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. 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 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. Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues. Population pharmacokinetic analysis of sparse concentration-time data of doxycycline following standard of care intravenous and oral dosing in 44 pediatric patients (2 to 18 years of age) showed that allometrically -scaled clearance (CL) of doxycycline in pediatric patients >2 to 8 to 18 years of age (3. 12] L/h/70 kg, N=33). For pediatric patients weighing 2 to 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 to 18 years of age (0. 121] L/kg/h, N=25). No clinically significant difference in CL between oral and IV dosing was observed in the small cohort of pediatric patients who received the oral (N=19) or IV (N=21) formulation alone. 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 Acinetobacter Bartonella bacilliformis Brucella Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella Neisseria gonorrhoeae Shigella Vibrio cholerae Vibrio fetus Yersinia pestis Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae Clostridium Fusobacterium fusiforme Propionibacterium acnes Nocardiae and Actinomyces Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum pertenue Ureaplasma urealyticum Balantidium coli Entamoeba Plasmodium falciparum * * Plasmodium falciparum P. falciparum 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.
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 Acinetobacter Bartonella bacilliformis Brucella Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella Neisseria gonorrhoeae Shigella Vibrio cholerae Vibrio fetus Yersinia pestis Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae Clostridium Fusobacterium fusiforme Propionibacterium acnes Nocardiae and Actinomyces Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum pertenue Ureaplasma urealyticum Balantidium coli Entamoeba Plasmodium falciparum * * Plasmodium falciparum P. falciparum 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.
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
Gram-Positive Bacteria
Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae
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.

Gram-Negative Bacteria
Acinetobacter Bartonella bacilliformis Brucella Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella Neisseria gonorrhoeae Shigella Vibrio cholerae Vibrio fetus Yersinia pestis
INDICATIONS AND USAGE
To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline capsules and other antibacterial drugs, doxycycline capsules 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: 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 psittaci. 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 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 cholerae Campylobacter fetus infections caused by Campylobacter fetus Brucellosis due to Brucella species Bartonellosis due to Bartonella bacilliformis. Granuloma inguinale caused by 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 Respiratory tract infections caused by Haemophilus influenzae. Respiratory tract and urinary tract infections caused by 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: Upper respiratory infections caused by Streptococcus pneumoniae Anthrax due to Bacillus anthracis, Bacillus anthracis. 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 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 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. The usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours or 50 mg every 6 hours) followed by a maintenance dose of 100 mg/day. 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 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) 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. Acute Epididymo-orchitis Caused by N. gonorrhoeae 100 mg, by mouth, twice a day for at least 10 days. Primary and Secondary Syphilis 300 mg a day in divided doses for at least 10 days. Uncomplicated Urethral, Endocervical, or Rectal Infection in Adults Caused by Chlamydia trachomatis 100 mg, by mouth, twice a day for at least 7 days. Nongonococcal Urethritis Caused by C. trachomatis U. urealyticum 100 mg, by mouth, twice a day for at least 7 days. Acute Epididymo-orchitis Caused by C. trachomatis 100 mg, by mouth, twice a day for at least 10 days. Inhalational Anthrax (Post-Exposure) ADULTS: 100 mg of doxycycline, by mouth, twice a day for 60 days. CHILDREN: weighing less than 45 kg 2. 2 mg/kg of body weight, by mouth, twice a day for 60 days. Children weighing 45 kg or more should receive the adult dose.

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. Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and 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. Rare 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 Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above (See WARNINGS Rise in BUN has been reported and is apparently dose related (See WARNINGS Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported with tetracyclines. Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines (See 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.
Gastrointestinal
Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and 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. Rare 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
Skin
Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above (See WARNINGS
Blood
Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported with tetracyclines.

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

Pregnancy
Teratogenic Effects. 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. 1 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. , 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. 2 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.
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. 4 WARNINGS
Pediatric Use:
Because of the effects of drugs of the tetracycline en 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) 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. Acute Epididymo-orchitis Caused by N. gonorrhoeae 100 mg, by mouth, twice a day for at least 10 days. Primary and Secondary Syphilis 300 mg a day in divided doses for at least 10 days. Uncomplicated Urethral, Endocervical, or Rectal Infection in Adults Caused by Chlamydia trachomatis 100 mg, by mouth, twice a day for at least 7 days. Nongonococcal Urethritis Caused by C. trachomatis U. urealyticum 100 mg, by mouth, twice a day for at least 7 days. Acute Epididymo-orchitis Caused by C. trachomatis 100 mg, by mouth, twice a day for at least 10 days. Inhalational Anthrax (Post-Exposure) ADULTS: 100 mg of doxycycline, by mouth, twice a day for 60 days. CHILDREN: weighing less than 45 kg 2.2 mg/kg of body weight, by mouth, twice a day for 60 days. Children weighing 45 kg or more should receive the adult dose.

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 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.

Anaerobes
Clostridium Fusobacterium fusiforme Propionibacterium acnes
Other Bacteria
Nocardiae and Actinomyces Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum pertenue Ureaplasma urealyticum
Parasites
Balantidium coli Entamoeba Plasmodium falciparum * * 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.fda.gov/STIC.
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. 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 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.
Other
Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines (See 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.
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
Friedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS) Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil Hale T. Medications and Mothers Milk Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

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