ATRIDOX- doxycycline hyclate

United States - English - NLM (National Library of Medicine)

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Active ingredient:
DOXYCYCLINE HYCLATE (UNII: 19XTS3T51U) (DOXYCYCLINE ANHYDROUS - UNII:334895S862)
Available from:
Den-Mat Holdings, LLC
INN (International Name):
DOXYCYCLINE HYCLATE
Composition:
DOXYCYCLINE ANHYDROUS 50 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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. ATRIDOX® should not be used in patients who are hypersensitive to doxycycline or any other drug in the tetracycline class.
Product summary:
The final blended product is 500 mg of formulation containing 50 mg of doxycycline hyclate (doxycycline hyclate, 10%). ATRIDOX® is available in a tray containing a doxycycline hyclate syringe (50 mg), an ATRIGEL® Delivery System syringe (450 mg), and a blunt cannula. The trayed product is available in a professional sample box of two (NDC 59883-100-02) or a box of six (NDC 59883-100-06). Each ATRIDOX® syringe system is intended for use in only one patient. Do not use if packaging has been previously opened or damaged. Store at 2° - 30°C (36° - 86°F). Rx Only
Authorization status:
New Drug Application
Authorization number:
59883-100-01, 59883-100-02, 59883-100-06, 59883-101-01, 59883-102-01

ATRIDOX- doxycycline hyclate

Den-Mat Holdings, LLC

----------

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

H N O HCI) C H OH O

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

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 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.

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.

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)

Pediatric Use

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

Doxycycline Vehicle

Verbatim Terms

n=609

n=413 n=204 n=210

Circulatory

High blood pressure

1.6%

0.2% 0.0% 0.0%

Digestive

Gum discomfort, pain or soreness; loss of attachment; increased

pocket depth

18.1%

23.0% 20.1% 21.0%

Toothache, pressure sensitivity

14.3%

14.3% 10.3% 18.1%

Periodontal abscess, exudate, infection, drainage, extreme

mobility, suppuration

9.9%

10.9% 10.3% 8.6%

Thermal tooth sensitivity

7.7%

8.5% 4.4% 6.7%

Gum inflammation, swelling, sensitivity

4.1%

5.8% 5.4% 5.7%

Soft tissue erythema, sore mouth, unspecified pain

4.3%

5.3% 2.7% 6.2%

Indigestion, upset stomach, stomachache

3.6%

4.1% 2.9% 3.8%

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, congestion

5.6%

7.7% 2.9% 4.8%

Sore throat

5.7%

6.5% 2.0% 3.3%

Sinus infection

5.3%

2.7% 1.0% 1.9%

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 tray, use an airtight container.

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

Continue with immediate use instructions.

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 in a tray containing a doxycycline hyclate syringe (50 mg), an ATRIGEL®

Delivery System syringe (450 mg), and a blunt cannula. The trayed product is available in a professional

sample box of two (NDC 59883-100-02) or a box of six (NDC 59883-100-06).

Each ATRIDOX syringe system is intended for use in only one patient. Do not use if packaging has

been previously opened or damaged.

Storage and Handling

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.

Manufactured by TOLMAR Inc.

Fort Collins, CO 80526

Distributed by Den-Mat Holdings, LLC

1017 W. Central Ave., Lompoc, CA 93436

Part Number: 44406 Rev. 7 10/16

ATRIDOX®

(doxycycline hyclate) 10%

in the ATRIGEL® Delivery System

for controlled release in

subgingival application

To Order Call: 1-800-433-6628

www.denmat.com

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

2 pack carton

6 pack carton

ATRIDOX

doxycycline hyclate kit

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:59 8 8 3-10 0

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:59 8 8 3-10 0 -0 2

2 in 1 CARTON

12/0 1/20 16

1

NDC:59 8 8 3-10 0 -0 1

1 in 1 TRAY; Type 0 : No t a Co mbinatio n Pro duct

2

NDC:59 8 8 3-10 0 -0 6

6 in 1 CARTON

12/0 1/20 16

2

NDC:59 8 8 3-10 0 -0 1

1 in 1 TRAY; Type 0 : No t a Co mbinatio n Pro duct

Quantity of Parts

Part #

Package Quantity

Total Product Quantity

Pa rt 1

1 SYRINGE

Pa rt 2

1 SYRINGE

450 mg

Part 1 of 2

DOXYCYCLINE HYCLATE

doxycycline hyclate powder

Product Information

Ite m Code (Source )

NDC:59 8 8 3-10 1

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DO XYCYCLINE HYCLATE (UNII: 19 XTS3T51U) (DOXYCYCLINE ANHYDROUS -

UNII:3348 9 5S8 6 2)

DOXYCYCLINE

ANHYDROUS

50 mg

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:59 8 8 3-10 1-0 1

1 in 1 SYRINGE; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 50 751

Part 2 of 2

ATRIGEL

atrigel powder

Product Information

Ite m Code (Source )

NDC:59 8 8 3-10 2

Route of Administration

ORAL

Inactive Ingredients

Ingredient Name

Stre ng th

METHYL PYRRO LIDO NE (UNII: JR9 CE6 3FPM)

PO LY( DL-LACTIC-CO -GLYCO LIC ACID) , ( 50 :50 ; 4 6 0 0 0 MW) (UNII: LQ35R50 VR1)

Packag ing

Den-Mat Holdings, LLC

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:59 8 8 3-10 2-0 1 450 mg in 1 SYRINGE; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 50 751

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 50 751

12/0 1/20 16

Labeler -

Den-Mat Holdings, LLC (809857704)

Revised: 11/2018

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