Doxycycline Hyclate: Package Insert and Label Information

DOXYCYCLINE HYCLATE- doxycycline hyclate tablet, film coated
MedVantx, Inc.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate 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. The chemical designation of this light-yellow crystalline powder is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate is soluble in water, while doxycycline monohydrate is very slightly soluble in water.

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

Each tablet, for oral administration, contains doxycycline hyclate equivalent to 100 mg doxycycline.

In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, FD&C Red No. 40, FD&C Yellow No. 6, hypromellose, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, stearic acid and titanium dioxide.

CLINICAL PHARMACOLOGY

Tetracyclines are readily absorbed and are bound to plasma proteins in varying degree. They are concentrated by the liver in the bile, and excreted in the urine and feces at high concentrations and in a biologically active form. Doxycycline is virtually completely absorbed after oral administration. Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 mcg/mL of doxycycline at 2 hours decreasing to 1.45 mcg/mL at 24 hours. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage excretion may fall as low as 1 to 5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min). Studies have shown no significant difference in serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function.

Hemodialysis does not alter serum half-life.

Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.

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 organisms. Cross-resistance of these organisms to tetracyclines is common.

Gram-Negative Bacteria

• Neisseria gonorrhoeae

• Calymmatobacterium granulomatis

• Haemophilus ducreyi

• Haemophilus influenzae

• Yersinia pestis (formerly Pasteurella pestis)

• Francisella tularensis (formerly Pasteurella tularensis)

• Vibrio cholerae (formerly Vibrio comma)

• Bartonella bacilliformis

• Brucella species

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:

• Escherichia coli

• Klebsiella species

• Enterobacter aerogenes

• Shigella species

• Acinetobacter species (formerly Mima species and Herellea species)

• Bacteroides species

Gram-Positive Bacteria

Because many strains of the following groups of gram-positive microorganisms have been shown to be resistant to tetracycline, culture and susceptibility testing are recommended. Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracycline should not be used for streptococcal disease unless the organism has been demonstrated to be susceptible.

• Streptococcus pyogenes

• Streptococcus pneumoniae

• Enterococcus group (Streptococcus faecalis and Streptococcus faecium)

• Alpha-hemolytic streptococci (viridans group)

Other Microorganisms

• Rickettsiae • Clostridium species

• Chlamydia psittaci • Fusobacterium fusiforme

• Chlamydia trachomatis • Actinomyces species

• Mycoplasma pneumoniae • Bacillus anthracis

• Ureaplasma urealyticum • P ropionibacterium acnes

• Borrelia recurrentis • Entamoeba species

• Treponema pallidum • Balantidium coli

• Treponema pertenue • Plasmodium falciparum

Doxycycline 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 Tests

Diffusion Techniques

Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standard procedure¹ which has been recommended for use with disks to test susceptibility of organisms to doxycycline, uses the 30-mcg tetracycline-class disk or the 30-mcg doxycycline disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for tetracycline or doxycycline, respectively.

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

Zone Diameter (mm) Interpretation
Tetracycline	Doxycycline
≥ 19	≥ 16	Susceptible
15 to 18	13 to 15	Intermediate
≤ 14	≤ 12	Resistant

A report of “Susceptible” indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of “Intermediate” suggests that the organism would be susceptible if a high dosage is used or if the infection is confined to tissues and fluids in which high antimicrobial levels are attained. A report of “Resistant” indicates that achievable concentrations are unlikely to be inhibitory, and other therapy should be selected.

Standardized procedures require the use of laboratory control organisms. The 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk should give the following zone diameters:

Organism	Zone Diameter (mm)
	tetracycline	doxycycline
E. coli ATCC 25922	18 to 25	18 to 24
S. aureus ATCC 25923	19 to 28	23 to 29

Dilution Techniques

Use a standardized dilution method² (broth, agar, microdilution) or equivalent with tetracycline powder. The MIC values obtained should be interpreted according to the following criteria:

MIC (mcg/mL)	Interpretation
≤ 4	Susceptible
8	Intermediate
≥ 16	Resistant

As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard tetracycline powder should provide the following MIC values:

Organism	MIC (mcg/mL)
E. coli ATCC 25922	1 to 4
S. aureus ATCC 29213	0.25 to 1
E. faecalis ATCC 29212	8 to 32
P. aeruginosa ATCC 27853	8 to 32

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate 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.

Treatment

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 Chlamydia 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 (formerly Pasteurella pestis).

• Tularemia due to Francisella tularensis (formerly Pasteurella tularensis).

• Cholera caused by Vibrio cholerae (formerly Vibrio comma).

• Campylobacter fetus infections caused by Campylobacter fetus (formerly Vibrio 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 (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 Diplococcus 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.

• 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.

Prophylaxis

Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (< 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains see DOSAGE AND ADMINISTRATION section and Information for Patients subsection of the PRECAUTIONS section).

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 it 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, 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 fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 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 embryotoxicity has also been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking this drug, 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.