Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. Monodox® 100 mg and 50 mg capsules contain doxycycline monohydrate equivalent to 100 mg or 50 mg of doxycycline for oral administration. The chemical designation of the light-yellow crystalline powder is alpha-6-deoxy-5-oxytetracycline.
C 22 H 24 N 2 O 8 ·H 2 O 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.
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:
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 section has not been documented.
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:
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.
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 1 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.
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:
Use a standardized dilution method 2 (broth, agar, microdilution) or equivalent with tetracycline powder. The MIC values obtained should be interpreted according to the following criteria:
As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard tetracycline powder should provide the following MIC values:
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:
Enterobacter aerogenes (formerly Aerobacter aerogenes )
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' 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.
This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.
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 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.
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 ).
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 ).
Pediatric Use: See and DOSAGE AND ADMINISTRATION sections.
Due to oral doxycycline' 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 .)
Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See .)
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.
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.
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 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%.
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 55515-260-06. 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 55515-259-04 and in bottles of 250 capsules, NDC 55515-259-07.
Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4 , and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4 , and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.
Minocycline, tetracycline PO 4 , 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.
A Division of Watson Pharma, Inc., Corona, CA 92880
by Vintage Pharmaceuticals, Inc., Charlotte, N.C.
Revised April 28, 1998 02-18391/R7