DOXYCYCLINE HYCLATE - doxycycline hyclate tablet 
Larken Laboratories, Inc.

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DOXYCYCLINE HYCLATE TABLETS, USP

DESCRIPTION

Doxycycline hyclate is available as a 20 mg tablet formulation of doxycycline for oral administration.

The structural formula of doxycycline hyclate is:

Figure 1

structure

with a structural formula of (C22H24N2O8•HCl)2•C2H6O•H2O and a molecular weight of 1025.89.  The chemical designation for doxycycline is 4-(dimethylamino)-1,4,4(,5,5(,6,11,12(-octahydro-3,5,10,12,12(-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.

INACTIVE INGREDIENT

Colloidal silicon dioxide, hypromellose, anhydrous lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, talc, and titanium oxide.  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 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.2,3  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 microorganism 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 microorganism associated with periodontitis.

Pharmacokinetics

The pharmacokinetics of doxycycline 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 Pharmacokinetic parameters for doxycycline hyclate following single oral doses and at steady-state in healthy subjects are presented as follows:

Pharmacokinetic Parameters for Doxycycline Hyclate

nCmax*(ng/mL)Tmax**(hr)Cl/F*(L/hr)(hr)
Single dose Single dose 20 mg (tablet)20362 ± 1011.4(1.0 - 2.5)3.85 ± 1.318.1 ± 4.85
Steady-State20 mg BID***30790 ± 2852(0.98 – 12.0)3.76 ± 1.06Not Determined

* Mean ± SD

** Mean and range

*** Steady-State data were obtained from normal volunteers administered a bioequivalent formulation.

Absorption: Doxycycline is well absorbed after oral administration.  In a single-dose study, concomitant administration of doxycycline hyclate with a 1000 calorie, high-fat, high-protein meal which included dairy products, in healthy volunteers, resulted in a decrease in the rate and extent of absorption and delay in the time to maximum concentrations.

Distribution:  Doxycycline is greater than 90% bound to plasma proteins.  Its apparent volume of distribution is variously reported as between 52.6 and 134L.4,6

Metabolism:  Major metabolites of doxycycline have not been identified.  However, enzyme inducers such as barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

Excretion:  Doxycycline is excreted in the urine and feces as unchanged drug.  It is variously reported that between 29% and 55.4% of an administered dose can be accounted for in the urine by 72 hours.5,6  Half-life averaged 18 hours in subjects receiving a single 20 mg doxycycline dose.

Special Populations

Geriatric Use

Doxycycline pharmacokinetics have not been evaluated in geriatric patients.

Pediatric Use

Doxycycline pharmacokinetics have not been evaluated in pediatric patients (See WARNINGS section).

Gender:  Doxycycline pharmacokinetics were compared in 9 men and 11 women under fed and fasted conditions.  While female subjects had a higher rate (Cmax) and extent of absorption (AUC), these differences are thought to be due to differences in body weight/lean body mass.  Differences in other pharmacokinetic parameters were not significant.

Race:  Differences in doxycycline pharmacokinetics among racial groups have not been evaluated.

Renal Insufficiency:  Studies have shown no significant difference in serum half-life of doxycycline in patients with normal and severely impaired renal function.  Hemodialysis does not alter the half-life of doxycycline.

Hepatic Insufficiency:  Doxycycline pharmacokinetics have not been evaluated in patients with hepatic insufficiency.¶

Drug Interactions

(See PRECAUTIONS section)

Clinical Study

In a randomized, multi-centered, double-blind, 9-month Phase 3 study involving 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 of oral administration of 20 mg twice a day of doxycycline hyclate (using a bioequivalent capsule formulation) plus scaling and root planing (SRP) were compared to placebo control plus SRP.  Both treatment groups were administered a course of scaling and root planing in 2 quadrants at Baseline.  Measurements of Alv, PD and bleeding-on-probing (BOP) were obtained at Baseline, 3, 6, and 9 months 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: 0-3 mm (no disease), 4-6 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.

Clinical Results at Nine Months of Doxycycline Hyclate Capsules,

20 mg, as an Adjunct to SRP

(Bioequivalent to Doxycycline Hyclate Tablets, 20 mg)

ParameterBaseline Pocket Depth
0 -3  mm4 - 6 mm≥ 7 mm
Number of Patients  (Doxycycline Hyclate 20mg BID)909079
Number of Patients  (Placebo)939378
Mean Gain (SDff) in ALv√  Doxycycline hyclate 20mg BID  Placebo0.25 (0.29) mm0.20 (0.29) mm1.03 (0.47) mm*0.86 (0.48) mm1.55 (1.16) mm**1.17 (1.15 )mm
Mean Gain (SDff)in PD√√  Doxycycline hyclate 20mg BID  Placebo0.16 (0.19) mm**0.05 (0.19) mm0.95 (0.47) mm**0.69 (0.48) mm1.68 (1.07) mm**1.20 (1.06 ) mm
% of Sites (SDff) with lossof ALv√ ≥ 2mm  Doxycycline hyclate 20mg BID  Placebo1.9 (4.2)%2.2 (4.1)%1.3 (4.5)%2.4 (4.4)%0.3 (9.4)%*3.6 (9.4)%*
% of Sites (SDff) with BOPf  Doxycycline hyclate 20mg BID  Placebo39 (19)%**46 (19)%  64 (18)%*70 (18)%75 (29)%80 (29)%

* p<0.050 vs. the placebo control group.   **  p<0.010 vs the placebo control group.

√ Alv = Clinical Attachment Level   √√ PD = Pocket Depth   fBOP = Bleeding on Probing

ffSD = Standard Deviation

INDICATIONS AND USAGE

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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate 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.

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 and 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 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 drug-resistant 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 coexistent oral candidiasis.

If superinfection is suspected, appropriate measures should be taken.

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 β–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 & OR 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

The use of doxycycline hyclate in infancy and childhood is contraindicated.  (See WARNINGS section).

Information for Patients

Patients should be counseled that antibacterial drugs including doxycycline hyclate should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline hyclate is 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 or other antibacterial drugs in the future.

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 – 12 month period.  The most frequent adverse reactions occurring in studies involving treatment with a bioequivalent form of doxycycline hyclate capsules or placebo are listed below:

Incidence (%) of Adverse Reactions in Clinical Trials of Doxycycline

Hyclate Capsules, 20mg

(Bioequivalent to Doxycycline Hyclate Tablets, 20mg) vs. Placebo

Adverse ReactionDoxycycline HyclateCapsules 20 mg BID(n=213)Placebo(n=215)
Headache55 (26%)56 (26%)
Common Cold47 (22%)46 (21%)
Flu Symptoms24 (11%)40 (19%)
Tooth Ache14 (7%)28 (13%)
Periodontal Abscess8 (4%)21 (10%)
Tooth Disorder13 (6%)19 (9%)
Nausea17 (8%)12 (6%)
Sinusitis7 (3%)18 (8%)
Injury11 (5%)18 (8%)
Dyspepsia13 (6%)5 (2%)
Sore Throat11 (5%)13 (6%)
Joint Pain12 (6%)8 (4%)
Diarrhea12 (6%)8 (4%)
Sinus Congestion11 (5%)11 (5%)
Coughing9 (4%)11 (5%)
Sinus Headache8 (4%)8 (4%)
Rash8 (4%)6 (3%)
Back Pain7 (3%)8 (4%)
Back Ache4 (2%)9 (4%)
Menstrual Cramp9 (4%)5 (2%)
Acid Indigestion8 (4%)7 (3%)
Pain8 (4%)5 (2%)
Infection4 (2%)6 (3%)
Gum Pain1 (<1%)6 (3%)
Bronchitis7 (3%))5 (2%)
Muscle Pain2 (1%)6 (3%)

Note: Percentages are based on total number of study participants in each treatment group.

Adverse Reactions for Tetracyclines:  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.

DOSAGE AND ADMINISTRATION

THE DOSAGE OF DOXYCYCLINE HYCLATE 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 20 mg twice daily as an adjunct following scaling and root planing may be administered for up to 9 months. Doxycycline hyclate should be taken twice daily at 12 hour intervals, usually in the morning and evening.  It is recommended that if doxycycline hyclate 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.

Administration of adequate amounts of fluid along with the tablets is recommended to wash down the drug and reduce the risk of esophageal irritation and ulceration.  (See ADVERSE REACTIONS Section).

HOW SUPPLIED

Doxycycline hyclate are white film coated, round, biconvex tablet, debossed LL714 on one side and plain on the other side containing doxycycline hyclate equivalent to 20 mg doxycycline.  Bottle of 60 tablets (NDC 68047-714-60) and Bottle of 100 tablets (NDC 68047-714-01).

Storage and Handling

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature].

Dispense in tight, light-resistant containers (USP).

Manufactured for:

Larken Laboratories, Inc.

Canton, MS 39046

500398     Rev. 05/10

REFERENCES

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.

Golub L.M., Cianco 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.

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.

Saivain S., Houin G.: Clincial Pharmacokinetics of Doxycycline and Minocycline.  Clin. Pharmacokinetics 1988; 15; 355-366.

Schach von Wittenau M., Twomey T.: The Disposition of Doxycycline by Man and Dog.  Chemotherapy 1971; 16: 217-228.

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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Figure 2: 60 count Label

63d79530-figure-02

Figure 3: 100 count Label

63d79530-figure-03
DOXYCYCLINE HYCLATE 
doxycycline hyclate tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:68047-714
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
DOXYCYCLINE HYCLATE (DOXYCYCLINE) DOXYCYCLINE20 mg
Inactive Ingredients
Ingredient NameStrength
SILICON DIOXIDE 
HYPROMELLOSE 2910 (3 MPA.S) 
HYPROMELLOSE 2910 (6 MPA.S) 
ANHYDROUS LACTOSE 
MAGNESIUM STEARATE 
CELLULOSE, MICROCRYSTALLINE 
POLYETHYLENE GLYCOL 400 
POLYSORBATE 80 
SODIUM STARCH GLYCOLATE TYPE A POTATO 
TALC 
TITANIUM DIOXIDE 
Product Characteristics
ColorYELLOW (STRAW) Scoreno score
ShapeROUND (BICONVEX) Size8mm
FlavorImprint Code LL714
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:68047-714-6060 in 1 BOTTLE
2NDC:68047-714-01100 in 1 BOTTLE
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA06528711/15/2010
Labeler - Larken Laboratories, Inc. (791043719)
Registrant - Larken Laboratories, Inc. (791043719)
Establishment
NameAddressID/FEIBusiness Operations
Sovereign Pharmaceuticals, LLC623168267MANUFACTURE

Revised: 11/2010
Document Id: 63d79530-85a9-4939-a0e1-a78722ab4f07
Set id: 49f82130-6f8a-412c-b625-e75906e74675
Version: 1
Effective Time: 20101115
 
Larken Laboratories, Inc.