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Investigational

Doxycycline  Audio icon

Other Names: Doryx, Doxy 100, doxycycline calcium, doxycycline hyclate, doxycycline monohydrate, Monodox, Vibramycin Calcium, Vibramycin Hyclate, Vibramycin Monohydrate
Drug Class: Opportunistic Infections and Coinfections
Chemical Images:
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doxycycline calcium
doxycycline calcium
Molecular Weight: 520.562
doxycycline hyclate
doxycycline hyclate
Molecular Weight: 1025.8802
doxycycline  monohydrate
doxycycline monohydrate
Molecular Weight: 462.4524
Patent Version Content

Several FDA-approved drug labels may be available for doxycycline. AIDSinfo provides the following drug label solely as an example of the labels available for doxycycline. Inclusion or absence of a drug label on the AIDSinfo site does not imply endorsement or lack thereof by AIDSinfo. Search Drugs@FDA to access more information on doxycycline, including additional drug labels and any generic equivalents.

Doxycycline Tablets

Rx Only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline tablets and other antibacterial drugs, doxycycline tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. Doxycycline 150 mg, 100 mg, 75 mg and 50 mg tablets contain doxycycline monohydrate equivalent to 150 mg, 100 mg, 75 mg or 50 mg of doxycycline for oral administration. Inactive ingredients include colloidal silicon dioxide, FD&C yellow #6, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and titanium dioxide. In addition, Doxycycline 100 mg and 50 mg tablets contain hypromellose 3cP, hypromellose 6cP, D&C yellow #10 lake, polyethylene glycol 400, polysorbate 80; Doxycycline 75 mg and 150 mg tablets contain hypromellose 15cP, lactose monohydrate, yellow iron oxide and triethyl citrate. Its molecular weight is 462.46. The chemical designation of the light-yellow crystalline powder is alpha-6-deoxy-5-oxytetracycline.

Structural formula:

this is the structure

C 22H24N2O8•H2O

Doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.

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: The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including doxycycline, have a similar antimicrobial spectrum of activity against a wide range of gram-positive and gram-negative microorganisms. Cross-resistance of these microorganisms to tetracyclines is common.

Doxycycline has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic Gram-Positive Microorganisms:

Because many strains of the following groups of gram-positive microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended:

Bacillus anthracis

Staphylococcus aureus*

*Doxycycline is not the drug of choice in the treatment of any type of staphylococcal infection.

Streptococcus pneumoniae

Aerobic Gram-Negative Microorganisms:

Bartonella bacilliformis

Brucella species

Calymmatobacterium granulomatis

Campylobacter fetus

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Neisseria gonorrhoeae

Vibrio cholerae

Yersinia pestis

Because many strains of the following groups of gram-negative microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended:

Acinetobacter species

Enterobacter aerogenes

Escherichia coli

Klebsiella species

Shigella species

Anaerobic Microorganisms:

Actinomyces israelii

Clostridium species

Fusobacterium fusiforme

Other Microorganisms:

Borrelia recurrentis

Chlamydia psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae

Treponema pallidum

Treponema pertenue

Susceptibility Tests:

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 procedure. Standardized procedures are based on a dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tetracycline powder. The MIC values should be interpreted according to the following criteria:

Interpretive criteria for Enterobacteriaceae, Staphylococcus aureus and Acinetobacter spp.
Microorangism MIC Interpretive Data (mcg/mL)
Susceptible (S) Intermediate (I) Resistant (R)
Enterobacteriaceae ≤4 8 ≥16
Staphylococcus aureus
Acinetobacter spp.
Interpretive Criteria for Haemophilus influenzaea
Microorganism MIC Interpretive Data (mcg/mL)
Susceptible (S) Intermediate (I) Resistant (R)
Haemophilus influenzae ≤2 4 ≥8

Bacteria found to be susceptible to tetracycline can be considered susceptible to doxycycline.

Interpretive Criteria for Neisseria gonorrhoeaeb
Microorganism MIC Interpretive Data (mcg/mL)
Susceptible (S) Intermediate (I) Resistant (R)
Neisseria gonorrhoeae ≤0.25 0.5 - 1 ≥2

Bacteria found to be susceptible to tetracycline can be considered susceptible to doxycycline.

Interpretive Criteria for Streptococcus pneumoniaec
Microorganism MIC Interpretive Data (mcg/mL)
Susceptible (S) Intermediate (I) Resistant (R)
Streptococcus pneumoniae ≤2 4 ≥8

Bacteria found to be susceptible to tetracycline can be considered susceptible to doxycycline

  1. Interpretative criteria applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM).1,3
  2. Interpretative criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.1,3
  3. Interpretative criteria applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.1,3
    Interpretive Criteria for Bacillus anthracis and Brucella spp.
    Microorganism MIC Interpretive Data (mcg/mL)
    Susceptible (S) Intermediate (I) Resistant (R)
    Bacillus anthracis ≤1 ----- -----
    Brucella spp.

Broth Microdilution performed in unsupplemented Brucella broth pH adjusted to 7.1 ± 0.1 for Brucella spp. 5

For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining results for categories other than “susceptible”. For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed.

Incubation in 5% CO2 may be required for growth of some strains of Brucella spp. especially B. abortus. Incubation broth MIC tests in CO2 may decrease the MIC of tetracyclines, usually by one doubling dilution. 5

Bacteria found to be susceptible to tetracycline can be considered susceptible to doxycycline.

Interpretive Criteria for Bulkholderia mallei, Bulkholderia pseudomallei and Yersinia pestis
Microorganism MIC Interpretive Data (mcg/mL)
Susceptible (S) Intermediate (I) Resistant (R)
Bulkholderia mallei
Bulkholderia pseudomallei ≤4 8 ≥8
Yersinia pestis
Interpretive Criteria for Franciscella tularensis
Microorganism MIC Interpretive Data (mcg/mL)
Susceptible (S) Intermediate (I) Resistant (R)
Franciscella tularensis ≤4 ----- -----

Both Microdilutions performed in Cation-Adjusted Mueller-Hinton broth with 2% defined growth supplement for Franciscella tularensis. 5

For some organism/antimicrobial agent combinations, the absence or rare occurrence of resistant strains precludes defining results for categories other than “susceptible”. For strains yielding results suggestive of a “nonsusceptible” category, organism identification and antimicrobial susceptibility test results should be confirmed.

Bacteria found to be susceptible to tetracycline can be considered susceptible to doxycycline.

Reporting results

Recommended interpretive criteria are based on usual dosage regiment and routes of administration in the U.S. Susceptible, intermediate, or resistant interpretations of zone diameter measurements are reported and defined as follows:

1. Susceptible (S)

The “susceptible” category implies that isolates are inhibited by the usually achievable concentration of antimicrobial agent when the recommended dosage is used for the site of infection.

2. Intermediate (I)

The “intermediate” category includes isolates with antimicrobial agent MIC’s that approach usually attainable blood and tissue levels and for which response rates may be lower than for susceptible isolates. The intermediate category implies clinical efficacy in body sites where the drugs are physiologically concentrated (e.g., quinolones and ß-lactams in urine) or when a higher than normal dosage of a drug can be used (e.g., ß-lactams). This category also includes a buffer zone, which should prevent small, uncontrolled, technical factors from causing major disappearances in interpretations, especially for drugs without narrow pharmaceutical margins.

3. Resistant (R)

The “resistant” category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules, and/or that demonstrate zone diameters that fall in the range where specific microbial resistance mechanisms (e.g., beta-lactamases) are likely, and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard tetracycline powder should provide the following MIC values:

Quality Control Ranges for MIC Broth Dilution Method
Microorganism MIC (mcg/ml)
Escherichia coli ATCC 25922 0.5-2
Haemophilus influenzaea ATCC 49247 4-32
Neisseria gonorrhoeaeb ATCC 49226 0.25-1
Staphylococcus aureus ATCC 29213 0.12-1
Streptococcus pneumoniaec ATCC 49619 0.06 - 0.5
  1. Range applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM).1,3
  2. Range applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.1,3
  3. Range applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.1,3

Diffusion techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg tetracycline or 30 mcg doxycycline to test the susceptibility of microorganisms to doxycycline.

Reports from the laboratory providing results of the standard single-disk susceptibility test with 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk should be interpreted according to the following criteria:

Disk Diffusion Interpretive Criteria for Enterobacteriaceae:
Antimicrobial Agent Zone Diameter (mm)
Susceptible (S) Intermediate (I) Resistant (R)
Tetracycline ≥15 12-14 ≤11
Doxycycline ≥14 11-13 ≤10
Disk Diffusion Interpretive Criteria for Staphylococcus aureus:
Antimicrobial Agent Zone Diameter (mm)
Susceptible (S) Intermediate (I) Resistant (R)
Tetracycline ≥19 15-18 ≤14
Doxycycline ≥16 13-15 ≤12
Disk Diffusion Interpretive Criteria for Acinetobactor spp
Antimicrobial Agent Zone Diameter (mm)
Susceptible (S) Intermediate (I) Resistant (R)
Tetracycline ≥15 12-4 ≤11
Doxycycline ≥13 10-12 ≤9
Disk Diffusion Interpretive Criteria for Haemophilus spp.a
Antimicrobial Agent Zone Diameter (mm)
Susceptible (S) Intermediate (I) Resistant (R)
Tetracycline ≥29 26-28 ≤25
Disk Diffusion Interpretive Criteria for Neisseria gonorrhoeae b
Antimicrobial Agent Zone Diameter (mm)
Susceptible (S) Intermediate (I) Resistant (R)
Tetracycline ≥38 31-37 ≤30

Gonococci with 30 mcg tetracycline disk zone diameters <19 mm usually indicate a plasmid-mediated tetracycline-resistant N. gonorrhoeae (TRNG) isolate. These strains should be confirmed by the dilution test (MIC >16 mcg/mL).

Disk Diffusion Interpretive Criteria for Streptococcus pneumoniae c:
Antimicrobial Agent Zone Diameter (mm)
Susceptible (S) Intermediate (I) Resistant (R)
Tetracycline ≥23 19-22 ≤18
  1. Interpretative criteria applicable only to tests performed by disk diffusion method using a 30 mcg tetracycline-class disk and using Haemophilus Test Medium (HTM) and incubated with 5% CO2.2,3
  2. Interpretative criteria applicable only to tests performed by disk diffusion method using a 30 mcg tetracycline-class disk and using GC agar base with 1% defined growth supplement and incubated with 5% CO2.2,3
  3. Interpretative criteria applicable only to tests performed by disk diffusion method using a 30 mcg tetracycline-class disk and using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated with 5% CO2.2,3

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for tetracycline or doxycycline, respectively.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism Zone Diameter (mm)
tetracycline doxycycline
Escherichia coli ATCC 25922 18-25 18-24
Haemophilus influenzaea ATCC 49247 14-22 -----
Neisseria gonorrhoeaeb ATCC 49226 30-42 ------
Staphylococcus aureus ATCC 25923 24-30 23-29
Streptococcuspneumoniaec ATCC 49619 27-31 ------
  1. Range applicable only to tests performed by disk diffusion method using a 30 mcg tetracycline-class disk and using Haemophilus Test Medium (HTM) and incubated with 5% CO2 .2,3
  2. Range applicable only to tests performed by disk diffusion method using a 30 mcg tetracycline-class disk and using GC agar base with 1% defined growth supplement and incubated with 5% CO2 .2,3
  3. Range applicable only to tests performed by disk diffusion method using a 30 mcg tetracycline-class disk and using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated with 5% CO2.2,3

Anaerobic techniques:

For anaerobic bacteria, the susceptibility to tetracycline as MICs can be determined by standardized test methods.4 The MIC values obtained should be interpreted according to the following criteria:

Agar Dilution Interpretive Criteria for Anaerobes
MIC (mcg.mL) Interpretation
≤4 Susceptible (S)
8 Intermediate (I)
≥16 Resistant (R)

Interpretation is identical to that stated above for results using dilution techniques.

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized tetracycline powder should provide the following MIC values:

Quality control Ranges for MIC Agar Dilution Method
Microorganism MIC (mcg/mL)
Bacteroides fragilisa ATCC 25285 0.12 - 0.5
Bacteroides thetaiotaomicrona ATCC 29741 8 - 32
  1. Range applicable only to tests performed by the reference agar dilution method.

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline tablets and other antibacterial drugs, doxycycline tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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 Mycoplasmapneumoniae.

Lymphogranuloma venereum caused by Chlamydiatrachomatis.

Psittacosis (ornithosis) caused by Chlamydiapsittaci.

Trachoma caused by Chlamydiatrachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence.

Inclusion conjunctivitis caused by Chlamydiatrachomatis.

Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydiatrachomatis.

Nongonococcal urethritis caused by Ureaplasmaurealyticum.

Relapsing fever due to Borreliarecurrentis.

Doxycycline is also indicated for the treatment of infections caused by the following gram-negative microorganisms:

Chancroid caused by Haemophilusducreyi.

Plague due to Yersiniapestis (formerly Pasteurellapestis).

Tularemia due to Francisellatularensis (formerly Pasteurellatularensis).

Cholera caused by Vibriocholerae (formerly Vibriocomma).

Campylobacter fetus infections caused by Campylobacterfetus (formerly Vibriofetus).

Brucellosis due to Brucella species (in conjunction with streptomycin).

Bartonellosis due to Bartonellabacilliformis.

Granuloma inguinale caused by Calymmatobacteriumgranulomatis.

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 (formerly Aerobacter aerogenes)

Shigella species

Acinetobacter species (formerly Mima species and Herellea 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 (formerly Diplococcuspneumoniae).

Skin and skin structure infections caused by Staphylococcus aureus.

Anthrax due to Bacillusanthracis, including inhalational anthrax (post-exposure); to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.

Doxycycline 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 Fusobacteriumfusiforme.

Actinomycosis caused by Actinomycesisraelii.

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.

CONTRAINDICATIONS

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

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 associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline, 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 A and B 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 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.

PRECAUTIONS

General:

As with other antibiotic preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted.

Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was discontinued.

Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy when indicated.

Prescribing doxycycline tablets in the absence of a proven or strongly suspected bacterial infection or a 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 DrugInteractions.)

–not to use outdated or poorly stored doxycycline.

–that the use of doxycycline might increase the incidence of vaginal candidiasis.

Diarrhea is a 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 should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Monodox is prescribed to treat a 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 or other antibacterial drugs in the future.

Laboratory Tests

In venereal disease when coexistent syphilis is suspected, a 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 and/or Laboratory Test Interactions

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

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 antibiotics, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in invitro mammalian cell assays have been reported for related antibiotics (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 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. a

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. b

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

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 unknown. 8 Because of the potential for adverse reactions in nursing infants from doxycycline, a 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.

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: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity has been reported(b)(4).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: Bulging fontanels in infants and intracranial hypertension in adults. (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.

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 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 pediatric patients above eight years of age: The recommended dosage schedule for pediatric patients weighing 100 pounds or less is 2 mg/lb of body weight divided into two doses on the first day of treatment, followed by 1 mg/lb of body weight given as a single daily dose or divided into two doses, on subsequent days. For more severe infections up to 2 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 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.

Nongonococcal urethritis caused by C. trachomatis and 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 100 pounds (45 kg): 1 mg/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.) If gastric irritation occurs, doxycycline may be given with food. Ingestion of a 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%.

HOW SUPPLIED

Doxycycline Tablets 50 mg are a yellow, film coated, round, biconvex tablet, debossed “par” on one side and “091” on the other side. Each tablet contains doxycycline monohydrate equivalent to 50 mg of doxycycline. They are supplied as follows:

Bottles of 100 NDC 49884-091-01

Doxycycline Tablets 75 mg are a light orange, film coated, round, biconvex tablet, debossed “par” on one side and “092” on the other side. Each tablet contains doxycycline monohydrate equivalent to 75 mg of doxycycline. They are supplied as follows:

Bottles of 100 NDC 49884-092-01

Doxycycline Tablets 100 mg are a yellow, film coated, round, biconvex tablet, debossed “par” on one side and “093” on the other side. Each tablet contains doxycycline monohydrate equivalent to 100 mg of doxycycline. They are supplied as follows:

Bottles of 50 NDC 49884-093-03
Bottles of 250 NDC 49884-093-04

Doxycycline Tablets 150 mg are a peach colored, film coated, round, scored, biconvex tablet debossed “par” on one side and “236” on the other side. Each tablet contains doxycycline monohydrate equivalent to 150 mg of doxycycline. They are supplied as follows:

Bottles of 30 NDC 49884-236-11

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room temperature].

DISPENSE IN A TIGHT LIGHT RESISTANT CONTAINER AS DEFINED IN THE USP/NF.

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.

REFERENCES

  1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically - Seventh Edition. Approved Standard CLSI Document M07-A8, Vol. 29, No. 2, CLSI, Wayne, PA; 2009.
  2. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests - Ninth Edition. Approved Standard CLSI Document M02 – A10, Vol. 29, No. 1, CLSI, Wayne, PA; 2009.
  3. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twenty- First Informational Supplement. CLSI Document M100-S21, Vol. 31, No. 1, CLSI, Wayne, PA, January, 2011.
  4. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Seventh Edition. Approved Standard CLSI Document M11-A7, Vol. 27, No. 2, CLSI, Wayne, PA; December 200
  5. Clinical and Laboratory Standards Institute. Methods or Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria: Approved Guidelines – 2nd Edition. CLSI Document M45-A2. CLSI, Wayne, PA, 2011
  1. Friedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: 149-195.
  2. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524-528.
  3. Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: 315-317.
  4. Hale T. Medications and Mothers Milk. 9th edition. Amarillo, TX: Pharmasoft Publishing 2000; 225-226.

Manufactured by:

PAR PHARMACEUTICAL COMPANIES, INC.

Spring Valley, NY 10977 USA

Revised: 02/2012 OS091-01-1-08

PRINCIPAL DISPLAY PANEL 50MG TABLETS

This is the 50mg label

PRINCIPAL DISPLAY PANEL 75MG TABLETS

This is the 75mg label

PRINCIPAL DISPLAY PANEL 100MG TABLETS

This is the 100mg label

PRINCIPAL DISPLAY PANEL 150MG TABLETS

The is the 150mg label

DOXYCYCLINE  
doxycycline tablet
Product Information
Product Type Item Code (Source) 49884-093
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOXYCYCLINE (DOXYCYCLINE ANHYDROUS) DOXYCYCLINE ANHYDROUS 100 mg
Inactive Ingredients
Ingredient Name Strength
COLLOIDAL SILICON DIOXIDE  
MAGNESIUM STEARATE  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TITANIUM DIOXIDE  
POLYETHYLENE GLYCOL 400  
POLYSORBATE 80  
Product Characteristics
Color YELLOW Score no score
Shape ROUND (biconvex) Size 9mm
Flavor Imprint Code par;093
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 49884-093-03 50 TABLET ( TABLET) in 1 BOTTLE None
2 49884-093-04 250 TABLET ( TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA065070 12/15/2000

DOXYCYCLINE  
doxycycline tablet
Product Information
Product Type Item Code (Source) 49884-092
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOXYCYCLINE (DOXYCYCLINE ANHYDROUS) DOXYCYCLINE ANHYDROUS 75 mg
Inactive Ingredients
Ingredient Name Strength
COLLOIDAL SILICON DIOXIDE  
FD&C YELLOW NO. 6  
MAGNESIUM STEARATE  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TITANIUM DIOXIDE  
LACTOSE MONOHYDRATE  
TRIETHYL CITRATE  
Product Characteristics
Color ORANGE (Light) Score no score
Shape ROUND (biconvex) Size 9mm
Flavor Imprint Code par;092
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 49884-092-01 100 TABLET ( TABLET) in 1 BOTTLE None
2 49884-092-05 500 TABLET ( TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA065070 12/15/2000

DOXYCYCLINE  
doxycycline tablet
Product Information
Product Type Item Code (Source) 49884-236
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOXYCYCLINE (DOXYCYCLINE ANHYDROUS) DOXYCYCLINE ANHYDROUS 150 mg
Inactive Ingredients
Ingredient Name Strength
COLLOIDAL SILICON DIOXIDE  
FD&C YELLOW NO. 6  
MAGNESIUM STEARATE  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TITANIUM DIOXIDE  
LACTOSE MONOHYDRATE  
TRIETHYL CITRATE  
Product Characteristics
Color ORANGE (Peach) Score 2 pieces
Shape ROUND (biconvex) Size 10mm
Flavor Imprint Code par;236
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 49884-236-11 30 TABLET ( TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA065070 12/15/2000

DOXYCYCLINE  
doxycycline tablet
Product Information
Product Type Item Code (Source) 49884-091
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOXYCYCLINE (DOXYCYCLINE ANHYDROUS) DOXYCYCLINE ANHYDROUS 50 mg
Inactive Ingredients
Ingredient Name Strength
COLLOIDAL SILICON DIOXIDE  
MAGNESIUM STEARATE  
POLYSORBATE 80  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
TITANIUM DIOXIDE  
Product Characteristics
Color yellow Score no score
Shape ROUND (biconvex) Size 8mm
Flavor Imprint Code Par;091
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 49884-091-01 100 TABLET ( TABLET) in 1 BOTTLE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA065070 12/15/2000

Labeler - Par Pharmaceutical Inc (092733690)
Registrant - Par Pharmaceutical Inc (092733690)
Establishment
Name Address ID/FEI Operations
Par Pharmaceutical Inc. 092733690 manufacture

Revised: 03/2012 Par Pharmaceutical Inc

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