Professional Information — Monodox

Indications and Usage

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain effectiveness of MONODOX and other antibacterial drugs, MONODOX 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, 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 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, 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 pallidum subspecies 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.

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.

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 and 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 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 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.

Contraindications

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

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, 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 .)

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.

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.

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.

Description

Doxycycline is a broad-spectrum antibacterial synthetically derived from oxytetracycline. MONODOX 100 mg, 75 mg, and 50 mg capsules contain doxycycline monohydrate equivalent to 100 mg, 75 mg, or 50 mg of doxycycline for oral administration. The chemical designation of the light-yellow crystalline powder is alpha-6-deoxy-5-oxytetracycline.

Structural formula:

C₂₂H₂₄N₂O₈ • H₂O      M.W. = 462.45

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.

Inert ingredients: colloidal silicon dioxide; magnesium stearate; microcrystalline cellulose; sodium starch glycolate; and a hard gelatin capsule which contains black iron oxide, red iron oxide, titanium dioxide, and yellow iron oxide for the 100 mg and 75 mg strengths, titanium dioxide and yellow iron oxide for the 50 mg strength. The capsules are printed with edible ink containing black iron oxide, red iron oxide, and yellow iron oxide for the 50 mg and 100 mg strengths and black iron oxide, FD&C Blue No. 2, FD&C Red No. 40, FD&C Blue No. 1, and D&C Yellow No. 10 for the 75 mg strength.

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:

Average Observed Values

Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage excretion may fall as low as 1-5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min). Studies have shown no significant difference in serum half-life of doxycycline (range 18-22 hours) in individuals with normal and severely impaired renal function.

Hemodialysis does not alter serum half-life.

Microbiology:

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 and in clinical infections (see INDICATIONS AND USAGE ).

GramNegative Bacteria
Acinetobacter species
Bartonella bacilliformis
Brucella species
Campylobacter fetus
Enterobacter aerogenes
Escherichia coli
Francisella tularensis
Haemophilus ducreyi
Haemophilus influenzae
Klebsiella granulomatis
Klebsiella species
Neisseria gonorrhoeae
Shigella species
Vibrio cholerae
Yersinia pestis

GramPositive Bacteria
Bacillus anthracis
Listeria monocytogenes
Streptococcus pneumoniae

Anaerobic Bacteria
Clostridium species
Fusobacterium fusiforme
Propionibacterium acnes

Other Bacteria
Nocardiae and other Actinomyces species
Borrelia recurrentis
Chlamydophila psittaci
Chlamydia trachomatis
Mycoplasma pneumoniae
Rickettsiae
Treponema pallidum
Treponema pallidum subspecies pertenue
Ureaplasma urealyticum

Parasites
Balantidium coli
Entamoeba species

Susceptibility Testing Methods
When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar).^1,2,4,6,7 The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion Techniques
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.^1,3,4 This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of microorganisms to doxycycline. The disk diffusion interpretive criteria are provided in Table 1.

Anaerobic Techniques
For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method.^{1, 5} The MIC values obtained should be interpreted according to the criteria provided in Table 1

A report of Susceptible (S) indicates that the antimicrobial is likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.^{1,2,3,4,5,6,7} Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk or 30 mcg tetracycline disk, the criteria noted in should be achieved.

How Supplied / Storage and Handling

MONODOX 50 mg Capsules have a white opaque body with a yellow opaque cap. The capsule bears the inscription “MONODOX 50” in brown and “M 260” in brown. Each capsule contains doxycycline monohydrate equivalent to 50 mg doxycycline.

MONODOX 50 mg is available in:
      Bottles of 100 capsules ......................................................NDC 16110-260-06

MONODOX 75 mg Capsules have a white opaque body with a brown opaque cap. The capsule bears the inscription "MONODOX 75" in black and "M 075" in black. Each capsule contains doxycycline monohydrate equivalent to 75 mg doxycycline.

MONODOX 75 mg is available in:
      Bottles of 100 capsules ......................................................NDC 16110-075-01

MONODOX 100 mg Capsules have a yellow opaque body with a brown opaque cap. The capsule bears the inscription “MONODOX 100” in white and “M 259” in brown. Each capsule contains doxycycline monohydrate equivalent to 100 mg of doxycycline.

MONODOX 100 mg is available in:
      Bottles of 50 capsules ........................................................NDC 16110-259-04
      Bottles of 250 capsules ......................................................NDC 16110-259-07

STORE AT 20° - 25°C (68° - 77°F) WITH EXCURSIONS PERMITTED TO 15° C TO 30°C (59° TO 86°F). [SEE USP CONTROLLED ROOM TEMPERATURE.]

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

Patient Counseling Information

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 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 MONODOX 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 MONODOX or other antibacterial drugs in the future.