DOXYCYCLINE- doxycycline_capsule

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. 1.02 2.26 2.67 3.01 3.16 3.03 2.03 1.62 0.95 0.37 0.15 (mcg/mL) 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 1-5%/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 see INDICATIONS AND USAGE Gram-Negative Bacteria Acinetobacter Bartonella bacilliformis Brucella Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella Neisseria gonorrhoeae Shigella Vibrio cholera Yersinia pestis Gram-Positive Bacteria Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae Anaerobic Bacteria Clostridium Fusobacterium fusiforme Propionibacterium acnes Other Bacteria Nocardiae Actinomyces Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Treponema pallidum Treponema pallidum pertenue Ureaplasma urealyticum Parasites Balantidium coli Entamoeba When available, the clinical microbiology laboratory should provide cumulative reports of in vitro 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). 1,2,4,6,7 Error! Hyperlink reference not valid. Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. 1,3,4 Error! Hyperlink reference not valid. For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method. 1,5 Error! Hyperlink reference not valid. Table 1: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline * Organisms susceptible to tetracycline are also considered susceptible to doxycycline. However, dagger double dagger Neisseria gonorrhoeae 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. Anaerobes Bacillus anthracis dagger Brucella species dagger Enterobacteriaceae Franciscella tularensis dagger Haemophilus influenzae Mycoplasma pneumoniae dagger Neisseria gonorrhoeae double dagger Nocardiae Actinomyces dagger Streptococcus pneumoniae Vibrio cholerae Yersinia pestis Ureaplasma urealyticum A report of Susceptible (S) Intermediate (I) Resistant (R) 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 Error! Hyperlink reference not valid. Error! Hyperlink reference not valid. Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline * ATCC is the American Type Culture Collection QC Strain Minimal Inhibitory Concentration (mcg per mL) Zone Diameter (mm) Agar Dilution (mcg per mL) Enterococcus faecalis Escherichia coli Eggerthella lenta Haemophilus influenzae Neisseria gonorrhoeae Staphylococcus aureus Staphylococcus aureus Streptococcus pneumoniae Bacteroides fragilis Bacteroides thetaiotaomicron Mycoplasma pneumoniae Ureaplasma urealyticum.
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. 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 Gram-Negative Bacteria Acinetobacter Bartonella bacilliformis Brucella Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella Neisseria gonorrhoeae Shigella Vibrio cholera Yersinia pestis Gram-Positive Bacteria Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae Anaerobic Bacteria Clostridium Fusobacterium fusiforme Propionibacterium acnes Other Bacteria Nocardiae Actinomyces Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Treponema pallidum Treponema pallidum pertenue Ureaplasma urealyticum Parasites Balantidium coli Entamoeba
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). 1,2,4,6,7 Error! Hyperlink reference not valid.
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 should be determined using a standardized test method. 1,3,4 Error! Hyperlink reference not valid.
ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY
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.

To reduce the development of drug-resistant bacteria and maintain 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 the empiric selection of therapy. Doxycycline is indicated for the treatment of the following infections: Mycoplasma pneumoniae Chlamydia trachomatis Chlamydophila psittaci Chlamydia trachomatis Chlamydia trachomatis hlamydia trachomatis Ureaplasma urealyticum Borrelia recurrentis Doxycycline is also indicated for the treatment of infections caused by the following gram-negative microorganisms: Haemophilus ducreyi Yersinia pestis Francisella tularensis Vibrio cholerae Campylobacter fetus Brucella species Bartonella bacilliformis Klebsiella 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 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 species Haemophilus influenzae Klebsiella species Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Streptococcus pneumoniae Bacillus anthracis Bacillus anthracis When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: Neisseria gonorrhoeae Treponema pallidum Treponema pallidum pertenue Listeria monocytogenes Fusobacterium fusiforme Actinomyces israelii 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 all pediatric patients weighing less than 45 kg with severe or life-threatening infections (e. anthrax, Rocky Mountain spotted fever), the recommended dosage is 2. 2 mg/kg of body weight administered every 12 hours. Children weighing 45 kg or more should receive the adult dose (see WARNINGS PRECAUTIONS For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule 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 twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage. 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 If gastric irritation occurs, it is recommended that doxycycline be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of doxycycline in patients with renal impairment. 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 U. urealyticum Acute epididymo-orchitis caused by C. trachomatis Inhalational anthrax (post-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: DOSAGE AND ADMINISTRATION Skin: WARNINGS Renal Toxicity: WARNINGS Hypersensitivity Reactions: Blood: Other: 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. To report SUSPECTED ADVERSE REACTIONS, contact G&W Laboratories, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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

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 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
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 WARNINGS
Pediatric Use:
Because of the effects of drugs of the tetracyclineen dashclass, 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.g. anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. (see WARNINGS DOSAGE AND ADMINISTRATION
Pediatric Patients:
For all pediatric patients weighing less than 45 kg with severe or life-threatening infections (e.g. anthrax, Rocky Mountain spotted fever), the recommended dosage is 2.2 mg/kg of body weight administered every 12 hours. Children weighing 45 kg or more should receive the adult dose (see WARNINGS PRECAUTIONS For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule 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 twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage. 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 If gastric irritation occurs, it is recommended that doxycycline be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of doxycycline in patients with renal impairment. 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 U. urealyticum Acute epididymo-orchitis caused by C. trachomatis Inhalational anthrax (post-exposure):

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/Laboratory Test Interactions:
False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

Susceptibility Testing Methods
When available, the clinical microbiology laboratory should provide cumulative reports of in vitro
Anaerobic Techniques
For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method. 1,5 Error! Hyperlink reference not valid. Table 1: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline * Organisms susceptible to tetracycline are also considered susceptible to doxycycline. However, dagger double dagger Neisseria gonorrhoeae 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. Anaerobes Bacillus anthracis dagger Brucella species dagger Enterobacteriaceae Franciscella tularensis dagger Haemophilus influenzae Mycoplasma pneumoniae dagger Neisseria gonorrhoeae double dagger Nocardiae Actinomyces dagger Streptococcus pneumoniae Vibrio cholerae Yersinia pestis Ureaplasma urealyticum A report of Susceptible (S) Intermediate (I) Resistant (R)
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 Error! Hyperlink reference not valid. Error! Hyperlink reference not valid. Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline * ATCC is the American Type Culture Collection QC Strain Minimal Inhibitory Concentration (mcg per mL) Zone Diameter (mm) Agar Dilution (mcg per mL) Enterococcus faecalis Escherichia coli Eggerthella lenta Haemophilus influenzae Neisseria gonorrhoeae Staphylococcus aureus Staphylococcus aureus Streptococcus pneumoniae Bacteroides fragilis Bacteroides thetaiotaomicron Mycoplasma pneumoniae Ureaplasma urealyticum
WARNINGS
The use of drugs of the tetracycline class, including doxycycline, 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 it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use of 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.g. anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. Clostridium difficile C.difficile C. difficile C. difficile If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile C. difficile Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline capsules. 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 capsules 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. 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,Mutagenesis, 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
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. 2. 3. 4. 5. . 6. 7. . 8. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS) 9. Obstet Gynecol 10. Int J Fertil 11. Medications and Mothers Milk. th Rx only Manufactured for: Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320 8-DOXYGW3

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DOXYCYCLINE- doxycycline_capsule Product manual source documgent