Alodox

OCuSOFT INC.
OCuSOFT INC.

Alodox Convenience Kit

FULL PRESCRIBING INFORMATION: CONTENTS*

• ALODOX DESCRIPTION:
• CLINICAL PHARMACOLOGY:
• Mechanism of Action:
• Microbiology:
• Pharmacokinetics:
• ALODOX INDICATIONS AND USAGE:
• ALODOX CONTRAINDICATIONS:
• WARNINGS:
• PRECAUTIONS:
• Information for Patients:
• Laboratory Tests:
• Drug Interactions:
• Drug/Laboratory Test Interactions:
• Carcinogenesis, Mutagenesis, Impairment of Fertility:
• Pregnancy:
• Nonteratogenic effects:
• Labor and Delivery:
• Nursing Mothers:
• Pediatric Use:
• ALODOX ADVERSE REACTIONS
• OVERDOSAGE
• ALODOX DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• REFERENCES

FULL PRESCRIBING INFORMATION

DESCRIPTION:

The structural formula of doxycycline hyclate is:

with a molecular formula of (C₂₂H₂₄N₂O_8.HCI)_2.C₂H₆O.H₂O and a molecular weight of 1025.89. The chemical designation for doxycycline is 4-(dimethylamino)-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydro-3, 5, 10, 12, 12a-pentahydroxy-6 -methyl-1, 11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate.

Doxycycline hyclate is a yellow to light-yellow crystalline powder which is soluble in water.

Each tablet for oral administration contains 23mg doxycycline hyclate equivalent to 20 mg of doxycycline. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, carnauba wax, croscarmellose sodium, hypromellose, magnesum stearate, microcrystalline cellulose, poldextrose, polyethylene glycol, titanium dioxide, and triacetin.

CLINICAL PHARMACOLOGY:

After oral administration, doxycycline hyclate is rapidly and nearly completely absorbed from the gastrointestinal tract. Doxycycline is eliminated with a half-life of approximately 18 hours by renal and fecal excretion of unchanged drug.

Mechanism of Action:

Doxycycline has been shown to inhibit collagenase activity in vitro. ¹ Additional studies have shown that doxycycline reduces the elevated collagenase activity in the gingival crevicular fluid of patients with adult periodontitis.²³ The clinical significance of these findings is not known.

Microbiology:

Doxycycline is a member of the tetracycline class of antibiotics. The dosage of doxycycline achieved with this product during administration is well below the concentration required to inhibit microorganisms commonly associated with adult periodontitis. Clinical studies with this product demonstrated no effect on total anaerobic and facultative bacteria in plaque samples from patients administered this dose regimen for 9 to 18 months. This product should not be used for reducing the numbers of or eliminating those microorganisms associated with periodontitis.

Pharmacokinetics:

The pharmacokinetics of doxycline following oral administration of doxycycline hyclate were investigated in 4 volunteer studies involving 107 adults. Additionally, doxycycline pharmacokinetics have been characterized in numerous scientific publications^4.

INDICATIONS AND USAGE:

To reduce the development of drug-resistant bacteria and maintain the effectiveness
of Doxycycline Hyclate Tablets and other antibacterial drugs, Doxycycline Hyclate
Tablets should be used only to treat or prevent 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.
Doxycycline hyclate is indicated for use as an adjunct to scaling and root planing to
promote attachment level gain and to reduce pocket depth in patients with adult
periodontitis.

CONTRAINDICATIONS:

This drug is contraindicated in persons who have shown hypersensitivity to
doxycycline or any of the other tetracyclines.

WARNINGS:

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 (YELLOW-GRAY-BROWN). 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 AND IN
PREGNANT OR NURSING MOTHERS UNLESS THE POTENTIAL BENEFITS
MAY BE ACCEPTABLE DESPITE THE POTENTIAL RISKS

All tetracyclines form a stable calcium complex in any bone forming tissue. A
decrease in fibula growth rate has been observed in premature infants given oral
tetracyclines in doses of 25 mg/kg every 6 hours. This reaction was shown to be
reversible when the drug was discontinued.

Doxycycline can cause fetal harm when administered to a pregnant woman. 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
retardation of skeletal development). Evidence of embryotoxicity has also been
noted in animals treated early in pregnancy. If any tetracyclines are used during
pregnancy, or if the patient becomes pregnant while taking this drug, the patient
should be apprised of the potential hazard to the fetus.

The catabolic action of the tetracyclines may cause an increase in BUN. Previous
studies have not observed an increase in BUN with the use of doxycycline in
patients with impaired renal function.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed
in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight
or ultraviolet light should be advised that this reaction can occur with tetracycline
drugs, and treatment should be discontinued at the first evidence of skin erythema.

PRECAUTIONS:

General: Prescribing Doxycycline Hyclate Tablets in the absence of a proven or
strongly suspected bacterial infection or a prophylactic indication is unlikely to
provide benefit to the patient and increases the risk of the development of drugresistant
bacteria.

While no overgrowth by opportunistic microorganisms such as yeast were noted
during clinical studies, as with other antimicrobials, doxycycline hyclate therapy
may result in overgrowth of nonsusceptible
microorganisms including fungi.

The use of tetracyclines may increase the incidence of vaginal candidiasis.

Doxycycline hyclate should be used with caution in patients with a history or
predisposition to oral candidiasis. The safety and effectiveness of doxycycline
hyclate has not been established for the treatment of periodontitis in patients with
coexistant oral candidiasis.

If superinfection is suspected, appropriate measures should be taken.

Information for Patients:

Patients should be counseled that antibacterial drugs
including Doxycycline Hyclate Tablets should only be used to treat bacterial
infections. They do not treat viral infections (e.g., the common cold). When
Doxycycline Hyclate Tablets are prescribed to treat a bacterial infection, patients
should be told that although it is common to feel better early in the course of therapy,
the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Doxycycline Hyclate Tablets or other antibacterial drugs in the future.

Laboratory Tests:

In long term therapy, periodic laboratory evaluations of organ
systems, including hematopoietic, renal, and hepatic studies should be performed.

Drug Interactions:

Because tetracyclines have been shown to depress plasma
prothrombin activity, patients who are on anticoagulant therapy may require
downward adjustment of their anticoagulant dosage.

Since bacterial antibiotics, such as the tetracycline class of antibiotics, may interfere
with the bactericidal action of members of the ‚-lactam (e.g., penicillin) class of
antibiotics, it is not advisable to administer these antibiotics concomitantly.

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or
magnesium, and iron-containing preparations, and by bismuth subsalicylate.

Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

The concurrent use of tetracycline and methoxyflurane has been reported to result
in fatal renal toxicity.

Concurrent use of tetracyclines may render oral contraceptives less effective.

Drug/Laboratory Test Interactions:

False elevations of urinary catecholamine
levels may occur due to interference with the fluorescence test.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Doxycycline hyclate was assessed for potential to induce carcinogenesis in a study in which the compound
was administered to Sprague-Dawley rats by gavage at dosages of 20, 75, and 200
mg/kg/day for two years. An increased incidence of uterine polyps was observed in
female rats that received 200 mg/kg/day, a dosage that resulted in a systemic
exposure to doxycycline approximately nine times that observed in female humans
that used doxycycline hyclate (exposure comparison based upon AUC values). No
impact upon tumor incidence was observed in male rats at 200 mg/kg/day, or in
either gender at the other dosages studied. Evidence of oncogenic activity was
obtained in studies with related compounds, i.e., oxytetracycline (adrenal and
pituitary tumors), and minocycline (thyroid tumors).

Doxycycline hyclate demonstrated no potential to cause genetic toxicity in an in
vitro point mutation study with mammalian cells (CHO/HGPRT forward mutation
assay) or in an in vivo micronucleus assay conducted in CD-1 mice. However, data
from an in vitro assay with CHO cells for potential to cause chromosomal aberrations
suggest that doxycycline hyclate is a weak clastogen.

Oral administration of doxycycline hyclate to male and female Sprague-Dawley rats
adversely affected fertility and reproductive performance, as evidenced by increased
time for mating to occur, reduced sperm motility, velocity, and concentration,
abnormal sperm morphology, and increased pre-and post-implantation losses.
Doxycycline hyclate induced reproductive toxicity at all dosages that were examined
in this study, as even the lowest dosage tested (50 mg/kg/day) induced a statistically
significant reduction in sperm velocity. Note that 50 mg/kg/day is approximately 10
times the amount of doxycycline hyclate contained in the recommended daily dose
of doxycycline hyclate for a 60 kg human when compared on the basis of body
surface area estimates (mg/m2). Although doxycycline impairs the fertility of rats
when administered at sufficient dosage, the effect of doxycycline hyclate on human
fertility is unknown.

Pregnancy:

Teratogenic Effects: Pregnancy Category D. (See WARNINGS
Section). Results from animal studies indicate that doxycycline crosses the placenta
and is found in fetal tissues.

Nonteratogenic effects:

(See WARNINGS Section).

Labor and Delivery:

The effect of tetracyclines on labor and delivery is unknown.

Nursing Mothers:

Tetracyclines are excreted in human milk. Because of the
potential for serious adverse reactions in nursing infants from doxycycline, the use
of doxycycline hyclate in nursing mothers is contraindicated. (See WARNINGS
Section).

Pediatric Use:

Pediatric Use: The use of doxycycline hyclate tablets in infancy and childhood is contraindicated. (See WARNINGS Section).

ADVERSE REACTIONS

The following adverse reactions have been
observed in patients receiving tetracyclines:
Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia,
enterocolitis, and inflammatory lesions (with vaginal candidiasis) in the anogenital
region. Hepatotoxicity has been reported rarely. Rare instances of esophagitis and
esophageal ulcerations have been reported in patients receiving the capsule forms
of the drugs in the tetracycline class. Most of these patients took medications
immediately before going to bed. (See DOSAGE AND ADMINISTRATION Section).
Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been
reported but is uncommon. Photosensitivity is discussed above. (See WARNINGS
Section).
Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See
WARNINGS Section).
Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis,
anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic
lupus erythematosus.
Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have
been reported.

OVERDOSAGE

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdose.

ALODOX DOSAGE AND ADMINISTRATION

THE DOSAGE OF DOXYCYCLINE HYCLATE TABLETS DIFFERS FROM THAT
OF DOXYCYCLINE USED TO TREAT INFECTIONS. EXCEEDING THE
RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF
SIDE EFFECTS INCLUDING THE DEVELOPMENT OF RESISTANT
MICROORGANISMS.
Doxycycline hyclate tablets 20 mg twice daily as an adjunct following scaling and
root planing may be administered for up to 9 months. Doxycycline hyclate tablets
should be taken twice daily at 12 hour intervals, usually in the morning and evening.
It is recommended that if doxycycline hyclate tablets is taken close to meal times,
allow at least one hour prior to or two hours after meals. Safety beyond 12 months
and efficacy beyond 9 months have not been established.

HOW SUPPLIED

Doxycycline hyclate tablets USP equivalent to 20 mg of doxycycline, round, white,
unscored, film coated tablet, debossed MP 573 on one side and blank on the other
side.
Bottles of 60 NDC 54799-533-60
Store at 20° to 25°C (68° to 77°F)
[See USP Controlled Room Temperature]
DISPENSE IN A TIGHT, LIGHT-RESISTANT CONTAINER.

REFERENCES

1. Golub L.M., Sorsa T., Lee H-M, Ciancio S., Sorbi D., Ramamurthy N.S., Gruber
B., Salo T.,Konttinen Y.T.: Doxycycline inhibits Neutrophil (PMN)-type Matrix
Metalloproteinases in Human Adult Periodontitis Gingiva. J. Clin. Periodontol
1995; 22: 100-109.
2. Golub L.M., Ciancio S., Ramamurthy N.S., Leung M., McNamara T.F.: Low-dose
Doxycycline Therapy: Effect on Gingival and Crevicular Fluid Collagenase
Activity in Humans. J. Periodont Res 1990; 25: 321-330.
3. Golub L.M., Lee H.M., Greenwald R.A., Ryan M.E., Salo T., Giannobile W.V.: A
Matrix Metalloproteinase Inhibitor Reduces Bone-type Collagen Degradation
Fragments and Specific Collegenases in Gingival Crevicular Fluid During Adult
Periodontitis. Inflammation Research 1997; 46: 310-319.
4. Saivain S., Houin G.: Clinical Pharmacokinetics of Doxycycline and Minocycline.
Clin. Pharmacokinetics 1988; 15: 355-366.
5. Schach von Wittenau M., Twomey T.: The Disposition of Doxycycline by Man
and Dog. Chemotherapy 1971; 16: 217-228.
6. Campistron G., Coulais Y., Caillard C., Mosser J., Pontagnier H., Houin G.:
Pharmacokinetics and Bioavailability of Doxycycline in Humans. Arzneimittel
Forschung 1986; 36: 1705-1707.