DOXYCYCLINE

6 ADVERSE REACTIONS Some of the most common adverse reactions (incidence >2% and more common than with placebo) are nasopharyngitis, sinusitis, diarrhea, hypertension and aspartate aminotransferase increase. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials of Doxycycline: In controlled clinical trials of adult subjects with mild to moderate rosacea, 537 subjects received Doxycycline or placebo over a 16-week period. The following table summarizes selected adverse reactions that occurred in the clinical trials at a rate of ≥1% for the active arm: Table 1. Incidence (%) of Selected Adverse Reactions in Clinical Trials of Doxycycline (n=269) v.s. Placebo (n=268) Doxycycline Placebo Nasopharyngitis 13 (5) 9 (3) Pharyngolaryngeal Pain 3 (1) 2 (1) Sinusitis 7 (3) 2 (1) Nasal Congestion 4 (2) 2 (1) Fungal Infection 5 (2) 1 (0) Influenza 5 (2) 3 (1) Diarrhea 12 (5) 7 (3) Abdominal Pain Upper 5 (2) 1 (0) Abdominal Distention 3 (1) 1 (0) Abdominal Pain 3 (1) 1 (0) Stomach Discomfort 3 (1) 2 (1) Dry Mouth 3 (1) 0 (0) Hypertension 8 (3) 2 (1) Blood Pressure Increase 4 (2) 1 (0) Aspartate Aminotransferase Increase 6 (2) 2 (1) Blood Lactate Dehydrogenase Increase 4 (2) 1 (0) Blood Glucose Increase 3 (1) 0 (0) Anxiety 4 (2) 0 (0) Pain 4 (2) 1 (0) Back Pain 3 (1) 0 (0) Sinus Headache 3 (1) 0 (0) Note: Percentages based on total number of study participants in each treatment group. Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients receiving tetracyclines at higher, antimicrobial doses: Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with vaginal candidiasis) in the anogenital region. Hepatotoxicity, Esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the drugs in the tetracycline-class. Most of the patients experiencing esophagitis and/or esophageal ulceration took their medication immediately before lying down [ see Dosage and Administration (2) ]. Renal toxicity: Rise in BUN has been reported and is apparently dose-related [ see Warnings and Precautions (5.4) ]. Skin: maculopapular and erythematous rashes. Exfoliative dermatitis . Photosensitivity is discussed above [see Warnings and Precautions (5.5) ]. Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia. 6.2 Postmarketing Experience 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. The following adverse reactions have been identified during post approval use of Doxycycline: Nervous system : Pseudotumor cerebri (benign intracranial hypertension), headache.

4 CONTRAINDICATIONS ​This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any of the other tetracyclines. Doxycycline is contraindicated in persons who have shown hypersensitivity to doxycycline or other tetracyclines. ( 4 )

11 DESCRIPTION Doxycycline Capsules 40 mg are hard gelatin capsule shells filled with two types of doxycycline beads (30 mg immediate release and 10 mg delayed release) that together provide a dose of 40 mg of anhydrous doxycycline (C 22 H 24 N 2 O 8 ). The structural formula of doxycycline, USP is: with an empirical formula of C 22 H 24 N 2 O 8 •H 2 O and a molecular weight of 462.46. The chemical designation for doxycycline is 2-Naphthacenecar-boxamide,4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-, [4S-(4α, 4aα, 5α, 5aα, 6α,12aα)]-, monohydrate. It is very slightly soluble in water. Inert ingredients in the formulation are: hard gelatin capsule, hypromellose, methacrylic acid copolymer, Opadry beige, sugar spheres, talc, and triethyl citrate. oracea-chem-struct

2 DOSAGE AND ADMINISTRATION Take one Doxycycline capsule (40 mg) once daily in the morning on an empty stomach, preferably at least one hour prior to or two hours after meals. ( 2.1 ) Exceeding the recommended dosage may result in an increased incidence of side effects including the development of resistant microorganisms. ( 2.2 , 5.9 ) 2.1 General Dosing Information Take one Doxycycline capsule (40 mg) once daily in the morning on an empty stomach, preferably at least one hour prior to or two hours after meals. Administration of adequate amounts of fluid along with the capsules is recommended to wash down the capsule to reduce the risk of esophageal irritation and ulceration [ see Adverse Reactions (6) ]. 2.2 Important Considerations for Dosing Regimen The dosage of Doxycycline 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 organisms.

1 INDICATIONS AND USAGE Doxycycline is a tetracycline-class drug indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. ( 1.1 ) Limitations of Use This formulation of doxycycline has not been evaluated in the treatment or prevention of infections. Do not use Doxycycline for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease. ( 1.2 ) Doxycycline has not been evaluated for the treatment of the erythematous, telangiectatic, or ocular components of rosacea. ( 1.2 ) 1.1 Indication Doxycycline is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. No meaningful effect was demonstrated for generalized erythema (redness) of rosacea. 1.2 Limitations of Use This formulation of doxycycline has not been evaluated in the treatment or prevention of infections. Do not use Doxycycline for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease. To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, Doxycycline should be used only as indicated. Doxycycline has not been evaluated for the treatment of the erythematous, telangiectatic, or ocular components of rosacea.

7 DRUG INTERACTIONS • Patients on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. ( 7.1 ) • Some bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin. ( 7.2 ) • The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. ( 7.3 ) 7.1 Anticoagulants Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 7.2 Penicillin Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin. 7.3 Methoxyflurane The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. 7.4 Antacids and Iron Preparations Absorption of tetracyclines is impaired by bismuth subsalicylate, proton pump inhibitors, antacids containing aluminum, calcium or magnesium and iron-containing preparations. 7.5 Oral Retinoids There have been reports of pseudotumor cerebri (benign intracranial hypertension) associated with the concomitant use of isotretinoin and tetracyclines. Since both oral retinoids, including isotretinoin and acitretin, and the tetracyclines, primarily minocycline, can cause increased intracranial pressure, the concurrent use of an oral retinoid and a tetracycline should be avoided. 7.6 Barbiturates and Anti-epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. 7.7 Drug/Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of Doxycycline in the treatment of inflammatory lesions of rosacea is unknown. 12.3 Pharmacokinetics Doxycycline capsules are not bioequivalent to other doxycycline products. The pharmacokinetics of doxycycline following oral administration of Doxycycline was investigated in 2 volunteer studies involving 61 adults. Pharmacokinetic parameters for Doxycycline following single oral doses and at steady-state in healthy subjects are presented in Table 2. Table 2. Pharmacokinetic Parameters [Mean (± SD)] for Doxycycline N C max Mean (ng/mL) T max Median (hr) AU 0-∞ (ng●hr/mL) t ½ (hr) Single Dose 40 mg capsules 30 510 ± 220.7 3.00 (1.0 - 4.1) 9227 ± 3212.8 21.2 ± 7.6 Steady-State Day 7 40 mg capsules 31 600 ± 194.2 2.00 (1.0 - 4.0) 7543 ± 2443.9 23.2 ± 6.2 Absorption: In a single-dose food-effect study involving administration of Doxycycline to healthy volunteers, concomitant administration with a 1000 calorie, high-fat, high-protein meal that included dairy products, resulted in a decrease in the rate and extent of absorption (C max and AUC) by about 45% and 22%, respectively, compared to dosing under fasted conditions. This decrease in systemic exposure can be clinically significant, and therefore if Doxycycline is taken close to meal times, it is recommended that it be taken at least one hour prior to or two hours after meals. Distribution: Doxycycline is greater than 90% bound to plasma proteins. 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 reported that between 29% and 55.4% of an administered dose can be accounted for in the urine by 72 hours. Terminal half-life averaged 21.2 hours in subjects receiving a single dose of Doxycycline . Special Populations Geriatric: Doxycycline pharmacokinetics have not been evaluated in geriatric patients. Pediatric: Doxycycline pharmacokinetics have not been evaluated in pediatric patients [ see Warnings and Precautions (5.1) ] Gender: The pharmacokinetics of Doxycycline were compared in 16 male and 14 female subjects under fed and fasted conditions. While female subjects had a higher C max and AUC than male subjects, these differences were thought to be due to differences in body weight/lean body mass. 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 serum half-life of doxycycline. Hepatic Insufficiency: Doxycycline pharmacokinetics have not been evaluated in patients with hepatic insufficiency. Gastric Insufficiency: In a study in healthy volunteers (N=24) the bioavailability of doxycycline is reported to be reduced at high pH. This reduced bioavailability may be clinically significant in patients with gastrectomy, gastric bypass surgery or who are otherwise deemed achlorhydric. Drug Interactions: [ see Drug Interactions (7) ]. 12.4 Microbiology Doxycycline is a member of the tetracycline-class of drugs. The plasma concentrations of doxycycline achieved with Doxycycline during administration [ see Clinical Pharmacology (12.3) and Dosage and Administration (2.2) ] are less than the concentration required to treat bacterial diseases. Doxycycline should not be used for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease [ see Indications and Usage (1.2) ]. In vivo microbiological studies utilizing a similar drug exposure for up to 18 months demonstrated no detectable long term effects on bacterial flora of the oral cavity, skin, intestinal tract and vagina.

12.1 Mechanism of Action The mechanism of action of Doxycycline in the treatment of inflammatory lesions of rosacea is unknown.

12.3 Pharmacokinetics Doxycycline capsules are not bioequivalent to other doxycycline products. The pharmacokinetics of doxycycline following oral administration of Doxycycline was investigated in 2 volunteer studies involving 61 adults. Pharmacokinetic parameters for Doxycycline following single oral doses and at steady-state in healthy subjects are presented in Table 2. Table 2. Pharmacokinetic Parameters [Mean (± SD)] for Doxycycline N C max Mean (ng/mL) T max Median (hr) AU 0-∞ (ng●hr/mL) t ½ (hr) Single Dose 40 mg capsules 30 510 ± 220.7 3.00 (1.0 - 4.1) 9227 ± 3212.8 21.2 ± 7.6 Steady-State Day 7 40 mg capsules 31 600 ± 194.2 2.00 (1.0 - 4.0) 7543 ± 2443.9 23.2 ± 6.2 Absorption: In a single-dose food-effect study involving administration of Doxycycline to healthy volunteers, concomitant administration with a 1000 calorie, high-fat, high-protein meal that included dairy products, resulted in a decrease in the rate and extent of absorption (C max and AUC) by about 45% and 22%, respectively, compared to dosing under fasted conditions. This decrease in systemic exposure can be clinically significant, and therefore if Doxycycline is taken close to meal times, it is recommended that it be taken at least one hour prior to or two hours after meals. Distribution: Doxycycline is greater than 90% bound to plasma proteins. 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 reported that between 29% and 55.4% of an administered dose can be accounted for in the urine by 72 hours. Terminal half-life averaged 21.2 hours in subjects receiving a single dose of Doxycycline . Special Populations Geriatric: Doxycycline pharmacokinetics have not been evaluated in geriatric patients. Pediatric: Doxycycline pharmacokinetics have not been evaluated in pediatric patients [ see Warnings and Precautions (5.1) ] Gender: The pharmacokinetics of Doxycycline were compared in 16 male and 14 female subjects under fed and fasted conditions. While female subjects had a higher C max and AUC than male subjects, these differences were thought to be due to differences in body weight/lean body mass. 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 serum half-life of doxycycline. Hepatic Insufficiency: Doxycycline pharmacokinetics have not been evaluated in patients with hepatic insufficiency. Gastric Insufficiency: In a study in healthy volunteers (N=24) the bioavailability of doxycycline is reported to be reduced at high pH. This reduced bioavailability may be clinically significant in patients with gastrectomy, gastric bypass surgery or who are otherwise deemed achlorhydric. Drug Interactions: [ see Drug Interactions (7) ].

20221031

3

3 DOSAGE FORMS AND STRENGTHS 40 mg beige opaque capsule imprinted with “GLD 40” • 40 mg capsule. ( 3 )

SPL listing data elements section DOXYCYCLINE DOXYCYCLINE Doxycycline Doxycycline Anhydrous Hypromellose, Unspecified Ferric Oxide Red Ferric Oxide Yellow Polyethylene Glycol, Unspecified Sucrose Talc Titanium Dioxide Triethyl Citrate Methacrylic Acid And Ethyl Acrylate Copolymer beige GLD;40 label-image-30ct-bottle

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Doxycycline 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 12.2 times that observed in female humans who use Doxycycline [exposure comparison based upon area under the curve (AUC) values]. No impact upon tumor incidence was observed in male rats up to at 200 mg/kg/day, or in females at the lower dosages studied. Doxycyline was assessed for potential to induce carcinogenesis in CD-1 mice by gavage at dosages 20, 75, and 150 mg/kg/day in males and at dosages of 20, 100, and 300 mg/kg/day in females. No impact upon tumor incidence was observed in male and female mice at systemic exposures approximately 4.2 and 8.3 times that observed in humans, respectively. Doxycycline 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 mammalian chromosomal aberration assay conducted with CHO cells suggest that doxycycline is a weak clastogen. Oral administration of doxycycline 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 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 3.6 times the amount of doxycycline contained in the recommended daily dose of Doxycycline when compared on the basis of AUC estimates. Although doxycycline impairs the fertility of rats when administered at sufficient dosage, the effect of Doxycycline on human fertility is unknown.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Doxycycline 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 12.2 times that observed in female humans who use Doxycycline [exposure comparison based upon area under the curve (AUC) values]. No impact upon tumor incidence was observed in male rats up to at 200 mg/kg/day, or in females at the lower dosages studied. Doxycyline was assessed for potential to induce carcinogenesis in CD-1 mice by gavage at dosages 20, 75, and 150 mg/kg/day in males and at dosages of 20, 100, and 300 mg/kg/day in females. No impact upon tumor incidence was observed in male and female mice at systemic exposures approximately 4.2 and 8.3 times that observed in humans, respectively. Doxycycline 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 mammalian chromosomal aberration assay conducted with CHO cells suggest that doxycycline is a weak clastogen. Oral administration of doxycycline 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 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 3.6 times the amount of doxycycline contained in the recommended daily dose of Doxycycline when compared on the basis of AUC estimates. Although doxycycline impairs the fertility of rats when administered at sufficient dosage, the effect of Doxycycline on human fertility is unknown.

NDA050805

DOXYCYCLINE

DOXYCYCLINE

68308-668

HUMAN PRESCRIPTION DRUG

ORAL

12.4 Microbiology Doxycycline is a member of the tetracycline-class of drugs. The plasma concentrations of doxycycline achieved with Doxycycline during administration [ see Clinical Pharmacology (12.3) and Dosage and Administration (2.2) ] are less than the concentration required to treat bacterial diseases. Doxycycline should not be used for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease [ see Indications and Usage (1.2) ]. In vivo microbiological studies utilizing a similar drug exposure for up to 18 months demonstrated no detectable long term effects on bacterial flora of the oral cavity, skin, intestinal tract and vagina.

PACKAGE LABEL NDC 68308-668-30 Doxycycline Capsules, USP 40 mg* * 30 mg IMMEDIATE RELEASE & 10 mg DELAYED RELEASE BEADS RX ONLY 30 Capsules maynepharma Distributed by: Mayne Pharma, Raleigh, NC 27609 All trademarks are the property of their respective owners. 31650-1022

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Patients taking Doxycycline Capsules 40 mg should receive the following information and instructions: Advise pregnant women that doxycycline, like other tetracycline-class drugs, may cause permanent discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimesters of pregnancy [ see Warnings and Precautions (5.1 and 5.2) and Use in Specific Populations (8.1) ]. Advise women not to breastfeed during treatment with Doxycycline and for 5 days after the last dose [ see Use in Specific Populations (8.2) ]. Advise patients that use of tetracycline class drugs orally during tooth development (infancy and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Advise patients that use of doxycycline, like other tetracycline-class drugs, may cause inhibition of bone growth when administered during infancy and childhood. Advise patients that pseudomembranous colitis can occur with doxycycline therapy. If patients develop watery or bloody stools, they should seek medical attention. Advise patients that pseudotumor cerebri can occur with doxycycline therapy. If patients experience headache or blurred vision they should seek medical attention. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including doxycycline. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using doxycycline. If patients need to be outdoors while using doxycycline, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. Treatment should be discontinued at the first evidence of sunburn. Autoimmune syndromes, including drug-induced lupus-like syndrome, autoimmune hepatitis, vasculitis and serum sickness have been observed with tetracycline-class drugs, including doxycycline. Symptoms may be manifested by arthralgia, fever, rash and malaise. Patients who experience such symptoms should be cautioned to stop the drug immediately and seek medical help. Counsel patients about discoloration of skin, scars, teeth or gums that can arise from doxycycline therapy. Advise patients to take Doxycycline exactly as directed. Increasing doses beyond 40 mg every morning may increase the likelihood that bacteria will develop resistance and will not be treatable by other antibacterial drugs in the future.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials of Doxycycline: In controlled clinical trials of adult subjects with mild to moderate rosacea, 537 subjects received Doxycycline or placebo over a 16-week period. The following table summarizes selected adverse reactions that occurred in the clinical trials at a rate of ≥1% for the active arm: Table 1. Incidence (%) of Selected Adverse Reactions in Clinical Trials of Doxycycline (n=269) v.s. Placebo (n=268) Doxycycline Placebo Nasopharyngitis 13 (5) 9 (3) Pharyngolaryngeal Pain 3 (1) 2 (1) Sinusitis 7 (3) 2 (1) Nasal Congestion 4 (2) 2 (1) Fungal Infection 5 (2) 1 (0) Influenza 5 (2) 3 (1) Diarrhea 12 (5) 7 (3) Abdominal Pain Upper 5 (2) 1 (0) Abdominal Distention 3 (1) 1 (0) Abdominal Pain 3 (1) 1 (0) Stomach Discomfort 3 (1) 2 (1) Dry Mouth 3 (1) 0 (0) Hypertension 8 (3) 2 (1) Blood Pressure Increase 4 (2) 1 (0) Aspartate Aminotransferase Increase 6 (2) 2 (1) Blood Lactate Dehydrogenase Increase 4 (2) 1 (0) Blood Glucose Increase 3 (1) 0 (0) Anxiety 4 (2) 0 (0) Pain 4 (2) 1 (0) Back Pain 3 (1) 0 (0) Sinus Headache 3 (1) 0 (0) Note: Percentages based on total number of study participants in each treatment group. Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients receiving tetracyclines at higher, antimicrobial doses: Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with vaginal candidiasis) in the anogenital region. Hepatotoxicity, Esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the drugs in the tetracycline-class. Most of the patients experiencing esophagitis and/or esophageal ulceration took their medication immediately before lying down [ see Dosage and Administration (2) ]. Renal toxicity: Rise in BUN has been reported and is apparently dose-related [ see Warnings and Precautions (5.4) ]. Skin: maculopapular and erythematous rashes. Exfoliative dermatitis . Photosensitivity is discussed above [see Warnings and Precautions (5.5) ]. Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia.

8.5 Geriatric Use Clinical studies of Doxycycline 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 elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

8.2 Lactation Risk Summary Based on available published data, doxycycline is likely to be present in human breast milk but the specific concentration in breastmilk is not clear. There is no information on the effects of doxycycline on the breastfed infant or the effects on milk production. Because there are other antibacterial drug options available to treat rosacea in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with Doxycycline and for 5 days after the last dose.

8.4 Pediatric Use Doxycycline should not be used in infants and children less than 8 years of age [ see Warnings and Precautions (5.1) ]. Doxycycline has not been studied in children of any age with regard to safety or efficacy, therefore use in children is not recommended.

8.1 Pregnancy Risk Summary Doxycycline may cause reversible inhibition of bone growth and permanent discoloration of deciduous teeth when administered during the second and third trimesters of pregnancy [see Warnings and Precautions (5.1 and 5.2)]. Available data from published studies have not shown a difference in major birth defect risk with doxycycline exposure in the first trimester of pregnancy compared to unexposed pregnancies. Avoid use of Doxycycline during the second and third trimester of pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Data Human Data Published studies, including epidemiological and observational studies, with use of doxycycline during the first trimester of pregnancy have not identified drug-related increases in major birth defects. The use of tetracycline during tooth development (second and third trimester of pregnancy) may cause permanent discoloration of deciduous teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been observed following repeated short- term courses. Animal Data Results from animal studies indicate that doxycycline crosses the placenta and is found in fetal tissues.

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended ( 8.2 ) 8.1 Pregnancy Risk Summary Doxycycline may cause reversible inhibition of bone growth and permanent discoloration of deciduous teeth when administered during the second and third trimesters of pregnancy [see Warnings and Precautions (5.1 and 5.2)]. Available data from published studies have not shown a difference in major birth defect risk with doxycycline exposure in the first trimester of pregnancy compared to unexposed pregnancies. Avoid use of Doxycycline during the second and third trimester of pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Data Human Data Published studies, including epidemiological and observational studies, with use of doxycycline during the first trimester of pregnancy have not identified drug-related increases in major birth defects. The use of tetracycline during tooth development (second and third trimester of pregnancy) may cause permanent discoloration of deciduous teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been observed following repeated short- term courses. Animal Data Results from animal studies indicate that doxycycline crosses the placenta and is found in fetal tissues. 8.2 Lactation Risk Summary Based on available published data, doxycycline is likely to be present in human breast milk but the specific concentration in breastmilk is not clear. There is no information on the effects of doxycycline on the breastfed infant or the effects on milk production. Because there are other antibacterial drug options available to treat rosacea in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with Doxycycline and for 5 days after the last dose. 8.4 Pediatric Use Doxycycline should not be used in infants and children less than 8 years of age [ see Warnings and Precautions (5.1) ]. Doxycycline has not been studied in children of any age with regard to safety or efficacy, therefore use in children is not recommended. 8.5 Geriatric Use Clinical studies of Doxycycline 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 elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING Doxycycline (beige opaque capsule imprinted with “GLD 40”) containing doxycycline, USP in an amount equivalent to 40 mg of anhydrous doxycycline. Bottle of 30 (NDC 68308-668-30). Storage: All products are to be stored at controlled room temperatures of 59°F - 86°F (15°C - 30°C) and dispensed in tight, light-resistant containers (USP). Keep out of reach of children.