DOXYCYCLINE HYCLATE- doxycycline hyclate_tablet, coated

Doxycycline is a tetracycline-class antimicrobial drug [see Microbiology ( 12. 4 Absorption Doxycycline hyclate tablets: Following administration of a single 300 mg dose to adult volunteers, average peak plasma doxycycline levels were 3. 0 mcg per mL at 3 hours, decreasing to 1. 18 mcg per mL at 24 hours. The mean C max 0-infinity Excretion Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40% per 72 hours in individuals with a creatinine clearance of about 75 mL per minute. This percentage may fall as low as 1% per 72 hours to 5% per 72 hours in individuals with a creatinine clearance below 10 mL per minute. Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life. Pediatric Patients Population pharmacokinetic analysis of sparse concentration-time data of doxycycline following standard of care intravenous and oral dosing in 44 children (2-18 years of age) showed that allometrically-scaled clearance of doxycycline in children >=2 to <=8 years of age (median [range] 3. 82] L/h/70 kg, N=11) did not differ significantly from children >8 to 18 years of age (3. 12] L/h/70 kg, N=33). For pediatric patients weighing <=45 kg, body weight normalized doxycycline CL in those >=2 to <=8 years of age (median [range] 0. 202] L/kg/h, N=10) did not differ significantly from those >8 to 18 years of age (0. 126] L/kg/h, N=8). In pediatric patients weighing >45 kg no clinically significant differences in body weight normalized doxycycline CL were observed between those >=2 to <=8 years (0. 050 L/kg/h, N=1) and those >8 years of age (0. 121] L/kg/h, N=25). No clinically significant difference in CL differences between oral and IV were observed in the small cohort of pediatric patients who received the oral (N=19) or IV (N=21) formulation alone. Mechanism of Action Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria. Resistance Cross resistance with other tetracyclines is common. Antimicrobial Activity Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro [see Indications and Usage ( 1 ) ]. Gram-negative Bacteria Acinetobacter Gram-positive Bacteria Bacillus anthracis Anaerobic Bacteria Clostridium Other Bacteria Nocardiae and Actinomyces Borrelia recurrentis Rickettsiae Treponema pallidum Treponema pallidum pertenue Ureaplasma urealyticum Parasites Balantidium coli * Plasmodium falciparum P. falciparum Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.

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 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. 10 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 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 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 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 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 Acinetobacter Urinary tract infections caused by Klebsiella Doxycycline hyclate tablets are indicated for treatment of the following ophthalmic infections: Trachoma caused by Chlamydia trachomatis Inclusion conjunctivitis caused by Chlamydia trachomatis Doxycycline hyclate tablets are indicated for the treatment of Anthrax due to Bacillus anthracis Bacillus anthracis Doxycycline hyclate 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 pertenue Listeriosis due to Listeria monocytogenes Vincent’s infection caused by Fusobacterium fusiforme Actinomycosis caused by Actinomyces israelii Infections caused by Clostridium species 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. Doxycycline hyclate tablets are indicated for the prophylaxis of malaria due to Plasmodium falciparum [see Dosage and Administration ( 2. 4 17 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 Doxycycline hyclate tablets (150 mg) can be broken into two-thirds or one-third to provide a 50 mg and 100 mg strength, respectively. 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. 1 In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. 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. , 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. 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. 3 See Full Prescribing Information for additional indication specific dosage information and important administration instructions for doxycycline hyclate tablets. 5 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]. 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: 1. Streptococcal infections, therapy should be continued for 10 days. Uncomplicated urethral, endocervical, or rectal infection caused by Chlamydia trachomatis: 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. Nongonococcal urethritis (NGU) caused by C. trachomatis U. urealyticum: 5. Syphilis en dash 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: 8. Acute epididymo-orchitis caused by C. trachomatis: For all pediatric patients weighing less than 45 kg with severe or life threatening infections (e. , anthrax, Rocky Mountain spotted fever), the recommended dosage of doxycycline hyclate tablets is 2. 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 tablets is 4. 2 mg per kg of body weight (given as a single daily dose or divided into twice daily doses). For adults, the recommended dose of doxycycline hyclate tablets is 100 mg daily. For pediatric patients 8 years of age and older, the recommended dosage of doxycycline hyclate tablets is 2 mg per kg of body weight administered once daily. 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. 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 tablets is 2. 2 mg per kg of body weight, by mouth, twice-a-day for 60 days.

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 [See Warnings and Precautions ( 5. 1 [see Dosage and Administration ( 2. 1 Skin: Warnings and Precautions 5. 4 Renal: Warnings and Precautions 5. 7 Hypersensitivity reactions: Blood: I ntracranial Hypertension: Warnings and Precautions 5. 6 Thyroid Gland Changes: Psychiatric Adverse reactions observed in patients receiving tetracyclines include anorexia, nausea, vomiting, diarrhea, rash, photosensitivity, urticaria, and hemolytic anemia.

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

Lactation: Breastfeeding is not recommended. 2 Risk Summary Doxycycline hyclate tablets, 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. 2) 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. 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. 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. 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 hylcate tablets and for 5 days after the last dose. 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) Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline 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. , anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies [see Warnings and Precautions ( 5. 5 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.

Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 1 Avoid co-administration of tetracyclines with penicillin. 2 Absorption of tetracyclines, including doxycycline is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations. 3 Concurrent use of tetracyclines, including doxycycline may render oral contraceptives less effective. 4 Barbiturates, carbamazepine and phenytoin decrease the half-life of doxycycline. 5 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, including doxycycline in conjunction with penicillin. Absorption of tetracyclines, including doxycycline is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. Concurrent use of tetracyclines, including doxycycline may render oral contraceptives less effective. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. False elevations of urinary catecholamines may occur due to interference with the fluorescence test.

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.
NONCLINICAL TOXICOLOGY
Long-term studies in animals to evaluate carcinogenic potential of doxycycline hyclate have not been conducted. However, a 2 year carcinogenicity study with doxycycline administered daily by oral gavage to adult rats (20, 75, 200 mg/kg/day) demonstrated an increase in uterine polyps in female rats at 200 mg/kg/day (10 times the maximum recommended daily adult dose of doxycycline hyclate tablets based on body surface area comparison) with no change in tumor incidence in male rats at the same dose. A 2-year carcinogenicity study with doxycycline administered daily by oral gavage to adult male (maximum dose 150 mg/kg/day) and female (maximum dose 300 mg/kg/day) mice showed no changes in tumor incidence, at approximately 4 and 7 times the maximum recommended daily adult dose of doxycycline hyclate tablets, based on a body surface area comparison, respectively. Mutagenesis and fertility studies have not been conducted with doxycycline hyclate tablets. Mutagenesis studies with doxycycline demonstrated no potential to cause genetic toxicity in an in vitro in vivo in vitro Hyperpigmentation of the thyroid has been produced by members of the tetracycline-class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4 4 Minocycline, tetracycline PO 4 Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline. Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.
REFERENCES
1 Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS) 2 Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524­- 528. 3 Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 4 Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); [Last Revision Date 2018 Oct 31; cited 2019 Jun]. Doxycycline; LactMed Record Number: 100; [about 3 screens]. Available from: http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

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DOXYCYCLINE HYCLATE- doxycycline hyclate_tablet, coated Product manual source documgent