ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Due to oral doxycyclines 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: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. 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).Renal Toxicity: Rise in BUN has been reported and is apparently dose related (see WARNINGS).Hypersensitivity Reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus.Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported with tetracyclines.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.To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

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 biologically active form. Doxycycline is virtually completely absorbed after oral administration.Following 200 mg dose of doxycycline monohydrate, 24 normal adult volunteers averaged the following serum concentration values:Time: (hr)0.51.01.52.03.04.08.012.024.048.072.0Conc. (mcg/mL):1.022.262.673.013.163.032.031.620.950.370.15Average Observed ValuesMaximum Concentration3.61 mcg/mL (+- 0.9 sd)Time of Maximum Concentration2.60 hr (+- 1.10 sd)Elimination Rate Constant0.049 per hr (+- 0.030 sd)Half-Life16.33 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 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.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 years of age (median [range] 3.58 [2.27 to 10.82] L/h/70 kg, =11) did not differ significantly from pediatric patients >8 to 18 years of age (3.27 [1.11 to 8.12] 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] 0.071 [0.041 to 0.202] L/kg/h, N=10) did not differ significantly from those >8 to 18 years of age (0.081 [0.035 to 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 to 18 years of age (0.044 [0.014 to 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.. Microbiology:. Mechanism of Action. Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against 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 and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for doxycycline capsules.Gram-Negative BacteriaAcinetobacter speciesBartonella bacilliformisBrucella speciesEnterobacter aerogenesEscherichia coliFrancisella tularensisHaemophilus ducreyiHaemophilus influenzaeKlebsiella granulomatisKlebsiella speciesNeisseria gonorrhoeaeShigella speciesVibrio choleraeVibrio fetusYersinia pestisGram-Positive BacteriaBacillus anthracisStreptococcus pneumoniaeAnaerobic BacteriaClostridium speciesFusobacterium fusiformePropionibacterium acnesOther BacteriaNocardiae and other aerobic Actinomyces speciesBorrelia recurrentisChlamydophila psittaciChlamydia trachomatisMycoplasma pneumoniaeRickettsiaeTreponema pallidumTreponema pallidum subspecies pertenueUreaplasma urealyticumParasitesBalantidium coliEntamoeba speciesPlasmodium falciparumDoxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum, but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known.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.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. 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: 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 hours) followed by maintenance dose of 100 mg/day. The maintenance dose may be administered as 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 pediatric patients above eight years of age: The recommended dosage schedule for pediatric patients weighing 100 pounds or less is mg/lb of body weight divided into two doses on the first day of treatment, followed by mg/lb of body weight given as single daily dose or divided into two doses, on subsequent days. For more severe infections up to mg/lb of body weight may be used. For pediatric patients over 100 pounds the usual adult dose should be used.Uncomplicated gonococcal infections in adults (except anorectal infections in men): 100 mg, by mouth, twice day for days. As an alternate single visit dose, administer 300 mg stat followed in one hour by second 300 mg dose.Acute epididymo-orchitis caused by N. gonorrhoeae: 100 mg, by mouth, twice day for at least 10 days.Primary and secondary syphilis: 300 mg 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 day for at least days.Nongonococcal urethritis caused by C. trachomatis and U. urealyticum: 100 mg, by mouth, twice day for at least days.Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice day for at least 10 days.Inhalational anthrax (post-exposure): ADULTS: 100 mg of doxycycline, by mouth, twice day for 60 days. CHILDREN: weighing less than 100 pounds (45 kg); mg/lb (2.2 mg/kg) of body weight, by mouth, twice 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). If gastric irritation occurs, doxycycline may be given with food. Ingestion of high fat meal has been shown to delay the time to peak plasma concentrations by an average of one hour and 20 minutes. However, in the same study, food enhanced the average peak concentration by 7.5% and the area under the curve by 5.7%.

GENERAL PRECAUTIONS SECTION.

General:. As with other antibacterial preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, doxycycline capsules should be discontinued and appropriate therapy instituted.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 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.Incision and drainage or other surgical procedures should be performed in conjunction with antibacterial therapy when indicated.Prescribing doxycycline capsules in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. 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: Rocky mountain spotted fever, typhus fever and the typhus group, 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, although the infectious agent is not always eliminated as judged by immunofluorescence. 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 (in conjunction with streptomycin). 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 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 speciesAcinetobacter 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, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized 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 pertenue. Listeriosis due to Listeria monocytogenes. Vincents infection caused by Fusobacterium fusiforme. Actinomycosis caused by Actinomyces israelii. Infections caused by Clostridium species.In acute intestinal amebiasis, doxycycline may be useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy.

INFORMATION FOR PATIENTS SECTION.

Information for Patients:. All patients taking doxycycline should be advised:- to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered (see WARNINGS).- to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration (see ADVERSE REACTIONS).- that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk (see Drug Interactions).- that the absorption of tetracyclines is reduced when taking bismuth subsalicylate (see Drug Interactions).- not to use outdated or poorly stored doxycycline.- that the use of doxycycline might increase the incidence of vaginal candidiasis. Diarrhea is common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.Patients should be counseled that antibacterial drugs including doxycycline capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline capsules are prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by doxycycline capsules or other antibacterial drugs in the future.

MECHANISM OF ACTION SECTION.

Mechanism of Action. Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against 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 and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for doxycycline capsules.Gram-Negative BacteriaAcinetobacter speciesBartonella bacilliformisBrucella speciesEnterobacter aerogenesEscherichia coliFrancisella tularensisHaemophilus ducreyiHaemophilus influenzaeKlebsiella granulomatisKlebsiella speciesNeisseria gonorrhoeaeShigella speciesVibrio choleraeVibrio fetusYersinia pestisGram-Positive BacteriaBacillus anthracisStreptococcus pneumoniaeAnaerobic BacteriaClostridium speciesFusobacterium fusiformePropionibacterium acnesOther BacteriaNocardiae and other aerobic Actinomyces speciesBorrelia recurrentisChlamydophila psittaciChlamydia trachomatisMycoplasma pneumoniaeRickettsiaeTreponema pallidumTreponema pallidum subspecies pertenueUreaplasma urealyticumParasitesBalantidium coliEntamoeba speciesPlasmodium falciparumDoxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum, but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known.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.

MICROBIOLOGY SECTION.

Microbiology:. Mechanism of Action. Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against 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 and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for doxycycline capsules.Gram-Negative BacteriaAcinetobacter speciesBartonella bacilliformisBrucella speciesEnterobacter aerogenesEscherichia coliFrancisella tularensisHaemophilus ducreyiHaemophilus influenzaeKlebsiella granulomatisKlebsiella speciesNeisseria gonorrhoeaeShigella speciesVibrio choleraeVibrio fetusYersinia pestisGram-Positive BacteriaBacillus anthracisStreptococcus pneumoniaeAnaerobic BacteriaClostridium speciesFusobacterium fusiformePropionibacterium acnesOther BacteriaNocardiae and other aerobic Actinomyces speciesBorrelia recurrentisChlamydophila psittaciChlamydia trachomatisMycoplasma pneumoniaeRickettsiaeTreponema pallidumTreponema pallidum subspecies pertenueUreaplasma urealyticumParasitesBalantidium coliEntamoeba speciesPlasmodium falciparumDoxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum, but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known.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.

PRECAUTIONS SECTION.

PRECAUTIONS. General:. As with other antibacterial preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, doxycycline capsules should be discontinued and appropriate therapy instituted.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 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.Incision and drainage or other surgical procedures should be performed in conjunction with antibacterial therapy when indicated.Prescribing doxycycline capsules in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.. Information for Patients:. All patients taking doxycycline should be advised:- to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered (see WARNINGS).- to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration (see ADVERSE REACTIONS).- that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk (see Drug Interactions).- that the absorption of tetracyclines is reduced when taking bismuth subsalicylate (see Drug Interactions).- not to use outdated or poorly stored doxycycline.- that the use of doxycycline might increase the incidence of vaginal candidiasis. Diarrhea is common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.Patients should be counseled that antibacterial drugs including doxycycline capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline capsules are prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by doxycycline capsules or other antibacterial drugs in the future.. Laboratory Tests:. In venereal disease when coexistent syphilis is suspected, dark-field examination should be done before treatment is started and the blood serology repeated monthly for at least four months.In long-term therapy, periodic laboratory evaluations of organ systems, including hematopoietic, renal, and hepatic studies should be performed.. 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.. 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 mammalian cell assays have been reported for related antibacterial (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.. 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 pregnan-cy by TERIS the Teratogen Information System concluded that therapeutic doses during pregnancy are unlikely to pose 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 risk1.A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows 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 marginal relationship with neural tube defect based on only two exposed cases2. 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 year of age3.. Labor and Delivery:. The effect of tetracyclines on labor and delivery is unknown.. 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 unknown4. Because of the potential for adverse reactions in nursing infants from doxycycline, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see WARNINGS).. Pediatric Use:. See WARNINGS and DOSAGE AND ADMINISTRATION sections.

PREGNANCY SECTION.

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 pregnan-cy by TERIS the Teratogen Information System concluded that therapeutic doses during pregnancy are unlikely to pose 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 risk1.A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows 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 marginal relationship with neural tube defect based on only two exposed cases2. 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 year of age3.

TERATOGENIC EFFECTS SECTION.

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 pregnan-cy by TERIS the Teratogen Information System concluded that therapeutic doses during pregnancy are unlikely to pose 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 risk1.A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows 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 marginal relationship with neural tube defect based on only two exposed cases2. 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 year of age3.

WARNINGS SECTION.

WARNINGS. THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY, AND CHILDHOOD TO THE AGE OF 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.Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline capsules, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.C. difficile produces toxins and which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.All tetracyclines form stable calcium complex in any bone-forming tissue. 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.