DOXYCYCLINE HYCLATE

1 INDICATIONS AND USAGE Doxycycline hyclate delayed-release tablets are a tetracycline-class drug indicated for: • Rickettsial infections ( 1.1 ) • Sexually transmitted infections ( 1.2 ) • Respiratory tract infections ( 1.3 ) • Specific bacterial infections ( 1.4 ) • Ophthalmic infections ( 1.5 ) • Anthrax, including inhalational anthrax (post-exposure) ( 1.6 ) • Alternative treatment for selected infections when penicillin is contraindicated ( 1.7 ) • Adjunctive therapy in acute intestinal amebiasis and severe acne ( 1.8 ) • Prophylaxis of malaria ( 1.9 ) Usage 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 bacteria. ( 1.10 ) 1.1 Rickettsial Infections Doxycycline hyclate delayed-release tablets are indicated for treatment of Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae . 1.2 Sexually Transmitted Infections Doxycycline hyclate delayed-release tablets are indicated for treatment of the following 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 . 1.3 Respiratory Tract Infections Doxycycline hyclate delayed-release tablets are indicated for treatment of the following respiratory 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 micro-organisms, 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 . 1.4 Specific Bacterial Infections Doxycycline hyclate delayed-release tablets are 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. Doxycycline hyclate delayed-release tablets are 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. 1.5 Ophthalmic Infections Doxycycline hyclate delayed-release tablets are 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 . 1.6 Anthrax, Including Inhalational Anthrax (Post-Exposure) Doxycycline hyclate delayed-release tablets are indicated for the treatment of Anthrax due to Bacill…

2 DOSAGE AND ADMINISTRATION • Dosage in Adult Patients: ο The usual dosage is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg daily. ( 2.1 ) ο In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. ( 2.1 ) • Dosage in Pediatric Patients: ο For all pediatric patients weighing less than 45 kg with severe or life-threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dose 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. ( 2.1 ) ο For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dose 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 two doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. ( 2.1 ) 2.1 Important Dosage and Administration Instructions • Doxycycline hyclate delayed-release tablets are not substitutable on a mg per mg basis with other oral doxycyclines. To avoid prescribing errors, do not substitute doxycycline hyclate delayed-release tablets for other oral doxycyclines on a mg per mg basis because of differing bioavailability. • Do not chew or crush tablets [see Dosage and Administration ( 2.4 )]. • The recommended dosage, frequency of administration and weight-based dosage recommendations of doxycycline hyclate delayed-release tablets differ from that of the other tetracyclines [see Dosage and Administration ( 2.2, 2.3 , 2.4 ) ] . Exceeding the recommended dosage may result in an increased incidence of adverse reactions. • Administer doxycycline hyclate delayed-release tablets with an adequate amount of fluid to wash down the drug and reduce the risk of esophageal irritation and ulceration [see Adverse Reactions ( 6.1 )] . • If gastric irritation occurs, doxycycline hyclate delayed-release tablets may be given with food or milk [see Clinical Pharmacology ( 12.3 )] . 2.3 Dosage in Adult Patients • The usual dosage of doxycycline hyclate delayed-release tablets 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. 2.4 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 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 ( 5.1 )] . • 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. 2.5 Dosage for Prophylaxis of Malaria For adults, the recommended dose of doxycycline hyclate delayed-release tablets is 100 mg daily. For pediatric patients 8 years of age and older, the recommended dose is 2 mg/kg administered once daily up to the adult dose. 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…

5 WARNINGS AND PRECAUTIONS • 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). ( 5.1 ) • Clostridioides difficile-associated diarrhea (CDAD) has been reported: Evaluate patients if diarrhea occurs. ( 5.2 ) • Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Limit sun exposure. ( 5.3 ) • Overgrowth of non-susceptible organisms, including fungi, may occur. If such infections occur, discontinue use and institute appropriate therapy. ( 5.4 ) 5.1 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. 5.2 Clostridioides difficile -Associated Diarrhea Clostridioides 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. 5.3 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. 5.4 Potential for Microbial Overgrowth 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. 5.5 Severe Skin Reactions 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. Fixed drug eruptions have occurred with doxycycline and have been associated with worsening severity upon subsequent administrations, including generalized bullous fixed drug eruption [see Adverse Reactions ( 6 )] . If severe skin reactions occur discontinue doxycycline, immediately and institute appropriate therapy. 5.6 Intracranial Hypertension Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline including doxycycline hyclate delayed-release tablets. Clinical manifestations o…

4 CONTRAINDICATIONS Doxycyline is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. Doxycycline is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. ( 4 )

7 DRUG INTERACTIONS • Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage ( 7.1 ) • Avoid co-administration of tetracyclines with penicillin ( 7.2 ) • Absorption of tetracyclines, including doxycycline hyclate delayed-release tablets, is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations ( 7.3 ) • Concurrent use of tetracyclines, including doxycycline hyclate delayed-release tablets, may render oral contraceptives less effective ( 7.4 ) • Barbiturates, carbamazepine and phenytoin decrease the half-life of doxycycline ( 7.5 ) 7.1 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. 7.2 Penicillin Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. 7.3 Antacids and Iron Preparations Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. 7.4 Oral Contraceptives Concurrent use of tetracycline may render oral contraceptives less effective. 7.5 Barbiturates and Anti-Epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. 7.6 Drug/Laboratory Test Interactions False elevations of urinary catecholamines may occur due to interference with the fluorescence test.

6 ADVERSE REACTIONS Adverse reactions observed in patients receiving tetracyclines include anorexia, nausea, vomiting, diarrhea, rash, photosensitivity, urticaria, and hemolytic anemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Solco Healthcare LLC at 1-866-257-2597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 were 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 reactions 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 doxycycline hyclate capsules reference treatment group. Most adverse reactions were mild in intensity. The most commonly reported adverse reactions 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 Adverse Reactions Doxycycline Hyclate Delayed-Release Tablets, 200 mg N = 246 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. 6.2 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, 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. 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 and Precautions ( 5.1 )] . 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 ( 2.1 )] . Skin : Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and fixed drug eruption have been reported. Photosensitivity is discussed above [see Warnings and Precautions ( 5.3 )] . Renal : Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions ( 5.8 )] . Hypersensitivity reactions : Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus, and drug reaction with eosinophilia and systemic symptoms (DRESS). Blood : Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. Intracranial Hypertension : Intracranial hypertension (IH, pseudotumor cerebri) has been associ…