DOXYCYCLINE HYCLATE

Doxycycline hyclate tablets, USP contain doxycycline hyclate, USP, a tetracycline class drug synthetically derived from oxytetracycline, in an immediate release formulation for oral administration. The molecular formula of doxycycline hyclate is (C 22 H 24 N 2 O 8 · HCl) 2 · C 2 H 6 O · H 2 O and the molecular weight of doxycycline hyclate is 1025.87. The chemical name for doxycycline hyclate is: 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. The structural formula for doxycycline hyclate is: Figure 1: Structure of Doxycycline Hyclate Doxycycline hyclate is a yellow to light yellow powder which is freely soluble in water and in methanol; sparingly soluble in alcohol; practically insoluble in chloroform and in ether. It dissolves in aqueous solutions of alkali hydroxides and carbonates. Doxycycline hyclate tablets are available as 75 mg and 150 mg tablets. Each 75 mg tablet contains 86.559 mg of doxycycline hyclate equivalent to 75 mg of doxycycline. Each 150 mg tablet contains 173.117 mg of doxycycline hyclate equivalent to 150 mg of doxycycline. Inactive ingredients in the tablet formulation are: microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium and magnesium stearate. Film-coating contains: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow, FD&C Blue #1 (75 mg Tablet) and FD&C Blue #2 (150 mg Tablet). Doxycycline hyclate tablets, USP meets USP Dissolution Test 3 . Structure

Doxycycline hyclate tablets are tetracycline class drugs 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 for acute intestinal amebiasis and severe acne (1.8) · Prophylaxis of malaria (1.9) To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate tablets and other antibacterial drugs, doxycycline hyclate 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 tablets are indicated for treatment of Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsial pox, and tick fevers caused by Rickettsiae . 1.2 Sexually Transmitted Infections Doxycycline hyclate 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 tablets are 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 . 1.4 Specific Bacterial Infections Doxycycline hyclate 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 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 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 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 tablets are indicted 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. 1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne In acute intestinal amebiasis, doxycycline hyclate tablets may be a useful adjunct to amebicides. In severe acne, doxycycline hyclate tablets may be useful adjunctive therapy. 1.9 Prophylaxis of Malaria Doxycycline hyclate 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 (2.4) and Patient Counseling Information (17)] . 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate tablets and other antibacterial drugs, doxycycline hyclate 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.

· Important Administration Instructions for Doxycycline Hyclate Tablets: o Doxycycline hyclate tablets (150 mg) can be broken into two-thirds or one-third to provide a 50 mg and 100 mg strength, respectively. (2.1) · Dosage in Adults for Doxycycline Hyclate Tablets : o 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) o 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 for Doxycycline Hyclate Tablets : o 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. (2.3) o 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. (2.3) · See Full Prescribing Information for additional indication specific dosage information and important administration instructions for doxycycline hyclate tablets. (2.1, 2.4, 2.5) 2.1 Important Administration Instructions · The usual dosage and frequency of administration of doxycycline hyclate tablets differs from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of adverse reactions. · Administer doxycycline hyclate tablets with adequate amounts of fluid to wash down the drugs and reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6)] . · If gastric irritation occurs, doxycycline hyclate tablets may be given with food or milk [see Clinical Pharmacology (12.3)] · Doxycycline hyclate tablets (150 mg) can be broken into two-thirds or one-third to provide a 100 mg and 50 mg strength, respectively [see FDA-approved patient labeling]. 2.2 Dosage in Adult Patients · The usual dosage of doxycycline hyclate tablet 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. · For certain selected specific indications, the recommended duration or dosage and duration of doxycycline hyclate tablets in adult patients are as follows: 1. Streptococcal infections, therapy should be continued for 10 days. 2. Uncomplicated urethral, endocervical, or rectal infection caused by Chlamydia trachomatis : 100 mg by mouth twice-a-day for 7 days. 3. 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. 4. Nongonococcal urethritis (NGU) caused by C. trachomatis and U. urealyticum: 100 mg by mouth twice-a-day for 7 days. 5. Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 2 weeks. 6. 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. 7. Acute epididymo-orchitis caused by N. gonorrhoeae : 100 mg by mouth, twice-a-day for at least 10 days. 8. Acute epididymo-orchitis caused by C. trachomatis : 100 mg, by mouth, twice-a-day for at least 10 days. 2.3 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 hyclate tablet 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 hyclate tablet 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. 2.4 Dosage for Prophylaxis of Malaria For adults, the recommended dose of doxycycline hyclate tablet is 100 mg daily. For pediatric patients 8 years of age and older, the recommended dosage of doxycycline hyclate tablet is 2 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. 2.5 Dosage for Inhalational Anthrax (Post-Exposure) For adults, the recommended dosage is 100 mg, of doxycycline hyclate tablets, by mouth, twice-a-day for 60 days. For pediatric patients weighing less than 45 kg, the recommended dosage of doxycycline hyclate tablet is 2.2 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.

Doxycycline hyclate tablets are contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. Doxycycline hyclate tablets are contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. (4)

The following adverse reactions have been identified during clinical trials or post-approval use of tetracycline-class drugs, including 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. 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)] . Instances of 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, and erythema multiforme have been reported. Photosensitivity has been reported [see Warnings and Precautions (5.4)]. Renal: Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions (5.7)]. Hypersensitivity reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, 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 tetracyclines [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. 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 FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

· 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 tablet is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations. (7.3) · Concurrent use of tetracyclines, including doxycycline hyclate 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, including doxycycline hyclate tablets in conjunction with penicillin. 7.3 Antacids and Iron Preparations Absorption of tetracyclines, including doxycycline hyclate tablet is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. 7.4 Oral Contraceptives Concurrent use of tetracyclines, including doxycycline hyclate tablets may render oral contraceptives less effective. 7.5 Barbiturates and Anti-Epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. 7.6 Penthrane® The concurrent use of tetracycline and Penthrane ® (methoxyflurane) has been reported to result in fatal renal toxicity. 7.7 Drug and Laboratory Test Interactions False elevations of urinary catecholamines may occur due to interference with the fluorescence test.