DOXYCYCLINE HCL
DESCRIPTION:
Doxycycline is a broad-spectrum antibiotic synthetically derived from
oxytetracycline. The chemical designation of the light-yellow crystalline powder
is alpha-6-deoxy- 5-oxytetracycline.
C22H24N2O8.H2O : M.W.=462.46
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; hard gelatin capsule; magnesium
stearate; microcrystalline cellulose; and sodium starch glycolate.
ACTIONS/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 0.5 1.0 1.5 2.0 3.0 4.0 8.0 12.0 24.0 48.0 72.0
(hr):
--------------------------------------------------------------------------------------------------------------------------------
Conc. 1.02 2.26 2.67 3.01 3.16 3.03 2.03 1.62 0.95 0.37 0.15
(mcgm/mL)
Average Observed Values
Maximum Concentration : 3.61 mcgm/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 1-5%/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: 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.
While In Vitro studies have demonstrated the susceptibility of most strains of
the following microorganisms, clinical efficacy for infections other than those
included in the INDICATIONS AND USAGE section has not been documented.
GRAM-NEGATIVE BACTERIA:
-- Neisseria Gonorrhoeae
-- 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 tetracyclines, 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, tetracyclines should not be used to treat
streptococcal infections 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:
-- Chlamydia Psittaci
-- Chlamydia Trachomatis
-- Ureaplasma Urealyticum
-- Borrelia Recurrentis
-- Treponema Pallidum
-- Treponema Pertenue
-- Clostridium species
-- Fusobacterium Fusiforme
-- Actinomyces species
-- Bacillus Anthracis
-- Propionibacterium Acnes
-- Entamoeba species
-- Balantidium Coli
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 procedure (REF. 1) which has been recommended for use with
disks to test susceptibility of organisms to doxycycline uses the 30-mcgm
tetracycline- class disk or the 30-mcgm 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-mcgm tetracycline-class disk or the 30-mcgm
doxycycline disk should be interpreted according to the following criteria.
ZONE DIAMETER (MM) INTERPRETATION
tetracycline doxycycline
>/=19 >/=16 Susceptible
15-18 13-15 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-
mcgm tetracycline-class disk or the 30-mcgm doxycycline disk should give the
following zone diameters:
ORGANISM ZONE DIAMETER
tetracycline doxycycline
E. coli ATCC 25922 18-25 18-24
S. aureus ATCC 25923 19-28 23-29
DILUTION TECHNIQUES:
Use a standardized dilution method (REF. 2) (broth, agar, microdilution) or
equivalent with tetracycline powder. The MIC values obtained should be
interpreted according to the following criteria:
MIC (MCGM/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 (MCGM/ML)
S. aureus ATCC 29213 0.25-1
E. faecalis ATCC 29212 8-32
E. coli ATCC 25922 1-4
P. aeruginosa ATCC 27853 8-32
INDICATIONS AND USAGE:
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 (omithosis) 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).
Skin and skin structure infections caused by Staphylococcus Aureus. 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.
Anthrax due to Bacillus Anthracis.
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.
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 UNLESS OTHER
DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED.
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 25mg/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.
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/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 antibiotics, 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 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: Pregnancy Category D. (See WARNINGS).
LABOR AND DELIVERY: The effect of tetracyclines on labor and delivery is
unknown.
NURSING MOTHERS: Tetracyclines are present in the milk of lactating women who
are taking a drug in this class. Because of the potential for serious adverse
reactions in nursing infants from the tetracyclines, a decision should be made
whether to discontinue nursing or 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.
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.
(See Also PRECAUTIONS)
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. 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. 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, 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 200mg 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 lbs 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.
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.
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%.
ANIMAL PHARMACOLOGY:
ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY
Hyperpigmentation of the thyroid has been produced by members of the
tetracycline class in the following species: in rats by oxytetracycline,
doxycycline, tetracycline 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. National Committee for Clinical Laboratory Standards, Performance Standards
For Antimicrobial Disk Susceptibility Tests, Fourth Edition. Approved Standard
NCCLS Document M2-A4, Vol. 10, No. 7 NCCLS, Villanova, PA, April 1990.
2. National Committee for Clinical Laboratory Standards, Methods For Dilution
Antimicrobial Susceptibility Tests For Bacteria That Grow Aerobically, Second
Edition. Approved Standard NCCLS Document M7-A2, Vol. 10, No. 8 NCCLS,
Villanova, PA, April 1990.
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