Doxycycline Hyclate

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

1 INDICATIONS AND USAGE Doxycycline hyclate is 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 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 C …

2 DOSAGE & ADMINISTRATION Important Administration Instructions for Doxycycline Hyclate Tablets: 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: 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 ) 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: 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 ) 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 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. For certain selected specific indications, the recommended duration or dosage and duration of doxycycline hyclate tablets in adult patients are as follows: Streptococcal infections, therapy should be continued for 10 days. Uncomplicated urethral, endocervical, or rectal infection caused by Chlamydia trachomatis : 100 mg by mouth twice-a-day for 7 days. 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. Nongonococcal urethritis (NGU) caused by C. trachomatis and U. urealyticum: 100 mg by mouth twice-a-day for 7 days. Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 2 weeks. 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. Acute epididymo-orchitis caused by N. gonorrhoeae : 100 mg by mouth, twice-a-day for at least 10 days. 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 …

3 DOSAGE FORMS AND STRENGTHS Doxycycline Hyclate Tablets, USP: Doxycycline Hyclate Tablets, USP 75 mg are blue colored, round-shaped, biconvex, film-coated tablets with ‘DY’ debossed on one side of the tablet and ‘2’ debossed on the other (each tablet contains 75 mg doxycycline, USP as 86.6 mg doxycycline hyclate, USP). Doxycycline Hyclate Tablets, USP 150 mg are yellowish-green to green colored, capsule-shaped, biconvex, film-coated tablets. Each side of the functionally scored tablet has two parallel score lines for splitting into 3 equal portions with ‘D’ or ‘Y’ or ‘1’ debossed on either portion of one side of the tablet, and no debossing on the other (each tablet contains 150 mg doxycycline, USP as 173.2 mg doxycycline hyclate, USP). Doxycycline hyclate tablets, USP: 75 mg and 150 mg (functionally scored) ( 3 )

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

ADVERSE REACTIONS sdverse Reactions in Clinical Trials of a bioequivalent form of doxycycline hyclate capsules: In clinical trials of adult patients with periodontal disease 213 patients received 20 mg BID over a 9 - 12 month period. The most frequent adverse reactions occurring in studies involving treatment with a bioequivalent form of doxycycline hyclate capsules or placebo are listed below: Incidence (%) of Adverse Reactions in Clinical Trials of Doxycycline Hyclate Capsules, 20 mg(Bioequivalent to Doxycycline Hyclate Tablets, 20 mg) vs. Placebo Adverse Reaction Doxycycline Hyclate Capsules 20 mg BID (n=213) Placebo (n=215) Note: Percentages are based on total number of study participants in each treatment group. Headache 55 (26%) 56 (26%) Common Cold 47 (22%) 46 (21%) Flu Symptoms 24 (11%) 40 (19%) Tooth Ache 14 (7%) 28 (13%) Periodontal Abscess 8 (4%) 21 (10%) Tooth Disorder 13 (6%) 19 (9%) Nausea 17 (8%) 12 (6%) Sinusitis 7 (3%) 18 (8%) Injury 11 (5%) 18 (8%) Dyspepsia 13 (6%) 5 (2%) Sore Throat 11 (5%) 13 (6%) Joint Pain 12 (6%) 8 (4%) Diarrhea 12 (6%) 8 (4%) Sinus Congestion 11 (5%) 11 (5%) Coughing 9 (4%) 11 (5%) Sinus Headache 8 (4%) 8 (4%) Rash 8 (4%) 6 (3%) Back Pain 7 (3%) 8 (4%) Back Ache 4 (2%) 9 (4%) Menstrual Cramp 9 (4%) 5 (2%) Acid Indigestion 8 (4%) 7 (3%) Pain 8 (4%) 5 (2%) Infection 4 (2%) 6 (3%) Gum Pain 1(<1%) 6 (3%) Bronchitis 7 (3%) 5 (2%) Muscle Pain 2 (1%) 6 (3%) Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients receiving tetracyclines: Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with vaginal candidiasis) in the anogenital region. Hepatotoxicity has been reported rarely. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See DOSAGE AND ADMINISTRATION section). Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (See WARNINGS section). Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See WARNINGS section). Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. Psychiatric: Depression, anxiety, suicidal ideation, insomnia, abnormal dreams, hallucination. To report SUSPECTED ADVERSE REACTIONS, contact Larken Laboratories, Inc. at 1-601-855-7678 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Drug Interactions Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations. Absorption of tetracyclines is impaired by bismuth subsalicylate. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and Penthrane ® (methoxyflurane) has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective. Drug/Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterial drugs, oxytetracycline (adrenal and pituitary tumors), and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibacterial drugs (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied. Pregnancy Teratogenic Effects 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 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 8 . 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 fifty-six (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 (i.e., 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 9 . 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 10 . Nonteratogenic Effects: (See WARNINGS ). Labor and Delivery The effect of tetracyclines on labor and delivery is unknown. Nursing Mothers 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; however, the effects of prolonged exposure to doxycycline in breast milk are unknown 11 . Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue th …

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended. ( 8.2 ) 8.1 Pregnancy Risk Summary Doxycycline hyclate, like other tetracycline-class antibacterial drugs, may cause discoloration deciduous teeth, and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy [see Warnings and Precautions ( 5.1 ) and ( 5.2 )] . Available data from published studies over decades have not shown a difference in major birth defect risk compared to unexposed pregnancies with doxycycline exposure in the first trimester of pregnancy (see Data). There are no available data on the risk of miscarriage following exposure to doxycycline in pregnancy. Advise the patient of the potential risk to the fetus if doxycycline hyclate is used during pregnancy. The estimated 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% to 4% and 15% to 20%, respectively. Data Human Data A retrospective cohort study of 1,690 pregnant patients who received doxycycline prescriptions in the first trimester of pregnancy compared to an unexposed pregnant cohort showed no difference in the major malformation rate. There is no information on the dose or duration of treatment, or if the patients actually ingested the doxycycline that was prescribed. Other published studies on exposure to doxycycline in the first trimester of pregnancy have small sample sizes; however, these studies have not shown an increased risk of major malformations. The use of tetracyclines during tooth development (second and third trimester of pregnancy) 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. [see Warnings and Precautions ( 5.1 , 5.2 )]. Animal Data 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. 8.2 Lactation Risk Summary Based on available published data, doxycycline is present in human milk. There are no data that inform the levels of doxycycline in breastmilk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with doxycycline hyclate and for 5 days after the last dose. 8.3 Females and Males of Reproductive Potential Infertility Based on findings from a fertility study in animals, doxycycline may impair female and male fertility. The reversibility of this finding is unclear. [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline hyclate 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 Warnings and Precautions ( 5.1 , 1.1 ) and Dosage and Administration ( 2.1 , 2.5 )] . 8.5 Geriatric Use Clinical studies of doxycycline hyclate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Doxycycline hyclate tablets each contains less than 1 mg of sodi …

Mechanism of Action: Doxycycline has been shown to inhibit collagenase activity in vitro . 1 Additional studies have shown that doxycycline reduces the elevated collagenase activity in the gingival crevicular fluid of patients with adult periodontitis. 2,3 The clinical significance of these findings is not known.

11 DESCRIPTION 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, USP is a yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates. Doxycycline Hyclate Tablets, USP: Doxycycline hyclate, USP is available as 75 mg and 150 mg tablets. Each 75 mg tablet contains 86.6 mg of doxycycline hyclate, USP equivalent to 75 mg of doxycycline, USP. Each 150 mg tablet contains 173.2 mg of doxycycline hyclate, USP equivalent to 150 mg of doxycycline, USP. Inactive ingredients in the tablet formulation are: silicified microcrystalline cellulose, sodium lauryl sulfate and magnesium stearate. Film-coating contains: hypromellose, titanium dioxide, polyethylene glycol, FD&C Blue #2 (75 mg Tablet), FD&C Yellow #6 (75 mg Tablet), FD&C Blue #2 (150 mg Tablet) and yellow iron oxide (150 mg Tablet). Doxycycline hyclate tablets, USP 75 mg contain 0.03 mg (0.0013 mEq) of sodium. Doxycycline hyclate tablets, USP 150 mg contain 0.06 mg (0.0026 mEq) of sodium. Doxycycline hyclate tablets meets USP Dissolution Test 3. 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 How Supplied Doxycycline Hyclate Tablets, USP 75 mg are blue colored, round-shaped, biconvex, film-coated tablets with ‘DY’ debossed on one side of the tablet and ‘2’ debossed on the other. Each 75 mg tablet contains 86.6 mg of doxycycline hyclate, USP equivalent to 75 mg of doxycycline, USP. Bottles of 60 tablets with child-resistant closure: NDC 27241-153-02 Doxycycline Hyclate Tablets, USP 150 mg are yellowish-green to green colored, capsule-shaped, biconvex, film-coated tablets. Each side of the functionally scored tablet has two parallel score lines for splitting into 3 equal portions with ‘D’ or ‘Y’ or ‘1’ debossed on either portion of one side of the tablet, and no debossing on the other. Each 150 mg tablet contains 173.2 mg of doxycycline hyclate, USP equivalent to 150 mg of doxycycline, USP. Bottles of 60 tablets with child-resistant closure: NDC 27241-154-02 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.