Doxycycline Hyclate

RECENT MAJOR CHANGES Warnings and Precautions, Severe Skin Reactions ( 5.5 ) 3/2025 Warnings and Precautions, Severe Skin Reactions ( 5.5 ) 3/2025

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: 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: 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. (2.1) 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. (2.1) 2.1 Important Dosage and Administration Instructions • Doxycycline hyclate delayed-release tablet is 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 tablet 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 tablet 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 tablet may be given with food or milk [see Clinical Pharmacology (12.3)]. 2.2 Switching from Doxycycline Hyclate Delayed-Release Tablets 50 mg, 75 mg, 80 mg, 100 mg, 150 mg and 200 mg to Doxycycline Hyclate Delayed-Release Tablets 60 mg and 120 mg When switching from doxycycline hyclate delayed-release tablets 50 mg, 75 mg, 80 mg, 100 mg, 150 mg and 200 mg to doxycycline hyclate delayed-release tablets 60 mg and 120 mg: • A 60 mg dose of doxycycline hyclate delayed-release tablets will replace a 50 mg dose of doxycycline hyclate delayed-release tablets • A 120 mg dose of doxycycline hyclate delayed-release tablets will replace a 100 mg dose of doxycycline hyclate delayed-release tablets 2.3 Dosage in Adult Patients • The usual dosage of doxycycline hyclate delayed-release 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 delayed-release tablets 60 mg and 120 mg 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 C. 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 followed in one hour by a second 300 mg dose. 4. Nongonococcal urethritis (NGU) caused by U. urealyticum: 100 mg, by mouth, twice-a-day for 7 days. 5. Syphi …

3 DOSAGE FORMS AND STRENGTHS Doxycycline hyclate delayed-release tablets, USP 75 mg are white to off white capsule shaped biconvex coated tablets embedded with yellowish pellets, with breakline on both sides and debossed with "I'' and "15" on either side of the breakline on one side. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 75 mg of doxycycline. Doxycycline hyclate delayed-release tablets, USP 100 mg are white to off white capsule shaped biconvex coated tablets embedded with yellowish pellets, with breakline on both sides and debossed with "I'' and "16" on either side of the breakline on one side. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 100 mg of doxycycline. Doxycycline hyclate delayed-release tablets, USP 150 mg are white to off white, rectangular coated dual-scored tablets embedded with yellowish pellets and debossed with "I|1|7" on one side and dual-scored on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 150 mg of doxycycline. Doxycycline hyclate delayed-release tablets, USP 200 mg are white to off white, oval biconvex coated tablets embedded with yellowish pellets, with breakline on both sides and debossed with "I1" and "18" on either side of the breakline on one side. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 200 mg of doxycycline. Doxycycline hyclate delayed-release tablets, USP 75 mg, 100 mg, 150 mg and 200 mg ( 3 )

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

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 Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) 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 was 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 …

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 Penthrane The concurrent use of tetracycline and Penthrane ® (methoxyflurane) has been reported to result in fatal renal toxicity. 7.7 Drug/Laboratory Test Interactions False elevations of urinary catecholamines may occur due to interference with the fluorescence test.

8 USE IN SPECIFIC POPULATIONS Tetracycline-class drugs can cause fetal harm when administered to a pregnant woman, but data for doxycycline are limited. ( 5.6 , 8.1 ) Tetracyclines are excreted in human milk; however, the extent of absorption of doxycycline in the breastfed infant is not known. Doxycycline hyclate delayed-release tablets use during nursing should be avoided if possible. ( 8.2 ) 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk (see Data ) . 1 In the US general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Embryo/Fetal Risk Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1 , 5.6) ]. Data Human Data A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (that is, in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases. 2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age. 3 8.2 Lactation Risk Summary Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated. The effects of prolonged exposure to doxycycline in breast milk production and breast fed neonates, infants and children are unknown 4 . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for doxycycline hyclate delayed-release tablets and any potential adverse effects on the breast fed child from doxycycline hyclate delayed-release tablets or from the underlying maternal condition [ see Warnings and Precautions (5.1 , 5.6) ]. 8.4 Pediatric use Because of the effects of drugs of the tetracycline-class on tooth development and growth, 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 [ see Dosage and Administration (2.1 , 2.3) a …

12.1 Mechanism of Action Doxycycline is a tetracycline-class antimicrobial drug [see Microbiology ( 12.4 )] .

11 DESCRIPTION Doxycycline hyclate delayed-release tablets, USP contain specially coated pellets of doxycycline hyclate, USP, a tetracycline class drug synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration. The structural formula for doxycycline hyclate, USP is: with a molecular formula of C 22 H 24 N 2 O 8 , HCl, 1⁄2 C 2 H 6 O, 1⁄2 H 2 O and a molecular weight of 512.9. The chemical name for doxycycline hyclate is [4S(4aR,5S,5aR,6R,12aS)] -4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-deoxonaphthacene-2- carboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate, USP is a yellow to light yellow powder, 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 has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. Each tablet contains doxycycline 75 mg, 100 mg, 150 mg and 200 mg (equivalent to doxycycline hyclate 86.55 mg, 115.41 mg, 173.11 mg and 230.82). Inactive ingredients in the tablet formulation are: colloidal silicon dioxide, corn starch, croscarmellose sodium, crospovidone, hypromellose, hypromellose phthalate, lactose anhydrous, lactose monohydrate, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 6000, povidone (K-30), sodium chloride, talc and triethyl citrate. Each doxycycline hyclate delayed-release tablets 75 mg contains 4.7 mg (0.204 mEq) of sodium, each doxycycline hyclate delayed-release tablets 100 mg contains 6.3 mg (0.274 mEq) of sodium, each doxycycline hyclate delayed-release tablets 150 mg contains 9.4 mg (0.409 mEq) of sodium and each doxycycline hyclate delayed-release tablets 200 mg contains 12.6 mg (0.548 mEq) of sodium. This drug product meets USP Dissolution Test 5. structure

10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING Doxycycline hyclate delayed-release tablets USP, 75 mg having functional scoring are white, oval tablets containing yellow specks, debossed with “L241” on one side and score line on the other side. Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 75 mg of doxycycline. NDC 46708-481-60 bottle of 60 tablets NDC 46708-481-31 bottle of 100 tablets NDC 46708-481-91 bottle of 1000 tablets Doxycycline hyclate delayed-release tablets USP, 100 mg having functional scoring are white, oval tablets containing yellow specks, debossed with “L242” on one side and score line on the other side.Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 100 mg of doxycycline. NDC 46708-482-60 bottle of 60 tablets NDC 46708-482-31 bottle of 100 tablets NDC 46708-482-91 bottle of 1000 tablets Doxycycline hyclate delayed-release tablets USP, 150 mg having functional scoring are white, rectangular tablets containing yellow specks. Tablets have two parallel score lines on both side, debossed with “2|4|3” on one side and “|L|” on the other side. Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 150 mg of doxycycline. NDC 46708-483-30 bottle of 30 tablets NDC 46708-483-60 bottle of 60 tablets NDC 46708-483-31 bottle of 100 tablets NDC 46708-483-71 bottle of 500 tablets Doxycycline hyclate delayed-release tablets USP, 200 mg having functional scoring are white, oval tablets containing yellow specks, debossed with “L594” on one side and score line on the other side. Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 200 mg of doxycycline. NDC 46708-484-30 bottle of 30 tablets NDC 46708-484-60 bottle of 60 tablets NDC 46708-484-31 bottle of 100 tablets NDC 46708-484-71 bottle of 500 tablets Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container (USP).