188957-2

188957-2 Front 12.25" x 8.75" Fold 1.25" x 1.25" Prints Black 12/22/11 Size Sml 7pt Lrg 8pt Helv cond and Bold Doxycycline Hyclate Tablets, USP
Hepatic Insufficiency: Doxycycline pharmacokinetics have not been evaluated in
patients with hepatic insufficiency.
Drug Interactions: (See PRECAUTIONS section)
To reduce the development of drug-resistant bacteria and maintain the effectiveness Clinical Study
of doxycycline hyclate tablets and other antibacterial drugs, doxycycline hyclate In a randomized, multi-centered, double-blind, 9-month Phase 3 study involving tablets should be used only to treat or prevent infections that are proven or strongly 190 adult patients with periodontal disease [at least two probing sites per quadrant of between 5 and 9 mm pocket depth (PD) and attachment level (ALv)], the effects DESCRIPTION
of oral administration of 20 mg twice a day of doxycycline hyclate (using a Doxycycline hyclate tablets, USP is available as a 20 mg tablet formulation of bioequivalent capsule formulation) plus scaling and root planing (SRP) were doxycycline for oral administration.
compared to placebo control plus SRP. Both treatment groups were administereda course of scaling and root planing in 2 quadrants at Baseline. Measurements of The structural formula of doxycycline hyclate is: ALv, PD and bleeding-on-probing (BOP) were obtained at Baseline, 3, 6, and 9months from each site about each tooth in the two quadrants that received SRP using the UNC-15 manual probe. Each tooth site was categorized into one of three strata based on Baseline PD: 0 to 3 mm (no disease), 4 to 6 mm (mild/moderate disease), ≥ 7 mm (severe disease). For each stratum and treatment group, the following were calculated at month 3, 6, and 9; mean change in ALv from baseline, mean change in PD from baseline, mean percentage of tooth sites per patient exhibiting attachment loss of ≥ 2 mm from baseline, and percentage of tooth sites with bleeding on probing. The results are summarized in the following table.
with an empirical formula of (C22H24N2O8•HCl)2•C2H6O•H2O and a molecular weight Clinical Results at Nine Months of Doxycycline Hyclate Capsules,
of 1025.89. The chemical designation for doxycycline is 4-(dimethylamino)- 20 mg, as an Adjunct to SRP
1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo- (Bioequivalent to Doxycycline Hyclate Tablets, 20 mg)
2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol Parameter
Baseline Pocket Depth
Doxycycline hyclate is a yellow to light yellow crystalline powder which is soluble in In addition it also contains the following inactive ingredients: hypromellose, anhydrous lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide.
Each tablet contains 23 mg of doxycycline hyclate equivalent to 20 mg of doxycycline.
CLINICAL PHARMACOLOGY
After oral administration, doxycycline hyclate is rapidly and nearly completely Mean Decrease (SDƒƒ) in PD√√ absorbed from the gastrointestinal tract. Doxycycline is eliminated with a half-life 0.16 (0.19)mm** 0.95 (0.47)mm** 1.68 (1.07)mm** of approximately 18 hours by renal and fecal excretion of unchanged drug.
Mechanism of Action: Doxycycline has been shown to inhibit collagenase activity
in vitro1. Additional studies have shown that doxycycline reduces the elevated collagenase activity in the gingival crevicular fluid of patients with adult periodontitis2,3. 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 Doxycycline
adult periodontitis. Clinical studies with this product demonstrated no effect on total Hyclate Tablets, USP
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.
*p<0.050 vs. the placebo control group.
**p<0.010 vs. the placebo control group.
√ALv = Clinical Attachment Level Pharmacokinetics
The pharmacokinetics of doxycycline following oral administration of doxycycline hyclate INDICATIONS AND USAGE
tablets were investigated in 4 volunteer studies involving 107 adults. Additionally, doxycycline pharmacokinetics have been characterized in numerous scientific To reduce the development of drug-resistant bacteria and maintain the effectiveness publications4. Pharmacokinetic parameters for doxycycline hyclate tablets following of doxycycline hyclate tablets and other antibacterial drugs, doxycycline hyclate single oral doses and at steady-state in healthy subjects are presented as follows: tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture susceptibility Pharmacokinetic Parameters for Doxycycline Hyclate Tablets
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 tablets, USP are indicated for use as an adjunct to scaling and root planing to promote attachment level gain and to reduce pocket depth in CONTRAINDICATIONS
This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any of the other tetracyclines.
WARNINGS
*** Steady-State data were obtained from normal volunteers administered a bioequivalent THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY AND CHILDHOOD TO THE AGE OF 8 YEARS) Absorption: Doxycycline is well absorbed after oral administration. In a single-
MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOW-GRAY- dose study, concomitant administration of doxycycline hyclate tablets with a 1000 BROWN). This adverse reaction is more common during long-term use of the drugs calorie, high-fat, high-protein meal which included dairy products, in healthy but has been observed following repeated short-term courses. Enamel hypoplasia has volunteers, resulted in a decrease in the rate and extent of absorption and delay in 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.
Distribution: Doxycycline is greater than 90% bound to plasma proteins. Its
apparent volume of distribution is variously reported as between 52.6 and 134 L4,6.
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 Metabolism: Major metabolites of doxycycline have not been identified. However,
tetracyclines in doses of 25 mg/kg every 6 hours. This reaction was shown to be enzyme inducers such as barbiturates, carbamazepine, and phenytoin decrease reversible when the drug was discontinued.
Doxycycline can cause fetal harm when administered to a pregnant woman. Results Excretion: Doxycycline is excreted in the urine and feces as unchanged drug. It is
of animal studies indicate that tetracyclines cross the placenta, are found in fetal variously reported that between 29% and 55.4% of an administered dose can be tissues, and can have toxic effects on the developing fetus (often related to accounted for in the urine by 72 hours5,6. Half-life averaged 18 hours in subjects retardation of skeletal development).
receiving a single 20 mg doxycycline dose.
Evidence of embryotoxicity has also been noted in animals treated early in pregnancy.
Special Populations
If any tetracyclines are used during pregnancy, or if the patient becomes pregnant while Geriatric: Doxycycline pharmacokinetics have not been evaluated in geriatric patients.
taking this drug, the patient should be apprised of the potential hazard to the fetus.
Pediatric: Doxycycline pharmacokinetics have not been evaluated in pediatric
The catabolic action of the tetracyclines may cause and increase in BUN. Previous patients (See WARNINGS section).
studies have not observed an increase in BUN with the use of doxycycline in Gender: Doxycycline pharmacokinetics were compared in 9 men and 11 women
patients with impaired renal function.
under fed and fasted conditions. While female subjects had a higher rate (Cmax) Photosensitivity manifested by an exaggerated sunburn reaction has been observed and extent of absorption (AUC), these differences are thought to be due to in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight differences in body weight/lean body mass. Differences in other pharmacokinetic 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.
Race: Differences in doxycycline pharmacokinetics among racial groups have not
PRECAUTIONS
Renal Insufficiency: Studies have shown no significant difference in serum half-
Prescribing doxycycline hyclate tablets in the absence of a proven or strongly life of doxycycline in patients with normal and severely impaired renal function.
suspected bacteria infection or a prophylactic indication is unlikely to provide benefit Hemodialysis does not alter the half-life of doxycycline.
to the patient and increase the risk of the development of drug-resistant bacteria.
While no overgrowth by opportunistic microorganisms such as yeast were noted during clinical studies, as with other antimicrobials, doxycycline hyclate tablets therapy may result in overgrowth of nonsusceptible microorganisms including fungi.
The use of tetracyclines may increase the incidence of vaginal candidiasis.
Doxycycline hyclate tablets should be used with caution in patients with a history or predisposition to oral candidiasis. The safety and effectiveness of doxycycline hyclate tablets have not been established for the treatment of periodontitis inpatients 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.
Note: Percentages are based on total number of study participants in each treatment group.
Laboratory Tests: In long term therapy, periodic laboratory evaluations of organ
Adverse Reactions for Tetracyclines: The following adverse reactions have been
systems, including hematopoietic, renal, and hepatic studies should be performed.
observed in patients receiving tetracyclines: Drug Interactions: Because tetracyclines have been shown to depress plasma
Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, prothrombin activity, patients who are on anticoagulant therapy may require enterocolitis, and inflammatory lesions (with vaginal candidiasis) in the anogenital downward adjustment of their anticoagulant dosage.
region. Hepatotoxicity has been reported rarely. Rare instances of esophagitis and Since bacterial antibiotics, such as the tetracycline class of antibiotics, may esophageal ulcerations have been reported in patients receiving the capsule forms interfere with the bactericidal action of members of the β-lactam (e.g. penicillin) of the drugs in the tetracycline class. Most of these patients took medications class of antibiotics, it is not advisable to administer these antibiotics concomitantly.
immediately before going to bed. (See DOSAGE AND ADMINISTRATION Section).
Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported or magnesium, and iron-containing preparations, and by bismuth subsalicylate.
but is uncommon. Photosensitivity is discussed above. (See WARNINGS Section).
Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.
Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See WARNINGS Section).
The concurrent use of tetracycline and methoxyflurane has been reported to result Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic Concurrent use of tetracyclines may render oral contraceptives less effective.
Drug/Laboratory Test Interactions: False elevations of urinary catecholamine levels
Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have 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 OVERDOSAGE
was administered to Sprague-Dawley rats by gavage at dosages of 20, 75, and 200 In case of overdosage, discontinue medication, treat symptomatically and institute mg/kg/day for two years. An increased incidence of uterine polyps was observed supportive measures. Dialysis does not alter serum half-life and thus would not be in female rats that received 200 mg/kg/day, a dosage that resulted in a systemic of benefit in treating cases of overdose.
exposure to doxycycline approximately nine times that observed in female humans DOSAGE AND ADMINISTRATION
that used doxycycline hyclate tablets (exposure comparison based upon AUC THE DOSAGE OF DOXYCYCLINE HYCLATE TABLETS DIFFERS FROM THAT OF 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 DOXYCYCLINE USED TO TREAT INFECTIONS. EXCEEDING THE RECOMMENDED activity was obtained in studies with related compounds, i.e., oxytetracycline DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS (adrenal and pituitary tumors), and minocycline (thyroid tumors).
INCLUDING THE DEVELOPMENT OF RESISTANT MICROORGANISMS.
Doxycycline hyclate demonstrated no potential to cause genetic toxicity in an in Doxycycline hyclate tablets 20 mg twice daily as an adjunct following scaling and vitro point mutation study with mammalian cells (CHO/HGPRT forward mutation root planing may be administered for up to 9 months. Doxycycline hyclate tablets assay) or in an in vivo micronucleus assay conducted in CD-1 mice. However, data should be taken twice daily at 12 hour intervals, usually in the morning and evening.
from an in vitro assay with CHO cells for potential to cause chromosomal It is recommended that if doxycycline hyclate tablets is taken close to meal times, aberrations suggest that doxycycline hyclate is a weak clastogen.
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.
Oral administration of doxycycline hyclate to male and female Sprague-Dawley rats adversely affected fertility and reproductive performance, as evidenced by increased Administration of adequate amounts of fluid along with the tablets is recommended time for mating to occur, reduced sperm motility, velocity, and concentration, abnormal to wash down the drug and reduce the risk of esophageal irritation and ulceration.
sperm morphology, and increased pre-and post-implantation losses. Doxycycline hyclate (See ADVERSE REACTIONS Section).
induced reproductive toxicity at all dosages that were examined in this study, as even the HOW SUPPLIED
lowest dosage tested (50 mg/kg/day) induced a statistically significant reduction in Doxycycline hyclate tablets USP, 20 mg are supplied as white, round film coated sperm velocity. Note that 50 mg/kg/day is approximately 10 times the amount of tablets debossed “cor” over “152” on one side and other side is plain.
doxycycline hyclate contained in the recommended daily dose of doxycycline hyclate tablets 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 Bottles of 100 tablets (NDC 64720-152-10) dosage, the effect of doxycycline hyclate tablets on human fertility is unknown.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Pregnancy: Teratogenic Effects: Pregnancy Category D. (See WARNINGS Section).
Dispense in tight, light-resistant containers as defined in the USP.
Results from animal studies indicate that doxycycline crosses the placenta and is KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN.
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 tablets in nursing mothers is contraindicated. (See WARNINGS Section).
Pediatric Use: The use of doxycycline hyclate tablets in infancy and childhood is
contraindicated. (See WARNINGS section.)
ADVERSE REACTIONS
Adverse Reactions in Clinical Trials of a bioequivalent form of doxycycline
hyclate capsules: In clinical trials of adult patients with periodontal disease 213
patients received 20 mg BID over a 9 to 12 month period. The most frequent REFERENCES
adverse reactions occurring in studies involving treatment with a bioequivalent 1. Golub L.M., Sorsa T., Lee H-M, Ciancio S., Sorbi D., Ramamurthy N.S., Gruber form of doxycycline hyclate capsules or placebo are listed below: B., Salo T., Konttinen Y.T.: Doxycycline Inhibits Neutrophil (PMN)-type Matrix Incidence (%) of Adverse Reactions in Clinical Trials of
Metalloproteinases in Human Adult Periodontitis Gingiva. J. Clin. Periodontol: Doxycycline Hyclate Capsules, 20 mg
(Bioequivalent to Doxycycline Hyclate Tablets, 20 mg) vs. Placebo
2. Golub L.M., Ciancio S., Ramamurthy N.S., Leung M., McNamara T.F.: Low-dose Adverse Reactions
Doxycycline Hyclate
Doxycycline Therapy: Effect on Gingival and Crevicular Fluid Collagenase Activity Capsules 20 mg BID
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. Inflamation 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

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