DOXYCYCLINE

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 capsules for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease. ( 1.2 ) Doxycycline capsules have not been evaluated for the treatment of the erythematous, telangiectatic, or ocular components of rosacea. ( 1.2 ) 1.1 Indication Doxycycline capsules are 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 capsules 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 capsules should be used only as indicated. Doxycycline capsules have not been evaluated for the treatment of the erythematous, telangiectatic, or ocular components of rosacea.

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 capsules 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.

5 WARNINGS AND PRECAUTIONS The use of doxycycline capsules during tooth development (the second and third trimesters of pregnancy, infancy and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and reversible inhibition of bone growth. ( 5.1 , 5.2 , 8.1 , 8.4 ) Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of Clostridium difficile . If C. difficile associated diarrhea occurs, discontinue doxycycline capsules. ( 5.3 ) If renal impairment exists, doxycycline capsules doses may need to be adjusted to avoid excessive systemic accumulations of the drug and possible liver injury. ( 5.4 ) Photosensitivity can occur with doxycycline capsules; Patients should minimize or avoid exposure to natural or artificial sunlight. ( 5.5 ) Tetracyclines have been associated with the development of autoimmune syndromes; if symptoms develop, discontinue doxycycline capsules immediately. ( 5.6 ) Doxycycline capsules may cause pseudotumor cerebri (benign intracranial hypertension). Discontinue doxycycline capsules if symptoms occur. ( 5.8 ) Bacterial resistance to tetracyclines may develop in patients using doxycycline capsules. It should only be used as indicated. ( 5.9 ) 5.1 Inhibition of Bone Growth During Fetal and Pediatric Development Doxycycline, like other tetracycline-class drugs, may cause inhibition of bone growth when administered during the second and third trimesters of pregnancy, infancy, and childhood. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. If doxycycline is used during the second or third trimester of pregnancy, advise the patient of the potential risk to the fetus [see Use in Specific Populations (8.1) ] . 5.2 Tooth Discoloration During Fetal and Pediatric Development The use of tetracycline class drugs orally during tooth development (last half of pregnancy, infancy, and childhood up 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 drug but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use of tetracycline drugs is not recommended during tooth development [see Use in Specific Populations (8.1) ] . 5.3 Clostridium difficile Associated Diarrhea (CDAD) Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including doxycycline, 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate management should be instituted as clinically indicated. 5.4 Metabolic Effects The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulati…

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

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.

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 capsules 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.

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 AiPing Pharmaceutical, Inc. at 1-844-374-0016 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 Capsules: In controlled clinical trials of adult subjects with mild to moderate rosacea, 537 subjects received doxycycline capsules 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 Capsules (n=269) vs. Placebo (n=268) Doxycycline Capsules 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 Adverse Reactions 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 capsules. Nervous system: Pseudotumor cerebri (benign intracranial hypertension), headache. Skin: fixed drug eruption Psychiatric: depression, anxiety, suicidal ideation, insomnia, abnormal dreams, hallucination