Doxycycline Hyclate

Doxycycline hyclate tablets and doxycycline hyclate capsules 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 and other antibacterial drugs, doxycycline hyclate 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 and capsules 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 and capsules 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 and capsules 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 and capsules 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 and capsules 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 and capsules 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 and capsules 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 and capsules 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 and capsules may be a useful adjunct to amebicides. In severe acne, doxycycline hyclate tablets and capsules may be useful adjunctive therapy.

1.9 Prophylaxis of Malaria Doxycycline hyclate tablets and capsules 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 and other antibacterial drugs, doxycycline hyclate 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.

Doxycycline Hyclate Tablets, USP: Doxycycline Hyclate Tablets, USP 75 mg are round convex light blue, film-coated, compressed tablet with “ 75'' debossed on one side of the tablet and "AQ" over "101" debossed on the other (each tablet contains 75 mg doxycycline as 86.6 mg doxycycline hyclate). Doxycycline Hyclate Tablets, USP 150 mg are capsule-shaped, convex, mossy-green, film-coated compressed tablet. Each side of the tablet is trisected with an " A " debossed on each portion of one side of the tablet, and no debossing on the other (each tablet contains 150 mg doxycycline as 173.1 mg doxycycline hyclate). Doxycycline Hyclate Capsules, USP: Doxycycline Hyclate Capsules, USP 75 mg are size #2, hard gelatin capsules, blue opaque cap with white opaque body, imprinted with “ CE ” on the cap and “ 227 ” on the body in black ink, filled with yellow powder (each capsule contains 75 mg doxycycline as 86.6 mg doxycycline hyclate). Doxycycline Hyclate Tablets, USP: 75 mg and 150 mg (functionally scored) ( 3 ) Doxycycline Hyclate Capsules, USP: 75 mg ( 3 )

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

The use of doxycycline hyclate 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) and enamel hypoplasia Advise the patient of the potential risk to the fetus during pregnancy. ( 2.2 , 5.1 , 8.1 , 8.4 ) The use of doxycycline hyclate during the second and third-trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. Advise the patient of the potential risk to the fetus during pregnancy. ( 5.2 , 8.1 , 8.4 ) Clostridioides difficile -associated diarrhea (CDAD) has been reported. Evaluate patients if diarrhea occurs. ( 5.3 ) Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Limit sun exposure. ( 5.4 ) Overgrowth of non-susceptible organisms, including fungi, may occur. If such infections occur, discontinue use and institute appropriate therapy. ( 5.10 )

5.1 Tooth Development The use of doxycycline hyclate 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 of the tetracycline class, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with drugs of the tetracycline class. Advise the patient of the potential risk to the fetus if doxycycline hyclate is used during pregnancy [see Use in Specific Populations ( 8.1 , 8.4 )]. 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.

5.2 Inhibition of Bone Growth The use of doxycycline hyclate during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if doxycycline hyclate tablets and capsules are used during pregnancy [see Use in Specific Populations ( 8.1 , 8.4 )] .

5.3 Clostridioides difficile Associated Diarrhea Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline hyclate , 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 antibacterial 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.

5.4 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.

5.5 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 hyclate tablets and doxycycline hyclate capsules immediately and institute appropriate therapy.

5.6 Intracranial Hypertension Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline hyclate. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and doxycycline hyclate should be avoided because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.

5.7 Antianabolic Action The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.

5.8 Incomplete Suppression of Malaria Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains. Doxycycline does not suppress P. falciparum’s sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas.

5.9 Development of Drug-Resistant Bacteria Prescribing doxycycline hyclate in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.10 Potential for Microbial Overgrowth Doxycycline hyclate may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue use and institute appropriate therapy.

5.11 Laboratory Monitoring for Long-Term Therapy In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic studies should be performed.

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, erythema multiforme, and fixed drug eruption 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. Psychiatric: Depression, anxiety, suicidal ideation, insomnia, abnormal dreams, hallucination. 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 Chartwell RX, LLC. at 1-845-232-1683, or 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 is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations. ( 7.3 ) Concurrent use of tetracyclines, including doxycycline hyclate 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 in conjunction with penicillin.

7.3 Antacids and Iron Preparations Absorption of tetracyclines, including doxycycline hyclate 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 may render oral contraceptives less effective.

7.5 Barbiturates and Anti-Epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

7.7 Drug and Laboratory Test Interactions False elevations of urinary catecholamines may occur due to interference with the fluorescence test.

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 sodium.