Prescription Drugs

CLINICAL PHARMACOLOGY Tetracyclines are readily absorbed and are bound to plasma proteins in varying degree. They are concentrated by the liver in the bile, and excreted in the urine and feces at high concentrations and in a biologically active form. Following a single 100 mg dose administered in a concentration of 0.4 mg/mL in a one-hour infusion, normal adult volunteers average a peak of 2.5 mcg/mL, while 200 mg of a concentration of 0.4 mg/mL administered over two hours averaged a peak of 3.6 mcg/mL. Excretion of doxycycline by the kidney is about 40 percent/72 hours in individuals with normal function (creatinine clearance about 75 mL/min.). This percentage excretion may fall as low as 1-5 percent/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min.). Studies have shown no significant difference in serum half-life of doxycycline (range 18-22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter this serum half-life of doxycycline. Microbiology Mechanism Of Action Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria. Resistance Cross resistance with other tetracyclines is common. Antimicrobial Activity Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for VIBRAMYCIN. Gram-Negative Bacteria Acinetobacter species Bartonella bacilliformis Brucella species Klebsiella species Klebsiella granulomatis Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenza Neisseria gonorrhoeae Shigella species Vibrio cholera Yersinia pestis Gram-Positive Bacteria Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae Anaerobic Bacteria Clostridium species Fusobacterium fusiforme Propionibacterium acnes Other Bacteria Nocardiae and other aerobic Actinomyces species Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum subspecies pertenue Ureaplasma urealyticum Parasites Balantidium coli Entamoeba species Plasmodium falciparum* *Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum, but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known. Susceptibility Testing Methods When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,2,4 (broth or agar). The MIC values should be interpreted according to criteria provided in Table 1. Diffusion Techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. 1,3,4  The zone size should be determined using a standardized test method.This procedure uses paper disks impregnated with 30-μg doxycycline to test the susceptibility of microorganisms to doxycycline. The disk diffusion interpretive criteria are provided in Table 1. Anaerobic Techniques For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method5. The MIC values obtained should be interpreted according to the criteria provided in Table 1. Table 1: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline Bacteriaa Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL) S I R S I R S I R Acinetobacter spp. Doxycycline ≤4 8 ≥16 ≥13 10-12 ≤9 - - - Tetracycline ≤4 8 ≥16 ≥15 12-14 ≤11 - - - Anaerobes Tetracycline - - - - - - ≤4 8 ≥16 Bacillus anthracisb Doxycycline ≤1 - - - - - - - - Tetracycline ≤1 - - - - - - - - Brucella speciesb Doxycycline ≤1 - - - - - - - - Tetracycline ≤1 - - - - - - - - Enterobacteriaceae Doxycycline ≤4 8 ≥16 ≥14 11-13 ≤10 - - - Tetracycline ≤4 8 ≥16 ≥15 12-14 ≤11 - - - Franciscella tularensisb Doxycycline ≤4 - - - - - - - - Tetracycline ≤4 - - - - - - - - Haemophilus influenzae Tetracycline ≤2 4 ≥8 ≥29 26-28 ≤25 - - - Mycoplasma pneumoniaeb Tetracycline - - - - - - ≤2 - - Nocardiae and other aerobic Actinomyces speciesb Doxycycline ≤1 2-4 ≥8 - - - - - - Neisseria gonorrhoeaec Tetracycline - - - ≥38 31-37 ≤30 ≤0.25 0.5- 1 ≥2 Streptococcus pneumoniae Doxycycline ≤0.25 0.5 ≥1 ≥28 25-27 ≤24 - - - Tetracycline ≤1 2 ≥4 ≥28 25-27 ≤24 - - - Vibrio cholerae Doxycycline ≤4 8 ≥16 - - - - - - Tetracycline ≤4 8 ≥16 - - - - - - Yersinia pestis Doxycycline ≤4 8 ≥16 - - - - - - Tetracycline ≤4 8 ≥16 - - - - - - Ureaplasma urealyticum Tetracycline - - - - - - ≤1 - ≥2 a Organisms susceptible to tetracycline are also considered susceptible to doxycycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline. b The current absence of resistance isolates precludes defining any results other than “Susceptible”. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. c Gonococci with 30 mcg tetracycline disk zone diameters of <19 mm usually indicate a plasmid-mediated tetracycline resistant Neisseria gonorrhoeae isolate. Resistance in these strains should be confirmed by a dilution test (MIC ≥ 16 mcg/mL). A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3,4,5,6,7 Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 2 should be achieved. Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline QC Strain Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL) Enterococcusfaecalis ATCC 29212 Doxycycline 2-8 - - Tetracycline 8-32 - - Escherichia coli ATCC 25922 Doxycycline 0.5-2 18-24 - Tetracycline 0.5-2 18-25 - Eggerthella lenta ATCC 43055 Doxycycline 2-16 - - Haemophilus influenzae ATCC 49247 Tetracycline 4-32 14-22 - Neisseriagonorrhoeae ATCC 49226 Tetracycline - 30-42 0.25-1 Staphylococcus aureus ATCC 25923 Doxycycline - 23-29 - Tetracycline - 24-30 - Staphylococcus aureus ATCC 29213 Doxycycline 0.12-0.5 - - Tetracycline 0.12-1 - - Streptococcus pneumoniae ATCC 49619 Doxycycline 0.015-0.12 25-34 - Tetracycline 0.06-0.5 27-31 - Bacteroidesfragilis ATCC 25285 Tetracycline - - 0.12-0.5 Bacteroides thetaiotaomicron ATCC 29741 Doxycycline 2-8 - - Tetracycline - - 8-32 Mycoplasma pneumoniae ATCC 29342 Tetracycline 0.06-0.5 - 0.06-0.5 Ureaplasma urealyticum ATCC 33175 Tetracycline - - ≥8 REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Sixth Informational Supplement, CLSI document M100-S26 [2016]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA. 2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Tenth Edition. CLSI document M07-A10 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA. 3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition CLSI document M02-A12 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA. 4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – Third Edition CLSI document M45-A3 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA. 5. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard -Eighth Edition. CLSI document M11-A8 [2012]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA. 6. Clinical and Laboratory Standards Institute. Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard—Second Edition. CLSI document M24-A2[2011]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA. 7. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A [2011]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA.

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 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 doxycycline following oral administration of Periostat® (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 Periostat® (doxycycline hyclate) following single oral doses and at steady-state in healthy subjects are presented as follows: Pharmacokinetic Parameters for Periostat® (doxycycline hyclate) n Cmax* (ng/mL) Tmax** (hr) Cl/F* (L/hr) t½* (hr) Single dose 20 mg (tablet) 20 362 ± 101 1.4 (1.0-2.5) 3.85 ± 1.3 18.1 ± 4.85 Steady-State 20 mg 20 mg BID*** 30 790 ± 285 2 (0.98 - 12.0) 3.76 ± 1.06 Not 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 Periostat® (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 134 L.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: Doxycycline pharmacokinetics have not been evaluated in geriatric patients. Pediatric: 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) Parameter Baseline Pocket Depth 0-3 mm 4-6 mm ≥ 7 mm Number of Patients (Periostat®20mg BID) 90 90 79 Number of Patients (Placebo) 93 93 78 Mean Gain (SDƒƒ) in ALv√ Periostat® 20 mg BID 0.25 (0.29) mm 1.03 (0.47) mm* 1.55 (1.16) mm* Placebo 0.20 (0.29) mm 0.86 (0.48) mm 1.17 (1.15) mm Mean Decrease (SDƒƒ) in PD√√ Periostat® 20 mg BID 0.16 (0.19) mm** 0.95 (0.47) mm** 1.68 (1.07) mm** Placebo 0.05 (0.19) mm** 0.69 (0.48) mm** 1.20 (1.06) mm** % of Sites (SDƒƒ) with loss of ALv√ ≥ 2 mm Periostat® 20 mg BID 1.9 (4.2)% 1.3 (4.5)% 0.3 (9.4)%* Placebo 2.2 (4.1)% 2.4 (4.4)% 3.6 (9.4)%* % of Sites (SDƒƒ) with BOPƒ Periostat® 20 mg BID 39 (19)%** 64 (18)%* 75 (29)% Placebo 46 (19)%** 70 (18)% 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 ƒBOP = Bleeding on Probing ƒƒSD = Standard Deviation 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.

CLINICAL PHARMACOLOGY Mechanism Of Action Doxycycline is an antibacterial drug [see Microbiology]. Pharmacokinetics Doxycycline is virtually completely absorbed after oral administration. Following single and multiple-dose administration of Doxycycline Hyclate Delayed-Release Tablets, 200 mg to adult volunteers, average peak plasma doxycycline concentration (Cmax) was 4.6 mcg/mL and 6.3 mcg/mL, respectively with median tmax of 3 hours; the corresponding mean plasma concentration values 24 hours after single and multiple doses were 1.5 mcg/mL and 2.3 mcg/mL, respectively. The mean Cmax and AUC 0-∞ of doxycycline are 24% and 13% lower, respectively, following single dose administration of Doxycycline Hyclate Delayed-Release Tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean Cmax of doxycycline is 19% lower and the AUC 0-∞ is unchanged following single dose administration of Doxycycline Hyclate Delayed-Release Tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown. Doxycycline bioavailability from Doxycycline Hyclate Delayed-Release Tablets, 200 mg was not affected by food, but the incidence of nausea was higher in fasted subjects. The 200 mg tablets may be administered without regard to meals. When Doxycycline Hyclate Delayed-Release Tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly. Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a creatinine clearance below 10 mL/min. Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life. Microbiology Mechanism Of Action Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria. Cross-resistance between tetracyclines is common. Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for Doxycycline Hyclate Delayed-Release Tablets [see INDICATIONS AND USAGE]. Gram-Negative Bacteria Acinetobacter species Bartonella bacilliformis Brucella species Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella species Neisseria gonorrhoeae Shigella species Vibrio cholerae Yersinia pestis Gram-Positive Bacteria Bacillus anthracis Streptococcus pneumoniae Anerobic Bacteria Clostridium species Fusobacterium fusiforme Propionibacterium acnes Other Bacteria Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Norcardiae and other aerobic Actinomyces species Rickettsiae Treponema pallidum Treponema pallidum subspecies pertenue Ureaplasma urealyticum Parasites Balantidium coli Entamoeba species Plasmodium falciparum* *Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known. Susceptibility Test Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar)5,6,8. The MIC values should be interpreted according to the criteria provided in Table 2. Diffusion Techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. Zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standard test method5,7,8. This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of bacteria to doxycycline. The disk diffusion interpretive criteria are provided in Table 2. Anaerobic Techniques For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method9. The MIC values obtained should be interpreted according to the criteria provided in Table 2. Table 2: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline Bacteriaa Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL) S I R S I R S I R Acinetobacter spp. Doxycycline ≤ 4 8 ≥ 16 ≥ 13 10-12 ≤ 9 - - - Tetracycline ≤ 4 8 ≥ 16 ≥ 15 12-14 ≤ 11 - - - Anaerobes Tetracycline - - - - - - ≤ 4 8 ≥ 16 Bacillus anthracisb Doxycycline ≤ 1 - - - - - - - - Tetracycline ≤ 1 - - - - - - - - Brucella speciesb Doxycycline ≤ 1 - - - - - - - - Tetracycline ≤ 1 - - - - - - - - Enterobacteriaceae Doxycycline ≤ 4 8 ≥ 16 ≥ 14 11-13 ≤ 10 - - - Tetracycline ≤ 4 8 ≥ 16 ≥ 15 12-14 ≤ 11 - - - Francisella tularensisb Doxycycline ≤ 4 - - - - - - - - Tetracycline ≤ 4 - - - - - - - - Haemophilus influenzae Tetracycline ≤ 2 4 ≥ 8 ≥ 29 26-28 ≤ 25 - - - Mycoplasma pneumoniaeb Tetracycline - - - - - - ≤ 2 - - Nocardiae and other aerobic Actinomyces speciesab Doxycycline ≤ 1 2-4 ≥ 8 - - - Neisseria gonorrhoeaec Tetracycline - - - ≥ 38 31-37 ≤ 30 ≤ 0.25 0.5-1 ≥ 2 Streptococcus pneumoniae Doxycycline ≤ 0. 25 0.5 ≥ 1 ≥ 28 25-27 ≤ 24 - - - Tetracycline ≤ 1 2 ≥ 4 ≥ 28 25-27 ≤ 24 - - - Vibrio cholerae Doxycycline ≤ 4 8 ≥ 16 - - - - - - Tetracycline ≤ 4 8 ≥ 16 - - - - - - Yersinia pestis Doxycycline ≤ 4 8 ≥ 16 - - - - - - Tetracycline ≤ 4 8 ≥ 16 - - - - - - Ureaplasma urealyticum Tetracycline - - - - - - ≤ 1 ≥ 2 aOrganisms susceptible to tetracycline are also considered susceptible to doxycycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline. bThe current absence of resistance isolates precludes defining any results other than “Susceptible”. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. cGonococci with 30 mcg tetracycline disk zone diameters of less than 19 mm usually indicate a plasmidmediated tetracycline resistant Neisseria gonorrhoeae isolate. Resistance in these strains should be confirmed by a dilution test (MIC greater than or equal to 16 mcg/mL). A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the bacteria is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test5,6,7,8,9,10,11. Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 3. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 3 should be achieved. Table 3: Acceptable Quality Control Ranges for Susceptiblity Testing for Doxycycline and Tetracycline QC Strain Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL) Enterococcus faecalis ATCC 29212 Doxycycline 2 -8 - - Tetracycline 8 -32 - - Escherichia coli ATCC 25922 Doxycycline 0.5 - 2 18 -24 - Tetracycline 0.5 -2 18 -25 - Eubacteria lentum ATCC 43055 Doxycycline 2-16 Haemophilus influenzae ATCC 49247 Tetracycline 4 -32 14 -22 - Neisseria gonorrhoeae ATCC 49226 Tetracycline - 30 -42 0.25 - 1 Staphylococcus aureus ATCC 25923 Doxycycline - 23 -29 - Tetracycline - 24 -30 - Staphylococcus aureus ATCC 29213 Doxycycline 0.12 -0.5 - Tetracycline 0.12 - 1 - Staphylococcus pneumoniae ATCC 49619 Doxycycline 0.015 -0.12 25 -34 - Tetracycline 0.06 -0.5 27 -31 - Bacteroides fragilis ATCC 25285 Tetracycline - - 0.125 -0.5 Bacteroides thetaiotaomicron ATCC 29741 Doxycycline 2-8 - Tetracycline - - 8 -32 Mycoplasma pneumoniae ATCC 29342 Tetracycline 0.06 -0.5 - 0.06 -0.5 Ureaplasma urealyticum ATCC 33175 Tetracycline - - ≥ 8 Animal Toxicology And/Or Pharmacology Hyperpigmentation of the thyroid has been produced by members of the tetracycline-class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline. Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl, were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet. Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline. Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues. Clinical Studies This was a randomized, double-blind, active-controlled, multicenter trial which enrolled 495 subjects, between 19 to 45 years of age with a confirmed diagnosis of urogenital C. trachomatis infection less than 14 days prior to enrollment, or partner(s) of a subject with a known positive test for urogenital C. trachomatis infection. The primary purpose of this study was to evaluate the efficacy and safety of Doxycycline Hyclate Delayed-Release Tablets, 200 mg once daily versus doxycycline hyclate capsules, 100 mg twice daily for seven days for the treatment of uncomplicated urogenital C. trachomatis infection. The primary efficacy objective was to demonstrate non-inferiority of the Doxycycline Hyclate Delayed-Release Tablets 200 mg once daily treatment regimen versus the doxycycline 100 mg twice daily treatment regimen for the indication using a negative nucleic acid amplification test (NAAT) at the test of cure visit (day 28) in the mITT population (subjects who were positive at baseline and took at least one day of study drug). Table 4: Primary Efficacy Outcome – Microbiological Cure of C. trachomatis at Day 28 mITT Population Doxycycline Hyclate Delayed-Release Tablets, 200 mg once daily Cure Rate (%) Doxycycline hyclate capsules, 100 mg twice daily Cure Rate (%) Difference (%) N 188 190 Microbiological Cure, n (%) 163 (86.7) 171 (90.0) -3.3% 95% Confidence Interval for Cure Rate -10.3, 3.7 REFERENCES 5. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement, CLSI document M100-S24. Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2014. 6. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Ninth Edition. CLSI document M07-A9, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012. 7. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012. 8. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – Second Edition CLSI document M45-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2010. 9. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – Eighth Edition. CLSI document M11-A8, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012. 10. Clinical and Laboratory Standards Institute (CLSI). Methods for Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard – Second Edition. CLSI document M24-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2011. 11. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2011.

CLINICAL PHARMACOLOGY Mechanism Of Action Doxycycline is a tetracycline-class antimicrobial drug [see Microbiology]. Pharmacokinetics Absorption Following administration of a single dose of DORYX MPC under fasting conditions, the AUCinf and Cmax were 26.7 mcg-h/mL and 1.6 mcg/mL, respectively. The Tmax was 2.8 hours. In a single-dose study to evaluate the relative bioavailability in healthy adult subjects under fasted conditions, DORYX MPC 120 mg Tablets were found to be bioequivalent to Doryx 100 mg Tablets. When a single dose of DORYX MPC 120 mg Tablet was administered with a standardized high-fat high-calorie meal, (937kcal consisting of approximately 55% fat, 30% carbohydrate and 15% protein), the Cmax was approximately 30% lower, but there was no significant difference in the AUCinf compared to administration under fasting conditions [see DOSAGE AND ADMINISTRATION]. Excretion Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a creatinine clearance below 10 mL/min. Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life. Microbiology Mechanism Of Action Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria. Resistance Cross-resistance between tetracyclines is common. Antimicrobial Activity Doxycycline has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see INDICATIONS AND USAGE]. Gram-negative Bacteria Acinetobacter species Bartonella bacilliformis Brucella species Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella species Neisseria gonorrhoeae Shigella species Vibrio cholerae Yersinia pestis Gram-positive Bacteria Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae Anerobic Bacteria Clostridium species Fusobacterium fusiforme Propionibacterium acnes Other Bacteria Norcardiae and other aerobic Actinomyces species Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumonia Rickettsiae Treponema pallidum Treponema pallidum subspecies pertenue Ureaplasma urealyticum Parasites Balantidium coli Entamoeba species Plasmodium falciparum* *Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known. Susceptibility Testing Methods When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antibacterial drugs used in local hospitals and practice areas as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method5,6,8,10,11 (broth and/or agar). The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standard test method.5,7,8 This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of bacteria to doxycycline. The disk diffusion interpretive criteria are provided in Table 1. Anaerobic Techniques For anaerobic bacteria the susceptibility to doxycycline can be determined by a standardized test method.5,9 The MIC values obtained should be interpreted according to the criteria provided in Table 1. Table 1: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline Bacteriaa Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL) S I R S I R S I R Acinetobacter spp, Doxycycline ≤4 8 ≥16 ≥13 10-12 ≤9 - - - Tetracycline ≤4 8 ≥16 ≥15 12-14 ≤11 - - - Anaerobes Tetracycline - - - - - - ≤4 8 ≥16 Bacillus anthracisab Doxycycline ≤1 - - - - - - - - Tetracycline ≤1 - - - - - - - - Brucella speciesab Doxycycline ≤1 - - - - - - - - Tetracycline ≤1 - - - - - - - - Enterobacteriaceae Doxycycline ≤4 8 ≥16 ≥14 11-13 ≤10 - - - Tetracycline ≤4 8 ≥16 ≥15 12-14 ≤11 - - - FrancisceIIa tularensisab Doxycycline ≤4 - - - - - - - - Tetracycline ≤4 - - - - - - - - Haemophilus influenzae Tetracycline ≤2 4 ≥8 ≥29 26-28 ≤25 - - - Mycoplasma pneumoniae Tetracycline - - - - - - ≤2 - - Nocardiae and other aerobic Actinomyces speciesab Doxycycline ≤1 2-4 ≥8 Neisseria gonorrhoeaec Tetracycline - - - ≥38 31-37 ≤30 ≤0.25 0.5-1 ≥2 Streptococcus pneumoniae Doxycycline ≤0.25 0.5 ≥1 ≥28 25-27 ≤24 - - - Tetracycline ≤1 2 ≥4 ≥28 25-27 ≤24 - - - Vibrio cholerae Doxycycline ≤4 8 ≥16 - - - - - - Tetracycline ≤4 8 ≥16 - - - - - - Yersinia pestis Doxycycline ≤4 8 ≥16 - - - - - - Tetracycline ≤4 8 ≥16 - - - - - - UreapIasma urealyticum Tetracycline - - - - - - ≤1 - ≥2 aOrganisms susceptible to tetracycline are also considered susceptible to doxycycline, However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline. bThe current absence of resistance isolates precludes defining any results other than “Susceptible”. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. cGonococci with 30 mcg tetracycline disk zone diameters of less than 19 mm usually indicate a plasmid-mediated tetracycline resistant N. gonorrhoeae isolate. Resistance in these strains should be confirmed by a dilution test (MIC greater than or equal to 16 mcg/mL). A report of Susceptible (S) indicates that the antimicrobial is likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.5,6,7,8,9,10,11 Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 2 should be achieved. Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline QC Strain Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL) Enterococcus faecalis ATCC * 29212 Doxycycline 2-8 - - Tetracycline 8-32 - - Escherichia coli ATCC 25922 Doxycycline 0.5-2 18-24 - Tetracycline 0.5-2 18-25 - Eggerthella lenta ATCC 43055 Doxycycline 2 -16 - - Haemophilus influenzae ATCC 49247 Tetracycline 4-32 14-22 - Neisseria gonorrhoeae ATCC 49226 Tetracycline - 30-42 0.25-1 Staphylococcus aureus ATCC 25923 Doxycycline - 23-29 - Tetracycline - 24-30 - Staphylococcus aureus ATCC 29213 Doxycycline 0.12-0.5 - Tetracycline 0.12-1 - StaphyIococcus pneumoniae ATCC 49619 Doxycycline 0.015-0.12 25-34 - Tetracycline 0.06-0.5 27-31 - Bacteroides fragiIis ATCC 25285 Tetracycline - - 0.125-0.5 Bacteroides thetaiotaomicron ATCC 29741 Doxycycline 2 -8 - - Tetracycline - - 8-32 Mycoplasma pneumoniae ATCC 29342 Tetracycline 0.06-0.5 - 0.06-0.5 Ureaplasma urealyticum ATCC 33175 Tetracycline - - ≥8 *ATCC is the American Type Culture Collection Animal Toxicology And/Or Pharmacology Hyperpigmentation of the thyroid has been produced by members of the tetracycline-class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline. Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl, were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet. Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has be en observed in goats and rats treated with oxytetracycline. Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues. REFERENCES 5. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-sixth Informational Supplement. CLSI document M100S-S27 [ 2017]. Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA. 6. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Tenth Edition. CLSI document M07-A10 [2015], Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA. 7. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard -Twelfth Edition. CLSI document M02-A12 [2015], Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA. 8. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – Third Edition. CLSI document M45-A3 [2015], Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA. 9. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – Eighth Edition. CLSI document M11-A8 [2012], Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA. 10. Clinical and Laboratory Standards Institute (CLSI). Methods for Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard – Second Edition. CLSI document M24-A2 [2011], Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA. 11. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A [2011], Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA.

CLINICAL PHARMACOLOGY Microbiology Doxycycline is a broad-spectrum semisynthetic tetracycline.1 Doxycycline is bacteriostatic, inhibiting bacterial protein synthesis due to disruption of transfer RNA and messenger RNA at ribosomal sites.1 In vitro testing has shown that Porphyromonas gingivalis, Prevotella intermedia, Campylobacter rectus, and Fusobacterium nucleatum, which are associated with periodontal disease, are susceptible to doxycycline at concentrations ≤ 6.0 μg/mL.2 A single-center, single-blind, randomized, clinical study in 45 subjects with periodontal disease demonstrated that a single treatment with ATRIDOX (doxycycline hyclate) ® resulted in the reduction in the numbers of P. gingivalis, P. intermedia, C. rectus, F. nucleatum, Bacteroides forsythus, and E. corrodens in subgingival plaque samples. Levels of aerobic and anaerobic bacteria were also reduced after treatment with ATRIDOX (doxycycline hyclate) ®. The clinical significance of these findings, however, is not known. During these studies, no overgrowth of opportunistic organisms such as Gram-negative bacilli and yeast were observed. However, as with other antibiotic preparations, ATRIDOX (doxycycline hyclate) ® therapy may result in the overgrowth of nonsusceptible organisms including fungi. (See PRECAUTIONS) Pharmacokinetics In a clinical pharmacokinetic study, subjects were randomized to receive either ATRIDOX (doxycycline hyclate) ® covered with Coe-Pak™ periodontal dressing (n=13), ATRIDOX (doxycycline hyclate) ® covered with Octyldent™ periodontal adhesive (n=13), or oral doxycycline (n=5) (according to package dosing instructions). The doxycycline release characteristics in gingival crevicular fluid (GCF), saliva, and serum were evaluated. Doxycycline levels in GCF peaked (~1,500 μg/mL and ~2000 μg/mL for Coe-Pak™ and Octyldent™ groups, respectively) 2 hours following treatment with ATRIDOX (doxycycline hyclate) ®. These levels remained above 1000 μg/mL through 18 hours, at which time the levels began to decline gradually. However, local levels of doxycycline remained well above the minimum inhibitory concentration (MIC90) for periodontal pathogens ( ≤ 6.0 μg/mL)2 through Day 7. In contrast, subjects receiving oral doxycycline had peak GCF levels of ~2.5 μg/mL at 12 hours following the initial oral dosing with levels declining to ~0.2 μg/mL by Day 7. High variability was observed for doxycycline levels in GCF for both oral and ATRIDOX (doxycycline hyclate) ® treatment groups. The ATRIDOX (doxycycline hyclate) ® doxycycline release profile in GCF is illustrated in the figure below. The maximum concentration of doxycycline in saliva was achieved at 2 hours after both treatments with ATRIDOX (doxycycline hyclate) ®, with means of 4.05 μg/mL and 8.78 μg/mL and decreased to 0.36 μg/mL and 0.23 μg/mL at Day 7 for the Coe-Pak™ group and the Octyldent™ group, respectively. The concentration of doxycycline in serum following treatment of ATRIDOX (doxycycline hyclate) ® never exceeded 0.1 μg/mL. Clinical Studies In two well-controlled, multicenter, parallel-design, nine-month clinical trials, 831 patients (Study 1=411; Study 2=420) with chronic adult periodontitis characterized by a mean probing depth of 5.9 to 6.0 mm were enrolled. Subjects received one of four treatments: 1) ATRIDOX (doxycycline hyclate) ®, 2) Scaling and Root Planing, 3) Vehicle Control, or 4) Oral Hygiene. Treatment was administered to sites with probing depths 5 mm or greater that bled on probing. Subjects with detectable subgingival calculus on greater than 80% of all tooth surfaces were excluded from enrollment. All subjects received a second administration of the initially randomized treatment four months after their Baseline treatment. Changes in the efficacy parameters, attachment level, pocket depth, and bleeding on probing, between Baseline and Month 9 showed that: 1) ATRIDOX (doxycycline hyclate) ® was superior to Vehicle Control and Oral Hygiene, and 2) ATRIDOX (doxycycline hyclate) ® met the decision rule of being at least 75% as good as Scaling and Root Planing (SRP) (the standard of at least 75% as good as SRP is required for any product approved as a stand alone therapy for periodontitis). Clinicians should note that the studies were of nine months duration. Additional research would be necessary to establish long term comparability to SRP. The results of Studies #1 and 2 for efficacy parameters of attachment level gain and probing depth reduction are included in the following graphs. * denotes statistically significant superiority of ATRIDOX (doxycycline hyclate) ® and Sc/RP vs. Vehicle and Oral Hygiene † denotes statistically significant superiority of ATRIDOX (doxycycline hyclate) ® vs. Vehicle and Oral Hygiene Data were not collected at months 3 and 7 * denotes statistically significant superiority of ATRIDOX (doxycycline hyclate) ® and Sc/RP vs. Vehicle and Oral Hygiene † denotes statistically significant superiority of ATRIDOX (doxycycline hyclate) ® vs. Vehicle and Oral Hygiene Data were not collected at months 3 and 7 A third clinical trial was conducted to determine whether the product can be left in the pocket to bioabsorb or be expelled naturally and achieve comparable clinical results. In this study the product was retained with Octyldent™ dental adhesive rather than Coe-Pak™ periodontal dressing as in the previously mentioned studies. This was a 3-arm, randomized, controlled, parallel group, single blind trial that enrolled 605 subjects. The patient population studied and study design were comparable to that in Studies 1 and 2. Subjects received one of three treatments: 1) ATRIDOX (doxycycline hyclate) ® with Coe-Pak™ removed after 7 days as in the pivotal trials, 2) ATRIDOX (doxycycline hyclate) ® retained with Octyldent™ and left to bioabsorb or be expelled naturally or 3) Vehicle Control with Octyldent™ left to bioabsorb or be expelled naturally. Changes in the efficacy parameters, attachment level, pocket depth and bleeding on probing were equivalent to those observed in Studies 1 and 2. The results of the third study support the use of ATRIDOX (doxycycline hyclate) ® retained with Octyldent™ and left to bioabsorb or be expelled naturally. REFERENCES 1. Stratton CW, Lorian V. Mechanisms of action for antimicrobial agents: general principles and mechanisms for selected classes of antibiotics. Antibiotics in Laboratory Medicine, 4th edition, Williams and Wilkins, Baltimore, MD, 1996. 2. Slots J, Rams TE. Antibiotics in periodontal therapy: advantages and disadvantages. J Clin Periodontol 1990; 17:479-493.

VIBRAMYCIN® (doxycycline hyclate) for Injection FOR INTRAVENOUS USE ONLY To reduce the development of drug-resistant bacteria and maintain the effectiveness of Vibramycin® and other antibacterial drugs, Vibramycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION Vibramycin (doxycycline hyclate for injection) Intravenous is an antibacterial drug synthetically derived from oxytetracycline, and is available as Vibramycin Hyclate (doxycycline hydrochloride hemiethanolate hemihydrate). The chemical designation of this light-yellow crystalline powder is alpha-6-deoxy-5-oxytetracycline. Doxycycline has a high degree of lipoid solubility and a low affinity for calcium binding. It is highly stable in normal human serum.

PERIOSTAT® (doxycycline hyclate) 20 mg Tablets DESCRIPTION Periostat® (doxycycline hyclate) is available as a 20 mg tablet formulation of doxycycline for oral administration. The structural formula of doxycycline hyclate is: with an empirical formula of (C22H24N2O8•HCl)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-3,5,10,12,12 apentahydroxy - 6 - methyl - 1 , 1 1 - 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. Inert ingredients in the formulation are: hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin. Each tablet contains 23 mg of doxycycline hyclate equivalent to 20 mg of doxycycline.

Doxycycline Hyclate Delayed-release Tablets, for Oral Administration DESCRIPTION Doxycycline Hyclate Delayed-Release Tablets, for oral administration, contain specially coated pellets of doxycycline hyclate, a broad-spectrum antibacterial synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration. The structural formula for doxycycline hyclate is: with a molecular formula of C22H24N2O8, HCl, ½ C2H6O, ½ H2O and a molecular weight of 512.9. The chemical designation for doxycycline hyclate is [4S(4aR,5S,5aR,6R,12aS)] -4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6methyl-1,11-deoxonaphthacene-2-carboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate is a yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates. Doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. Inactive ingredients in the tablet formulation are: lactose monohydrate; microcrystalline cellulose; sodium lauryl sulfate; sodium chloride; talc; anhydrous lactose; corn starch; crospovidone; magnesium stearate; cellulosic polymer coating.

Find Lowest Prices on DORYX MPC (doxycycline hyclate) Delayed-release Capsules DESCRIPTION Doryx MPC (doxycycline hyclate) delayed-release tablets for oral use, contain doxycycline hyclate, a tetracycline class drug synthetically derived from oxytetracycline, in a delayed-release formulation consisting of pellets with a modified polymer enteric coat that has increased acid resistance. The structural formula for doxycycline hyclate is: with a molecular formula of C22H24N2O8, HCl, ½ C2H6O, ½ H2O and a molecular weight of 512.9. The chemical name for doxycycline hyclate is [4S(4aR,5S,5aR,6R,12aS)]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11deoxonaphthacene-2-carboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate is a yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates. Doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. Each tablet contains doxycycline 60 mg or 120 mg (equivalent to doxycycline hyclate 69.4 mg or 138.8 mg). Inactive ingredients in the tablet formulation are: lactose monohydrate; microcrystalline cellulose; sodium lauryl sulfate; sodium chloride; talc; anhydrous lactose; corn starch; crospovidone; magnesium stearate; cellulosic polymer coating. Each DORYX MPC 60 mg Tablet contains 3.6 mg (0.157 mEq) of sodium and each DORYX MPC 120 mg Tablet contains 7.2 mg (0.313 mEq) of sodium.

Find Lowest Prices on ATRIDOX (doxycycline hyclate) ® (doxycycline hyclate) 10% in the ATRIGEL® Delivery System for controlled release in subgingival application DESCRIPTION The ATRIDOX (doxycycline hyclate) ® product is a subgingival controlled-release product composed of a two syringe mixing system. Syringe A contains 450 mg of the ATRIGEL® Delivery System, which is a bioabsorbable, flowable polymeric formulation composed of 36.7% poly(DLlactide) (PLA) dissolved in 63.3% N-methyl-2-pyrrolidone (NMP). Syringe B contains 50 mg of doxycycline hyclate which is equivalent to 42.5 mg doxycycline. The constituted product is a pale yellow to yellow viscous liquid with a concentration of 10% of doxycycline hyclate. Upon contact with the crevicular fluid, the liquid product solidifies and then allows for controlled release of drug for a period of 7 days. Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. The structural formula of doxycycline hyclate is: Empirical Formula: (C22H24N2O8•HCI)2•C2H6O•H2O

INDICATIONS To reduce the development of drug-resistant bacteria and maintain effectiveness of Vibramycin and other antibacterial drugs, Vibramycin 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 is indicated in infections caused by the following microorganisms: Rickettsiae (Rocky Mountain spotted fever, typhus fever, and the typhus group, Q fever, rickettsialpox and tick fevers). Mycoplasma pneumoniae (PPLO, Eaton Agent). Agents of psittacosis and ornithosis. Agents of lymphogranuloma venereum and granuloma inguinale. The spirochetal agent of relapsing fever (Borrelia recurrentis). The following gram-negative microorganisms: Haemophilus ducreyi (chancroid), Yersinia pestis Francisella tularensis, Bartonella bacilliformis, Bacteroides species, Vibrio cholerae and Campylobacte fetus, Brucella species (in conjunction with streptomycin). Because many strains of the following groups of microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Escherichia coli, Enterobacter aerogenes, Shigella species, Acinetobacter species, Haemophilus influenzae (respiratory infections), Klebsiella species (respiratory and urinary infections). Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Streptococcus Species Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracyclines should not be used for streptococcal disease unless the organism has been demonstrated to be sensitive. For upper respiratory infections due to group A beta-hemolytic streptococci, penicillin is the usual drug of choice, including prophylaxis of rheumatic fever. Streptococcus Pneumoniae Staphylococcus aureus, respiratory skin and soft tissue infections. Tetracyclines are not the drugs of choice in the treatment of any type of staphylococcal infections. Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of infections due to: Neisseria gonorrhoeae and N. meningitidis, Treponema pallidum and Treponema pallidum subspecies pertenue (syphilis and yaws), Listeria monocytogenes, Clostridium species, Fusobacterium fusiforme (Vincent's infection), Actinomyces species. In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. Doxycycline is indicated in the treatment of trachoma, although the infectious agent is not always eliminated, as judged by immunofluorescence. DOSAGE AND ADMINISTRATION Note: Rapid administration is to be avoided. Parenteral therapy is indicated only when oral therapy is not indicated. Oral therapy should be instituted as soon as possible. If intravenous therapy is given over prolonged periods of time, thrombophlebitis may result. The usual dosage and frequency of administration of Vibramycin I.V. (100-200 mg/day) differs from that of the other tetracyclines (1-2 g/day). Exceeding the recommended dosage may result in an increased incidence of side effects. Studies to date have indicated that Vibramycin at the usual recommended doses does not lead to excessive accumulation of doxycycline in patients with renal impairment. Adults The usual dosage of Vibramycin I.V. is 200 mg on the first day of treatment administered in one or two infusions. Subsequent daily dosage is 100 to 200 mg depending upon the severity of infection, with 200 mg administered in one or two infusions. In the treatment of primary and secondary syphilis, the recommended dosage is 300 mg daily for at least 10 days. In the treatment of inhalational anthrax (post-exposure) the recommended dose is 100 mg of doxycycline, twice a day. Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time. Oral therapy should be instituted as soon as possible. Therapy must continue for a total of 60 days. Pediatric Patients For all pediatric patients weighing less than 45 kg with severe or life-threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dosage is 2.2 mg/kg of body weight administered every 12 hours. Children weighing 45 kg or more should receive the adult dose. (See WARNINGS and PRECAUTIONS) For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule is 4.4 mg/kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg/kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. In the treatment of inhalational anthrax (post-exposure) the recommended dose is 2.2 mg/kg of body weight, twice a day in children weighing less than 45 kg. Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time. Oral therapy should be instituted as soon as possible. Therapy must continue for a total of 60 days. General: The duration of infusion may vary with the dose (100 to 200 mg per day), but is usually one to four hours. A recommended minimum infusion time for 100 mg of a 0.5 mg/mL solution is one hour. Therapy should be continued for at least 24-48 hours after symptoms and fever have subsided. The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage. Intravenous solutions should not be injected intramuscularly or subcutaneously. Caution should be taken to avoid the inadvertent introduction of the intravenous solution into the adjacent soft tissue. Preparation Of Solution To prepare a solution containing 10 mg/mL, the contents of the vial should be reconstituted with 10 mL (for the 100 mg/vial container) or 20 mL (for the 200 mg/vial container) of Sterile Water for Injection or any of the ten intravenous infusion solutions listed below. Each 100 mg of Vibramycin (i.e., withdraw entire solution from the 100 mg vial) is further diluted with 100 mL to 1000 mL of the intravenous solutions listed below. Each 200 mg of Vibramycin (i.e., withdraw entire solution from the 200 mg vial) is further diluted with 200 mL to 2000 mL of the following intravenous solutions: Sodium Chloride Injection, USP 5% Dextrose Injection, USP Ringer's Injection, USP Invert Sugar, 10% in Water Lactated Ringer's Injection, USP Dextrose 5% in Lactated Ringer's Normosol-M® in D5-W (Abbott) Normosol-R® in D5-W (Abbott) Plasma-Lyte® 56 in 5% Dextrose (Travenol) Plasma-Lyte® 148 in 5% Dextrose (Travenol) This will result in desired concentrations of 0.1 to 1.0 mg/mL. Concentrations lower than 0.1 mg/mL or higher than 1.0 mg/mL are not recommended. Stability Vibramycin IV is stable for 48 hours in solution when diluted with Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to concentrations between 1.0 mg/mL and 0.1 mg/mL and stored at 25°C. Vibramycin IV in these solutions is stable under fluorescent light for 48 hours, but must be protected from direct sunlight during storage and infusion. Reconstituted solutions (1.0 to 0.1 mg/mL) may be stored up to 72 hours prior to start of infusion if refrigerated and protected from sunlight and artificial light. Infusion must then be completed within 12 hours. Solutions must be used within these time periods or discarded. Vibramycin IV, when diluted with Ringer's Injection, USP, or Invert Sugar, 10% in Water, or Normosol-M® in D5-W (Abbott), or Normosol-R® in D5-W (Abbott), or Plasma-Lyte® 56 in 5% Dextrose (Travenol), or Plasma-Lyte® 148 in 5% Dextrose (Travenol) to a concentration between 1.0 mg/mL and 0.1 mg/mL, must be completely infused within 12 hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. Reconstituted solutions (1.0 to 0.1 mg/mL) may be stored up to 72 hours prior to start of infusion if refrigerated and protected from sunlight and artificial light. Infusion must then be completed within 12 hours. Solutions must be used within these time periods or discarded. When diluted with Lactated Ringer's Injection, USP, or Dextrose 5% in Lactated Ringer's, infusion of the solution (ca. 1.0 mg/mL) or lower concentrations (not less than 0.1 mg/mL) must be completed within six hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. Solutions must be used within this time period or discarded. Solutions of Vibramycin (doxycycline hyclate for injection) at a concentration of 10 mg/mL in Sterile Water for Injection, when frozen immediately after reconstitution are stable for 8 weeks when stored at -20°C. If the product is warmed, care should be taken to avoid heating it after the thawing is complete. Once thawed the solution should not be refrozen. HOW SUPPLIED Vibramycin (doxycycline hyclate for injection) Intravenous is available as a sterile powder in a vial containing doxycycline hyclate equivalent to 100 mg of doxycycline with 480 mg of ascorbic acid; packages of 5 (0049-0960-77), and in individually packaged vials containing doxycycline hyclate equivalent to 200 mg of doxycycline with 960 mg of ascorbic acid (0049-0980-81). Distributed by: Roerig, Division of Pfizer Inc, NY, NY 10017. Revised: July 2017

INDICATIONS Periostat® (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. DOSAGE AND ADMINISTRATION THE DOSAGE OF PERIOSTAT® (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. Periostat® (doxycycline hyclate) 20 mg twice daily as an adjunct following scaling and root planing may be administered for up to 9 months. Periostat® (doxycycline hyclate) should be taken twice daily at 12 hour intervals, usually in the morning and evening. It is recommended that if Periostat® (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 Periostat® (doxycycline hyclate) (white tablet imprinted with a PS20) containing doxycycline hyclate equivalent to 20 mg doxycycline. Bottle of 60 (NDC 64682-008-01), Bottle of 100 (NDC 64682-008-02) and Bottle of 1000 (NDC 64682-008-03). Storage: All products are to be stored at controlled room temperatures of 15°C - 30°C (59°F - 86°F) and dispensed in tight, light-resistant containers (USP). Manufactured by: Pharmaceutical Manufacturing Research Services, Inc., Horsham, PA 19044. Marketed by: CollaGenex Pharmaceuticals, Inc., Newtown, PA, 18940. FDA revision date: 3/31/2004

INDICATIONS To reduce the development of drug-resistant bacteria and maintain the effectiveness of Doxycycline Hyclate Delayed-Release Tablets and other antibacterial drugs, Doxycycline Hyclate Delayed-Release 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 is a tetracycline-class antibacterial indicated in the following conditions or diseases: Rickettsial Infections Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. Sexually Transmitted Infections Uncomplicated urethral, endocervical or rectal infections caused by Chlamydia trachomatis. Nongonococcal urethritis caused by Ureaplasma urealyticum. Lymphogranuloma venereum caused by Chlamydia trachomatis. Granuloma inguinale caused by Klebsiella granulomatis. Uncomplicated gonorrhea caused by Neisseria gonorrhoeae. Chancroid caused by Haemophilus ducreyi. Respiratory Tract Infections Respiratory tract infections caused by Mycoplasma pneumoniae. Psittacosis (ornithosis) caused by Chlamydophila psittaci. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Respiratory tract infections caused by Haemophilus influenzae. Respiratory tract infections caused by Klebsiella species. Upper respiratory infections caused by Streptococcus pneumoniae. Specific Bacterial Infections Relapsing fever due to Borrelia recurrentis. Plague due to Yersinia pestis. Tularemia due to Francisella tularensis. Cholera caused by Vibrio cholerae. Campylobacter fetus infections caused by Campylobacter fetus. Brucellosis due to Brucella species (in conjunction with streptomycin). Bartonellosis due to Bartonella bacilliformis. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Escherichia coli Enterobacter aerogenes Shigella species Acinetobacter species Urinary tract infections caused by Klebsiella species. Ophthalmic Infections Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence. Inclusion conjunctivitis caused by Chlamydia trachomatis. Anthrax Including Inhalational Anthrax (post-exposure) Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. Alternative Treatment For Selected Infections When Penicillin Is Contraindicated When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: Syphilis caused by Treponema pallidum. Yaws caused by Treponema pallidum subspecies pertenue. Vincent's infection caused by Fusobacterium fusiforme. Actinomycosis caused by Actinomyces israelii. Infections caused by Clostridium species. Adjunctive Therapy For Acute Intestinal Amebiasis And Severe Acne In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy. Prophylaxis Of Malaria Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains [see DOSAGE AND ADMINISTRATION and PATIENT INFORMATION]. DOSAGE AND ADMINISTRATION Usual Dosage And Administration The usual dosage and frequency of administration of doxycycline differs from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of side effects. Adults The usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours), followed by a maintenance dose of 100 mg daily. The maintenance dose may be administered as a single dose or as 50 mg every 12 hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. Pediatric Patients For all pediatric patients weighing less than 45 kg with severe or life threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dosage of doxycycline is 2.2 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose [see WARNINGS AND PRECAUTIONS]. For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule of doxycycline is 4.4 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg per kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline-class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration [see ADVERSE REACTIONS]. If gastric irritation occurs, doxycycline may be given with food or milk [see CLINICAL PHARMACOLOGY]. When used in streptococcal infections, therapy should be continued for 10 days. Uncomplicated urethral, endocervical, or rectal infection caused by Chlamydia trachomatis: 100 mg by mouth twice a day for 7 days. As an alternate dosing regimen for uncomplicated urethral or endocervical infection caused by Chlamydia trachomatis, administer 200 mg by mouth once-a-day for 7 days. Uncomplicated gonococcal infections in adults (except anorectal infections in men): 100 mg, by mouth, twice-a-day for 7 days. As an alternate single visit dose, administer 300 mg stat followed in one hour by a second 300 mg dose. Nongonococcal urethritis (NGU) caused by U. urealyticum: 100 mg by mouth twice-aday for 7 days. Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 2 weeks. Syphilis of more than one year's duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 4 weeks. Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice-a-day for at least 10 days. For Prophylaxis Of Malaria For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should begin 1 or 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area. Inhalational Anthrax (post-exposure) Adults: 100 mg, of doxycycline, by mouth, twice-a-day for 60 days. Children: weighing less than 45 kg, 2.2 mg/kg of body weight, by mouth, twice-a-day for 60 days. Children weighing 45 kg or more should receive the adult dose. Sprinkling The Tablet Over Applesauce Doxycycline Hyclate Delayed-Release Tablets may also be administered by carefully breaking up the tablet and sprinkling the tablet contents (delayed-release pellets) on a spoonful of applesauce. The delayed-release pellets must not be crushed or damaged when breaking up the tablet. Any loss of pellets in the transfer would prevent using the dose. The applesauce/Doxycycline Hyclate Delayed-Release Tablets mixture should be swallowed immediately without chewing and may be followed by a glass of water if desired. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. In the event that a prepared dose of applesauce/Doxycycline Hyclate Delayed-Release Tablets cannot be taken immediately, the mixture should be discarded and not stored for later use. HOW SUPPLIED Dosage Forms And Strengths Doxycycline Hyclate Delayed-Release Tablets, 75 mg are white, oval, scored tablets containing yellow pellets and debossed with “D|5” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 75 mg of doxycycline. Doxycycline Hyclate Delayed-Release Tablets, 100 mg are white, oval, scored tablets containing yellow pellets and debossed with “D|0” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 100 mg of doxycycline. Doxycycline Hyclate Delayed-Release Tablets, 150 mg are white, rectangular, dual scored tablets containing yellow pellets and debossed with “D|I|I” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 150 mg of doxycycline. Doxycycline Hyclate Delayed-Release Tablets, 200 mg are white, oval, scored tablets containing yellow pellets and debossed with “D|D” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 200 mg of doxycycline. Storage And Handling Doxycycline Hyclate Delayed-Release Tablets, 75 mg are white, oval, scored tablets containing yellow pellets and debossed with “D|5” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 75 mg of doxycycline. Bottles of 60 tablets NDC 68308-775-60 Doxycycline Hyclate Delayed-Release Tablets, 100 mg are white, oval, scored tablets containing yellow pellets and debossed with “D|0” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 100 mg of doxycycline. Bottles of 100 tablets NDC 68308-710-10 Doxycycline Hyclate Delayed-Release Tablets, 150 mg are white, rectangular, dual scored tablets containing yellow pellets and debossed with “D|I|I” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 150 mg of doxycycline. Bottles of 100 tablets NDC 68308-715-10 Doxycycline Hyclate Delayed-Release Tablets, 200 mg are white, oval, scored tablets containing yellow pellets and debossed with “D|D” on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 200 mg of doxycycline. Bottles of 60 tablets NDC 68308-716-60 Store at 25° C (77° F); excursions permitted to 15 – 30° C (59 – 86° F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container (USP). Distributed by: Mayne Pharma, Greenville, NC 27834 1-844-825-8500. Manufactured by: Mayne Pharma International Pty Ltd, Salisbury South, SA 5106 Australia. Revised: Apr 2016

INDICATIONS Rickettsial Infections DORYX MPC is indicated for treatment of Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. Sexually Transmitted Infections DORYX MPC is indicated for treatment of the following sexually transmitted infections: Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis. Nongonococcal urethritis caused by Ureaplasma urealyticum. Lymphogranuloma venereum caused by Chlamydia trachomatis. Granuloma inguinale caused by Klebsiella granulomatis. Uncomplicated gonorrhea caused by Neisseria gonorrhoeae. Chancroid caused by Haemophilus ducreyi. Respiratory Tract Infections DORYX MPC is indicated for treatment of the following respiratory tract infections: Respiratory tract infections caused by Mycoplasma pneumoniae. Psittacosis (ornithosis) caused by Chlamydophila psittaci. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Respiratory tract infections caused by Haemophilus influenzae. Respiratory tract infections caused by Klebsiella species. Upper respiratory infections caused by Streptococcus pneumoniae. Specific Bacterial Infections DORYX MPC is indicated for treatment of the following specific bacterial infections: Relapsing fever due to Borrelia recurrentis. Plague due to Yersinia pestis. Tularemia due to Francisella tularensis. Cholera caused by Vibrio cholerae. Campylobacter fetus infections caused by Campylobacter fetus. Brucellosis due to Brucella species (in conjunction with streptomycin). Bartonellosis due to Bartonella bacilliformis. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. DORYX MPC is indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Escherichia coli Enterobacter aerogenes Shigella species Acinetobacter species Urinary tract infections caused by Klebsiella species. Ophthalmic Infections DORYX MPC is indicated for treatment of the following ophthalmic infections: Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence. Inclusion conjunctivitis caused by Chlamydia trachomatis. Anthrax Including Inhalational Anthrax (Post-Exposure) DORYX MPC is indicated for treatment of Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. Alternative Treatment For Selected Infections When Penicillin Is Contraindicated DORYX MPC is indicated as an alternative treatment for the following selected infections when penicillin is contraindicated: Syphilis caused by Treponema pallidum. Yaws caused by Treponema pallidum subspecies pertenue. Listeriosis due to Listeria monocytogenes. Vincent’s infection caused by Fusobacterium fusiforme. Actinomycosis caused by Actinomyces israelii. Infections caused by Clostridium species. Adjunctive Therapy For Acute Intestinal Amebiasis And Severe Acne In acute intestinal amebiasis, DORYX MPC may be a useful adjunct to amebicides. In severe acne, DORYX MPC may be useful adjunctive therapy. Prophylaxis Of Malaria DORYX MPC is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains [see DOSAGE AND ADMINISTRATION and PATIENT INFORMATION]. Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORYX MPC and other antibacterial drugs, DORYX MPC 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. DOSAGE AND ADMINISTRATION Important Dosage And Administration Instructions DORYX MPC is not substitutable on a mg per mg basis with other oral doxycyclines. To avoid prescribing errors, do not substitute DORYX MPC for other oral doxycyclines on a mg per mg basis because of differing bioavailability. Do not chew or crush tablets. The recommended dosage, frequency of administration and weight-based dosage recommendations of DORYX MPC differ from that of the other tetracyclines [see Switching From DORYX To DORYX MPC, Dosage In Adult Patients, Dosage In Pediatric Patients]. Exceeding the recommended dosage may result in an increased incidence of adverse reactions. Administer DORYX MPC with an adequate amount of fluid to wash down the drug and reduce the risk of esophageal irritation and ulceration [see ADVERSE REACTIONS]. If gastric irritation occurs, DORYX MPC may be given with food or milk [see CLINICAL PHARMACOLOGY]. Switching From DORYX To DORYX MPC When switching from DORYX to DORYX MPC: A 60 mg dose of DORYX MPC will replace a 50 mg dose of DORYX A 120 mg dose of DORYX MPC will replace a 100 mg dose of DORYX Dosage In Adult Patients The usual dosage of DORYX MPC is 240 mg on the first day of treatment (administered 120 mg every 12 hours) followed by a maintenance dose of 120 mg daily. The maintenance dose may be administered as a single dose or as 60 mg every 12 hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 120 mg every 12 hours is recommended. For certain selected specific indications, the recommended duration or dosage and duration of DORYX MPC in adult patients are as follows: Streptococcal infections, therapy should be continued for 10 days. Uncomplicated urethral, endocervical, or rectal infection caused by C. trachomatis: 120 mg, by mouth, twice-a-day for 7 days. Uncomplicated gonococcal infections in adults (except anorectal infections in men): 120 mg, by mouth, twice-a-day for 7 days. As an alternate single visit dose, administer 360 mg followed in one hour by a second 360 mg dose. Nongonococcal urethritis (NGU) caused by C. trachomatis and U. urealyticum: 120 mg, by mouth, twice-a-day for 7 days. Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 120 mg, by mouth, twice-a-day for 2 weeks. Syphilis of more than one year’s duration: Patients who are allergic to penicillin should be treated with doxycycline 120 mg, by mouth, twice-a-day for 4 weeks. Acute epididymo-orchitis caused by N. gonorrhoeae: 120 mg, by mouth, twice-a-day for at least 10 days. Acute epididymo-orchitis caused by C. trachomatis: 120 mg, by mouth, twice-a-day for at least 10 days Dosage In Pediatric Patients For all pediatric patients weighing less than 45 kg with severe or life threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dosage of DORYX MPC is 2.6 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose [see WARNINGS AND PRECAUTIONS]. For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule of DORYX MPC is 5.3 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.6 mg per kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. Dosage For Prophylaxis Of Malaria For adults, the recommended dose of DORYX MPC is 120 mg daily. For pediatric patients 8 years of age and older, the recommended dosage of DORYX MPC is 2.4 mg per kg of body weight administered once daily. Pediatric patients weighing 45 kg or more should receive the adult dose. Prophylaxis should begin 1 or 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area. Dosage For Inhalational Anthrax (Post-Exposure) For adults, the recommended dosage is 120 mg, of DORYX MPC, by mouth, twice-a-day for 60 days. For pediatric patients weighing less than 45 kg, the recommended dosage of DORYX MPC is 2.6 mg per kg of body weight, by mouth, twice-a-day for 60 days. Pediatric patients weighing 45 kg or more should receive the adult dose. HOW SUPPLIED Dosage Forms And Strengths DORYX MPC (doxycycline hyclate delayed-release tablets), 60 mg and 120 mg are white, oval tablets containing yellow pellets and debossed on one face with “D6” and “DC”, respectively, and plain on the other. Each tablet contains doxycycline 60 mg or 120 mg (equivalent to doxycycline hyclate 69.4 mg or 138.8 mg). Storage And Handling DORYX MPC (doxycycline hyclate delayed-release tablets), 60 mg and 120 mg are white, oval tablets containing yellow pellets and debossed on one face with “D6” and “DC”, respectively, and plain on the other. Each tablet contains doxycycline 60 mg or 120 mg (equivalent to doxycycline hyclate 69.4 mg or 138.8 mg). The 60 mg tablet is supplied in bottles of 120 tablets NDC 51862-560-12 The 120 mg tablet is supplied in bottles of 60 tablets. NDC 51862-559-60 Store at 25° C (77° F); excursions permitted to 15°C to 30° C (59°F to 86° F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container (USP). Manufactured by: Mayne Pharma International Pty Ltd 1538 Main North Road Salisbury South, SA 5106 Australia. Revised: May 2017

INDICATIONS ATRIDOX (doxycycline hyclate) ® is indicated for use in the treatment of chronic adult periodontitis for a gain in clinical attachment, reduction in probing depth, and reduction in bleeding on probing. DOSAGE AND ADMINISTRATION ATRIDOX (doxycycline hyclate) ® is a variable dose product dependent on the size, shape, and number of pockets being treated. Preparation for Use 1. If refrigerated, remove the product from refrigeration at least 15 minutes prior to mixing. 2. Couple Syringe A (liquid delivery system) and Syringe B (drug powder). 3. Inject the liquid contents of Syringe A (indicated by red stripe) into Syringe B (doxycycline powder) and then push the contents back into Syringe A. This entire operation is one mixing cycle. 4. Complete 100 mixing cycles at a pace of one cycle per second using brisk strokes. If immediate use is desired, skip to step 7. 5. If necessary, the coupled syringes can be stored at room temperature for a maximum of three days. Some of the Atridox (doxycycline hyclate) systems are packaged in resealable pouches that can be used for this purpose. If the Atridox (doxycycline hyclate) system is packaged in a try, use an airtight container. 6. After storage, perform an additional ten mixing cycles just prior to use. Continue with immediate use instructions. 7. The contents will be in Syringe A (indicated by red stripe). Hold the coupled syringes vertically with Syringe A at the bottom. Pull back on the Syringe A plunger and allow the contents to flow down the barrel for several seconds. 8. Uncouple the two syringes and attach one of the provided cannulae to Syringe A. Product is now ready for application. Product Administration ATRIDOX (doxycycline hyclate) ® does not require local anesthesia for placement. Bend the cannula to resemble a periodontal probe and explore the periodontal pocket in a manner similar to periodontal probing. Keeping the cannula tip near the base of the pocket, express the product into the pocket until the formulation reaches the top of the gingival margin. Withdraw the cannula tip from the pocket. In order to separate the tip from the formulation, turn the tip of the cannula towards the tooth, press the tip against the tooth surface, and pinch the string of formulation from the tip of the cannula. Variations on this technique may be needed to achieve separation between ATRIDOX (doxycycline hyclate) ® and cannula. If desired, using an appropriate dental instrument, ATRIDOX (doxycycline hyclate) ® may be packed into the pocket. Dipping the edge of the instrument in water before packing will help keep ATRIDOX (doxycycline hyclate) ® from sticking to the instrument, and will help speed coagulation of ATRIDOX (doxycycline hyclate) ®. A few drops of water dripped onto the surface of ATRIDOX (doxycycline hyclate) ® once in the pocket will also aid in coagulation. If necessary, add more ATRIDOX (doxycycline hyclate) ® as described above and pack it into the pocket until the pocket is full. Cover the pockets containing ATRIDOX (doxycycline hyclate) ® with either Coe-Pak™ periodontal dressing or a cyanoacrylate dental adhesive. Application of ATRIDOX (doxycycline hyclate) ® may be repeated four months after initial treatment. HOW SUPPLIED The final blended product is 500 mg of formulation containing 50 mg of doxycycline hyclate (doxycycline hyclate, 10%). ATRIDOX (doxycycline hyclate) ® is available as a tray or pouch containing a doxycycline hyclate syringe (50 mg), an ATRIGEL® Delivery System syringe (450 mg), and a blunt cannula. The pouched product is available in a box of six (NDC 63646-191-00) a box of two (NDC63646-191-02), or a professional sample pouch (NDC 63646-191-01). The trayed product is available in a box of six (NDC 63646-191-05), a box of four (NDC 63646-191-04), or a professional sample box of two (NDC 63646-191-03). Each ATRIDOX (doxycycline hyclate) ® syringe system is intended for use in only one patient. Do not use if packaging has been previously opened or damaged. Storage Conditions Store at 2° - 30°C (36° - 86°F). Manufactured by TOLMAR Inc. Fort Collins, CO 80526. Distributed by Zila Therapeutics, Inc. Rev. 02/11.

PATIENT INFORMATION Patients taking doxycycline should be advised: to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered. (See WARNINGS) that the use of doxycycline might increase the incidence of vaginal candidiasis. Patients should be counseled that antibacterial drugs, including Vibramycin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Vibramycin 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 Vibramycin or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterials are discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

PATIENT INFORMATION Doxycycline Hyclate Delayed-Release Tablets, 75 mg, 100 mg, 150 mg and 200 mg Instructions for Breaking the 150 mg Doxycycline Hyclate Delayed-Release Tablets Dual-Scored Tablet Your doctor may find it necessary to adjust your dosage of Doxycycline Hyclate Delayed-Release Tablets to obtain the proper treatment response. The tablet is marked with separation lines (score lines) and may be broken at these score lines to provide any of the following doses. If your doctor prescribed: 150 mg treatment (taken the entire tablet) 100 mg treatment (two thirds of the tablet or two 50 mg tablet segments are taken) 50 mg treatment (one third of the tablet is taken) To break the tablet, hold the tablet between your thumbs and index fingers close to the appropriate score line. Then, with the score line facing you, apply enough pressure to snap the tablet segments apart (do not use segments that do not break along the score line).

PATIENT INFORMATION Advise patients taking DORYX MPC for malaria prophylaxis: that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria. to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (for example, staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent). that doxycycline prophylaxis: should begin 1 to 2 days before travel to the malarious area, should be continued daily while in the malarious area and after leaving the malarious area, should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area, should not exceed 4 months. Advise all patients taking DORYX MPC: to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototo xicity (for example, skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered [see WARNINGS AND PRECAUTIONS] to drink fluids liberally along with DORYX MPC to reduce the risk of esophageal irritation and ulceration [see ADVERSE REACTIONS] that the absorption of tetracyclines is reduced when taken with foods, especially those that contain calcium. [see DRUG INTERACTIONS] that if gastric irritation occurs, DORYX MPC may be given with food or milk [see CLINICAL PHARMACOLOGY] that the absorption of tetracyclines is reduced when taken with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations [see DRUG INTERACTIONS]. that the use of doxycycline might increase the incidence of vaginal candidiasis. Advise patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without s tomach cramps and fever) even as late as two or more months after having taken the last dose of antibacterial. If this occurs, patients should contact their physician as soon as possible. Counsel patients that antibacterial drugs including DORYX MPC should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When DORYX MPC is prescribed to treat a bacterial infection, patients should be to ld 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 DORYX MPC or other antibacterial drugs in the future.

PATIENT INFORMATION Mechanical oral hygiene procedures (i.e., tooth brushing, flossing) should be avoided on any treated areas for 7 days. Avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline. Doxycycline may decrease the effectiveness of birth control pills.

OVERDOSE No information provided. CONTRAINDICATIONS This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

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

OVERDOSE 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 overdosage. CONTRAINDICATIONS The drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

OVERDOSE 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 overdosage. CONTRAINDICATIONS DORYX MPC is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

OVERDOSE No information provided. CONTRAINDICATIONS ATRIDOX (doxycycline hyclate) ® should not be used in patients who are hypersensitive to doxycycline or any other drug in the tetracycline class.

SIDE EFFECTS Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development. (See WARNINGS) Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (See WARNINGS) Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See WARNINGS) Immune: Hypersensitivity reactions including urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus, and drug reaction with eosinophilia and systemic symptoms (DRESS). Other: Bulging fontanels in infants and intracranial hypertension in adults. (See WARNINGS) Blood: Hemolytic anemia, thrombocytopenia, neutropenia and eosinophilia have been reported. When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function studies are known to occur. 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 bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and Penthrane® (methoxyflurane) has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective.

SIDE EFFECTS 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 Reaction Doxycycline Hyclate Capsules 20 mg BID (n=213) Placebo (n=215) Headache 55 (26%) 56 (26%) Common Cold 47 (22%) 46 (21%) Flu Symptoms 24 (11%) 40 (19%) Tooth Ache 14 (7%) 28 (13%) Periodontal Abscess 8 (4%) 21 (10%) Tooth Disorder 13 (6%) 19 (9%) Nausea 17 (8%) 12 (6%) Sinusitis 7 (3%) 18 (8%) Injury 11 (5%) 18 (8%) Dyspepsia 13 (6%) 5 (2%) Sore Throat 11 (5%) 13 (6%) Joint Pain 12 (6%) 8 (4%) Diarrhea 12 (6%) 8 (4%) Sinus Congestion 11 (5%) 11 (5%) Coughing 9 (4%) 11 (5%) Sinus Headache 8 (4%) 8 (4%) Rash 8 (4%) 6 (3%) Back Pain 7 (3%) 8 (4%) Back Ache 4 (2%) 9 (4%) Menstrual Cramp 9 (4%) 5 (2%) Acid Indigestion 8 (4%) 7 (3%) Pain 8 (4%) 5 (2%) Infection 4 (2%) 6 (3%) Gum Pain 1 (

SIDE EFFECTS Clinical Trial Experience The safety and efficacy of Doxycycline Hyclate Delayed-Release Tablets, 200 mg as a single daily dose was evaluated in a multicenter, randomized, double-blind, active-controlled study. Doxycycline Hyclate Delayed-Release Tablets 200 mg was given orally once-a-day for 7 days and compared to doxycycline hyclate capsules 100 mg given orally twice daily for 7 days for the treatment of men and women with uncomplicated urogenital C. trachomatis infection. Adverse events in the Safety Population were reported by 99 (40.2%) subjects in the Doxycycline Hyclate Delayed-Release Tablets, 200 mg treatment group and 132 (53.2%) subjects in the doxycyclinehyclate capsules reference treatment group. Most AEs were mild in intensity. The most commonly reported adverse events in both treatment groups were nausea, vomiting, diarrhea, and bacterial vaginitis, Table 1. Table 1: Adverse Reactions Reported in Greater than or Equal to 2% of Subjects Doxycycline Hyclate Delayed-Release Tablets, 200 mg N = 246 Preferred Term n (%) Subjects with any AE 99 (40.2) Nausea 33 (13.4) Vomiting 20 (8.1) Headache 5 (2.0) Diarrhea 8 (3.3) Abdominal Pain Upper 5 (2.0) Vaginitis Bacterial 8 (3.3) Vulvovaginal Mycotic Infection 5 (2.0) Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in the clinical trial may not always reflect the rates observed in practice. Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate a causal relationship to drug exposure. Due to oral doxycycline's virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines: Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed [see DOSAGE AND ADMINISTRATION]. Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity is discussed above [see WARNINGS AND PRECAUTIONS]. Renal: Rise in BUN has been reported and is apparently dose-related [see WARNINGS AND PRECAUTIONS]. 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. Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline [see WARNINGS AND PRECAUTIONS] Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur. DRUG INTERACTIONS Anticoagulant Drugs Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Penicillin Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. Antacids And Iron Preparations Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. Oral Contraceptives Concurrent use of tetracycline may render oral contraceptives less effective. Barbiturates And Anti-Epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. Penthrane The concurrent use of tetracycline and Penthrane® (methoxyflurane) has been reported to result in fatal renal toxicity. Drug/Laboratory Test Interactions False elevations of urinary catecholamines may occur due to interference with the fluorescence test.

SIDE EFFECTS The following adverse reactions have been identified during post-approval use of doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Due to oral doxycycline’s virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines: Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed [see DOSAGE AND ADMINISTRATION]. Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity is discussed above [see WARNINGS AND PRECAUTIONS]. Renal: Rise in BUN has been reported and is apparently dose-related [see WARNINGS AND PRECAUTIONS]. 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. Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline [see WARNINGS AND PRECAUTIONS] Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur. DRUG INTERACTIONS Anticoagulant Drugs Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Penicillin Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines, including DORYX MPC in conjunction with penicillin. Antacids And Iron Preparations Absorption of tetracyclines including DORYX MPC is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. Oral Contraceptives Concurrent use of tetracyclines, including DORYX MPC may render oral contraceptives less effective. Barbiturates And Anti-Epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. Penthrane The concurrent use of tetracycline and Penthrane® (methoxyflurane) has been reported to result in fatal renal toxicity. Drug/Laboratory Test Interactions False elevations of urinary catecholamines may occur due to interference with the fluorescence test.

SIDE EFFECTS In clinical trials involving a total of 1436 patients, adverse experiences from all causalities were monitored across treatment groups. In the Circulatory System category, 10 subjects (1.6%) in the ATRIDOX (doxycycline hyclate) ® 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 (doxycycline hyclate) ® group (0.2% for both groups combined) reported adverse events consistent with a localized allergic response. Sex, age, race and smoking status did not appear to be correlated with adverse events. The following table lists the incidence of treatment-emergent adverse events from all causalities, across all treatment groups, occurring in ≥ 1% of the entire study population. Body System Verbatim Terms Doxycycline n=609 Vehicle n=413 OH n=204 SRP n=210 Circulatory High blood pressure 1.60% 0.20% 0.00% 0.00% Digestive Gum discomfort, pain or soreness; loss of attachment; increased pocket depth 18.10% 23.00% 20.10% 21.00% Toothache, pressure sensitivity 14.30% 14.30% 10.30% 18.10% Periodontal abscess, exudate, infection, drainage, extreme mobility, suppuration 9.90% 10.90% 10.30% 8.60% Thermal tooth sensitivity 7.70% 8.50% 4.40% 6.70% Gum inflammation, swelling, sensitivity 4.10% 5.80% 5.40% 5.70% Soft tissue erythema, sore mouth, unspecified pain 4.30% 5.30% 2.70% 6.20% Indigestion, upset stomach, stomachache 3.60% 4.10% 2.90% 3.80% Diarrhea 3.30% 2.40% 1.00% 1.00% Tooth mobility, bone loss 2.00% 0.70% 0.50% 2.40% Periapical abscess, lesion 1.50% 1.90% 1.00% 0.50% Aphthous ulcer, canker sores 0.70% 1.70% 1.00% 1.40% Fistula 0.80% 1.50% 1.50% 1.00% Endodontic abscess, pulpitis 1.50% 1.50% 0.00% 0.50% Jaw pain 1.10% 0.50% 1.00% 1.90% Tooth loss 0.80% 1.50% 1.50% 0.00% Bleeding gums 1.00% 0.70% 0.00% 2.40% Genitourinary Premenstrual tension syndrome 4.40% 3.10% 2.50% 3.30% Ill-Defined Conditions Headache 27.30% 28.10% 23.50% 23.80% Cough 3.60% 6.10% 2.90% 2.40% Sleeplessness 3.40% 1.50% 2.00% 2.90% Body aches, soreness 1.60% 1.20% 1.50% 1.40% Nausea and vomiting 1.80% 0.70% 2.50% 0.50% Fever 1.00% 1.90% 1.00% 1.90% Injury & Poisoning Broken tooth 5.10% 4.10% 4.90% 5.70% Mental Tension headache 1.80% 0.70% 0.00% 1.00% Musculoskeletal Muscle aches 6.40% 4.60% 4.90% 3.30% Backache 3.60% 5.30% 2.50% 6.20% Pain in arms or legs 1.50% 2.20% 2.00% 2.40% Lower back pain 1.60% 1.70% 0.50% 2.90% Neck pain 1.30% 1.70% 1.00% 1.90% Shoulder pain 1.00% 1.00% 1.50% 1.00% Nervous System Ear infection 1.60% 1.90% 2.00% 0.00% Respiratory Common cold 25.50% 25.20% 18.10% 16.70% Flu, respiratory 6.10% 9.00% 3.90% 6.70% Stuffy head, post nasal drip, congestion 5.60% 7.70% 2.90% 4.80% Sore throat 5.70% 6.50% 2.00% 3.30% Sinus infection 5.30% 2.70% 1.00% 1.90% Flu 2.80% 2.90% 2.90% 3.30% Bronchitis 2.30% 1.90% 1.50% 1.00% Allergies 1.00% 1.00% 1.00% 1.90% Skin & Subcutaneous Tissue Skin infection or inflammation 1.30% 1.00% 1.00% 1.00% DRUG INTERACTIONS No information provided.

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. Use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Vibramycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following the use of antibacterial drugs. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing use of antibacterial drugs not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline. (See ADVERSE REACTIONS) If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted. Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including Vibramycin. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and Vibramycin should be avoided because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. 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. The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function. PRECAUTIONS General As with other antibacterial drugs, use of Vibramycin may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, Vibramycin should be discontinued and appropriate therapy instituted. Incision and drainage or other surgical procedures should be performed in conjunction with antibacterial therapy, when indicated. Prescribing Vibramycin in the absence of 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. All infections due to group A beta-hemolytic streptococci should be treated for at least 10 days. Laboratory Tests In venereal diseases when coexistent syphilis is suspected, a dark field examination should be done before treatment is started and the blood serology repeated monthly for at least 4 months. In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed. Usage In Pregnancy (See WARNINGS about use during tooth development.) Vibramycin Intravenous has not been studied in pregnant patients. It should not be used in pregnant women unless, in the judgment of the physician, it is essential for the welfare of the patient. 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. Usage In Children The use of Vibramycin Intravenous in children under 8 years is not recommended because safe conditions for its use have not been established. Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. (See WARNINGS and DOSAGE AND ADMINISTRATION) As with other tetracyclines, doxycycline forms a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Tetracyclines are present in the milk of lactating women who are taking a drug in this class.

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-GRAYBROWN). 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 While no overgrowth by opportunistic microorganisms such as yeast were noted during clinical studies, as with other antimicrobials, Periostat® (doxycycline hyclate) therapy may result in overgrowth of nonsusceptible microorganisms including fungi. The use of tetracyclines may increase the incidence of vaginal candidiasis. Periostat® (doxycycline hyclate) should be used with caution in patients with a history or predisposition to oral candidiasis. The safety and effectiveness of Periostat® (doxycycline hyclate) has not been establishedfor the treatment of periodontitis in patients with coexistant 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. 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 Periostat (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 Periostat® (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 Periostat® (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 Periostat® (doxycycline hyclate) in nursing mothers is contraindicated. (See WARNINGS Section). Pediatric Use The use of Periostat® (doxycycline hyclate) in infancy and childhood is contraindicated. (See WARNINGS section.)

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Tooth Development 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 it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use Doxycycline Hyclate Delayed-Release Tablets in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. Clostridium Difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Doxycycline Hyclate Delayed-Release Tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Photosensitivity 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. Superinfection As with other antibacterial preparations, use of Doxycycline Hyclate Delayed-Release Tablets may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, the antibacterial should be discontinued and appropriate therapy instituted. Intracranial Hypertension Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline including Doxycycline Hyclate Delayed-Release Tablets. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Avoid concomitant use of isotretinoin and Doxycycline Hyclate Delayed-Release Tablets because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. Skeletal Development All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued. 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 also has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. Antianabolic Action The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function. Malaria Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains. Doxycycline does not suppress P. falciparum's sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas. Development Of Drug-Resistant Bacteria Prescribing Doxycycline Hyclate Delayed-Release 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 drug-resistant bacteria. Laboratory Monitoring For Long-Term Therapy In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed. Patient Counseling Information Patients taking doxycycline for malaria prophylaxis should be advised: that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria. to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (for example, staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent). that doxycycline prophylaxis: should begin 1 to 2 days before travel to the malarious area, should be continued daily while in the malarious area and after leaving the malarious area, should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area, should not exceed 4 months. All patients taking doxycycline should be advised: to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (for example, skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered [see WARNINGS AND PRECAUTIONS]. to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration [see ADVERSE REACTIONS]. that the absorption of tetracyclines is reduced when taken with foods, especially those that contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk [see DRUG INTERACTIONS]. that the absorption of tetracyclines is reduced when taken with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations [see DRUG INTERACTIONS]. that the use of doxycycline might increase the incidence of vaginal candidiasis. Diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of antibacterial. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including Doxycycline Hyclate Delayed-Release Tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When Doxycycline Hyclate Delayed-Release Tablets 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 Delayed-Release Tablets or other antibacterial drugs in the future. Instructions For Breaking The 150 mg Doxycycline Hyclate Delayed-Release Tablets Dual-Scored Tablet The tablet is marked with separation lines (score lines) and may be broken at these score lines to provide any of the following doses. 150 mg treatment (the entire tablet is taken) 100 mg treatment (two thirds of the tablet or two 50 mg tablet segments are taken) 50 mg treatment (one third of the tablet is taken) To break the tablet, the tablet is held between the thumbs and index fingers close to the appropriate score line. Then, with the score line facing the patient, enough pressure is applied to snap the tablet segments apart (segments that do not break along the score line should not be used). Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterials, 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 antibacterials (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. Use In Specific Populations Pregnancy Teratogenic Effects Pregnancy Category D: There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS -the Teratogen Information System -concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk.1 A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (that is, in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases.2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age.3 Nonteratogenic effects: [see WARNINGS AND PRECAUTIONS]. Nursing Mothers Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated. The effects of prolonged exposure to doxycycline in breast milk are unknown4. Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see WARNINGS AND PRECAUTIONS]. Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, use Doxycycline Hyclate Delayed-Release Tablets in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly, when there are no alternative therapies Doxycycline Hyclate Delayed-Release Tablets[see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]. Geriatric Use Clinical studies of Doxycycline Hyclate Delayed-Release Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Doxycycline Hyclate Delayed-Release Tablets 75 mg tablets contain 3 mg (0.196 mEq) of sodium Doxycycline Hyclate Delayed-Release Tablets 100 mg tablets contain 3 mg (0.261 mEq) of sodium Doxycycline Hyclate Delayed-Release Tablets 150 mg tablets contain 9 mg (0.392 mEq) of sodium Doxycycline Hyclate Delayed-Release Tablets 200 mg tablets contain 12 mg (0.522 mEq) of sodium. REFERENCES 1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Recredit for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: 149-195. 2. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524-528. 3. Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: 315-317. 4. Hale T. Medications and Mothers Milk. 9th edition. Amarillo, TX: Pharmasoft Publishing 2000; 225-226.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Tooth Development 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 it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use DORYX MPC in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. Clostridium Difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including DORYX MPC Tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Photosensitivity 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. Potential For Microbial Overgrowth DORYX MPC may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue use and institute appropriate therapy. Intracranial Hypertension Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline including DORYX MPC. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Avoid concomitant use of isotretinoin and DORYX MPC because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. Skeletal Development All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued. [See Use In Specific Populations]. Antianabolic Action The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function. Malaria Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains. Doxycycline does not suppress P. falciparum’s sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas. Development Of Drug-Resistant Bacteria Prescribing DORYX MPC 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. Laboratory Monitoring For Long-Term Therapy In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been ev idence of oncogenic activity in rats in studies with the related antibiotics, oxytetracycline (adrenal and pituitary tumors) a nd 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 antibacterials (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. Use In Specific Populations Pregnancy Risk Summary There are no adequate studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS -the Teratogen Information System -concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk.1 In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively [see Data]. Clinical Considerations Embryo/Fetal Risk 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 also has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. [see WARNINGS AND PRECAUTIONS]. Data Human Data A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases.2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age.3 Lactation Risk Summary Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not contraindicated. The effects of prolonged exposure to doxycycline on breast milk production and breast fed neonates, infants and children are unknown.4 The developmental and health benefits of breast feeding should be considered along with the mother’s clinical need for DORYX MPC and any potential adverse effects on the breast fed child from DORYX MPC or from the underlying maternal condition [see WARNINGS AND PRECAUTIONS]. Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, use DORYX MPC in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]. Geriatric Use Clinical studies of DORYX MPC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. DORYX MPC Tablets each contain less than 10 mg of sodium. REFERENCES 1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: 149-195. The TERIS (Teratogen Information System) is available at: http://www.micromedexsolutions.com/ (cited: 2016 Jan). 2. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524-528. 3. Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: 315-317. 4. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); [Last Revision Date 2015 March 10; cited 2016 Jan]. Doxycycline; LactMed Record Number: 100; [about 3 screens]. Available from: http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

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. This adverse reaction is more common during long-term use of the drugs, but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP, OR IN PREGNANT WOMEN, UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking doxycycline or other tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs. PRECAUTIONS General ATRIDOX (doxycycline hyclate) ® has not been clinically tested in pregnant women. ATRIDOX (doxycycline hyclate) ® has not been clinically evaluated in patients with conditions involving extremely severe periodontal defects with very little remaining periodontium. ATRIDOX (doxycycline hyclate) ® has not been clinically tested for use in the regeneration of alveolar bone, either in preparation for or in conjunction with the placement of endosseous (dental) implants or in the treatment of failing implants. ATRIDOX (doxycycline hyclate) ® has not been clinically tested in immunocompromised patients (such as patients immunocompromised by diabetes, chemotherapy, radiation therapy, or infection with HIV). As with other antibiotic preparations, ATRIDOX (doxycycline hyclate) ® therapy may result in overgrowth of nonsusceptible organisms, including fungi.1 The effects of prolonged treatment, greater than 6 months, have not been studied. ATRIDOX (doxycycline hyclate) ® should be used with caution in patients with a history of or predisposition to oral candidiasis. The safety and effectiveness of ATRIDOX (doxycycline hyclate) ® have not been established for the treatment of periodontitis in patients with coexistent oral candidiasis. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibiotics, oxytetracycline (adrenal and pituitary tumors), and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibiotics (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied. Pregnancy Category D. See WARNINGS section Nursing Mothers Tetracyclines appear in breast milk following oral administration. It is not known whether doxycycline is excreted in human milk following use of ATRIDOX (doxycycline hyclate) ® . Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (See WARNINGS section) Pediatrics The safety and effectiveness of ATRIDOX (doxycycline hyclate) ® in pediatric patients have not been established. Oral doses of doxycycline in children up to 8 years of age have caused permanent discoloration of teeth.