DOXYCYCLINE- doxycycline_capsule

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ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY
Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline. Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base, oxytetracycline HCl and tetracycline HCl were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet. 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.">CLINICAL PHARMACOLOGY
Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. Doxycycline is virtually completely absorbed after oral administration. Following a 200 mg dose of doxycycline monohydrate, 24 normal adult volunteers averaged the following serum concentration values: Time (hr): 0.5 1.0 1.5 2.0 3.0 4.0 8.0 12.0 24.0 48.0 72.0 Conc. (mcg/mL): 1.02 2.26 2.67 3.01 3.16 3.03 2.03 1.62 0.95 0.37 0.15 Average Observed Values Maximum Concentration 3.61 mcg/mL (+/- 0.9 sd) Time of Maximum Concentration 2.60 hr (+/- 1.10 sd) Elimination Rate Constant 0.049 per hr (+/- 0.030 sd) Half-Life 16.33 hr (+/- 4.53 sd) Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage excretion may fall as low as 1 to 5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/ min). Studies have shown no significant difference in serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter serum half-life. Microbiology 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. Cross resistance with other tetracyclines is common. Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro Gram-Negative Bacteria: Acinetobacter Bartonella bacilliformis Brucella Calymmatobacterium granulomatis Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella Neisseria gonorrhoeae Shigella Vibrio cholerae Yersinia pestis Gram-Positive Bacteria: Bacillus anthracis Streptococcus pneumonia Anaerobic Bacteria: Clostridium Fusobacterium fusiforme Propionibacterium acnes Other Bacteria: Nocardiae and Actinomyces Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pertenue Ureaplasma urealyticum Parasites Balantidium coli Entamoeba Susceptibility Testing Methods When available, the clinical microbiology laboratory should provide the results of in vitro Dilution techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar). 1,2,4 Table 1. Diffusion techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. 1,3,4 Table 1. Anaerobic techniques For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method. 5 Table 1 Table 1. Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline Bacteria* Minimal Inhibitory Concentration (mcg per mL) Zone Diameter (mm) Agar Dilution (mcg per mL) S I R S I R S I R Acinetobacter spp. Doxycyline Tetracycline <=4 <=4 >=16 >=16 >=13 >=15 10-12 12-14 <=9 <=11 - - - - - - Anaerobes Tetracycline - - - <=4 8 <=16 Bacillus anthracis Doxycycline Tetracycline <=1 <=1 - - - - Brucella speci Doxycycline Tetracycline <=1 <=1 - - - - Enterobacteriaceae Doxycycline Tetracycline <=4 <=4 >=16 >=16 >=14 >=15 11-13 12-14 <=10 <=11 - - - - - - Franciscella tularensis Doxycyline Tetracycline <=4 <=4 - - - - - - - - Haemophilus influenzae Tetracycline <=2 >=8 >=29 26-28 <=25 - - - Mycoplasma pneumoniae Tetracycline - - <=2 - - Neisseria gonorrhoeae Tetracycline - - >=38 31-37 <=30 <=0.25 0.5-1 >=2 Norcardiae and other aerobic Actinomyces Doxycycline <=1 2-4 >=8 - - - Streptococcus pneumoniae Tetracycline <=2 >=8 >=23 19-22 <=18 - - - Vibrio cholerae Doxycycline Tetracycline <=4 <=4 >=16 >=16 - - - Yersinia pestis Doxycycline Tetracycline <=4 <=4 >=16 >=16 - - - Ureaplasma urealyticum Tetracycline - - - <=1 >=2 * Organisms susceptible to tetracycline are also considered susceptible to doxycycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline. dagger The current absence of resistance isolates precludes defining any results other than "Susceptible". If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. double dagger Gonococci with 30 mcg tetracycline disk zone diameters of less than 19 mm usually indicate a plasmid-mediated tetracycline resistant Neisseria gonorrhoeae A report of Susceptible Intermediate Resistant Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. 1,2,3,4,5,6,7 Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 2 Table 2: Acceptable Quality Control Ranges For Susceptibility Testing for Doxycycline and Tetracycline QC Strain Minimal Inhibitory Concentration (mcg per mL) Zone Diameter (mm) Agar Dilution (mcg per mL) Enterococcus faecalis 2 - 8 8 - 32 Escherichia coli 0.5 - 2 0.5 - 2 18 - 24 18 - 25 Haemophilus influenzae 4 - 32 14 - 22 Neisseria gonorrhoeae ATCC 49226 Tetracycline - 30 - 42 0.25 - 1 Staphylococcus aureus 23 - 29 24 - 30 Staphylococcus aureus 0.12 - 0.5 0.12 - 1 Streptococcus pneumoniae 0.015 - 0.12 0.06 - 0.5 25 - 34 27 - 31 Bacteroides fragilis 0.125 - 0.5 Bacteroides thetaiotaomicron 8 - 32 Mycoplasma pneumoniae 0.06 - 0.5 0.06 - 0.5 Ureaplasma urealyticum >=8
ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY
Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline. Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base, oxytetracycline HCl and tetracycline HCl were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet. 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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline capsules USP and other antibacterial drugs, doxycycline capsules USP 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 empiric selection of therapy. Doxycycline Capsules USP is indicated for the treatment of the following infections: Rocky mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. Respiratory tract infections caused by Mycoplasma pneumoniae Lymphogranuloma venereum caused by Chlamydia trachomatis. Psittacosis (ornithosis) caused by Chlamydophila Trachoma caused by Chlamydia trachomatis Inclusion conjunctivitis caused by Chlamydia trachomatis Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis Nongonococcal urethritis caused by Ureaplasma urealyticum Relapsing fever due to Borrelia recurrentis Doxycycline Capsules USP is also indicated for the treatment of infections caused by the following gram-negative microorganisms: Chancroid caused by Haemophilus ducreyi. Plague due to Yersinia pestis. Tularemia due to Francisella tularensis. Cholera caused by Vibrio cholera. Campylobacter fetus infections caused by Campylobacter fetus. Brucellosis due to Brucella species Bartonellosis due to Bartonella bacilliformis. Granuloma inguinale caused by Calymmatobacterium granulomatis. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline Capsules USP is indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug: Escherichia coli Enterobacter aerogenes Shigella species Acinetobacter Respiratory tract infections caused by Haemophilus influenzae. Respiratory tract and urinary infections caused by Klebsiella Doxycycline Capsules USP is indicated for treatment of infections caused by the following gram-positive microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug: Upper respiratory infections caused by Streptococcuspneumoniae Skin and skin structure infections caused by Staphylococcus aureus. Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. Doxycycline Capsules USP is not the drug of choice in the treatment of any type of staphylococcal infections. When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: Uncomplicated gonorrhea caused by Neisseria gonorrhoeae Syphilis caused by Treponema pallidum. Yaws caused by Treponema 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 may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy.

THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF DOXYCYCLINE DIFFERS FROM THAT OF THE OTHER TETRACYCLINES. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS. Adults: For pediatric patients above eight years of age: Uncomplicated gonococcal infections in adults (except anorectal infections in men): Acute epididymo-orchitis caused by N. gonorrhoeae Primary and secondary syphilis: Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia trachomatis: Nongonococcal urethritis caused by C. trachomatis and U. urealyticum: Acute epididymo-orchitis caused by C. trachomatis: Inhalational anthrax (post-exposure) ADULTS: 100 mg of doxycycline, by mouth, twice a day for 60 days. CHILDREN: weighing less than 100 pounds (45 kgs): 1mg/lb (2.2 mg/kg) of body weight, by mouth, twice a day for 60 days. Children weighing 100 pounds or more should receive the adult dose. When used in streptococcal infections, therapy should be continued for 10 days. Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS

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: DOSAGE AND ADMINISTRATION Skin: WARNINGS Renal Toxicity: WARNINGS Hypersensitivity Reactions: Blood: Other: I PRECAUTIONS-General When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function are known to occur.

This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

Pregnancy: Teratogenic Effects.
Pregnancy Category D: There are no adequate and well-controlled studies on the use of doxycycline in pregnant 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 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 organogensis (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 c
Nursing Mothers
Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines, including doxycycline, by the breast-fed infant is not known. Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure by doxycycline in breast milk are unknown 11 WARNINGS
Pediatric Use
See WARNINGS DOSAGE AND ADMINISTRATION

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. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective.
Drug and/or Laboratory Test Interactions
False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

WARNINGS
THE USE OF DRUGS OF THE TETRACYCLINE CLASS 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 but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP, EXCEPT FOR ANTHRAX, INCLUDING INHALATIONAL ANTHRAX (POST-EXPOSURE), UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED. Clostridiumdifficile C. difficile difficile If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile difficile All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued. 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 embryo toxicity 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. 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. 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.
Carcinogenesis and Mutagenesis and Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with related antibacterial, 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 antibacterals (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.
Labor and Delivery
The effect of tetracyclines on labor and delivery is unknown.
OVERDOSAGE
In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life, and it would not be of benefit in treating cases of overdosage.
REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100S23, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2013 2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard en dashNinth Addition. CLSI document M07-A9, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012. 3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard en dash Eleventh Edition.CLSI Document M02-A11 Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012. 4. Clinical and Laboratory Standards Institute(CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria: Approved Guideline en dash Second Edition. CLSI Document M45-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2010. 5. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria, Approved Standard en dash Eighth Edition. CLSI Document M11-A8, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012. 6. Clinical and Laboratory Standards Institute (CLSI). Methods for Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard en dash Second Edition. CLSI Document M24-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2011. 7. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI Document M43-A, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2011. 8. Friedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS) 9. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 10. Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 11. Hale T. Medications and Mothers Milk PAR PHARMACEUTICAL COMPANIES, INC. Spring Valley, NY 10977 Revised: 02/2014 Repackaged by

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