vehicle and Oral Hygiene
† denotes statistically significant superiority of ATRIDOX® vs. Vehicle and Oral Hygiene
Data were not collected at months 3 and 7

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 1 of 3 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.

REFERENCES

1. Stratton CW, Lorian V. Mechanisms of action for antimicrobial agents: general principals and mechanisms for selected classes of antibiotics. Antibiotics in Laboratory Medicine. 4th ed. Baltimore, MD: Williams & Wilkings;1996.

2. Slots J, Rams TE. Antibiotics in periodontal therapy: advantages and disadvantages. J Clin Periodontal. 1990;17:479-493.

Mechanical oral hygiene procedures (ie, 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.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DOXYCYCLINE GEL - DENTAL

(dox-ee-SYE-kleen)

COMMON BRAND NAME(S): Atridox

USES: This medication is used to treat adult gum disease (periodontitis). Doxycycline belongs to a class of drugs known as tetracycline antibiotics. When applied to the infected tooth pockets, this medication works by preventing the growth of bacteria. This medication is a gel that your dental professional places into the infected tooth pocket. It becomes wax-like when it comes in contact with saliva. Doxycycline is then slowly released from the hardened gel over the next 7 days.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using doxycycline gel. If you have any questions, talk to your dentist or pharmacist.

Dosage is based on your medical condition and response to treatment.

The dental professional will prepare each dose before placing this product into the infected tooth pocket(s).

After this medication is placed in your tooth pocket(s), do not brush or floss around the treated teeth for 7 days. Avoid using the treated teeth to chew, and do not eat hard, crunchy, or chewy foods for at least 7 days. Your dentist may prescribe a dental rinse to be used during the time you should avoid brushing and flossing. Follow your dentist's directions carefully.

Do not worry if you see bits of this product come out of the treated tooth pockets. This product is harmless if swallowed.

Your dental professional may apply a second treatment with this product after 4 months. Keep all of your dental appointments while using this medication.

Tell your dentist if your condition persists or worsens.

SIDE EFFECTS: Gum discomfort/pain/soreness or toothache may occur. If any of these effects persist or worsen, tell your dentist or pharmacist promptly.

Remember that your dentist has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your dentist immediately if any of these unlikely but serious side effects occur: tooth loosening, jaw pain, sunburn.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using doxycycline gel, tell your dentist or pharmacist if you are allergic to it; or to other tetracyclines; or if you have any other allergies.

Before using this medication, tell your dentist or pharmacist your medical history, especially of: past/current fungal infections of mouth/vagina (e.g., thrush, yeast infection).

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

Caution is advised when using this drug in children younger than 8 years because they may be more likely to develop permanent staining of the teeth or problems with tooth growth.

This drug is not recommended for use during pregnancy. Consult your dentist before using this medication.

This drug passes into breast milk and has had undesirable effects on nursing infants. Therefore, using this medication while breast-feeding is not recommended. Consult your dentist or medical doctor before breast-feeding.

DRUG INTERACTIONS: Your dentist or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your dentist, medical doctor, or pharmacist first.

Before using this medication, tell your dentist or pharmacist of all prescription and nonprescription/herbal products you may use.

When given by mouth, doxycycline may decrease the effectiveness of combination-type birth control pills/patches. This can result in pregnancy. You may need to use an additional form of reliable birth control while using this medication. Consult your doctor or pharmacist for details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center.

NOTES: Proper dental hygiene (including tooth brushing and flossing) on a daily basis and having regular visits to your dentist may help to prevent tooth and gum problems. Discuss this with your dental professional.

MISSED DOSE: Not applicable.

STORAGE: Store at room temperature or in the refrigerator between 36-86 degrees F (2-30 degrees C) away from light and moisture. Keep this medication in the protective pouches before use. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.