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 Bacillus anthracis , including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis .

1.7 Alternative Treatment for Selected Infections When Penicillin is Contraindicated Doxycycline hyclate delayed-release tablets are 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 .

• Vincent’s infection caused by Fusobacterium fusiforme.

• Actinomycosis caused by Actinomyces israelii .

• Infections caused by Clostridium species.

1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne In acute intestinal amebiasis, doxycycline hyclate delayed-release tablets may be a useful adjunct to amebicides.

In severe acne, doxycycline may be useful adjunctive therapy.

1.9 Prophylaxis of Malaria Doxycycline hyclate delayed-release tablets are 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 ( 2.2 ) and Patient Counseling Information ( 17 )] .

1.10 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 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.

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 associated with the use of tetracycline [see Warnings and Precautions ( 5.

6)].

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.

Psychiatric: Depression, anxiety, suicidal ideation, insomnia, abnormal dreams, hallucination.