ATRIDOX
®
Product Monograph Page 1 of 25
PRODUCT MONOGRAPH
INCLUDING PATIENT MEDICATION INFORMATION
Pr
ATRIDOX
®
Doxycycline Hyclate
Controlled-Release Gel
contains 8.8% w/w Doxycycline
(as Hyclate) in ATRIGEL
®
Delivery System
Therapeutic Classification: Antimicrobial Agent for Periodontitis
Tolmar, Inc. Date of Initial Approval:
701 Centre Avenue July 5, 2000
Fort Collins, CO 80526
U.S.A.
Date of Revision:
January 23, 2019
Submission Control No: 211449
ATRIDOX
®
Product Monograph Page 2 of 25
RECENT MAJOR LABEL CHANGES
Not Applicable
TABLE OF CONTENTS
PART I: HEALTH PROFESSIONAL INFORMATION .................................................................... 4
1
INDICATIONS ................................................................................................................... 4
1.1
Pediatrics ............................................................................................................... 4
1.2
Geriatrics ............................................................................................................... 4
2
CONTRAINDICATIONS .................................................................................................... 4
3
SERIOUS WARNINGS AND PRECAUTIONS BOX .......................................................... 4
4
DOSAGE AND ADMINISTRATION ................................................................................... 4
4.1
Dosing Considerations ........................................................................................... 4
4.2
Recommended Dose and Dosage Adjustment ....................................................... 5
4.3
Administration ........................................................................................................ 5
4.4
Reconstitution ........................................................................................................ 5
4.5
Missed Dose .......................................................................................................... 6
5
OVERDOSAGE ................................................................................................................. 6
6
DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................ 6
7
WARNINGS AND PRECAUTIONS .................................................................................... 7
7.1
Special Populations ................................................................................................ 8
7.1.1
Pregnant Women ................................................................................................... 8
7.1.2
Breast-feeding ....................................................................................................... 8
7.1.3
Pediatrics ............................................................................................................... 8
7.1.4
Geriatrics ............................................................................................................... 8
8
ADVERSE REACTIONS .................................................................................................... 9
8.1
Adverse Reaction Overview ................................................................................... 9
8.2
Clinical Trial Adverse Reactions ............................................................................. 9
8.3
Less Common Clinical Trial Adverse Reactions .................................................... 10
8.4
Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other
Quantitative Data ................................................................................................. 10
8.5
Clinical Trial Adverse Reactions (Pediatrics) ........................................................ 11
8.6
Post-Market Adverse Reactions ........................................................................... 11
ATRIDOX
®
Product Monograph Page 3 of 25
9
DRUG INTERACTIONS ................................................................................................... 11
9.1
Serious Drug Interactions Box .............................................................................. 11
9.2
Overview
.............................................................................................................. 11
9.3
Drug-Drug Interactions ......................................................................................... 11
9.4
Drug-Food Interactions ......................................................................................... 11
9.5
Drug-Herb Interactions ......................................................................................... 11
9.6
Drug-Laboratory Test Interactions ........................................................................ 11
9.7
Drug-Lifestyle Interactions .................................................................................... 12
10
ACTION AND CLINICAL PHARMACOLOGY .................................................................. 12
10.1
Mechanism of Action ............................................................................................ 12
10.2
Pharmacodynamics ............................................................................................. 12
10.3
Pharmacokinetics ................................................................................................ 12
11
STORAGE, STABILITY AND DISPOSAL ....................................................................... 14
12
SPECIAL HANDLING INSTRUCTIONS .......................................................................... 14
PART II: SCIENTIFIC INFORMATION ........................................................................................ 15
13
PHARMACEUTICAL INFORMATION ............................................................................. 15
14
CLINICAL TRIALS .......................................................................................................... 15
14.1
Trial Design and Study Demographics.................................................................. 15
14.2
Study Results ....................................................................................................... 17
14.3
Comparative Bioavailability Studies ...................................................................... 18
15
MICROBIOLOGY ............................................................................................................ 18
16
NON-CLINICAL TOXICOLOGY ...................................................................................... 19
17
SUPPORTING PRODUCT MONOGRAPHS .................................................................... 22
PATIENT MEDICATION INFORMATION .................................................................................... 23
ATRIDOX
®
Product Monograph Page 4 of 25
PART I: HEALTH PROFESSIONAL INFORMATION
1
INDICATIONS
ATRIDOX
®
controlled-release doxycycline gel is indicated for use in the treatment of chronic adult
periodontitis for gain in clinical attachment, reduction in probing depth, and reduction in bleeding
on probing.
1.1
Pediatrics
Pediatrics (< 18 years of age): Based on the data submitted and reviewed by Health Canada, the
safety and efficacy of ATRIDOX
®
in pediatric patients has not been established; therefore,
Health
Canada has not authorized an indication for pediatric use. Oral doses of doxycycline in children up
to age 8 years have caused permanent discolouration of teeth. (See also CONTRAINDICATIONS)
1.2
Geriatrics
Geriatrics (> 65 years of age): No data are available to Health Canada; therefore, Health
Canada
has not authorized an indication for geriatric use.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ATRIDOX
®
and other antibacterial drugs, ATRIDOX
®
should be used only to treat infections that are proven or
strongly suspected to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or modifying antibacterial therapy.
In the absence of such data, local epidemiology and susceptibility patterns may contribute to the
empiric selection of therapy.
2
CONTRAINDICATIONS
ATRIDOX
®
is contraindicated in patients who are hypersensitive to this drug or to any
ingredient in
the formulation, including any non-medicinal ingredient, or component of the container. For a
complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• ATRIDOX
®
controlled-release doxycycline gel should not be used in patients who are
hypersensitive to any drug in the tetracycline class.
• ATRIDOX
®
should not be used during tooth development (second half of pregnancy,
infancy and childhood to age of twelve years).
• ATRIDOX
®
should not be given to pregnant patients or nursing mothers.
3
SERIOUS WARNINGS AND PRECAUTIONS BOX
Not Applicable. For a complete listing, see WARNINGS AND PRECAUTIONS.
4
DOSAGE AND ADMINISTRATION
4.1
Dosing Considerations
Not Applicable
ATRIDOX
®
Product Monograph Page 5 of 25
4.2
Recommended Dose and Dosage Adjustment
ATRIDOX
®
is considered a variable-dose unit dependent on the morphology and number of
periodontal pockets being treated.
Health Canada has not authorized an indication for pediatric use. (See INDICATIONS,
CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS)
4.3
Administration
ATRIDOX
®
requires no 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. 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 the cannula.
If desired, use an appropriate dental instrument to pack ATRIDOX
®
into the pocket. Dip the edge
of the instrument in water before packing to help keep ATRIDOX
®
from sticking to the instrument
and help speed coagulation of ATRIDOX
®
. A few drops of water dripped onto the surface of
ATRIDOX
®
once in the pocket may also aid in coagulation. If necessary, add more ATRIDOX
®
product as described and pack it into pocket until the pocket is full.
ATRIDOX
®
may be re-applied four months after initial application, or as needed.
4.4
Reconstitution
Preparation for Use
1. Remove the trayed product from refrigeration at least 15 minutes prior to mixing.
2. Couple Syringe A (liquid delivery system) and Syringe B (drug powder).
Syringe A Syringe B
3. Inject the contents of Syringe A (indicated by purple stripe) into Syringe B (liquid into
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.
5. 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.
ATRIDOX
®
Product Monograph Page 6 of 25
6. Uncouple the two syringes and attach the blunt cannula to Syringe A.
Product is now ready for application.
4.5
Missed Dose
Not Applicable
5
OVERDOSAGE
Overdose with ATRIDOX
®
is unlikely due to the small dose of doxycycline, extremely low serum
doxycycline levels, and professional placement of ATRIDOX
®
. There have been no overdoses in
ATRIDOX
®
clinical trials.
For management of a suspected drug overdose, contact your regional poison control centre.
6
DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
Route of
Administration
Dosage Form /
Strength/Composition
Non-medicinal Ingredients
Topical
(subgingivally)
Controlled-release gel supplied n a two-
syringe set with doxycycline hyclate in a
female Luer-Lok
TM
coupling syringe
(Syringe B) and the ATRIGEL
®
Delivery
System in a male Luer-Lok
TM
coupling
syringe (Syringe A).
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).
Dosage Form and Strength
ATRIDOX
®
controlled-release doxycycline gel is a controlled-release dosage form applied topically
(subgingivally) into periodontal pockets for the treatment of periodontal disease. Since the amount
of product applied is dependent upon the morphology and number of periodontal pockets treated,
ATRIDOX
®
is considered a variable-dose unit dependent on these factors.
The final blended product is 500 mg of formulation containing doxycycline hyclate equivalent to 44
mg doxycycline (8.8% w/w). It contains sufficient material to treat between 10 and 12 sites with
pocket depths averaging 6 mm.
ATRIDOX
®
is supplied in a two-syringe set with doxycycline hyclate in a female Luer-Lok
TM
coupling
syringe (Syringe B) and the ATRIGEL
®
Delivery System in a male Luer-Lok
TM
coupling syringe
(Syringe A). The clinician constitutes the product prior to use.
ATRIDOX
®
Product Monograph Page 7 of 25
Composition
The dosage form consists of USP grade doxycycline hyclate in Syringe B and the ATRIGEL
®
Delivery System which is a bioabsorbable, flowable polymeric formulation composed of 63.3% N-
methyl-2-pyrrolidone (NMP) and 36.7% poly(DL-lactide) (PLA) in Syringe A.
Packaging
The ATRIDOX
®
product is available as a tray containing a doxycycline hyclate syringe (Syringe B)
(50 mg), an ATRIGEL
®
Delivery System syringe (Syringe A) (450 mg), and a blunt-ended cannula.
Each ATRIDOX
®
product syringe system is intended for use in only one patient. Do not use if tray
has been previously opened or damaged.
7
WARNINGS AND PRECAUTIONS
General
THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT
(SECOND HALF OF PREGNANCY, INFANCY, AND CHILDHOOD TO TWELVE YEARS) MAY
CAUSE PERMANENT DISCOLOURATION 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. ATRIDOX
®
, THEREFORE, SHOULD NOT
BE USED IN THIS AGE GROUP, OR IN PREGNANT WOMEN. (See CONTRAINDICATIONS)
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 observed in animals treated early in pregnancy.
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.
Immune
ATRIDOX
®
has not been clinically tested in immunocompromised patients, such as patients
immunocompromised by diabetes, chemotherapy, radiation therapy or HIV infection.
Peri-Operative Considerations
ATRIDOX
®
has not been clinically tested in regenerating alveolar bone, either in preparation for or
in conjunction with placement of endosseous (dental) implants or in treatment of failing implants.
Renal
Accumulation of tetracyclines has been associated with renal failure. These effects have not been
studied in the low plasma concentrations associated with ATRIDOX
®
controlled-release
doxycycline gel.
Sensitivity/Resistance
As with other antibiotic preparations, ATRIDOX
®
therapy may result in overgrowth of
nonsusceptible organisms, including fungi. 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.
ATRIDOX
®
Product Monograph Page 8 of 25
Use of antibiotic preparations may result in the development of resistant bacteria. The effects of
prolonged ATRIDOX
®
treatment for periods greater than nine months have not been studied.
Susceptibility/Resistance
Development of Drug Resistant Bacteria
Prescribing ATRIDOX
®
in the absence of a proven or strongly suspected bacterial infection is
unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
Sexual Health
Fertility
Animal studies (to evaluate carcinogenic potential, mutagenic potential or effects on fertility) for
ATRIDOX
®
have not been performed. 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.
Skin
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. Treatment
should be discontinued at the first sign of cutaneous erythema.
Avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline.
7.1
Special Populations
7.1.1
Pregnant Women
Administration of tetracycline during pregnancy may cause permanent discolouration of the teeth
of offspring. Animal studies indicate that tetracyclines can cause retardation of fetal skeletal
development. Animal reproduction studies have not been conducted with ATRIDOX
®
. Also, it is
unknown whether ATRIDOX
®
can cause fetal harm when administered to a pregnant woman or
affects reproductive capacity. ATRIDOX
®
should not be given to a pregnant woman.
7.1.2
Breast-feeding
Tetracyclines appear in breast milk following oral administration. It is unknown whether doxycycline
is excreted in human milk following use of ATRIDOX
®
. Because of doxycycline’s potential for
serious adverse reactions in nursing infants, ATRIDOX
®
should not be used in nursing mothers.
7.1.3
Pediatrics
Pediatrics (< 18 years of age): Based on the data submitted and reviewed by Health Canada,
the
safety and efficacy of ATRIDOX
®
in pediatric patients has not been established; therefore,
Health Canada has not authorized an indication for pediatric use. Oral doses of doxycycline in
children up to age 8 years have caused permanent discolouration of teeth. (See also
CONTRAINDICATIONS)
7.1.4
Geriatrics
No data are available to Health Canada; therefore, Health
Canada has not authorized an indication
for geriatric use.
ATRIDOX
®
Product Monograph Page 9 of 25
8
ADVERSE REACTIONS
8.1
Adverse Reaction Overview
ATRIDOX
®
controlled-release doxycycline gel demonstrates a benign safety profile with no
increased risk of untoward or serious adverse events beyond those associated with standard
periodontal treatments. In two controlled, multi-centre, parallel-design, nine-month clinical trials,
treatment-related adverse events generally did not significantly differ among patients treated with
ATRIDOX
®
, scaling and root planing, oral hygiene, or placebo.
8.2
Clinical Trial Adverse Reactions
Because clinical trials are conducted under very specific conditions, the adverse reaction rates
observed in the clinical trials may not reflect the rates observed in practice and should not be
compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical
trials is useful for identifying drug-related adverse events and for approximating rates.
In eleven clinical trials with a total of 1827 patients, two patients in the placebo group reported
adverse events consistent with a localized allergic response. This represents a 0.2% incidence
rate (incidence includes total number of ATRIDOX
®
and placebo patients, n = 1022), indicating that
patients had a very low risk for an allergic response following the use of ATRIDOX
®
. Table 1 lists
the incidence of treatment-emergent adverse events from all-causalities, across all treatment
groups, occurring in ≥ 1% of subjects in Phase 3 clinical investigations.
Table 1: Treatment-Emergent Adverse Events from All-Causalities (occurring in ≥ 1% of
subjects in Phase 3 clinical investigations)
Body System
Verbatim Terms
Doxycycline
n=609
OH
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, stomachache
Diarrhea
Tooth mobility, bone loss
Periapical abscess, lesion
Aphthous ulcer, canker sores
Fistula
Endodontic abscess, pulpitis
Jaw pain
Tooth loss
Bleeding gums
Genitourinary
Premenstrual tension syndrome
1.6%
18.1%
14.3%
9.9%
7.7%
4.1%
4.3%
3.6%
3.3%
2.0%
1.5%
0.7%
0.8%
1.5%
1.1%
0.8%
1.0%
4.4%
0.0%
20.1%
10.3%
10.3%
4.4%
5.4%
2.7%
2.9%
1.0%
0.5%
1.0%
1.0%
1.5%
0.0%
1.0%
1.5%
0.0%
2.5%
0.0%
21.0%
18.1%
8.6%
6.7%
5.7%
6.2%
3.8%
1.0%
2.4%
0.5%
1.4%
1.0%
0.5%
1.9%
0.0%
2.4%
3.3%
ATRIDOX
®
Product Monograph Page 10 of 25
Body System
Verbatim Terms
Doxycycline
n=609
OH
n=204
SRP
n=210
Ill-Defined Conditions
Headache
Cough
Sleeplessness
Body aches, soreness
Nausea and vomiting
Fever
Injury & Poisoning
Broken tooth
Mental
Tension headache
Musculoskeletal
Muscle aches
Backache
Pain in arms or legs
Lower back pain
Neck pain
Shoulder pain
Nervous System
Ear infection
Respiratory
Common cold
Flu, respiratory
Stuffy head, post nasal drip, congestion
Sore throat
Sinus infection
Flu
Bronchitis
Allergies
Skin & Subcutaneous Tissue
Skin infection or inflammation
27.3%
3.6%
3.4%
1.6%
1.8%
1.0%
5.1%
1.8%
6.4%
3.6%
1.5%
1.6%
1.3%
1.0%
1.6%
25.5%
6.1%
5.6%
5.7%
5.3%
2.8%
2.3%
1.0%
1.3%
23.5%
2.9%
2.0%
1.5%
2.5%
1.0%
4.9%
0.0%
4.9%
2.5%
2.0%
0.5%
1.0%
1.5%
2.0%
18.1%
3.9%
2.9%
2.0%
1.0%
2.9%
1.5%
1.0%
1.0%
23.8%
2.4%
2.9%
1.4%
0.5%
1.9%
5.7%
1.0%
3.3%
6.2%
2.4%
2.9%
1.9%
1.0%
0.0%
16.7%
6.7%
4.8%
3.3%
1.9%
3.3%
1.0%
1.9%
1.0%
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.
8.3
Less Common Clinical Trial Adverse Reactions
Not Applicable
8.4
Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other
Quantitative Data
Not Applicable
ATRIDOX
®
Product Monograph Page 11 of 25
8.5
Clinical Trial Adverse Reactions (Pediatrics)
Not Applicable
8.6
Post-Market Adverse Reactions
Post-Market Adverse Reactions
Post-marketing adverse events for ATRIDOX
®
are generally consistent with those reported in
Clinical Trial Adverse Reactions above, with regard to severity, frequency, and/or character.
Adverse reactions which were not reported in the clinical trials are listed below (categorized by
MedDRA SOC).
Musculoskeletal:
Pain in jaw
Metabolism and Nutrition:
Blood glucose decreased
Nervous System:
Burning sensation
Skin and Subcutaneous Tissue:
Rash, rash pruritic, alopecia, nail disorder
9
DRUG INTERACTIONS
9.1
Serious Drug Interactions Box
Not Applicable
9.2
Overview
Tetracyclines, including doxycycline, may decrease the effectiveness of hormonal contraceptives.
Tetracyclines may also potentiate the effects of oral anticoagulants. Serious impairment of renal
function has been reported after concurrent use of methoxyflurane anesthesia and tetracyclines.
9.3
Drug-Drug Interactions
Tetracyclines may potentiate the effects of oral anticoagulants. These effects have not been
studied in the low plasma concentrations associated with ATRIDOX
®
controlled-release
doxycycline gel.
Concurrent use of methoxyflurane anesthesia and tetracyclines has been reported to seriously
impair renal function, leading in some cases to death. These effects have not been studied in the
low plasma concentrations associated with ATRIDOX
®
controlled-release doxycycline gel.
Doxycycline may decrease the effectiveness of birth control pills.
9.4
Drug-Food Interactions
Not Applicable
9.5
Drug-Herb Interactions
Not Applicable
9.6
Drug-Laboratory Test Interactions
Not applicable
ATRIDOX
®
Product Monograph Page 12 of 25
9.7
Drug-Lifestyle Interactions
Patients should avoid mechanical oral hygiene procedures (i.e. tooth brushing, flossing) on any
treated area for seven days.
Patients should avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline.
10
ACTION AND CLINICAL PHARMACOLOGY
10.1 Mechanism of Action
ATRIDOX
®
controlled-release doxycycline gel is a subgingival controlled-release product
containing doxycycline. Doxycycline is a semi-synthetic tetracycline. It is bacteriostatic and inhibits
bacterial protein synthesis due to the disruption of transfer and messenger RNA at ribosomal sites.
Doxycycline has a broad-spectrum of antimicrobial activity against gram-positive and gram-
negative aerobic and anaerobic bacteria, spirochetes, and mycoplasma. In vitro testing has shown
that periodontal pathogens such as Actinobacillus actinomycetemcomitans, Porphyromonas
gingivalis, Prevotella intermedia, Campylobacter rectus, and Fusobacterium nucleatum are
susceptible to < 6.0 µg/mL doxycycline. (For details, see MICROBIOLOGY.)
ATRIDOX
®
delivers doxycycline directly to the periodontal pocket over an extended period. It is a
flowable, bioabsorbable liquid which solidifies upon contact with aqueous fluids in the periodontal
pocket, resulting in a controlled-release delivery system for the incorporated doxycycline, with gain
in attachment level, reduction in probing depth and reduction in bleeding on probing between
Baseline and Month 9 in clinical studies. (For further details, see CLINICAL TRIALS.)
10.2 Pharmacodynamics
Not Applicable
10.3 Pharmacokinetics
In clinical pharmacokinetic studies, doxycycline concentrations in gingival crevicular fluid (GCF)
peaked (approx. 1500 µg/mL) two hours following treatment with ATRIDOX
®
. Levels remained
above 1000 µg/mL through 18 hours, when they began to gradually decline to 140 µg/mL at Day
7. Local levels of doxycycline remained well above the minimum inhibitory concentration (MIC
90
)
for periodontal pathogens (< 6.0 µg/mL) for seven days post-treatment. In comparison, 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. In comparison with administration of
oral doxycycline, treatment with ATRIDOX
®
resulted in 1) initial local GCF levels approximately 600
times greater than those achieved with oral doxycycline, and 2) seven day local GCF levels that
were approximately 740 times the levels achieved in GCF after seven days of oral doxycycline.
Following use of ATRIDOX
®
, the maximum doxycycline concentration in the saliva two hours post-
treatment was 4.05 µg/mL. This decreased to 0.36 µg/mL by Day 7. The concentration of
doxycycline in serum following treatment with the ATRIDOX
®
product never exceeded 0.1 µg/mL.
Extremely high levels of drug available at the periodontal site, relatively low levels in the saliva and
extremely low levels in serum indicate that this is a suitable method of delivering doxycycline
hyclate into periodontal pockets.
The pharmacokinetic profile of doxycycline hyclate from ATRIDOX
®
controlled-release doxycyline
gel was studied in two studies described in Table 2. Table 2 below outlines two pharmacokinetic
studies of doxycycline hyclate.
ATRIDOX
®
Product Monograph Page 13 of 25
Table 2: Human Pharmacokinetic Studies
Study
Study
Design
Objectives
Treatment
Subjects
Treatment
I
single-
centre,
single-blind,
randomized,
parallel
Characterize release
profile of
doxycycline in GCF,
saliva and serum of
subjects with chronic
adult periodontitis
ATRIDOX
®
& Coe-Pak
TM
ATRIDOX
®
& Octyldent
TM
Oral doxycycline 100-200
mg qd
13
13
6
7 days x 1
application
up to 3
months
x 1 application
8 days
II
(feasibility
study)
multi-centre,
open label,
randomized,
parallel
Quantitate and
compare
doxycycline release
characteristics of
ATRIDOX
®
Product
covered with
different retentive
material in GCF of
subjects with chronic
adult periodontitis
ATRIDOX
®
& Coe-Pak
TM
ATRIDOX
®
& Octyldent
TM
ATRIDOX
®
& No
retentive material
ATRIDOX
®
& Coe-Pak
TM
& Octyldent
TM
12
12
12
4*
Up to 28 days
x 1 application
Up to 6 hours
x 1 application
* Four supplemental subjects were enrolled to train investigators in GCF sampling procedures (ATRIDOX
®
product was removed at 6 hours)
Results of Study I showed doxycycline concentrations in GCF peaked at 2 hours in both the Coe-
Pak
TM
(mean value = 1500 µg/mL) and Octyldent
TM
(mean value = 2000 µg/mL) ATRIDOX
®
groups.
These levels remained above 1000 µg/mL in both groups through 18 hours at which time the levels
began to gradually decline. By Day 7, the mean GCF doxycycline concentrations in the Coe-
PakTM and OctyldentTM groups were 317 µg/mL and 148 µg/mL, respectively. In comparison,
subjects receiving oral doxycycline had a peak GCF level of 2.5 µg/mL at 12 hours following the
initial oral dose 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.
Doxycycline concentrations in saliva also peaked at two hours in both the Coe-Pak
TM
(mean value
= 4 µg/mL) and Octyldent
TM
(mean value = 9 µg/mL) groups. These levels dropped below 2 µg/mL
at 6 hours in the Coe-Pak
TM
group and at 24 hours in the Octyldent
TM
group. Minimal doxycycline
was detected in the saliva of subjects administered oral doxycycline, with the highest level achieved
at 18 hours on Day 1 (0.12 µg/mL).
Low levels of doxycycline were detectable in the serum in both ATRIDOX
®
groups. Mean
doxycycline concentrations of 0.08 to 0.10 µg/mL were measured from two to eight hours post
product application. Levels dropped to between 0.05 and 0.07 µg/mL from Hour 12 to Hour 24
(Day 1). After Day 2, serum levels of doxycycline were undetectable (limit of detection of assay =
0.04 µg/mL). In contrast, subjects receiving 100 mg oral doxycycline had serum doxycycline levels
ranging from 0.9 to 2.3 µg/mL over the eight days of treatment. Table 3 summarizes the
pharmacokinetic data for this study.
ATRIDOX
®
Product Monograph Page 14 of 25
Table 3: Pharmacokinetic Summary Comparing Treatment Groups
Body Fluid
Parameter
Coe-Pak
TM
(Mean Value)
Octyldent
TM
(Mean Value)
Oral doxycycline
(Mean Value)
GCF
1
C
max
(µg/mL)
2,640.00
3,110.00
3.50
AUC (µg-hr/mL)
120,000.00
93,000.00
115.00
T
max
(hours)
24.26
10.56
23.83
Serum
2
C
max
(µg/mL)
0.12
0.10
2.60
AUC (µg-hr/mL)
2.32
2.10
264.00
T
max
(hours)
5.14
5.08
15.85
Saliva
1
C
max
(µg/mL)
4.15
8.41
0.12
AUC (µg-hr/mL)
92.8
148.00
10.50
T
max
(hours)
3.68
2.30
18.03
1
Mean of GCF and Saliva data through Day 7
2
Mean of Serum data through Day 8
Study II was a feasibility study conducted prior to Study I. The results of this study demonstrated
that a single application of product provided high local levels of doxycycline in GCF through seven
days. There was an initial burst of doxycycline (approximately 950-1300 µg/mL) by two hours,
followed by controlled-release. Doxycycline levels in GCF remained well above MIC
90
levels (< 6
µg/mL) for periodontal pathogens through Day 7.
Both pharmacokinetic studies demonstrated high local levels of doxycycline in GCF for seven days
after a single application of ATRIDOX
®
. Evaluating drug levels in the serum demonstrated that a
single application of the treatment results in relatively low systemic exposure.
Table 4 compares doxycycline concentrations at various time points in dressing (Octyldent
TM
) and
no-dressing groups. Levels of doxycycline are well above the MIC
90
for suspected periodontal
pathogens (< 6 µg/mL) at all time points through Day 7 in both treatment groups. These data
support use of the product without use of a dressing.
Table 4: Summary of Doxycycline Concentration by Timepoint (Dressing and No-Dressing)
Time
Point
OCTYLDENT
TM
TREATMENT GROUP
(µg/mL)
NO-DRESSING TREATMENT GROUP
(µg/mL)
N
Mean
S.E.
N
Mean
S.E.
Baseline
12
0.00
0.00
12
0.00
0.00
Hour 2
12
928
211
12
918
233
Hour 4
12
330
120
12
599
110
Hour 6
12
569
127
12
589
209
Hour 8
12
442
8501
12
653
279
Hour 18
12
689
186
12
885
212
Day 1
12
819
346
12
565
105
Day 2
12
878
175
12
547
145
Day 3
12
1530
336
12
954
303
Day 5
12
151
43.8
12
149
57.3
Day 7
12
753
350
12
136
45.1
11 STORAGE, STABILITY AND DISPOSAL
Store at 2–8 °C (36-46 °F). After product constitution, the product is to be stored at room
temperature up to three days between 15–30°C.
12 SPECIAL HANDLING INSTRUCTIONS
Not Applicable
ATRIDOX
®
Product Monograph Page 15 of 25
PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: Doxycycline Hyclate Controlled-Release Gel
Chemical name: [4S-(4,4a,5,5a,6,12a)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-
octohydro-3,5,10,12,-12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide
monohydrate
Molecular formula and molecular mass:
(C
22
H
24
N
2
O
8
•HCl)
2
•C
2
H
6
O•H
2
O
The molecular weight of Doxycycline (C
22
H
24
N
2
O
8
) is 444.45.
The molecular weight of Doxycycline Hyclate is 1025.89.
Structural formula:
Monohydrate [4S-(4α,4aα,5α,5aα,6α,12aα)]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octohydro-
3,5,10,12,-12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphtacenecarboxamide
Physicochemical properties: Doxycycline hyclate is a light yellow, crystalline powder that is soluble
in water. It is an amphoteric substance, like all tetracyclines, with 3 acid groups of respective pk
a
3.4, 7.7, 9.7 and an isoelectric point at pH of 5.6, where the molecule is most lipophilic.
14 CLINICAL TRIALS
14.1 Trial Design and Study Demographics
Four controlled clinical trials were conducted with ATRIDOX
®
(See Table 5). These studies
mimicked the frequency of periodontal treatment in clinical practice where patients are usually seen
every four months for maintenance-type visit. Hence, subjects received two applications, at
Baseline and at Month 4. The primary clinical endpoint was attachment level, defined as the
distance from the cemento-enamel junction to the tip of the periodontal probe during periodontal
probing. The secondary clinical endpoints were change in probing depth and bleeding on probing.
In Study 1, a uniphase drug dosage form was used. This dosage form was the initial formulation
studied during drug development, with the same doxycycline concentration [8.8% w/w] and release
characteristics as the two-phase dosage form (ATRIDOX
®
) developed for the other clinical studies.
ATRIDOX
®
Product Monograph Page 16 of 25
Table 5: Well-Controlled Clinical Studies with ATRIDOX
®
Study
Study
Design
Objectives
Treatment
No. of
Subjects
Treatment
Study 1
(Polson
et al.
1
)
Randomized,
single-blind,
parallel
placebo
control
9 month
duration
Compare periodontal
effects of treatment for
chronic adult
periodontitis with:
i) Uniphase drug dosage
form vs. placebo control
ii) SaCl
2
vs. placebo
control
iii) ATRIDOX
®
vs. SaCl
5% SaCl
2
with
Coe-Pak
TM
Uniphase drug
dosage for with
Coe-Pak
TM
Placebo with Coe-
Pak
TM
60
61
59
7 days x 2
applications
Study 2
Randomized,
single-blind,
parallel
placebo
control, oral
hygiene
control, SRP
3
control
9 month
duration
Compare periodontal
effects of treatment for
chronic adult
periodontitis with:
i) ATRIDOX
®
vs.
placebo control
ii) ATRIDOX
®
vs. oral
hygiene
iii) ATRIDOX
®
vs. SRP
3
ATRIDOX
®
with
Coe-Pak
TM
Placebo with Coe-
Pak
TM
Oral hygiene
SRP
3
101
104
102
104
7 days x 2
applications
Study 3
Randomized,
single-blind,
parallel
placebo
control, oral
hygiene
control, SRP
3
control
Compare periodontal
effects of treatment for
chronic adult
periodontitis with:
i) ATRIDOX
®
vs.
placebo control
ii) ATRIDOX
®
vs. oral
hygiene
iii) ATRIDOX
®
vs. SRP
3
ATRIDOX
®
with
Coe-Pak
TM
Placebo with Coe-
Pak
TM
Oral hygiene
SRP
3
106
106
102
108
7 days x 2
applications
Study 4
Randomized,
single-blind,
parallel
placebo
control
Compare periodontal
effects of treatment for
chronic adult
periodontitis with:
i) ATRIDOX
®
left in vs.
ATRIDOX
®
removed @
day 7
Compare periodontal
effect of treatment for
chronic adult
periodontitis with:
i) ATRIDOX
®
left in vs.
Placebo left in
ii) ATRIDOX
®
removed
vs. Placebo left in
ATRIDOX
®
with
Octyldent
TM
ATRIDOX
®
with
Coe-Pak
TM
Placebo with
Octyldent
TM
198
204
203
7 days x 2
applications
1
Polson et al. Journal of Periodontology, February 1997 68:110-118; 68:119-126
2
ATRIGEL
®
Delivery System with 5% sanguinarium chloride (w/w)
3
Scaling and Root Planing
ATRIDOX
®
Product Monograph Page 17 of 25
14.2 Study Results
Results among the four trials were consistent (See Table 6). Doxycycline treatment was statistically
superior to placebo in terms of attachment level gain and pocket depth reduction at nine months
after initial treatment. Doxycycline was also superior to oral hygiene and clinically comparable to
SRP at nine months. Treatment with doxycycline also demonstrated reduced bleeding on probing
in all four studies. This was statistically superior to oral hygiene (Study 2, 3) and placebo (Study
1, 3, 4).
Doxycycline treatment resulted in a nine month attachment gain of 1.0 mm (Study 1) and 0.8 mm
(Study 2, 3, 4). This provides evidence for the efficacy of ATRIDOX
®
. Comparison of the
doxycycline treatment to SRP (Study 2, 3) indicated nearly identical clinical improvements, again
supporting the efficacy of ATRIDOX
®
. (See Table 6.)
Table 6: Efficacy Results
Study
Parameter
Treatment
Group
N
Baseline
Mean
Mean Change from Baseline
Month 4
Month 6
Month 9
Study 1
Attachment
Level
ATRIDOX
®
Placebo
SaCl
1
56
53
54
5.3
5.6
5.5
0.9*
0.6
0.8
1.2*
0.8
0.6
1.0*
0.6
0.5
Probing
Depth
ATRIDOX
®
Placebo
SaCl
56
53
54
6.0
6.0
6.0
1.5*
1.0
1.2
1.9*
1.2
1.2
1.8*
1.2
1.1
Study 2
Attachment
Level
ATRIDOX
®
Placebo
OH
2
SRP
3
95
94
95
99
6.1
6.1
6.2
5.8
0.6*†
0.3
0.4
0.6
0.8*†
0.1
0.3
0.7†
0.8*†
0.1
0.3
0.6†
Probing
Depth
ATRIDOX
®
Placebo
OH
SRP
95
94
95
99
6.0
5.9
6.0
5.9
0.9†
0.8
0.6
0.9†
1.1*†
0.8
0.5
1.1*†
1.1*†
0.8
0.5
0.9†
Study 3
Attachment
Level
ATRIDOX
®
Placebo
OH
SRP
96
96
94
103
5.6
5.9
6.0
5.7
0.7*†
0.4
0.5
0.6
0.8*†
0.4
0.5
0.7
0.8*†
0.5
0.5
0.9†
Probing
Depth
ATRIDOX
®
Placebo
OH
SRP
96
96
94
103
5.9
6.0
5.9
5.9
1.0*†
0.7
0.7
1.1†
1.3*†
0.9
0.9
1.3*†
1.3*†
1.0
0.9
1.3†
Study 4
Attachment
Level
ATRIDOX
®
left in
ATRIDOX
®
removed
Placebo left in
185
194
193
6.1
6.2
5.7
0.7*
0.7*
0.5
0.8*
0.8*
0.5
0.8*
0.8*
0.6
Probing
Depth
ATRIDOX
®
left in
ATRIDOX
®
removed
Placebo left in
185
194
193
5.9
5.9
5.8
0.9*
1.0*
0.7
1.1*
1.1*
0.9
1.1*
1.2*
0.8
1
ATRIGEL
®
Delivery System with 5% sanguinarium chloride (w/w)
2
OH = oral hygiene
3
SRP = scaling and root planing
* ATRIDOX
®
group statistically superior to Placebo (p < 0.05)
† ATRIDOX
®
or SRP group statistically superior to OH (p < 0.05)
Data from the four studies indicate use of the ATRIDOX
®
product with Coe-Pak
TM
, Octyldent
TM
or
no retentive material system.
ATRIDOX
®
Product Monograph Page 18 of 25
ATRIDOX
®
has a benign safety profile regardless of how long the product is retained in the
periodontal pocket. Nothing indicates that leaving the remaining product in the periodontal pocket
to bioabsorb or be expelled naturally leads to an increased risk of adverse events or adversely
affects clinical efficacy.
Early loss of the product following placement does not effect clinical responses (see Table 7).
Within patient comparisons between sites where product was lost early and where it was retained
for seven days show no differences in clinical efficacy.
Table 7: Clinical Response Following Early Loss of ATRIDOX
®
Clinical Index
Polymer
Retention
Period
# of
Subjects
Product Not Retained
Retained > 7 days
p-value*
Mean (s.e.)
# of
Sites
Mean (s.e.)
# of
Sites
Attachment
Level Gain
< 3 Days
32
0.85 (0.19)
142
0.88 (0.13)
360
0.833
< 5 Days
47
0.72 (0.15)
256
0.74 (0.19)
548
0.893
Probing Depth
Reduction
< 3 Days
43
-1.14 (0.17)
159
-1.19 (0.11)
588
0.802
< 5 Days
61
-1.05 (0.13)
280
-1.07 (0.09)
833
0.913
Bleeding on
Probing
Reduction
< 3 Days
43
-0.77 (0.10)
159
-0.70 (0.07)
588
0.575
< 5 Days
61
-0.72 (0.08)
280
-0.61 (0.06)
833
0.315
* Analysis is based on subject means
14.3 Comparative Bioavailability Studies
Not Applicable
15
MICROBIOLOGY
In vitro Susceptibility
Tetracyclines have a broad spectrum of antimicrobial activity against anaerobic, microaerophilic
and facultatively anaerobic gram-positive and gram-negative bacteria associated with periodontal
disease.
MIC
90
testing of doxycycline and tetracycline against various periodontal pathogens has been
performed using a broth microtube methodology. Table 8 lists the MIC
90
test results. The data
indicate a high degree of susceptibility to both doxycycline and tetracycline.
Table 8: Susceptibility of Periodontal Pathogens to Doxycycline and Tetracycline (MIC
90
)
Microorganism (No. of strains)
Doxycycline (µg/mL)
Tetracycline (µg/mL)
MIC
90
*
Range
MIC
90
*
Range
Actinobacillus actinomycetemcomitans (12)
Campylobacter rectus (5)
Fusobacterium nucleatum (10)
Porphyromonas gingivalis (5)
Prevotella intermedia (8)
4
0.25
0.063
0.063
0.5
0.063-0.8
0.063-0.25
0.063
0.063
< 0.063-1
16
0.5
0.125
0.125
1
0.063-16
0.063-0.5
0.063-0.25
0.063-0.125
< 0.063-2
* MIC
90
is the concentration at which the drug inhibits 90% of strains tested.
Antimicrobial Resistance to Doxycycline
Walker et al. determined the antibiotic susceptibilities of approximately 300 bacterial strains
isolated from adult periodontitis patients between 1991-1995. The MIC
90
values for this study were
compared to those generated in a similar study where the antibiotic susceptibilities were
determined for approximately 900 bacterial strains isolated from adult periodontitis patients
between 1980-1985. Comparison of the previous and recent susceptibilities resulted in a 172% and
ATRIDOX
®
Product Monograph Page 19 of 25
193% increase in resistance to tetracycline and doxycycline, respectively. The observed increase
in resistance to tetracyclines in the above study is after oral administration of the antibiotic. Such
resistance to tetracyclines is not observed after use of ATRIDOX
®
controlled-release doxycycline
gel since doxycycline is delivered directly to the periodontal pocket with minimal absorption into the
saliva.
Olsvik et al. examined periodontal bacteria resistant to 10 µg/mL tetracycline, which had been
isolated from patients treated systemically with the antibiotic for periodontitis. Researchers found
that 22.9% of the total cultivatable bacteria were resistant compared to 7.2% in an untreated control
group. Most of the resistant bacteria were streptococci.
Walker, et al. and Olsvik, et al. describe bacteria resistant to 4 and 10 µg/mL of doxycycline and
tetracycline, respectively, with controlled-release delivery systems placed directly into diseased
periodontal pockets, such as ATRIDOX
®
, much higher levels of drug can be sustained over longer
periods. In a primary pharmacokinetic study in humans using ATRIDOX
®
, mean doxycycline
concentrations in gingival crevicular fluid (GCF) were greater than 800 µg/mL throughout the first
24 hours following product administration, greater than 300 µg/mL on Days 2, 3, and 5 and greater
than 100 µg/mL on Day 7.
A randomized, well-controlled, single-blind, single-centre microbial resistance study was conducted
to observe the effect of ATRIDOX
®
on doxycycline-resistant microbiota. Forty-five subjects
received either ATRIDOX
®
through subgingival administration into periodontal pockets or oral
hygiene. Results showed an absence of large increases in doxycycline-resistant bacteria in the
subgingival plaque and only a transient increase in resistant bacteria in saliva immediately after
treatment with ATRIDOX
®
. Apparently, the types of doxycycline-resistant bacteria found
throughout the study (streptococci, Fusobacterium prausnitizii, Clostridium malenominatum,
Bifidobacterium, Campylobacter concisus) were part of the normal microbiota that were intrinsically
resistant to doxycycline as well as other antibiotics. Both ATRIDOX
®
and oral hygiene treatments
resulted in reduction of periodontal pathogens in treated periodontal pockets. However, the
magnitude of reductions was greater following ATRIDOX
®
treatment. Reduction in the periodontal
pathogens and total anaerobic bacteria was consistent with a microbial shift towards periodontal
health. No doxycycline resistance was observed in periodontal pathogens following treatment with
ATRIDOX
®
.
16
NON-CLINICAL TOXICOLOGY
Acute Toxicity
Doxycycline has a low acute toxicity potential for both oral and parenteral administration. The oral
LD
50
values in mice are 1007 mg/kg for males and 757 mg/kg for females, > 2000 mg/kg in rats and
> 500 mg/kg in dogs. After intraperitoneal injection, LD
50
values in mice, guinea pigs and rats are
204, 175, and 281 mg/kg respectively. There is no difference in LD
50
values between newborn and
adult rats.
Poly(DL-lactide) (PLA) is a well known biodegradable polymer approved for use in surgical sutures,
plates and screws. It is also used as an aid to prevent dry sockets when used in tooth extraction
sites. There are a number of published reports on the use of PLA in dental conditions. Olson et al.
found that a PLA mesh was well tolerated and did not interfere with the healing process in tooth
extraction sites in dogs. Magnusson et al.
used a model in the dog of healing after periodontal
surgery to compare the effects of PLA membranes, with a degradation time of 2 to 3 months, with
Millipore filters and untreated controls. Similar healing properties have been reported with
ATRISORB
®
GTR Barrier material, which contains PLA, in surgically-induced or naturally occurring
periodontitis in dogs by Polson et al.
ATRIDOX
®
Product Monograph Page 20 of 25
The biological process by which the alpha-polyesters such as PLA degrade is principally by
hydrolysis into lactic acid. Lactic acid generated in the aqueous environment of human tissues
becomes incorporated into the TCA cycle and is excreted by the lungs as carbon dioxide and water.
Brady et al., using
14
C-labelled PLA implanted into the abdominal wall of rats reported that less
than 0.3% of radioactivity was found in the tissues analyzed. The majority of the radiolabel after
168 days was found to be respired (29.4%) with only 4.6% and 2.8% in the urine and feces
respectively.
Overall, PLA is a well recognized and widely used material in surgical and dental conditions which
is well tolerated and degraded by natural processes.
N-methyl-2-pyrrolidone (NMP) - LD
50
values in mice and rats for NMP are found in Table 9.
Table 9: Median LD
50
values (and ranges) mg/kg in mice and rats for NMP
MOUSE
RAT
i.v.
i.p.
p.o.
i.v.
i.p.
p.o.
3.5
(3.1-3.9)
4.3
(4.0-4.6)
7.5
(5.9-9.6)
2.2
(2.1-2.4)
2.4
(2.3-2.6)
3.8
(3.1-4.4)
(from: Bartsch et.al., 197623)
Clark et al.
reported deaths in rats following dermal doses of 5 or 10 g/kg but not with 2.5 g/kg, mild
irritancy was observed. This low degree of toxicity was similar to LD
50
values in another dermal
study in rabbits with normal skin of 4 to 8 g/kg and with abraded skin of 2 to 4 g/kg. In a single
dose inhalation study in rats with exposure to NMP for 6 hours and observation for 2 weeks no
deaths occurred at 40 mg/L.
ATRIDOX
®
controlled-release doxycyline gel: In view of the low systemic absorption, and the
relative lack of non-clinical information on doxycycline toxicity in the literature, no acute toxicity
studies were conducted with ATRIDOX
®
.
Chronic Toxicity
Doxycycline: Chronic toxicity studies in the rat, dog, and monkey revealed the characteristic
tetracycline effect of non-reversible bone, teeth and thyroid staining. However, doxycycline was
not associated with toxicity.
PLA: No data available
NMP:
Table 10: Chronic Toxicity of NMP
Route
Species
NOEL/NOAEL*
Reference
Subcutaneous
Mice
25 mg
Van Esch and Kroes, 1972
Oral
Mice
277 mg/kg/day
BASF Report, 1995
Oral
Rat
90 mg/kg/day
Haskell Laboratory for Toxicology and Industrial
Medicine, 1995
Oral
Dog
250 mg/kg/day
Becci, 1982
Inhalation
Rat
0.4 mg/L
Lee et al., 1987
* NOEL = No Observed Effect Level; NOAEL = No Observed Adverse Effect Level
Oral toxicity studies of 90 days duration have been conducted to internationally recognized
guidelines in the mouse, rat and beagle dog. Overall, little toxicity has been shown.
ATRIDOX
®
Product Monograph Page 21 of 25
ATRIDOX
®
controlled-release doxycycline gel: No chronic toxicity studies were conducted with
ATRIDOX
®
.
Carcinogenesis and Mutagenesis
Animal studies (to evaluate carcinogenic potential and, mutagenic potential) for ATRIDOX
®
have
not been performed. 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: No data on the mutagenic or carcinogenic potential of doxycycline are available.
PLA: Although it is of limited relevance to the use of the NMP/PLA polymer formulation in
ATRIDOX
®
, a recent report of the experimental tumorigenicity of PLA plates is noted.
Plates of PLA
or control, medial grade polyethylene, were implanted subcutaneously in rats which were killed
after 2 years; sham operated rats acted as controls. Virtually no degradation of the PLA plates had
occurred after 2 years. Malignant tumors at the implantation site occurred in 22/50 and 23/50 rats
treated with PLA and polyethylene, respectively. Induction of foreign body tumors at implantation
sites is well recognized in rodents but the clinical importance of this finding is limited.
NMP: Several mutagenicity studies have been conducted on NMP.
No tests, either in vitro or in
vivo, revealed signs of mutagenic potential. In vitro studies in yeast demonstrated that NMP can
induce aneuploidy, without any genetic effects, but an in vivo micronucleus test with this organism
demonstrated a negative result.
Chinese hamsters exposed to six weeks of inhalation also
demonstrated a negative result for chromosome damage in the bone marrow.
Long-term studies
in mice and rats have shown no carcinogenic potential.
ATRIDOX
®
controlled-release doxycycline gel: Extensive administration of oral and parenteral
doxycycline for more than 30 years has shown no evidence of mutagenic or carcinogenic potential.
Since ATRIDOX
®
is essentially a single-use topical product, no studies on the product have been
conducted.
Reproductive Toxicity and Teratology
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.
In reproductive toxicity studies, no evidence of embryo toxicity or teratogenicity associated with
doxycycline has been observed with oral dosages of 20 mg/kg/day in the mouse, and 20 and 50
mg/kg/day in the rabbit.
Cahen and Fave reported that doses 100 times greater than the clinical
oral dose produced no fetal malformations, abortions, or fetal resorption in mice, rats and rabbits.
However, tetracyclines, as a class, cross the placenta and have been reported to be embryotoxic
in animals treated in early pregnancy. Additionally, permanent discolouration of the teeth can occur
during tooth development in late pregnancy and in children up to eight years. Tooth staining occurs
in pups when the bitch is given tetracycline during the last two to three weeks of pregnancy and to
pigs during their first month of life.
PLA: No data available
NMP: Studies where NMP is administered dermally to rats and orally to rabbits have demonstrated
embryolethality and increased incidences of malformations.
However, this occurs only in the
presence of significant maternal toxicity as shown by reductions in body weight and food
ATRIDOX
®
Product Monograph Page 22 of 25
consumption. Thus, NMP shows embryotoxicity and teratogenic potential at high oral or dermal
doses. Evidence indicates that the effects occur only at doses which induce maternal toxicity.
However, a direct effect of the compound cannot be ruled out.
ATRIDOX
®
controlled-release doxycycline gel: No reproductive toxicity studies were conducted on
ATRIDOX
®
, however it is contraindicated during pregnancy and lactation and in young children
because of the doxycycline content.
Local Irritation
Subgingival application of ATRIDOX
®
in the dog results in transient slight irritancy that quickly
resolves. The constituents of the polymer formulation, PLA and NMP, and the polymer itself, have
shown little, if any, increase in irritancy potential in comparison to control materials, such as saline
and USP Control Plastic. No dermal sensitizing potential for doxycycline or the polymer formulation
was observed in the guinea pig, predicting low clinical risk of contact sensitization.
17
SUPPORTING PRODUCT MONOGRAPHS
Not Applicable
ATRIDOX
®
Product Monograph Page 23 of 25
READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE
PATIENT MEDICATION INFORMATION
Pr
ATRIDOX
®
Doxycycline Hyclate Controlled-Release Gel
Read this carefully before you start taking ATRIDOX and each time you receive it in the future. This
leaflet is a summary and will not tell you everything about this drug. Talk to your healthcare
professional about your medical condition and treatment and ask if there is any new
information
about ATRIDOX.
What is ATRIDOX used for?
• ATRIDOX is used in adults to treat inflammation (swelling) of the tissue around the teeth
called “periodontitis”.
• Antibacterial drugs like ATRIDOX treat only bacterial infections. They do not treat viral
infections.
How does ATRIDOX work?
ATRIDOX is a gel that is injected by your dentist into the periodontal pocket (the space between
your gums and your teeth). ATRIDOX contains doxycycline, a tetracycline antibiotic, that stops the
growth of bacteria. Reducing the amount of bacteria in the periodontal pocket can help treat
“periodontitis”.
What are the ingredients in ATRIDOX?
Medicinal ingredients: doxycycline hyclate
Non-medicinal ingredients: ATRIGEL Delivery System (63.3% N-methyl-2-pyrrolidone and 36.7%
poly(DL-lactide))
ATRIDOX
comes in the following dosage forms:
Controlled-release gel: 8.8% w/w
Do not use ATRIDOX if you:
• are allergic (hypersensitive) to doxycycline or any other tetracycline antiobiotic.
• are pregnant.
• are breastfeeding.
• are under the age of 18 (ATRIDOX should not be used during tooth development).
To help avoid side effects and ensure proper use, talk to your healthcare professional
before you take ATRIDOX. Talk about any health conditions or problems you may
have,
including if you:
• have a history of liver failure.
• are sensitive to sunlight, have a history of sunburns, or are exposed to direct sunlight (or
ultraviolet light) on a regular basis.
• have diabetes.
• are receiving chemotherapy or radiation treatment.
• have HIV infection.
• have or have a history of thrush (a yeast infection in your mouth).
• have dental implants or are going to be getting dental implants.
ATRIDOX
®
Product Monograph Page 24 of 25
Other warnings you should know about:
Using tretracycline antibiotics, including ATRIDOX, during tooth development may cause
permanent discolouration of the teeth. ATRIDOX is therefore only to be used in adults. ATRIDOX
is not to be used during pregnancy or while breastfeeding.
In the area(s) where your dentist has injected ATRIDOX you should not brush or flossing for seven
days.
ATRIDOX can cause your skin to become sensitive to the sun and UV light. You should avoid
exposure to direct sunlight and UV light while you are being treated with ATRIDOX. If you are going
to be exposed to sunlight or UV light while you are being treated with ATRIDOX you must wear
protective clothing. If you get a sunburn or notice any skin reddening while you are being treated
with ATRIDOX contact your healthcare professional immediately.
Tell your healthcare professional about all the medicines you take, including any drugs,
vitamins, minerals, natural supplements or alternative medicines.
The following may interact with ATRIDOX:
• anticoagulant medications used to thin the blood and prevent blood clots.
• methoxyflurane anesthesia used to control pain in emergency settings.
• hormonal birth control (such as pills, patch or ring). ATRIDOX may decrease the
effectiveness of hormonal birth control.
How to take ATRIDOX:
Your healthcare professional will administer ATRIDOX.
• Although you may feel better early in treatment, ATRIDOX should be used exactly as
directed.
• Misuse or overuse of ATRIDOX could lead to the growth of bacteria that will not be killed
by ATRIDOX (resistance). This means that ATRIDOX may not work for you in the future.
• Do not share your medicine.
Usual adult dose:
Your dentist will decide how many periodontal pockets to treat and how much ATRIDOX to use.
Overdose:
Overdose with ATRIDOX is unlikely due to the small doses used however, if you think you
have been given too much ATRIDOX, contact your healthcare professional,
hospital
emergency department or regional poison control centre immediately, even if there
are no
symptoms.
What are possible side effects from using ATRIDOX?
These are not all the possible side effects you may feel when taking ATRIDOX. If you
experience
any side effects not listed here, contact your healthcare professional.
Side effects may include:
Gum discomfort/pain/soreness, gum swelling
Bleeding gums
Mouth sores, mouth pain
Toothache
Tooth sensitivity to hot/cold
ATRIDOX
®
Product Monograph Page 25 of 25
Serious side effects and what to do about them
Symptom / effect
Talk to your healthcare
professional
Stop taking drug
and get immediate
medical help
Only if severe
In all cases
Allergic reaction: rash, hives,
swelling of the face, lips, tongue
or throat, difficulty swallowing or
breathing
√
Periodontal abscess
(infection): deep, throbbing pain,
red and swollen gum that is
painful to touch, pus or other
discharge from around the tooth,
jaw pain
√
Loose teeth or tooth loss
√
If you have a troublesome symptom or side effect that is not listed here or becomes bad
enough to
interfere with your daily activities, talk to your healthcare professional.
Reporting Side Effects
You can report any suspected side effects associated with the use of health products to
Health Canada by:
Visiting the Web page on Adverse Reaction Reporting (https://www.canada.ca/en/health-
canada/services/drugs-health-products/medeffect-canada/adverse-reaction-
reporting.html) for information on how to report online,
by mail or by fax; or
Calling toll-free at 1-866-234-2345.
NOTE: Contact your health professional if you need information about how to manage your
side effects. The Canada Vigilance Program does not provide medical advice.
If you want more information about ATRIDOX:
Talk to your healthcare professional
Find the full product monograph that is prepared for healthcare professionals and
includes
this Patient Medication Information by visiting the Health Canada website
https://www.canada.ca/en/health-canada.html) or by calling
905-820-3475.
This leaflet was prepared by Tolmar, Inc.
Last Revised January 23, 2019